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Redefining Dementia Treatment: Berkeley Scientists Unveil Promising New Breakthrough

Research from UC Berkeley indicates that ongoing stress caused by protein aggregation is leading to the death of brain cells.

Numerous neurodegenerative conditions, including Alzheimer’s and Parkinson’s, involve the buildup of protein clusters, known as aggregates, within the brain. This phenomenon has prompted researchers to hypothesize that these protein masses are responsible for the death of brain cells. Despite this, efforts to develop treatments that break up and remove these tangled proteins have had little success.

But a new discovery by University of California, Berkeley , researchers suggests that the accumulation of aggregated proteins isn’t what kills brain cells. Rather, it’s the body’s failure to turn off these cells’ stress response.

In a study recently published in the journal Nature , the researchers reported that delivering a drug that forces the stress response to shut down saves cells that mimic a type of neurodegenerative disease known as early-onset dementia.

The Role of the SIFI Complex in Neurodegeneration

According to lead researcher Michael Rapé, the finding could offer clinicians another option for treatment for some neurodegenerative diseases, at least for those caused by mutations in the protein that switches off the cellular stress response. These include inherited diseases that lead to ataxia, or loss of muscle control, and early-onset dementia.

In addition, Rapé noted that other neurodegenerative diseases, including Mohr–Tranebjærg syndrome, childhood ataxia, and Leigh syndrome, are also characterized by stress responses in overdrive and have symptoms similar to those of the early onset dementia mimicked in the new study.

“We always thought that protein clumps directly kill neurons, for example by puncturing membrane structures within these cells. Yet, we now found that aggregates prevent the silencing of a stress response that cells originally mount to cope with bad proteins. The stress response is always on, and that’s what kills the cells,” said Rapé, head of the new division of molecular therapeutics in UC Berkeley’s Department of Molecular and Cell Biology and a Howard Hughes Medical Institute investigator. “We think that the same mechanisms may underlie more common pathologies that also show widespread aggregation, such as Alzheimer’s disease or frontotemporal dementia, but more work is needed to investigate the role of stress signaling in these diseases.”

Key to the discoveries by Rapé’s lab was the researchers’ finding that stress responses need to be turned off once a brain cell has successfully addressed a difficult situation. Rapé explained this finding to his son in simple terms: You not only need to clean up your room, but also turn out the light before going to bed. If you don’t turn off the light, you can’t fall asleep, but if you turn it off before you cleaned up your room, you would stumble if you had to get up in the dark.

Similarly, a cell has to clean up protein aggregates before turning off the stress response. If it doesn’t turn off the stress response, the cell will ultimately die.

“Aggregates don’t kill cells directly. They kill cells because they keep the light on,” he said. “But that means that you can treat these diseases, or at least the dozen or so neurodegenerative diseases that we found have kept their stress responses on. You treat them with an inhibitor that turns off the light. You don’t have to worry about completely getting rid of large aggregates, which changes how we think about treating neurodegenerative diseases. And most importantly, it makes this really doable.”

In their paper, Rapé and his colleagues describe a very large protein complex they discovered called SIFI (SIlencing Factor of the Integrated stress response). This machine serves two purposes: It cleans up aggregates and, afterward, turns off the stress response triggered by the aggregated proteins. The stress response controlled by SIFI is switched on to deal with specific intracellular problems — the abnormal accumulation of proteins that end up at the wrong location in the cell. If components of SIFI are mutated, the cell will accumulate protein clumps and experience an active stress response. But it is the stress response signaling that kills the cells.

“The SIFI complex would normally clear out the aggregating proteins. When there are aggregates around, SIFI is diverted from the stress response, and the signaling continues. When aggregates have been cleared — the room has been cleaned up before bedtime — then the SIFI is not diverted away anymore, and it can turn off the stress response,” he said. “Aggregates kind of hijack that natural stress response-silencing mechanism, interfere with it, stall it. And so that’s why silencing never happens when you have aggregates, and that’s why cells die.”

A future treatment, Rapé said, would likely involve the administration of a drug to turn off the stress response and a drug to keep SIFI turned on to clean up the aggregate mess.

Rapé, who is also the Dr. K. Peter Hirth Chair of Cancer Biology, studies the role of ubiquitin — a ubiquitous protein in the body that targets proteins for degradation — in regulating normal and disease processes in humans. In 2017, he discovered that a protein called UBR4 assembles a specific ubiquitin signal that was required for the elimination of proteins that tend to aggregate inside cells.

Only later did other researchers find that mutations in UBR4 are found in some inherited types of neurodegeneration. This discovery led Rapé to team up with colleagues at Stanford University to find out how UBR4 causes these diseases.

“This was a unique opportunity: We had an enzyme that makes an anti-aggregation signal, and when it’s mutated, it causes aggregation disease,” he said. “You put these two things together and you can say, ‘If you figure out how this UBR4 allows sustained cell survival, that probably tells you how aggregates kill cells.'”

They found that UBR4 is actually part of a much larger protein complex, which Rapé dubbed SIFI, and they found that this SIFI machinery was needed when a cell couldn’t sort proteins into its mitochondria. Such proteins that end up at the wrong location in cells tend to clump and, in turn, cause neurodegeneration.

“Surprisingly, though, we found that the core substrates of the SIFI complex were two proteins, one of which senses when proteins don’t make it into mitochondria. That protein detects that something is wrong, and it then activates a kinase that shuts down most of new protein synthesis as part of a stress response, giving the cell time to correct its problem with bringing proteins to the right location,” he said.

This kinase is also degraded through SIFI. A kinase is an enzyme that adds a phosphate group to another molecule, in this case, a protein, to regulate important activities in the cell. By helping degrade these two proteins, the SIFI complex turns off the stress response that is caused by clumpy proteins accumulating at the wrong location.

“That’s the very first time that we’ve seen a stress response turned off in an active manner by an enzyme — SIFI — that happens to be mutated in neurodegeneration,” Rapé said.

While investigating how SIFI can turn off the stress response at the right time — only after the room had been cleaned up — the researchers found that SIFI recognizes a short protein segment that acts as a kind of ZIP code that allows proteins or protein precursors to get into the mitochondria, where they are processed. When they are prevented from getting in, they accumulate in the cytoplasm, but SIFI homes in on that ZIP code to eliminate them. The ZIP code looks just like the light switch.

“When you have aggregates accumulating in the cytoplasm, now the ZIP code is still in the cytoplasm, and there’s a lot of it there,” he said. “And it’s the same signal as you would have in the proteins that you want to turn off. So it basically diverts the SIFI complex from the light switch back to the mess. SIFI tries to clean up the mess first, and it cannot turn off the light. And so when you have an aggregate in the cell, the light is always on. And if the light is always on, if stress signaling is always on, the cell will die. And that’s a problem.”

Implications for Treatment and Future Research

Rapé suspects that many intracellular protein aggregates characteristic of neurodegenerative diseases have similar consequences and may prevent the cell from switching off the stress response. If so, the fact that a drug can turn off the response and rescue brain cells bodes well for the development of treatments for potentially many neurodegenerative diseases.

Already, another stress response inhibitor, a drug called ISRIB discovered at UCSF in 2013, has been shown to improve memory in mice and reduce age-related cognitive decline.

“That means there is the prospect that by manipulating stress silencing, by turning off the light with chemicals, you might target other neurodegenerative diseases, as well,” he said. “At the very least, it’s another way we could help patients with these diseases. In the best possible way, I think it will change how we treat neurodegenerative diseases. That’s why this is a really important story, why I think it’s very exciting.”

Rapé, already a co-founder of two startups, Nurix Therapeutics Inc., and Lyterian Therapeutics, is now looking to develop therapies to silence the stress response while maintaining the cell’s cleanup of protein aggregates.

Reference: “Stress response silencing by an E3 ligase mutated in neurodegeneration” by Diane L. Haakonsen, Michael Heider, Andrew J. Ingersoll, Kayla Vodehnal, Samuel R. Witus, Takeshi Uenaka, Marius Wernig and Michael Rapé, 31 January 2024, Nature . DOI: 10.1038/s41586-023-06985-7

Co-authors with Rapé are postdoctoral fellows Diane Haakonsen, Michael Heider, and Samuel Witus and graduate student Andrew Ingersoll, all of UC Berkeley, and Kayla Vodehnal, Takeshi Uenaka, and Marius Wernig of Stanford. The work was supported primarily by the Stinehart–Reed Foundation and the National Institutes of Health (RF1 AG048131, T32MH020016-25).

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Lecanemab, the New Alzheimer’s Treatment: 3 Things To Know

BY CARRIE MACMILLAN July 24, 2023

Yale researcher discusses the recent FDA approval of a new Alzheimer's disease treatment.

[Originally published January 19, 2023. Updated: July 24, 2023.]

The Food and Drug Administration (FDA) recently granted full approval to a new Alzheimer’s treatment called lecanemab, which has been shown to moderately slow cognitive and functional decline in early-stage cases of the disease.

Alzheimer’s disease is a progressive disorder that damages and destroys nerve cells in the brain. Over time, the disease leads to a gradual loss of cognitive functions, including the ability to remember, reason, use language, and recognize familiar places. It can also cause a range of behavioral changes.

In January, the FDA gave the medication an accelerated approval based on amyloid plaque clearance. Christopher van Dyck, MD , director of Yale’s Alzheimer’s Disease Research Unit, was the lead author of a study published in the Jan. 5 issue of The New England Journal of Medicine that shared results of a Phase III clinical trial of lecanemab. (Dr. van Dyck is also a paid consultant for the pharmaceutical company Eisai, which funded the trials.)

Sold under the brand name Leqembi™ and made by Eisai in partnership with Biogen Inc., the drug is delivered by an intravenous infusion every two weeks. Lecanemab works by removing a sticky protein from the brain that is believed to cause Alzheimer’s disease to advance.

“It’s very exciting because this is the first treatment in our history that shows an unequivocal slowing of decline in Alzheimer’s disease,” says Dr. van Dyck.

This is the first time in two decades that the FDA has granted full approval to a drug for Alzheimer’s, but there is also a “black box” warning on the medication—the agency’s strongest caution—because of safety concerns.

We talked more with Dr. van Dyck, who answered three questions about the new treatment.

How effective is lecanemab for Alzheimer’s disease?

In a trial that involved 1,795 participants with early-stage, symptomatic Alzheimer’s, lecanemab slowed clinical decline by 27% after 18 months of treatment compared with those who received a placebo.

“The antibody treatment selectively targets the forms of amyloid protein that are thought to be the most toxic to brain cells,” says Dr. van Dyck.

Study participants who received the treatment had a significant reduction in amyloid burden in imaging tests, usually reaching normal levels by the end of the trial. Participants also showed a 26% slowing of decline in a key secondary measure of cognitive function and a 37% slowing of decline in a measure of daily living compared to the placebo group.

“Would I like the numbers to be higher? Of course, but I don’t think this is a small effect,” says Dr. van Dyck. “These results could also indicate a starting point for bigger effects. The data appear encouraging that the longer the treatment period, the better the effect. But we’ll need more studies to determine if that’s true.”

They also beg the question about still-earlier intervention, adds Dr. van Dyck. Lecanemab is already being tested in the global AHEAD study for individuals who are still cognitively normal but at high risk of symptoms due to elevated levels of brain amyloid.

Yale currently has the largest number of participants in the AHEAD study, which is funded by the National Institutes of Health (NIH) and Eisai and is enrolling participants as young as 55. “We may see a larger benefit if we intervene before significant brain damage has occurred,” he says.

Is lecanemab safe?

The most common side effect (26.4% of participants vs. 7.4% in the placebo group) of the treatment is an infusion-related reaction, which may include transient symptoms, such as flushing, chills, fever, rash, and body aches. The majority (96%) of these reactions were mild to moderate, and 75% happened after the first dose.

“We can medicate those individuals in advance if we find they have those side effects repeatedly,” says Dr. van Dyck. “We can use medications such as diphenhydramine or acetaminophen. But this is generally not an issue.”

Another potential side effect associated with lecanemab was amyloid-related imaging abnormalities with edema, or fluid formation on the brain. This occurred in 12.6% of trial participants compared to 1.7% in the placebo group. “It’s usually asymptomatic when it occurs, but we can detect it on MRI scans. We often don’t stop dosing if we see it, unless there are symptoms, in which case we would pause infusions until it fully resolves,” Dr. van Dyck says.

It’s important to note that the studies with lecanemab show substantially lower rates of this side effect than do published trials of other, similar drugs such as aducanumab—they're at about a third of the rate, explains Dr. van Dyck. “So, for drugs in this class, I think lecanemab has a favorable safety profile,” he says.

