In research published in JAMA Neurology on April 7, UF researchers studied Medicare claims data of older adults with Type 2 diabetes to assess the association among glucagon-like peptide-1 receptor agonists, or GLP-1RAs, sodium-glucose cotransporter-2 inhibitors, or SGLT2is, and the risk of Alzheimer’s disease and related dementias.

The research is supported by funding from the National Institute on Aging and the National Institute of Diabetes and Digestive and Kidney Diseases, both part of the National Institutes of Health.

The data showed a statistically significant association between a lower risk of Alzheimer’s and the use of GLP-1RAs and SGLT2is compared with other glucose-lowering medications. According to the researchers, the findings indicated that the two drugs may have neuroprotective effects for people without diabetes and may help slow the rate of cognitive decline in Alzheimer’s patients.

Serena