Lastly, 17.3% of trial participants experienced amyloid-related imaging abnormalities with brain bleeding compared to 9% in the placebo group.

“Most of the time we're really talking about microhemorrhages that are in the order of millimeters,” says Dr. van Dyck. “People with Alzheimer's disease are more prone to these events because of the amyloid deposits in their blood vessels, but a catastrophic bleed is quite rare.”

The medication’s label includes warnings about brain swelling and bleeding and that people with a gene mutation that increases their risk of Alzheimer’s disease are at greater risk of brain swelling on the treatment. The label also cautions against taking blood thinners while on the medication.

When will lecanemab be available for Alzheimer’s disease treatment?

Eisai set the price for Leqembi at $26,500 per year, and it has reportedly been largely unavailable while FDA full approval was pending. That may change now that Medicare has said it will cover 80% of the cost.

More news from Yale Medicine

New drug donanemab is 'a turning point in the fight against Alzheimer’s'

Dr Richard Oakley, Associate Director of Research at Alzheimer’s Society, has called breakthrough Alzheimer's drug donanemab, 'a turning point', as the full trial results were revealed.

Full results about the Alzheimer's disease drug donanemab have been released today, supporting earlier trial results that suggested the breakthrough drug may slow down the progression of the disease.

Dr Richard Oakley, Associate Director of Research and Innovation at Alzheimer’s Society, said:   

“Dementia is the biggest killer in the UK and over 60% of people living with dementia are thought to have Alzheimer’s disease.

This is truly a turning point in the fight against Alzheimer’s and science is proving that it is possible to slow down the disease.

"Treatments like donanemab are the first steps towards a future where Alzheimer’s disease could be considered a long-term condition alongside diabetes or asthma.

"People may have to live with it, but they could have treatments that allow them to effectively manage their symptoms and continue to live fulfilled lives.

“Today’s full results support what we heard about donanemab back in May, that the drug is able to slow down the progression of Alzheimer’s disease by more than 20%. This study adds to the growing evidence that treating people as early as possible may be more beneficial, with the effects of donanemab greater in people who were at an earlier stage of the disease. 

'A defining moment'

Kate Lee, Alzheimer’s Society CEO said:

This is a defining moment for dementia research. But new treatments could mean nothing if we don’t fix dementia diagnosis .

"We estimate around 720,000 people in the UK could potentially benefit from these emerging new Alzheimer’s disease treatments if they’re approved for use here. But the NHS is simply not ready to deliver them.

“Everyone living with dementia deserves access to a speedy, accurate diagnosis to get the support and treatments they need, now and in the future.” 

Our CEO also shared her thoughts about the donanemab results on Twitter:

‘I know that there is so much to be done in order to ensure that we can get these drugs into people at the right time.’ Our Chief Exec @KateLeeCEO reacts to today’s donanemab news. Read our full comment at https://t.co/RnxF6fnRNH . pic.twitter.com/T1PPMefyQy — Alzheimer's Society (@alzheimerssoc) July 17, 2023

Early Alzheimer's diagnosis key

Dr Oakley added:

Diagnosis will be key to the access of any new treatments. We can’t have a situation where treatments are approved for use in the UK but people aren’t diagnosed early or accurately enough to be eligible.

"We need early, and accurate, diagnoses available for everyone and the NHS ready to roll out treatments such as donanemab and lecanemab if and when they are approved in the UK.  

“It’s also important to note that side effects did occur, although serious side effects only occurred in 1.6% of people receiving the drug.

"Regulators will need to balance these side effects against the benefits of the drug. We should also note that themajority of people who took part in this trial were white – it’s crucial that in future trials we see more diversity to prove that new drug treatments have similar effects for everyone living with Alzheimer’s disease. 

Just as we’ve seen a transformation in cancer treatment in recent decades, we’re really hopeful we’re on the same path for dementia.

"We’re so proud that research Alzheimer’s Society funded 30 years ago led to the breakthroughs we’re seeing today, and the research we’re funding now will be pivotal in unlocking more breakthroughs.  

“We will only see progress in clinical trials for new treatments if people from all backgrounds have the opportunity to join them.

"It’s not all about taking new drugs or having invasive tests, some trials are as simple as answering surveys and anyone over 18 in the UK can sign up."

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Chief Marketing Officer, Alex Hyde-Smith, explains why a second airing of our advert The Long Goodbye is important to highlight the devastating impact of dementia on people's lives.

What is lecanemab?

Lecanemab (also known as Leqembi) has made headlines as the first drug ever approved in the UK by the MHRA that can slow down early-stage Alzheimer’s disease but it has not been recommended for use in the NHS at this stage. Here is what we know so far about this breakthrough Alzheimer's drug. 

Alzheimer's drug Lecanemab approved for use in the UK, but not on the NHS

The MHRA have approved lecanemab for some people with early-stage Alzheimer’s disease. However NICE does not recommend use on the NHS for any patients.

Prioritising research into action

In July 2024, Alzheimer’s Society launched the Dementia Healthcare Inequalities Initiative. We sat down with Professor Jennie Popay, the Chair of our Healthcare Inequalities Advisory Board to hear more about the innovative research applications she hopes to see.

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This Centre’s research focuses on ways to provide better care and services for people with dementia from their diagnosis through to the end of life. This Centre’s research aims to provide meaningful, real-life results that will change the lives of people living with dementia.

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Start of new era for alzheimer’s treatment.

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Expert discusses recent lecanemab trial, why it appears to offer hope for those with deadly disease

Researchers say we appear to be at the start of a new era for Alzheimer’s treatment. Trial results published in January showed that for the first time a drug has been able to slow the cognitive decline characteristic of the disease. The drug, lecanemab, is a monoclonal antibody that works by binding to a key protein linked to the malady, called amyloid-beta, and removing it from the body. Experts say the results offer hope that the slow, inexorable loss of memory and eventual death brought by Alzheimer’s may one day be a thing of the past.

The Gazette spoke with Scott McGinnis , an assistant professor of neurology at Harvard Medical School and Alzheimer’s disease expert at Brigham and Women’s Hospital , about the results and a new clinical trial testing whether the same drug given even earlier can prevent its progression.

Scott McGinnis

GAZETTE: The results of the Clarity AD trial have some saying we’ve entered a new era in Alzheimer’s treatment. Do you agree?

McGINNIS: It’s appropriate to consider it a new era in Alzheimer’s treatment. Until we obtained the results of this study, trials suggested that the only mode of treatment was what we would call a “symptomatic therapeutic.” That might give a modest boost to cognitive performance — to memory and thinking and performance in usual daily activities. But a symptomatic drug does not act on the fundamental pathophysiology, the mechanisms, of the disease. The Clarity AD study was the first that unambiguously suggested a disease-modifying effect with clear clinical benefit. A couple of weeks ago, we also learned a study with a second drug, donanemab, yielded similar results.

GAZETTE: Hasn’t amyloid beta, which forms Alzheimer’s characteristic plaques in the brain and which was the target in this study, been a target in previous trials that have not been effective?

McGINNIS: That’s true. Amyloid beta removal has been the most widely studied mechanism in the field. Over the last 15 to 20 years, we’ve been trying to lower beta amyloid, and we’ve been uncertain about the benefits until this point. Unfavorable results in study after study contributed to a debate in the field about how important beta amyloid is in the disease process. To be fair, this debate is not completely settled, and the results of Clarity AD do not suggest that lecanemab is a cure for the disease. The results do, however, provide enough evidence to support the hypothesis that there is a disease-modifying effect via amyloid removal.

GAZETTE: Do we know how much of the decline in Alzheimer’s is due to beta amyloid?

McGINNIS: There are two proteins that define Alzheimer’s disease. The gold standard for diagnosing Alzheimer’s disease is identifying amyloid beta plaques and tau neurofibrillary tangles. We know that amyloid beta plaques form in the brain early, prior to accumulation of tau and prior to changes in memory and thinking. In fact, the levels and locations of tau accumulation correlate much better with symptoms than the levels and locations of amyloid. But amyloid might directly “fuel the fire” to accelerated changes in tau and other downstream mechanisms, a hypothesis supported by basic science research and the findings in Clarity AD that treatment with lecanemab lowered levels of not just amyloid beta but also levels of tau and neurodegeneration in the blood and cerebrospinal fluid.

GAZETTE: In the Clarity AD trial, what’s the magnitude of the effect they saw?

McGINNIS: The relevant standards in the trial — set by the FDA and others — were to see two clinical benefits for the drug to be considered effective. One was a benefit on tests of memory and thinking, a cognitive benefit. The other was a benefit in terms of the performance in usual daily activities, a functional benefit. Lecanemab met both of these standards by slowing the rate of decline by approximately 25 to 35 percent compared to placebo on measures of cognitive and functional decline over the 18-month studies.

“In a perfect world, we’d have treatments that completely stop decline and even restore function. We’re not there yet, but this represents an important step toward that goal.”

Steven M. Smith

GAZETTE: What are the key questions that remain?

McGINNIS: An important question relates to the stages at which the interventions were done. The study was done in subjects with mild cognitive impairment and mild Alzheimer dementia. People who have mild cognitive impairment have retained their independence in instrumental activities of daily living — for example, driving, taking medications, managing finances, errands, chores — but have cognitive and memory changes beyond what we would attribute to normal aging. When people transition to mild dementia, they’re a bit further along. The study was for people within that spectrum but there’s some reason to believe that intervening even earlier might be more effective, as is the case with many other medical conditions.

We’re doing a study here called the AHEAD study that is investigating the effects of lecanemab when administered earlier, in cognitively normal individuals who have elevated brain amyloid, to see whether we see a preventative benefit. The hope is that we would at least see a delay to onset of cognitive impairment and a favorable effect not only on amyloid biomarkers, but other biomarkers that might capture progression of the disease.

GAZETTE: Is anybody in that study treatment yet or are you still enrolling?

McGINNIS: There’s a rolling enrollment, so there are people who are in the double-blind phase of treatment, receiving either the drug or the placebo. But the enrollment target hasn’t been reached yet so we’re still accepting new participants.

GAZETTE: Is it likely that we may see drug cocktails that go after tau and amyloid? Is that a future approach?

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McGINNIS: It has not yet been tried, but those of us in the field are very excited at the prospect of these studies. There’s been a lot of work in recent years on developing therapeutics that target tau, and I think we’re on the cusp of some important breakthroughs. This is key, considering evidence that spreading of tau from cell to cell might contribute to progression of the disease. Additionally, for some time, we’ve had a suspicion that we will likely have to target multiple different aspects of the disease process, as is the case with most types of cancer treatment. Many in our field believe that we will obtain the most success when we identify the most pertinent mechanisms for subgroups of people with Alzheimer’s disease and then specifically target those mechanisms. Examples might include metabolic dysfunction, inflammation, and problems with elements of cellular processing, including mitochondrial functioning and processing old or damaged proteins. Multi-drug trials represent a natural next step.

GAZETTE: What about side effects from this drug?

McGINNIS: We’ve known for a long time that drugs in this class, antibodies that harness the power of the immune system to remove amyloid, carry a risk of causing swelling in the brain. In most cases, it’s asymptomatic and just detected by MRI scan. In Clarity AD, while 12 to 13 percent of participants receiving lecanemab had some level of swelling detected by MRI, it was symptomatic in only about 3 percent of participants and mild in most of those cases.

Another potential side effect is bleeding in the brain or on the surface of the brain. When we see bleeding, it’s usually very small, pinpoint areas of bleeding in the brain that are also asymptomatic. A subset of people with Alzheimer’s disease who don’t receive any treatment are going to have these because they have amyloid in their blood vessels, and it’s important that we screen for this with an MRI scan before a person receives treatment. In Clarity AD, we saw a rate of 9 percent in the placebo group and about 17 percent in the treatment group, many of those cases in conjunction with swelling and mostly asymptomatic.

The scenario that everybody worries about is a hemorrhagic stroke, a larger area of bleeding. That was much less common in this study, less than 1 percent of people. Unlike similar studies, this study allowed subjects to be on anticoagulation medications, which thin the blood to prevent or treat clots. The rate of macro hemorrhage — larger bleeds — was between 2 and 3 percent in the anticoagulated participants. There were some highly publicized cases including a patient who had a stroke, presented for treatment, received a medication to dissolve clots, then had a pretty bad hemorrhage. If the drug gets full FDA approval, is covered by insurance, and becomes clinically available, most physicians are probably not going to give it to people who are on anticoagulation. These are questions that we’ll have to work out as we learn more about the drug from ongoing research.

GAZETTE: Has this study, and these recent developments in the field, had an effect on patients?

McGINNIS: It has had a considerable impact. There’s a lot of interest in the possibility of receiving this drug or a similar drug, but our patients and their family members understand that this is not a cure. They understand that we’re talking about slowing down a rate of decline. In a perfect world, we’d have treatments that completely stop decline and even restore function. We’re not there yet, but this represents an important step toward that goal. So there’s hope. There’s optimism. Our patients, particularly patients who are at earlier stages of the disease, have their lives to live and are really interested in living life fully. Anything that can help them do that for a longer period of time is welcome.

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• Azucena Perez-Canamas
• Stephen M. Strittmatter

News and Comment

Regulatory considerations for developing remote measurement technologies for Alzheimer’s disease research

The Remote Assessment of Disease and Relapse – Alzheimer’s Disease (RADAR-AD) consortium evaluated remote measurement technologies (RMTs) for assessing functional status in AD. The consortium engaged with the European Medicines Agency (EMA) to obtain feedback on identification of meaningful functional domains, selection of RMTs and clinical study design to assess the feasibility of using RMTs in AD clinical studies. We summarized the feedback and the lessons learned to guide future projects.

• Gül Erdemli
• Margarita Grammatikopoulou
• Anna-Katharine Brem

Proteomic aging signatures predict disease risk and mortality across diverse populations

In a large human population study of proteomic aging, we developed a proteomics-based age clock for UK Biobank participants and validated its accuracy in the China Kadoorie Biobank and FinnGen. Proteomic aging is associated with mortality, risk of 18 chronic diseases and numerous age-related traits, including cognitive function.

Disentangling clinical and biological trajectories of neurodegenerative diseases

In recent years, we have seen a shift towards defining sporadic neurodegenerative diseases as a biological continuum. Here, we discuss the risks associated with this shift, emphasize the importance of maintaining a strong connection between disease definitions and subsequent clinical outcomes, and suggest clinicobiological frameworks to disentangle multiple discrete nosological entities.

• Nicolas Villain
• Vincent Planche

Long-term cognitive change after COVID-19 in older individuals

Our study shows that older adults who survive severe COVID-19 suffer accelerated cognitive decline for 1 year after infection, after which the rate of decline decelerates. Long-lasting cognitive impairment occurs mostly in individuals who had severe COVID-19, showed cognitive impairments at 6 months after infection and had coexisting hypertension.

A clinical perspective on the revised criteria for diagnosis and staging of Alzheimer’s disease

A Comment that discusses how biomarkers might be used in clinical practice to improve the diagnostic work-up of Alzheimer’s disease. It also highlights key knowledge gaps that need addressing before global clinical implementation of such markers.

• Oskar Hansson
• Clifford R. Jack Jr.

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The Latest Advances in the Diagnosis and Treatment of Dementia

Rehab hafiz.

1 Family Medicine, Al Takassusi Primary Healthcare Center, Makkah, SAU

Lama Alajlani

2 College of Medicine, King Saud Bin Abdulaziz University for Health Sciences, Jeddah, SAU

Albatool Ali

Ghadah a algarni.

3 College of Medicine, Fakeeh College for Medical Sciences, Jeddah, SAU

Hassan Aljurfi

4 Family Medicine, Alfath Care Center, Madinah Health Cluster, Ministry of Health, Madinah, SAU

Omar Abdullah M Alammar

5 Internal Medicine, King Fahad Hospital, Al Hofuf, SAU

Maria Y Ashqan

Alanoud alkhashan.

Dementia is a debilitating neurological condition that is characterized by persistent cognitive decline. It is a global health challenge, with a rapidly increasing prevalence due to an increasing aging population. Although definitive diagnosis of various conditions of dementia is only possible by autopsy, clinical diagnosis can be performed by a specialist. The diagnostic process has evolved with recent breakthroughs in diagnostic tools, such as advanced imaging techniques and biomarkers. These tools facilitate early and accurate identification of the condition. Early diagnosis is vital, as it enables timely interventions to improve the quality of life for affected individuals. Treatment strategies for dementia encompass both pharmacological and non-pharmacological approaches. Non-pharmacological treatments include cognitive training and lifestyle modifications. Among pharmacological treatments, acetyl-cholinesterase inhibitors including donepezil, rivastigmine, and galantamine can be used in various doses based on the severity of the disease. Apart from these, N-methyl-D-aspartate receptor antagonists such as memantine can also be used. Furthermore, personalized treatments have also gained significant attention in dementia treatment. Interdisciplinary care, involving healthcare professionals, social workers, and support networks, is crucial for comprehensive and holistic dementia management.

Introduction and background

According to the World Health Organization (WHO), dementia is classified as a syndrome rather than a disease [ 1 ]. It is characterized by a progressive decline in the cognitive function of an individual across multiple cognitive domains, consequently impairing functional abilities. The term dementia has been replaced by major neurocognitive disorder (MND) in the Diagnostic and Statistical Manual of Mental Disorders-5 (DSM-5) [ 2 ]. However, due to the higher recognition of the term dementia, we will use it in this review. 

The cognitive decline seen in dementia is usually associated with the prior level of cognition of the patient. Furthermore, the decline is often persistent and is not associated with an isolated episode of delirium. The most frequent symptoms of dementia include progressive impairment in thinking, language, memory, learning, and judgment, difficulty in concentrating, being confused about time and place, and mood changes [ 3 , 4 ]. According to the DSM-5, there are 13 etiologies that can contribute to dementia. However, Alzheimer's disease (AD) is the underlying etiology in approximately 70% of all cases [ 5 ]. Other causes of dementia include Lewy body disease, traumatic brain injury, vascular disease, and frontotemporal lobar degeneration [ 6 ].

Several risk factors have been identified for dementia, such as being over the age of 65 and having hypertension, diabetes, smoking, and depression [ 4 , 5 ]. These factors make it more likely for older adults to develop dementia. With the growing population of individuals over 65, the number of dementia patients is expected to increase in the future [ 5 ]. Additionally, the prevalence of dementia has been linked to socioeconomic status and culture, with a higher occurrence seen in countries with lower and middle incomes [ 3 , 6 ].

Prevalence of dementia

According to WHO, almost 55 million people suffer from dementia across the globe [ 7 ]. The prevalence of dementia has been associated with socioeconomic level and culture [ 8 ]. The majority of dementia patients are from low-and middle-income countries. Furthermore, almost 10 million new cases are being added every year [ 7 ]. Among various risk factors, age above 65 years, hypertension, diabetes, smoking, and depression are the main contributors. Older adults are particular victims of this condition, as it is the most prevalent condition among neurological diagnoses in this age group [ 4 , 9 ]. As the number of individuals aged above 65 is increasing, the number of dementia patients is expected to increase to 131.5 million by the year 2050 [ 9 ]. A meta-analysis by Cao et al. reported that the prevalence of dementia is 244 times higher in individuals aged over 100 years compared to the 50-59 years age group. Furthermore, they revealed that the number of dementia patients doubles every five years [ 10 ]. The prevalence of dementia also varies according to the region. For example, a systemic review showed that there was a greater incidence in Latin America (8.5%) and a noticeably lower incidence in the four sub-Saharan African regions (2-4%) [ 11 ]. Similarly, a cross-sectional study from Saudi Arabia that included 1613 participants showed that 16.6% of older individuals were suffering from dementia [ 6 ].

Pathophysiology of dementia

The pathophysiology of dementia varies according to the sub-type of dementia. For example, gross examination of the brain of patients with AD indicates lower brain weight, which can be 100-200 g below average or higher depending on the severity of the disease. The temporal, frontal, and parietal regions show cortical atrophy. However, the thalamus, brainstem, cerebellar hemispheres, and basal ganglia typically show normal size and weight. Furthermore, senile plaques and neurofibrillary tangles are visible under a microscope [ 12 ]. Extracellular plaques consist of beta-amyloid, whereas intracellular neurofibrillary tangles are composed of hyperphosphorylated tau cytoskeletal filaments. The nucleus basalis, cortex, amygdala, and hippocampus are typically where these changes occur. The degree of clinical illness and cognitive deterioration is inversely correlated with the number of tangles. The damage that beta-amyloid causes to brain cells includes intracellular calcium accumulation, oxygen radical formation, nitric oxide synthesis, and inflammatory processes. The basal forebrain has injured cholinergic neurons, resulting in a diminished level of cholinergic neurotransmission. Further findings include the degeneration of the locus caeruleus and raphe nuclei, which leads to deficits in the neurotransmitters glutamate, noradrenaline (norepinephrine), serotonin, and corticotropin-releasing factor [ 12 - 14 ].

Similarly, different types of changes are seen in other types of dementia as well. Lewy body dementia (LBD) is characterized by the accumulation of aggregates of alpha-synuclein protein, called Lewy bodies [ 15 ]. HIV-associated dementia can cause neurodegeneration of the brain due to toxic inflammation by HIV [ 16 ]. Dementia due to alcohol consumption can be caused by cytotoxic processes [ 17 ]. 

Diagnosis of dementia

The definitive diagnosis of the various types of dementia is only possible by the autopsy of the patient. However, a clinical diagnosis of dementia can be made by a specialist in a primary care setting by clinical examination of the patient. Furthermore, neuroimaging, biomarkers, and digital tools can also be used by the physician. Early diagnosis of dementia is crucial for timely intervention and management of the disease. In recent decades, the diagnostic tools and techniques for dementia have improved significantly.

Neuroimaging  

Although diagnostic evaluations are primarily performed based on clinical criteria, the role of neuroimaging has also expanded significantly [ 18 ]. Advanced neuroimaging techniques, such as diffusion tensor imaging (DTI), functional MRI (fMRI), positron emission tomography (PET), and single-photon emission computed tomography (SPECT), have been shown to provide valuable information in the diagnosis of dementia. DTI can detect changes in the structural connectivity of white matter tracts, which can indicate the presence of dementia [ 19 ]. The use of fMRI can detect changes in brain activity patterns, which can indicate functional alterations in the brain associated with dementia [ 20 ]. PET and SPECT can detect changes in brain metabolism and blood flow, improving the accuracy of the diagnosis of dementia [ 21 ] Some studies have investigated the use of novel PET tracers that target specific pathological features of dementia, such as beta-amyloid and tau proteins [ 22 ]. Machine learning algorithms that analyze neuroimaging data have also been developed to aid in the diagnosis of dementia [ 23 ].

Biomarkers  

Recent studies have investigated the use of blood-based biomarkers, such as neurofilament light chain (NfL) and plasma phosphorylated tau (p-tau), for the detection of neurodegeneration in the brain. Elevated levels of these biomarkers indicate the presence of dementia, even before symptoms appear [ 24 ]. The use of blood biomarkers is potentially helpful in diagnosing the pathological features of AD. In addition to blood-based biomarkers, CSF biomarkers, such as amyloid beta, tau, and phosphorylated tau, have been shown to improve the accuracy of the diagnosis of AD [ 25 ]. Retinal biomarkers, such as retinal nerve fiber layer thickness and macular volume, have also been investigated as potential biomarkers for the early diagnosis of dementia [ 26 ]. 

Digital Tools

The modern healthcare industry has embraced technological advancements to improve the provision of care. Mobile-based applications technology is one such innovative and trending invention that supports increased patient care management and quick diagnostics [ 27 ]. Digital tools, such as artificial intelligence (AI) machine learning algorithms, smartphone apps, and wearable devices, have gained traction in the diagnosis of dementia. These tools can detect subtle changes in cognitive function and behavior, which can indicate the presence of dementia. AI algorithms can accurately predict the onset of AD even before symptoms appear, by analyzing neuroimaging data [ 28 ]. Smartphone apps such as Sea Hero Quest (Glitchers, Edinburgh, Scotland) have been developed to assess spatial navigation skills, which are often impaired in the early stages of dementia [ 29 ]. Wearable devices such as smartwatches and fitness trackers have also been used to monitor changes in physical activity and sleep patterns, which can be potential early indicators of dementia. BrainCheck Inc. (Austin, Texas, United States) has developed five distinct games designed based on gold-standard neurocognitive testing. Based on the outcomes of each game, the app shows a graph that indicates the degree of cognitive function relevant to executive function, cognitive processing, immediate memory, visual attention, and delayed recall skills of the user [ 30 ]. Early diagnosis of dementia is critical for timely intervention and management of the disease [ 31 ]. 

Management of dementia

Due to the neuronal cell loss in dementia, there is no curative treatment available so far. Therefore, symptomatic management remains the mainstay of treatment: treatment of behavioral disturbances, environmental manipulations that support function, and counseling about safety concerns [ 32 ]. The main aim of dementia management is to delay cognitive decline and relieve the patient from cognitive suffering. Both non-pharmacologic and pharmacologic approaches are employed, either alone or in combination. The current treatments for dementia vary based on the types of dementia. Two main types of medication have been approved for the treatment of dementia including cholinesterase inhibitors and memantine. AD-related dementia can be treated with acetylcholinesterase inhibitors (AChEIs) including donepezil, rivastigmine, and galantamine in various doses based on the severity of the disease. Apart from these, N-methyl-D-aspartate (NMDA) receptor antagonists such as memantine can also be used. Other types of dementia such as vascular dementia, Parkinson's disease dementia, Down syndrome dementia, LBD, and frontotemporal dementia can also use these pharmacological options. 

It has been shown that AChEIs such as galantamine, rivastigmine, and donepezil increase cholinergic transmission by halting cholinesterase at the synaptic cleft while providing modest symptomatic relief in certain patients suffering from dementia. It is the mainstay drug used in AD patients as they have lower cerebral content of choline acetyltransferase, resulting in diminished acetylcholine production and poor cortical cholinergic function. Donepezil has been found to significantly improve cognition, clinical assessment, and functional outcomes in the higher-dose group [ 33 - 36 ]. AChEIs are presently the gold standard for treating LBD-related cognitive and psychiatric symptoms. Rivastigmine is the only one of the three that is FDA-approved for treating LBD [ 37 - 40 ]. The remaining two are used off-label. There is no compelling evidence that one of the three is more effective than the others in treating LBD [ 41 - 43 ]. There is limited data on the use of AChEIs in treating frontotemporal dementia, and the available ones do not support the use of AChEIs in frontotemporal dementia [ 44 ]. The treatment of dementia in Parkinson's disease centers on the use of AChEIs. Most, but not all, trials with AChEIs in Parkinson's disease dementia found a slight to moderate benefit, albeit at the expense of an increased risk of adverse effects such as exacerbated tremors and nausea [ 45 , 46 ].

Memantine is an NMDA receptor antagonist. In contrast to cholinergic agents, memantine acts in a neuroprotective manner. Cortical and hippocampal neurons' main excitatory amino acid neurotransmitter is glutamate. Moreover, the NMDA receptor, which is involved in memory and learning, is one of the receptors that glutamate activates. It is currently used in treating AD jointly with AChEIs, especially in advanced AD. Agents that block pathologic stimulation of NMDA receptors may also prevent further harm in patients with vascular dementia (VaD), as excessive NMDA stimulation can be generated by ischemia and result in excitotoxicity. The residual neurons' physiological function might also be recovered, improving symptoms [ 47 ]. Many clinicians are turning to memantine because of the lack of other established treatments for VaD. Memantine is frequently used in conjunction with AChEIs in people who can afford it. According to the 2020 guidelines for treating LBD in general, AChEIs have the most evidence for usage in cognitive impairment, whereas memantine has mixed evidence [ 39 ]. There was no statistically significant difference in the usage of memantine in FTD [ 44 ]. Memantine was well-tolerated in some trials in patients with PDD. However, hallucinations and worsening neuropsychiatric symptoms have been recorded using memantine, indicating that it should be used cautiously in PDD [ 48 ]. 

Antioxidants

Vitamin E (alpha-tocopherol) and selegiline (a monoamine oxidase inhibitor) have been studied for their potential in treating AD. Research has shown that vitamin E, when administered at a specific dose, may provide a slight reduction in functional decline in patients with mild to moderate AD. However, its impact on cognitive function is not considered significant [ 49 , 50 ]. On the other hand, medications targeting serotonergic pathways, such as selective serotonin reuptake inhibitors (SSRIs) and trazodone, as well as atypical antipsychotic treatments, have been found to effectively manage specific behavioral symptoms associated with AD. However, it is important to note that these medications do not improve overall cognitive function. In the case of frontotemporal dementia, SSRIs like sertraline and fluvoxamine have shown positive effects on impulsivity, eating disorders, and anxiety based on case reports and short observational studies [ 51 ].

Most Recent Drugs: Lecanemab and Aducanumab

Recent advancements in the field of dementia treatment emphasize the significance of focusing on the underlying pathological mechanisms of the disease, like amyloid-beta plaques. By directly addressing these crucial pathophysiological characteristics of AD, both lecanemab and aducanumab have the potential to provide therapeutic benefits by slowing cognitive decline and enhancing measures of cognition and function in affected individuals.

The FDA has recently approved lecanemab, an anti-amyloid monoclonal antibody, for treating mild cognitive impairment (MCI) and mild dementia caused by AD [ 52 ]. This approval represents a significant breakthrough in dementia treatment. Lecanemab specifically targets the underlying causes of AD by binding to amyloid-beta plaques, which are one of the main pathological characteristics of the disease [ 53 , 54 ].

A notable study conducted by van Dyck et al. demonstrated the effectiveness of lecanemab in reducing amyloid markers in individuals with early-stage AD. The study showed that treatment with lecanemab resulted in a slower deterioration in measures of cognition and function over 18 months compared to a placebo [ 55 ]. However, it is important to note that adverse events were a major concern following treatment with lecanemab, highlighting the need for careful monitoring and management of potential side effects [ 55 ].

Another study by McDade et al. further supported the efficacy of lecanemab in reducing brain amyloid and slowing cognitive decline in patients with AD. The treatment regimen involved administering lecanemab at a dosage of 10 mg/kg biweekly [ 56 ]. These findings provide additional evidence for the potential benefits of lecanemab in managing the progression of AD.

Similarly, the efficacy of another anti-amyloid-beta monoclonal antibody, aducanumab, has been extensively documented in the literature. A systematic review conducted by Rahman et al. reported that the use of aducanumab led to a reduction of amyloid-beta plaques and a significant decrease in cognitive decline among AD patients [ 54 ]. The approval of aducanumab by the FDA in June 2021 further supports its effectiveness as a treatment option for AD.

Non-Pharmacological Treatments 

Although there is no single dietary intervention that has definitively shown to effectively prevent cognitive degeneration and dementia, it is important to consider various factors that can contribute to maintaining brain health and reducing the risk of AD. Along with maintaining a healthy and balanced diet, regular physical activity, sufficient sleep, and stress management are all important lifestyle factors that have been associated with a decreased risk of cognitive decline [ 57 , 58 ].

Mediterranean Diet (MedDiet) and Dietary Approaches to Stop Hypertension (DASH):

In prospective observational studies and trials, the MedDiet has been consistently seen to provide numerous benefits in preventing various non-communicable diseases. This includes cognitive decline and dementia, which are major concerns in aging populations. The MedDiet is characterized by a high consumption of plant-based foods such as fruits, vegetables, whole grains, legumes, nuts, and olive oil. It also involves moderate intake of fish and poultry, and limited consumption of red meat and processed foods. The diet is rich in nutrients such as antioxidants, omega-3 fatty acids, fiber, and vitamins, which have been associated with cognitive health [ 59 , 60 ].

Several studies have shown that individuals who closely follow the DASH and MedDiet, while also consuming more whole grains, nuts, and legumes, tend to achieve higher scores on the Mini-Mental State Examination (MMSE), a widely used cognitive assessment tool [ 59 - 62 ]. The MMSE evaluates various cognitive domains such as orientation, memory, attention, and language, with higher scores indicating better cognitive function. These findings suggest a strong association between a healthier dietary pattern and improved cognitive function. Furthermore, a systematic review conducted by Lourida et al. provides additional support for the positive impact of the MedDiet on cognitive health. The review analyzed multiple studies and concluded that adherence to the MedDiet is linked to a slower rate of cognitive decline and a reduced risk of AD [ 63 ].

The potential mechanisms underlying the beneficial effects of the MedDiet on cognitive health are multifactorial. The high intake of fruits, vegetables, and whole grains provides a rich source of antioxidants. These antioxidants help combat oxidative stress and inflammation, which are processes believed to contribute to cognitive decline. The MedDiet is also rich in omega-3 fatty acids, mainly from fish consumption, which have been associated with improved cognitive function and a lower risk of dementia. Additionally, the MedDiet promotes cardiovascular health by reducing the risk of hypertension, diabetes, and obesity. These conditions are known to increase the risk of cognitive impairment [ 61 - 63 ].

Ketogenic Diet

The ketogenic diet has been proposed as a potentially neuroprotective approach against cognitive decline. This diet is characterized by a low carbohydrate composition, moderate protein consumption, and high-fat consumption. In recent years, it has gained attention for its potential in preventing cognitive decline associated with aging. However, it is important to note that there is currently insufficient clinical trial data to draw definitive conclusions about the effectiveness of the ketogenic diet in preventing and treating cognitive decline and AD [ 64 , 65 ]. A systematic review conducted by Devranis et al. included seven studies on the ketogenic diet and reported that it may have the potential to reduce cognitive decline [ 66 ]. However, it is crucial to consider the limitations of the existing research. The number of studies available is relatively small, and the quality and design of the studies vary.

The ketogenic diet is believed to have neuroprotective effects due to several mechanisms. Firstly, the diet's low carbohydrate composition induces ketosis, a state where the body produces ketone bodies as an alternative fuel source for the brain. Ketone bodies, like beta-hydroxybutyrate, are believed to possess neuroprotective properties and offer an alternative energy source for brain cells, potentially enhancing their function [ 65 ].

Additionally, the ketogenic diet has been shown to reduce inflammation and oxidative stress, which are believed to play a role in the development and progression of neurodegenerative diseases. By limiting the intake of carbohydrates and promoting the consumption of healthy fats, the diet may help reduce the production of reactive oxygen species, which can damage brain cells and contribute to cognitive decline [ 65 ].

Furthermore, the ketogenic diet has been found to modulate various signaling pathways and gene expressions that are involved in neuronal health and function. For example, it has been shown to activate pathways that promote the synthesis of neurotrophic factors, such as brain-derived neurotrophic factor (BDNF), which supports the growth and survival of neurons [ 66 ]. The diet may also enhance mitochondrial function and increase the production of adenosine triphosphate (ATP), the primary energy currency of cells, which is essential for proper brain function [ 64 ].

Physical Activity

According to recent research, increasing physical activity levels has been found to have a preventive effect on approximately 3% of all dementia cases [ 67 , 68 ]. Additionally, engaging in physical activity and exercise has been shown to improve overall cognitive function in individuals with dementia [ 69 ]. This positive impact is likely attributed to multiple underlying processes. Firstly, physical activity and exercise help in managing cardiovascular risk factors that are associated with impaired cognitive performance. By promoting cardiovascular health, physical activity contributes to maintaining optimal brain function [ 70 ]. Furthermore, animal studies have demonstrated that physical activity and exercise can stimulate neurogenesis, the generation of new neurons, and synaptic plasticity, the ability of neurons to form connections with one another. These processes are crucial for maintaining brain health and cognitive function [ 70 , 71 ].

Sleep Patterns

Sleep disturbance is not only a symptom but also a risk factor for neurocognitive conditions, such as dementia [ 72 ]. Adequate sleep is now recognized as crucial for memory consolidation and the removal of excess beta-amyloid and hyperphosphorylated tau, which are characteristic biomarkers of AD. Sleep difficulties often precede the onset of AD pathology and cognitive decline [ 73 ]. Non-pharmacological sleep therapies have shown promise in improving sleep quality and may positively impact cognitive function in individuals with dementia. Multidomain approaches that address various aspects of sleep hygiene, including the sleep environment, bedtime routines, and relaxation techniques, have shown particular effectiveness [ 73 , 74 ]. However, it is important to note that the existing research on non-pharmacological sleep therapies for dementia is heterogeneous and limited.

Challenges of caring for individuals with dementia

There are multiple challenges in caring for patients with dementia. Behavioral changes such as agitation, aggression, delusions, and hallucinations make it difficult to provide care for patients with dementia. Agitation and aggression are caused by neuroleptic overdose, internal medical conditions, or pain. Cognitive deficit occurring in dementia patients makes it hard for them to express pain and in turn, it manifests as a state of agitation [ 75 ]. Sleep disturbance with increased nighttime wakefulness and reduction in the total amount of sleep time is associated with cognitive decline [ 76 ]. Another issue is safety, with later stages of dementia patients wandering and becoming lost is one problem that faces caregivers. [ 77 ] One more thing to consider is eating problems, which are common among demented patients and require nutritional support [ 78 ].

It is important to face the different challenges facing dementia patients' caregivers with a more holistic point of view taken towards dementia with an interdisciplinary team approach. Interventions should be individualized according to the needs of the patients. The effectiveness of psychosocial interventions tailored to the patient's needs for the management of neuropsychiatric symptoms has been demonstrated [ 79 ]. An essential aspect of effective management involves rehabilitation, which entails a collaborative effort with healthcare professionals to adopt a patient-centered approach that also incorporates the involvement of caregivers [ 80 ]. According to the WHO, rehabilitation is important to meet the needs of the affected people. Older adults and their caregivers have the potential to live an active and social life with interdisciplinary rehabilitation [ 80 ]. 

There is a plethora of challenges that caregivers of patients with dementia face. One example is that caregivers constantly need to be alert and involved in the medical treatment of dementia patients due to their cognitive impairment [ 81 ]. Care recipients may not value the assistance provided by their caregivers and sometimes even refrain from their medical treatment [ 82 ]. Several studies reported that patients sometimes believed that their given medications were poisonous and that they became doubtful and paranoid when given their treatment [ 82 , 83 ]. Another challenge is the behavioral changes of elderly patients with dementia that sometimes lead them to refuse care. Some patients lose insight regarding their condition and need for food or medications. As a result, it has been reported in a study that nutritional care may be complicated for patients with dementia as they can accumulate food or become hostile at mealtime [ 84 ]. Also, caregivers for dementia patients deal with complex treatment regimens. A study reported that care recipients often had around nine comorbidities and received more than 10 medications [ 85 ]. Lastly, data shows that caregivers did not receive enough information and teaching regarding their medical and nursing tasks. Several studies also showed that the lack of education and training for caregivers was attributed to the limited time available with the healthcare providers [ 82 , 86 ]. 

The treatment approach to people with dementia is complicated as they present with symptoms in multiple domains. These include impaired cognition, neuropsychiatric symptoms, daily activities, and often other medical and comorbidities. Interventions to treat dementia patients must consider their cognitive, physical, emotional, and psychosocial needs [ 67 ]. Thus, elderly people with dementia require rehabilitation involving several healthcare professionals to improve their independence to perform their daily activities. One study demonstrated that patients who received interdisciplinary care had stable and slightly improved cognitive status and performance of activities of daily living [ 87 ].

Conclusions

Dementia is a significant contributor to morbidity in elderly individuals. As the number of individuals aged above 65 years is increasing, there is also an increase in dementia cases, and it has emerged as a significant concern for healthcare systems and communities across the globe. However, the latest advances in the diagnosis and treatment of dementia have ushered in a new era of hope and progress in the battle against this debilitating condition. New diagnostic tools have helped early diagnoses of dementia. Currently, research is ongoing both on the pharmacological and non-pharmacological treatment of dementia. In the journey to combat dementia, knowledge is our greatest weapon. As we move forward, collaboration between researchers, healthcare providers, and caregivers is key to managing dementia.

The authors have declared that no competing interests exist.

Author Contributions

Concept and design:   Rehab Hafiz, Albatool Ali, Lama Alajlani

Critical review of the manuscript for important intellectual content:   Rehab Hafiz

Supervision:   Rehab Hafiz

Acquisition, analysis, or interpretation of data:   Hassan Aljurfi, Albatool Ali, Lama Alajlani, Maria Y. Ashqan, Ghadah A. Algarni , Omar Abdullah M. Alammar, Alanoud Alkhashan

Drafting of the manuscript:   Hassan Aljurfi, Albatool Ali, Lama Alajlani, Maria Y. Ashqan, Ghadah A. Algarni , Omar Abdullah M. Alammar, Alanoud Alkhashan

Appointments at Mayo Clinic

Alzheimer's treatments: what's on the horizon.

Despite many promising leads, new treatments for Alzheimer's are slow to emerge.

Current Alzheimer's treatments temporarily improve symptoms of memory loss and problems with thinking and reasoning.

These Alzheimer's treatments boost the performance of chemicals in the brain that carry information from one brain cell to another. They include cholinesterase inhibitors and the medicine memantine (Namenda). However, these treatments don't stop the underlying decline and death of brain cells. As more cells die, Alzheimer's disease continues to progress.

Experts are cautious but hopeful about developing treatments that can stop or delay the progression of Alzheimer's. Experts continue to better understand how the disease changes the brain. This has led to the research of potential Alzheimer's treatments that may affect the disease process.

Future Alzheimer's treatments may include a combination of medicines. This is similar to treatments for many cancers or HIV / AIDS that include more than one medicine.

These are some of the strategies currently being studied.

Taking aim at plaques

Some of the new Alzheimer's treatments target clumps of the protein beta-amyloid, known as plaques, in the brain. Plaques are a characteristic sign of Alzheimer's disease.

Strategies aimed at beta-amyloid include:

Recruiting the immune system. Medicines known as monoclonal antibodies may prevent beta-amyloid from clumping into plaques. They also may remove beta-amyloid plaques that have formed. They do this by helping the body clear them from the brain. These medicines mimic the antibodies your body naturally produces as part of your immune system's response to foreign invaders or vaccines.

The U.S. Food and Drug Administration (FDA) has approved lecanemab (Leqembi) and donanemab (Kisunla) for people with mild Alzheimer's disease and mild cognitive impairment due to Alzheimer's disease.

Clinical trials found that the medicines slowed declines in thinking and functioning in people with early Alzheimer's disease. The medicines prevent amyloid plaques in the brain from clumping.

Lecanemab is given as an IV infusion every two weeks. Your care team likely will watch for side effects and ask you or your caregiver how your body reacts to the drug. Side effects of lecanemab include infusion-related reactions such as fever, flu-like symptoms, nausea, vomiting, dizziness, changes in heart rate and shortness of breath.

Donanemab is given as an IV infusion every four weeks. Side effects of the medicine may include flu-like symptoms, nausea, vomiting, headache and changes in blood pressure. Rarely, donanemab can cause a life-threatening allergic reaction and swelling.

Also, people taking lecanemab or donanemab may have swelling in the brain or may get small bleeds in the brain. Rarely, brain swelling can be serious enough to cause seizures and other symptoms. Also in rare instances, bleeding in the brain can cause death. The FDA recommends getting a brain MRI before starting treatment. The FDA also recommends periodic brain MRIs during treatment for symptoms of brain swelling or bleeding.

People who carry a certain form of a gene known as APOE e4 appear to have a higher risk of these serious complications. The FDA recommends testing for this gene before starting treatment.

If you take a blood thinner or have other risk factors for brain bleeding, talk to your healthcare professional before taking lecanemab or donanemab. Blood-thinning medicines may increase the risk of bleeds in the brain.

More research is being done on the potential risks of taking lecanemab and donanemab. Other research is looking at how effective the medicines may be for people at risk of Alzheimer's disease, including people who have a first-degree relative, such as a parent or sibling, with the disease.

The monoclonal antibody solanezumab did not show benefits for individuals with preclinical, mild or moderate Alzheimer's disease. Solanezumab did not lower beta-amyloid in the brain, which may be why it wasn't effective.

Preventing destruction. A medicine initially developed as a possible cancer treatment — saracatinib — is now being tested in Alzheimer's disease.

In mice, saracatinib turned off a protein that allowed synapses to start working again. Synapses are the tiny spaces between brain cells through which the cells communicate. The animals in the study experienced a reversal of some memory loss. Human trials for saracatinib as a possible Alzheimer's treatment are now underway.

Production blockers. These therapies may reduce the amount of beta-amyloid formed in the brain. Research has shown that beta-amyloid is produced from a "parent protein" in two steps performed by different enzymes.

Several experimental medicines aim to block the activity of these enzymes. They're known as beta- and gamma-secretase inhibitors. Recent studies showed that the beta-secretase inhibitors did not slow cognitive decline. They also were associated with significant side effects in those with mild or moderate Alzheimer's. This has decreased enthusiasm for the medicines.

Keeping tau from tangling

A vital brain cell transport system collapses when a protein called tau twists into tiny fibers. These fibers are called tangles. They are another common change in the brains of people with Alzheimer's. Researchers are looking at a way to prevent tau from forming tangles.

Tau aggregation inhibitors and tau vaccines are currently being studied in clinical trials.

Reducing inflammation

Alzheimer's causes chronic, low-level brain cell inflammation. Researchers are studying ways to treat the processes that lead to inflammation in Alzheimer's disease. The medicine sargramostim (Leukine) is currently in research. The medicine may stimulate the immune system to protect the brain from harmful proteins.

Researching insulin resistance

Studies are looking into how insulin may affect the brain and brain cell function. Researchers are studying how insulin changes in the brain may be related to Alzheimer's. However, a trial testing of an insulin nasal spray determined that the medicine wasn't effective in slowing the progression of Alzheimer's.

Studying the heart-head connection

Growing evidence suggests that brain health is closely linked to heart and blood vessel health. The risk of developing dementia appears to increase as a result of many conditions that damage the heart or arteries. These include high blood pressure, heart disease, stroke, diabetes and high cholesterol.

A number of studies are exploring how best to build on this connection. Strategies being researched include:

• Current medicines for heart disease risk factors. Researchers are looking into whether blood pressure medicines may benefit people with Alzheimer's. They're also studying whether the medicines may reduce the risk of dementia.
• Medicines aimed at new targets. Other studies are looking more closely at how the connection between heart disease and Alzheimer's works at the molecular level. The goal is to find new potential medicines for Alzheimer's.
• Lifestyle choices. Research suggests that lifestyle choices with known heart benefits may help prevent Alzheimer's disease or delay its onset. Those lifestyle choices include exercising on most days and eating a heart-healthy diet.

Studies during the 1990s suggested that taking hormone replacement therapy during perimenopause and menopause lowered the risk of Alzheimer's disease. But further research has been mixed. Some studies found no cognitive benefit of taking hormone replacement therapy. More research and a better understanding of the relationship between estrogen and cognitive function are needed.

Speeding treatment development

Developing new medicines is a slow process. The pace can be frustrating for people with Alzheimer's and their families who are waiting for new treatment options.

To help speed discovery, the Critical Path for Alzheimer's Disease (CPAD) consortium created a first-of-its-kind partnership to share data from Alzheimer's clinical trials. CPAD 's partners include pharmaceutical companies, nonprofit foundations and government advisers. CPAD was formerly called the Coalition Against Major Diseases.

CPAD also has collaborated with the Clinical Data Interchange Standards Consortium to create data standards. Researchers think that data standards and sharing data from thousands of study participants will speed development of more-effective therapies.

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• Treatments and research. Alzheimer's Association. https://www.alz.org/alzheimers-dementia/research_progress/treatment-horizon. Accessed March 23, 2023.
• Cummings J, et al. Alzheimer's disease drug development pipeline: 2022. Alzheimer's and Dementia. 2022; doi:10.1002/trc2.12295.
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• Plascencia-Villa G, et al. Lessons from antiamyloid-beta immunotherapies in Alzheimer's disease. Handbook of Clinical Neurology. 2023; doi:10.1016/B978-0-323-85555-6.00019-9.
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• Piscopo P, et al. A systematic review on drugs for synaptic plasticity in the treatment of dementia. Ageing Research Reviews. 2022; doi:10.1016/j.arr. 2022.101726 .
• Facile R, et al. Use of Clinical Data Interchange Standards Consortium (CDISC) standards for real-world data: Expert perspectives from a qualitative Delphi survey. JMIR Medical Informatics. 2022; doi:10.2196/30363.
• Imbimbo BP, et al. Role of monomeric amyloid-beta in cognitive performance in Alzheimer's disease: Insights from clinical trials with secretase inhibitors and monoclonal antibodies. Pharmacological Research. 2023; doi:10.1016/j.phrs. 2022.106631 .
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• Zhong H, et al. Effect of peroxisome proliferator-activated receptor-gamma agonists on cognitive function: A systematic review and meta-analysis. Biomedicines. 2023; doi:10.3390/biomedicines11020246.
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• Kisunla (prescribing information). Eli Lilly and Company; 2024. https://www.lilly.com/. Accessed July 3, 2024.

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Alzheimer's researchers are looking beyond plaques and tangles for new treatments.

Jon Hamilton

Scientists say research into Alzheimer's needs to take a broader view of how the disease affects the brain — whether that's changes in the cortex or the role of inflammation. Matt York/AP hide caption

Scientists say research into Alzheimer's needs to take a broader view of how the disease affects the brain — whether that's changes in the cortex or the role of inflammation.

The field of Alzheimer's research is branching out.

After decades of focusing on the sticky amyloid plaques and tangled tau fibers associated with the disease, brain researchers are searching for other potential causes of impaired memory and thinking.

That search is on full display this week at the Alzheimer's Association International Conference in San Diego, where sessions are exploring factors including genes, brain injury, clogged arteries and inflammation.

A group of researchers from Seattle even unveiled a highly detailed atlas showing how different types of brain cells change in Alzheimer's. The goal is to help scientists identify new approaches to treatment.

"Certainly, plaques and tangles are a hallmark," says Maria Carrillo , chief science officer of the Alzheimer's Association. "It doesn't mean plaques are the cause of cell death."

Plaques are clumps of a protein called beta-amyloid that appear in the spaces between neurons. Tangles are made up of a protein called tau that appears inside a neuron.

Both proteins tend to accumulate in the brains of people with Alzheimer's. But their role in killing brain cells is still unclear.

Carrillo says the Alzheimer's field needs to look to cancer research where a deeper understanding of the disease has led to better treatments.

The shift comes after a series of experimental drugs have succeeded in removing amyloid plaques and tau tangles from the brain, but failed to halt the disease.

The Food and Drug Administration has approved one amyloid drug, Aduhelm, but is still evaluating whether it actually helps patients.

An Alzheimer's Atlas

The study that produced the atlas is emblematic of how researchers are recalibrating.

"What we're trying to do with this study is to look at cell vulnerability early on in disease, before [people] have plaques and tangles, before they have cognitive impairment," says Dr. C. Dirk Keene , a neuropathologist at the University of Washington.

To create the atlas, Keene and a team of researches analyzed more than a million cells from 84 brains donated by people who'd signed up for Alzheimer's research projects run by the University of Washington and Kaiser Permanente Washington Research Institute.

The brains came from donors "at all different stages of disease" Keene says, "so we can pinpoint what's happening from the earliest levels all the way through to people with advanced disease."

The effort is funded by the National Institute on Aging and grew out of the federal BRAIN initiative launched by President Obama in 2013.

The atlas came from the realization that "If we want to treat diseases of an extremely complex cellular organ, you need to understand that organ much better than we do," says Ed Lein , a senior investigator at the Allen Institute for Brain Science, which played a key role in analyzing the brain tissue.

So the team spent years studying cells in healthy brains before looking at brains affected by Alzheimer's.

"We've defined what a normal adult brain looks like," Lein says, "and now we can use that knowledge and look for changes that are happening in specific kinds of cells."

Future Alzheimer's Treatments Aim To Do More Than Clear Plaques From The Brain

Finding vulnerable brain cells.

At the Alzheimer's meeting, the team described changes they saw in more than 100 types of cells taken from the cortex — an area of the brain which is important to memory and thinking.

One finding was that neurons that make connections within the cortex itself were much more likely to die than those that connect to distant areas of the brain.

"What we're seeing is a profound effect on cortical circuitry that very plausibly is the reason we have cognitive decline," Lein says.

If so, a treatment designed to protect those vulnerable neurons might prevent declines in memory and thinking linked to Alzheimer's.

The team also found a proliferation of brain cells that contribute to inflammation. These included certain immune cells and a type of cell that responds to injury.

"So while the neurons are lost, the non-neuronal cells are actually increasing and changing" Lein says.

The finding supports the idea that inflammation plays an important role in Alzheimer's, and that anti-inflammatory drugs might help protect the brain.

The Seattle team hopes other scientists will use the brain cell atlas to come up with new treatments for Alzheimer's.

"We've created an open-access resource where the whole community can come and look at this data," Lein says. "They can mine it to speed up progress in the field as a whole."

Speeding up progress is one reason Kyle Travaglini , a researcher at the Allen Institute, jumped at the chance to work on the Alzheimer's project.

"My grandmother started developing Alzheimer's disease when I was just going off to college," says Travaglini, who received his PhD in 2021.

Travaglini says the atlas project is appealing because it isn't based on a preconceived idea about what causes Alzheimer's.

"It's like looking at the same disease that everyone has been looking at but in an entirely different way," he says.

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Scientists discover new cause of Alzheimer's, vascular dementia

by Erik Robinson, Oregon Health & Science University

Researchers have discovered a new avenue of cell death in Alzheimer's disease and vascular dementia.

A new study, led by scientists at Oregon Health & Science University and published in the journal Annals of Neurology , reveals for the first time that a form of cell death known as ferroptosis—caused by a buildup of iron in cells—destroys microglia cells, a type of cell involved in the brain 's immune response, in cases of Alzheimer's and vascular dementia .

The researchers conducted the study examining post-mortem human brain tissue of patients with dementia.

"This is a major finding," said senior author Stephen Back, M.D., Ph.D., a neuroscientist and professor of pediatrics in the OHSU School of Medicine.

Back has long studied myelin, the insulation-like protective sheath covering nerve fibers in the brain, including delays in forming myelin in premature infants. The new research extends that line of work by uncovering a cascading form of neurodegeneration triggered by deterioration of myelin. They made the discovery using a novel technique developed by the study's lead author Philip Adeniyi, Ph.D., a postdoctoral researcher in Back's laboratory.

The researchers discovered that microglia degenerates in the white matter of the brain of patients with Alzheimer's and vascular dementia.

Microglia are resident cells in the brain normally involved in clearing cellular debris as part of the body's immune system. When myelin is damaged, microglia swarm in to clear the debris. In the new study, researchers found that microglia themselves are destroyed by the act of clearing iron-rich myelin—a form of cell death known as ferroptosis.

Given the intense scientific focus on the underlying cause of dementia in older adults , Back called it amazing that researchers hadn't made the connection to ferroptosis until now.

"We've missed a major form of cell death in Alzheimer's disease and vascular dementia," Back said. "We hadn't been giving much attention to microglia as vulnerable cells, and white matter injury in the brain has received relatively little attention."

Co-author Kiera Degener-O'Brien, M.D., initially discovered the degeneration of microglia in tissue samples, Back said. Adeniyi subsequently developed a novel immunofluorescence technique to determine that iron toxicity was causing microglial degeneration in the brain. This was likely a result of the fact that the fragments of myelin are themselves rich in iron, Back said.

In effect, the immune cells were dying in the line of duty.

"Everyone knows that microglia are activated to mediate inflammation," Back said. "But no one knew that they were dying in such large numbers. It's just amazing that we missed this until now."

The study finds that the cascading effect of degenerating microglia appears to be a mechanism in advancing cognitive decline in Alzheimer's disease and vascular dementia , Back said. He expects pharmaceutical companies will use this new finding to develop compounds focused on reducing microglial degeneration in the brain.

"That's where the field will go next," he said. "A discovery like ours will stimulate a lot of excitement in the pharmaceutical industry to develop therapeutically important compounds."

He said the underlying cause initiating the cycle of decline likely relates to repeated episodes of low blood flow and oxygen delivery to the brain over time due to acute stroke or chronic conditions such as hypertension and diabetes.

"Dementia is a process that goes on for years and years," Back said. "We have to tackle this from the early days to have an impact so that it doesn't spin out of control."

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UC study: Boosting brain protein levels may slow decline from Alzheimer’s

Research published in the journal brain.

A study published in the journal Brain shows that increases in protein levels with new Alzheimer’s drugs can explain the slowing of cognitive impairment at least as well as the reduction in amyloid plaques. 

During a study challenging the idea that newly approved monoclonal antibodies reduce cognitive decline in Alzheimer's patients by clearing amyloid, University of Cincinnati researchers found that the unintended increase in levels of a critical brain protein correlates equally well with cognitive benefits. 

Led by UC’s Alberto Espay, MD, the research was published in the journal Brain Sept. 11 .

Study background

For decades, the prevailing theory in the field has stated that a protein made up of 42 amino acids called amyloid-beta 42 (Aβ42) hardens into clumps called amyloid plaques, and those plaques in the brain cause the damage and/or dysfunction that causes Alzheimer’s disease.

Espay and team have hypothesized that normal, soluble Aβ42 in the brain is crucial for neuron health and that the loss of Aβ42, rather than the buildup of plaques, drives Alzheimer’s. This includes published research that suggests dementia occurs not when plaque levels are high but when Aβ42 levels drop very low. 

According to Espay’s research, the transformation of Aβ42 into plaques appears to be the brain’s normal response to biological, metabolic or infectious stress. 

“Most of us will accrue amyloid plaques in our brains as we age, and yet very few of us with plaques go on to develop dementia,” said Espay, professor of neurology in the UC College of Medicine and director and endowed chair of the James J. and Joan A. Gardner Family Center for Parkinson’s Disease and Movement Disorders at the UC Gardner Neuroscience Institute. “Yet the plaques remain the center of our attention in biomarker development and therapeutic strategies.”

Alberto Espay, MD. Photo/Colleen Kelley/UC Marketing + Brand.

Study details

Recently, several new monoclonal antibody medications designed to remove amyloid from the brain were approved after showing they lessened cognitive decline in clinical trials. 

Espay and his colleagues noticed that these drugs unintentionally increased levels of Aβ42.  

“Amyloid plaques don’t cause Alzheimer’s, but if the brain makes too much of it while defending against infections, toxins or biological changes, it can’t produce enough Aβ42, causing its levels to drop below a critical threshold,” Espay explained. “That’s when dementia symptoms emerge.” 

The team analyzed data from nearly 26,000 patients enrolled in 24 randomized clinical trials of these new antibody treatments, assessing cognitive impairment and differences in levels of Aβ42 before and after treatment. They found that higher levels of Aβ42 after treatment were independently associated with slower cognitive impairment and clinical decline.  

“All stories have two sides — even the one we have told ourselves about how anti-amyloid treatments work: by lowering amyloid,” Espay said. “In fact, they also raise the levels of Aβ42. Even if this is unintended, it is why there may be a benefit. Our study shows that we can predict changes in cognitive outcomes in anti-amyloid trials at least as well by the increases in Aβ42 as by the decreases in amyloid.”

Espay said these findings fit well into his larger hypothesis about the root cause of Alzheimer’s, as increasing levels of Aβ42 appear to improve cognition.  

“If the problem with Alzheimer’s is the loss of the normal protein, then increasing it should be beneficial, and this study showed that it is,” he said. “The story makes sense: Increasing Aβ42 levels to within the normal range is desirable.” 

However, Espay believes these results also present a conundrum for clinicians because removing amyloid from the brain is toxic and may cause the brain to shrink faster after antibody treatment. 

“Do we give patients an anti-protein treatment to increase their protein levels? I think the end, increasing Aβ42, doesn’t justify the means, decreasing amyloid,” Espay said. Therapies that directly increase Aβ42 levels without targeting amyloid are a focus of research for Espay and his group.

Next Lives Here

The University of Cincinnati is classified as a Research 1 institution by the Carnegie Commission and is ranked in the National Science Foundation's Top-35 public research universities. UC's graduate students and faculty investigate problems and innovate solutions with real-world impact.  Next Lives Here .

Other coauthors of the study include UC’s Jesus Abanto, Alok K. Dwivedi of Texas Tech University and Bruno P. Imbimbo of Chiesi Farmaceutici of Parma, Italy. 

Featured photo at top of a model of a brain. Photo/Robina Weermeijer/Unsplash.

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Preventing and Treating Alzheimer’s Disease and Related Dementias

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NIH-funded trials of drug candidates

Behavioral and lifestyle interventions, enhancing diversity and inclusion in clinical trials, updates on drug discovery and development.

The Alzheimer’s community has seen remarkable progress in the past year, with the first disease-modifying therapy, lecanemab, receiving traditional approval from the U.S. Food and Drug Administration (FDA) for the treatment of early Alzheimer’s in July 2023, followed by donanemab receiving traditional approval in July 2024. While NIH did not fund the pivotal phase 3 clinical trials that led to the FDA approvals, NIH funding did enable the essential foundational work for these trials, including research that helped scientists understand the role of amyloid, the protein targeted by these drugs; and develop amyloid PET imaging, a technology central to these trials.

Although the approval of these drugs represents a significant scientific milestone, additional research is needed to understand the impact of these drugs, including addressing amyloid-related imaging abnormalities (ARIA) and other potentially serious concerns observed in some treated individuals. For example, both drugs were approved to treat early Alzheimer’s. There remains a need to test these and other drugs at different disease stages and in more diverse populations. NIH is funding additional trials to evaluate lecanemab in treating different stages of Alzheimer’s. Some of these trials are using an amyloid blood biomarker test, PrecivityAD — developed with NIH-funded research and small business support and now available in clinical practice — to aid in recruitment. Recent research indicates that the use of blood tests can reduce the cost and time needed to enroll individuals in trials. In addition, the use of this simple blood test may help lower barriers to trial participation and has the potential to expand recruitment to broader, more diverse communities. These drugs also may be combined with other therapeutic approaches to treat Alzheimer’s. NIH is funding a clinical trial of lecanemab in combination with a second drug candidate to remove tau protein from the brain.

Given the complexity of Alzheimer’s, it is unlikely that any one drug or other intervention will successfully treat it in all people living with the disease. While recent progress is encouraging, there remains a need for new drugs, alone and in combination with other drugs and/or non-pharmacologic interventions, to treat and prevent Alzheimer’s and related dementias. To that end, in fall 2023, NIH began funding the Alzheimer’s Disease Tau Platform Clinical Trial, which will test the ability of two tau-targeting therapies to reduce brain tau levels, either alone or in combination with a drug that reduces amyloid protein, in patients with early Alzheimer’s. NIH funds more than 230 active clinical trials testing new drug candidates and lifestyle interventions to prevent or treat Alzheimer’s and related dementias.

This is an exciting time of significant momentum in dementia drug development. Among the 230+ active NIH-funded clinical trials noted are more than 70 trials of promising drug candidates that target multiple disease processes.

To help save time and cost in developing dementia therapeutics, NIH-funded researchers continue to explore the potential of repurposing existing drugs that are already FDA-approved to treat other diseases and conditions. Through this approach, they have identified several potential candidates to treat Alzheimer’s and related dementias. For example, in a small, proof-of-concept clinical trial of cognitively normal individuals, the anti-insomnia drug suvorexant decreased overall amyloid levels and tau181 phosphorylation for short periods of time. Researchers have now launched a phase 2 clinical trial to investigate the effects of long-term use of suvorexant on brain amyloid levels.

In 2023, results from the Anti-Amyloid Treatment in Asymptomatic Alzheimer’s disease (A4) Study, a public-private partnership supported with NIH funding, were released . This phase 3 clinical trial of the drug candidate solanezumab, an anti-amyloid immunotherapy, included more than 1,100 cognitively normal older adults who had brain amyloid. Results indicated that the drug did not slow cognitive decline in cognitively healthy people at risk for Alzheimer’s. While overall results of this prevention trial were negative, data and biosamples from the study are being made available to the research community, helping further understanding of Alzheimer’s. Importantly, these data have already led to insights related to differences in the presence of Alzheimer’s biomarkers among participants from different ethnic and racial groups.

While NIH-funded researchers continue to pursue new drugs to prevent and treat dementia, many behavioral and lifestyle interventions also offer promise in reducing dementia risk and improving cognition and memory. Of the more than 230 clinical trials of interventions to treat or prevent dementia that NIH currently funds, nearly 160 are testing a wide range of behavioral and lifestyle interventions, including dietary supplements, cognitive training, and more.

Examples of progress in 2023 include:

• Hearing aids: An NIH-funded clinical trial found that hearing aids appeared to reduce cognitive decline over three years in a group of older adults with specific risk factors for cognitive decline. However, hearing aids did not appear to slow cognitive decline in people without these risk factors. Researchers are now conducting a trial to understand the long-term effects of hearing aid use on brain health.
• Multivitamins: An NIH-funded clinical trial found that a daily, broad-spectrum multivitamin modestly improves memory in older adults when compared to placebo. In addition, a meta-analysis of three trial substudies found that, after two years of daily use, participants taking multivitamins had better global cognition (a combined measure from 11 separate cognitive tests) compared to placebo.
• Personalized health coaching: A recent NIH-funded trial found that personalized health coaching improved cognition and reduced dementia risk in older adults with at least two modifiable risk factors for dementia (e.g., low physical activity, hypertension, diabetes, smoking). Those in the intervention group were coached in both setting and working toward personalized goals to reduce risk. After two years of personalized coaching, participants experienced modest improvements in cognition, quality of life, and dementia risk factors when compared to a control group that received health education materials but no coaching. Findings from this study can help inform larger-scale trials of dementia risk reduction interventions.

Behavioral and lifestyle interventions, such as listening to tailored music, also offer promise in reducing the symptoms of dementia, for example:

• Tailored music listening and sleep: In a small pilot trial in a racially diverse sample of older adults, researchers found that tailored music listening slightly increased total sleep duration . Scientists are now using information gathered in this trial to inform larger future trials.
• Tailored music and agitation: An NIH-funded trial of nearly 1,000 people living with dementia residing in nursing homes found that individuals who listened to their preferred music had less frequent incidents of verbally agitated behaviors than those in a control group. Music also appeared to increase observed pleasure in trial participants. While more research is needed, music may offer a safer alternative to the use of antipsychotic drugs in nursing home residents living with dementia.

Further, behavioral and lifestyle interventions may be useful in improving important skills in older adults, including those living with cognitive impairment.

• Remote computerized training: With NIH small business grant support, the company i-Function developed remote computerized training that helps older adults, including those with mild cognitive impairment, learn relevant technology skills, e.g., managing medication, navigating telephone menus for ordering prescription refills, and banking via ATMs and the internet. Further, improvement in these skills lasted beyond the end of training, with greater gains in older adults with mild cognitive impairment.

NIH remains committed to recruiting and retaining a broad range of clinical trial participants from underrepresented communities that are disproportionately affected by dementia. Clinical research inclusivity is fundamental to ensuring that scientific findings can be generalizable to the entire population.

To enhance researchers’ recruitment materials and outreach activities for clinical trials, NIH officially launched OutreachPro in September 2023. This online tool enables health care professionals in the community to easily produce tailored materials and strategies that can be branded locally to increase participant recruitment for clinical studies. OutreachPro currently contains a library of materials in five different languages (English, Spanish, Mandarin, Hindi, and Tagalog) and several different formats (brochures, posters, social media posts, videos, radio scripts, website banners), providing research teams with more than 200 outreach options. Since its official launch, OutreachPro has been used to create nearly 900 tailored materials for clinical study recruitment.

NIH has coupled efforts to promote enhanced study recruitment outreach with stronger monitoring and oversight of ongoing clinical trials. In 2021, NIA launched the Clinical Research Operations & Management System (CROMS) to provide NIA staff and grantees with near real-time tracking, reporting, and management of clinical research enrollment data, study documents, and activities. NIA-funded investigators are required to electronically submit participant enrollment data into CROMS on a monthly basis. NIA can then use these data to proactively identify studies that are at risk of not meeting planned enrollment targets and design corrective action plans to improve trial recruitment. Further, in April 2023, NIA published a notice of updated policies and procedures for reporting clinical trial enrollment data in CROMS. The notice also outlines potential actions that NIA is able to take for grants that are noncompliant with the required policies and procedures. In addition, NIA implemented a revised policy for larger grant applications that took effect in January 2024. The revised policy prioritizes applications that include a plan to enroll clinical trial participants, from minoritized populations and other groups experiencing health disparities. These approaches help NIA support advancements in science that appropriately represent the populations affected by dementia, ensure that research findings are generalizable to a broad range of groups, and maintain the highest level of stewardship of research funding.

Clinical trials for dementia build on years of extensive foundational research to identify key disease mechanisms, screen potential drug candidates, and develop and test the most promising therapeutics. NIH is committed to investing in a strong pipeline of preclinical and translational studies, which may pave the way for forthcoming therapies for clinical application. Importantly, NIH-funded researchers continue to develop, and make openly available, resources to validate new drug targets for the next generation of dementia therapeutics. As one example, NIH-funded scientists recently developed new chemical tools and strategies to engage a novel genetic target of dementia, which may help set the stage for future therapeutic development. In addition, NIH-funded researchers recently developed a data portal that enables systematic evaluation of drug candidates for entry into preclinical testing.

NIH funding is also crucial to advancing therapeutic development from its initial stages to proof-of-concept studies and beyond. As one example, aggregation of an improperly functioning protein, TDP-43, in the brain is implicated in the development of several neurodegenerative conditions, including frontotemporal dementia, amyotrophic lateral sclerosis (ALS), and a recently characterized form of dementia known as limbic-predominant age-related TDP-43 encephalopathy neuropathological change (LATE-NC). In a small proof-of-concept study in mice, NIH-funded researchers were able to use injections of a new therapy known as an antisense oligonucleotide to counteract some of the effects of TDP-43 aggregation. While much more research is needed, these findings suggest a possible avenue for future treatment of conditions associated with TDP-43.

These and similar research approaches enhance the drug development pipeline and accelerate efforts to find effective drugs for Alzheimer’s and related dementias. In fact, since 2006, NIH has supported the development of 20 new drug candidates for the treatment of dementia that have received FDA permission to enter clinical trials and are currently being evaluated in human trials. These new investigational drugs target a broad range of different biological processes, including inflammation, metabolism, growth factors, and hormones.

• Schindler SE, et al. Using Alzheimer's disease blood tests to accelerate clinical trial enrollment . Alzheimer’s & Dementia . 2023;19(4):1175-1183. doi: 10.1002/alz.12754.
• Lucey BP, et al. Suvorexant acutely decreases tau phosphorylation and Aβ in the human CNS . Annals of Neurology . 2023;94(1):27-40. doi: 10.1002/ana.26641.
• Sperling RA, et al. Trial of solanezumab in preclinical Alzheimer’s disease . The New England Journal of Medicine . 2023;389(12):1096-1107. doi: 10.1056/ NEJMoa2305032.
• Lin FR, et al. Hearing intervention versus health education control to reduce cognitive decline in older adults with hearing loss in the USA (ACHIEVE): A multicentre, randomised controlled trial . Lancet . 2023;402(10404):786-797. doi: 10.1016/S0140-6736(23)01406-X.
• Yeung LK, et al. Multivitamin supplementation improves memory in older adults: A randomized clinical trial . American Journal of Clinical Nutrition . 2023;118(1):273-282. doi: 10.1016/j.ajcnut.2023.05.011.
• Vyas CM, et al. Effect of multivitamin-mineral supplementation versus placebo on cognitive function: Results from the clinic subcohort of the COcoa Supplement and Multivitamin Outcomes Study (COSMOS) randomized clinical trial and meta-analysis of 3 cognitive studies within COSMOS . American Journal of Clinical Nutrition . 2024;119(3):692-701. doi: 10.1016/j.ajcnut.2023.12.011.
• Yaffe K, et al. Effect of personalized risk-reduction strategies on cognition and dementia risk profile among older adults: The SMARRT randomized clinical trial . JAMA Internal Medicine . 2024;184(1):54-62. doi: 10.1001/ jamainternmed.2023.6279.
• Petrovsky DV, et al. Tailored music listening in persons with dementia: A feasibility randomized clinical trial . American Journal of Alzheimer’s Disease & Other Dementias . 2023;38:15333175231186728. doi: 10.1177/15333175231186728.
• Sisti A, et al. Using structured observations to evaluate the effects of a personalized music intervention on agitated behaviors and mood in nursing home residents with dementia: Results from an embedded, pragmatic randomized controlled trial . American Journal of Geriatric Psychiatry . 2024;32(3):300-311. doi: 10.1016/j.jagp.2023.10.016.
• Dowell-Esquivel C, et al. Computerized cognitive and skills training in older people with mild cognitive impairment: Using ecological momentary assessment to index treatment-related changes in real-world performance of technology-dependent functional tasks . American Journal of Geriatric Psychiatry . 2024;32(4):446-459. doi: 10.1016/j.jagp.2023.10.014.
• Jesudason CD, et al. SHIP1 therapeutic target enablement: Identification and evaluation of inhibitors for the treatment of late-onset Alzheimer's disease . Alzheimer’s & Dementia . 2023;9(4):e12429. doi: 10.1002/ trc2.12429.
• Quinney SK, et al. STOP-AD portal: Selecting the optimal pharmaceutical for preclinical drug testing in Alzheimer's disease . Alzheimer’s & Dementia . 2023;19(11):5289-5295. doi: 10.1002/alz.13108.
• Baughn MW, et al. Mechanism of STMN2 cryptic splice-polyadenylation and its correction for TDP-43 proteinopathies . Science . 2023;379(6637):1140-1149. doi: 10.1126/science.abq5622.

Last updated: August 5, 2024

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New Study Links Hearing Loss With Dementia in Older Adults

Findings highlight potential benefit of hearing aid use

A new study led by researchers at the Johns Hopkins Bloomberg School of Public Health found that older adults with greater severity of hearing loss were more likely to have dementia , but the likelihood of dementia was lower among hearing aid users compared to non-users.

The findings, from a nationally representative sample of more than 2,400 older adults, are consistent with prior studies showing that hearing loss might be a contributing factor to dementia risk over time, and that treating hearing loss may lower dementia risk.

The findings are highlighted in a research letter published online January 10 in the Journal of the American Medical Association .

“This study refines what we’ve observed about the link between hearing loss and dementia, and builds support for public health action to improve hearing care access,” says lead author Alison Huang, PhD, MPH, a senior research associate in the Bloomberg School’s Department of Epidemiology and at the Cochlear Center for Hearing and Public Health, also at the Bloomberg School.

Hearing loss is a critical public health issue affecting two-thirds of Americans over 70. The growing understanding that hearing loss might be linked to the risk of dementia, which impacts millions, and other adverse outcomes has called attention to implementing possible strategies to treat hearing loss.

For the new study, Huang and colleagues analyzed a nationally representative dataset from the National Health and Aging Trends Study (NHATS). Funded by the National Institute on Aging, the NHATS has been ongoing since 2011, and uses a nationwide sample of Medicare beneficiaries over age 65, with a focus on the 90-and-over group as well as Black individuals.

The analysis covered 2,413 individuals, about half of whom were over 80 and showed a clear association between severity of hearing loss and dementia. Prevalence of dementia among the participants with moderate/severe hearing loss was 61 percent higher than prevalence among participants who had normal hearing. Hearing aid use was associated with a 32 percent lower prevalence of dementia in the 853 participants who had moderate/severe hearing loss.

The authors note that many past studies were limited in that they relied on in-clinic data collection, leaving out vulnerable populations that did not have the means or capacity to get to a clinic. For their study, the researchers collected data from participants through in-home testing and interviews.   

How hearing loss is linked to dementia isn’t yet clear, and studies point to several possible mechanisms. Huang’s research adds to a body of work by the Cochlear Center for Hearing and Public Health examining the relationship between hearing loss and dementia.

The study authors expect to have a fuller picture of the effect of hearing loss treatment on cognition and dementia from their Aging and Cognitive Health Evaluation in Elders (ACHIEVE) Study. Results from the three-year randomized trial are expected this year.

“Hearing loss and dementia prevalence in older adults in the United States” was co-authored by Alison Huang, Kening Jiang, Frank Lin, Jennifer Deal, and Nicholas Reed.

Support for the research was provided by the National Institute on Aging (K23AG065443, K01AG054693).

Reported Co-Author Disclosures: Nicholas Reed, AuD, serves on the scientific advisory board of Neosensory. Frank Lin, MD, PhD, is a consultant to Frequency Therapeutics and Apple and director of a research center funded in part by a philanthropic gift from Cochlear Ltd to the Johns Hopkins Bloomberg School of Public Health. Lin is also a board member of the nonprofit Access HEARS.

Media contacts: Molly Sheehan at [email protected] and Barbara Benham at [email protected] .

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Scientists Have Pinpointed Two New Dementia Risk Factors. Here's What They Are.

Strides have been made in the world of dementia research compared with even just a few years ago. There’s now a blood test that can diagnose Alzheimer’s accurately 90% of the time , and more is understood about the factors (many of which are lifestyle habits) that can put you at higher risk for the condition.

In a new dementia report published in The Lancet journal by researchers who are part of The Lancet Commission, two new modifiable risk factors have been identified: high cholesterol after 40 and untreated vision loss.

In 2020, these same researchers determined 12 modifiable risk factors that are known to put folks at higher risk of developing dementia. These are:

Physical inactivity

Excessive alcohol consumption

Air pollution

Head injury

Infrequent social contact

Less education

Hypertension

Hearing impairment

According to the report, these 12 factors, along with the two new ones, account for 49% of dementia cases across the world. Researchers determined these two new risk factors by looking at recent meta-analyses and studies on the topics; they looked at 14 papers on vision loss and 27 on high cholesterol.

“It makes a lot of mechanistic sense,” said Dr. Arman Fesharaki-Zadeh , a behavioral neurologist and neuropsychiatrist at Yale Medicine in Connecticut. “A lot of these factors are very much interrelated.” (Fesharaki-Zadeh is not affiliated with the report.)

“There are many sources of vision loss, of course, but it tends to be a lot more common in folks who have metabolic risk factors such as high blood pressure, such as poorly controlled diabetes, such as high cholesterol, which is the other risk factor [identified in the report],” he said.

Moreover, vision is our primary sensory organ — it’s how we process the world around us — and when you can’t see clearly, you’re less likely to spend time doing brain-boosting activities like puzzles, reading or even spending time with other people, said Fesharaki-Zadeh. And these activities are known to help prevent dementia.

When it comes to high LDL cholesterol (the so-called bad cholesterol), it can lead to the hardening of the blood vessels in the heart and brain, Fesharaki-Zadeh said, adding that high blood pressure and uncontrolled diabetes also affect the blood vessels.

This can make it more difficult for oxygen to get to the brain, which over time can lead to neuron damage — “and dementia is essentially an end product of the neurons dying out, so it’s a neurodegenerative process,” Fesharaki-Zadeh explained.

“I can’t tell you how often I see in our patient populations, especially folks above the age of 60, there are certain parts of the brain that are more vulnerable to damage ... and these are the areas that are especially vulnerable to hardening of blood vessels. Someone who has ... high cholesterol, the correlation between that and hardening of blood vessels is quite high, and we see it in our clinical setting very frequently as well.”

“The saying that I like to use with patients quite often is what affects your heart will affect your brain, and we see that time and time again,” the doctor said.

You can lower your risk. First, have a good medical team and primary care doctor.

“I cannot highlight the importance of a collaborative model between primary care physicians and specialties,” said Fesharaki-Zadeh. Having a primary care doctor who understands your health and is willing to share pertinent information with specialists, like cardiologists and neurologists, will help you stay on top of any issues putting your well-being at stake.

Your primary care doctor should also be proactively working to help you control the risk factors — like high cholesterol and high blood pressure — whether that’s through medication, diet or exercise.

Fesharaki-Zadeh said you and your doctor should focus on these lifestyle changes as early as possible, at least in midlife, not when you’re at the point when dementia starts to show up.

“The front line of medical care are primary care physicians. These are the folks that, by having early discussions ... can go a long distance to prevent the onset of dementia,” he explained.

There are also tests that can detect early signs of neurodegeneration and genetic markers of the disease. A primary care doctor can help you learn about these options.

“Up to 40% of dementias are potentially preventable,” he added, but it’s worth noting that dementia can also be genetic, which makes prevention trickier. But someone who is diagnosed with dementia or mild cognitive impairment can benefit from managing these risk factors, too.

“The research is also showing that if you have two groups of individuals, someone who has comorbid metabolic diseases such as hypertension, high cholesterol, diabetes, versus somebody who doesn’t, and both of these individuals have dementia, the rates of progression of dementia in somebody who doesn’t have metabolic risk factors tend to be slower,” explained Fesharaki-Zadeh.

It’s never too late to make changes and corrections, he noted, whether you’re a young, seemingly healthy person, in your 80s or 90s, or someone who has already been diagnosed with dementia.

Our brains are highly malleable, Fesharaki-Zadeh said. So if you decide to make healthy lifestyle changes at any point, your brain will respond and be healthier for it. This article originally appeared on HuffPost.

Frontiers | Science News

• Science News

Research Topics

Three research topics exploring dementia diagnosis and treatment.

Dementia is currently one of the leading causes of disability and dependency among older people, with over 55 million individuals worldwide living with dementia , as reported by the World Health Organization (WHO).

Contrary to popular belief, dementia is not a normal part of aging. This year's World Alzheimer's Month challenges this misconception, emphasizing that while age is the most substantial known risk factor, up to 40% of dementia cases can be prevented or delayed.

Dementia is a broad term that describes several brain diseases affecting memory, other cognitive abilities, and behavior, significantly interfering with a person's ability to carry out daily activities. Alzheimer's disease is the most prevalent form, contributing to 60–70% of dementia cases.

While dementia remains a complex challenge, scientists are making significant progress in understanding and treating it. With this in mind, we've selected three Research Topics that explore recent breakthroughs in diagnosis.

All articles are openly available to view and download.

1 | Translational Advances in Alzheimer's, Parkinson's, and other Dementia: Molecular Mechanisms, Biomarkers, Diagnosis, and Therapies, Volume III

162.100 views | 42 articles

This Research Topic brings a multidisciplinary perspective and updated insight into the most recent advances in dementia. It covers genetics, biomarkers -molecular and imaging-, computer-aided diagnosis, and therapies.

Alzheimer's disease (AD) is the most common devastating dementia and neurodegenerative disease in older adults. The importance of diagnosing AD in its early stage is paramount to the aging population as the pathology is irreversible. However, the detection of AD and other dementias in the early phase remains a challenge in the current standard of care.

This Research Topic is part of a series on translational advances in Alzheimer's, Parkinson's, and other neurodegenerative dementias: Volume I and Volume II

View Research Topic

2 | Early Indicators of Cognitive Decline, Alzheimer's Disease, and Related Dementias Captured by Neurophysiological Tools

45.000 views | 14 articles

The scientists leading this Research Topic provide a more accurate picture of brain integrity in older adults. They also highlight biomarker studies that provide opportunities for early detection of cognitive impairments in the predementia window, i.e., mild cognitive impairment (MCI) stage.

The goal is to gather scientific contributions on non-invasive methodologies to significantly improve the detection of early cognitive impairment and the ability to characterize individuals along the AD trajectory.

3 | Impacts of Public-Private Collaborative Research on Alzheimer's Disease: The Case of the Innovative Medicines Initiative

36.900 views | 12 articles

This research topic advances new knowledge and resources for the dementia research community and the patients to foster new approaches for translating research outputs into valuable outcomes for people with dementia.

AD burdens every aspect of a person’s life and has a significant socio-economic impact. There is no cure for such a condition, and available treatments only address (partially) some symptoms but do not slow disease progression. Additionally, only a fraction of people with dementia get a timely diagnosis, and many more are at risk.

To tackle these challenges, fostering an all-around approach that delivers solutions from the lab to the clinic is fundamental.

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September 09, 2024

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People with dementia may be at higher risk of having suicidal thoughts

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People with dementia are more likely to have suicidal thoughts but are not necessarily more likely to attempt or die by suicide than the general population, finds a new study led by UCL researchers.

The study, published in Ageing Research Reviews , analyzed 54 studies that investigated various aspects of mental health - including the prevalence and risk of suicide - in people with dementia, between 1991 and 2023.

Dementia is an escalating global health challenge, affecting an estimated 55 million people worldwide. Alongside impacting cognitive abilities, people with dementia often experience debilitating neurological and psychological symptoms such as depression, apathy, aggression and anxiety.

These symptoms can sometimes lead to heightened emotional distress and, in some cases, suicidal ideation.

The researchers pooled data from 20 studies that reported on suicidal thoughts in people with dementia, that involved more than 1.5 million people. They found that 10% of people with dementia had experienced suicidal thoughts compared to the World Health Organization's estimate of 2% for the general population.

Those with moderate dementia were more at risk of suicidal ideation than those with mild dementia.

However, after reviewing data from more than 3.7million people with dementia, the researchers found that the prevalence of attempted suicide or death by suicide was approximately the same as the prevalence found in the general population- with 0.8% of people with dementia attempting suicide within a two-year period.

The team found that 0.1% of people with dementia died by suicide, and younger people with dementia were about three times more likely to be affected than those who were older.

Even though men were less likely to report suicidal thoughts they were significantly more likely to attempt suicide and almost three times more likely to die by suicide than women.

Dementia is a growing global health issue as more people live long enough to develop it. People with dementia may be at higher risk of having suicidal thoughts and in particular certain groups such as men and younger people with dementia may be more at risk of dying by suicide, but this field has not been well studied,  The current NICE guidelines for the assessment, management and support of people living with dementia do not mention suicidality in this population or address how to assess or manage this risk. This means that clinicians do not routinely assess or actively manage this risk. This review highlights the importance of providing mental health support and suicide prevention in dementia care, with a focus on age, the severity of symptoms, and sex." Dr. Roopal Desai, Lead Author,  UCL Psychology & Language Sciences

In light of the study's findings, the researchers are now calling on clinicians and caregivers to be vigilant in assessing the emotional well-being of people with dementia, in order to ensure timely support and the safety of patients.

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Senior author, Dr Amber John said: "It is often assumed that suicide is not an issue in people living with dementia. This study shows that people with dementia are no less likely to attempt or die by suicide than the general population - and indeed are more likely to experience suicidal ideation.

"This means that suicide risk needs to be taken just as seriously in people living with dementia as in the general population. "

The research was supported by the Welsh National Health Service.

Mental Health Medical Director of Betsi Cadwaladr University Health Board (BCUHB), Prof Alberto Salmoiraghi, who co-authored the paper, said: "These findings are truly important for clinicians and paramount to inform future service developments, particularly in regard to risk assessments and pathways of care."

Study limitations

The study examined various ways people expressed suicidal thoughts and involved both clinical and community samples, which can influence incidence rates.

The researchers were also unable to analyse all the risk factors for suicide due to a lack of information from the existing studies.

In addition, the findings do not consider different subtypes of dementia (i.e. frontotemporal dementia may pose a higher suicide risk due to behavioural changes and aggression). 

University College London

Desai, R., et al . (2024). Suicide and dementia: A systematic review and meta-analysis of prevalence and risk factors.  Ageing Research Reviews . doi.org/10.1016/j.arr.2024.102445 .

Posted in: Medical Research News | Medical Condition News

Tags: Anxiety , Brain , Dementia , Depression , Frontotemporal Dementia , Global Health , Language , Mental Health , Psychology , Research

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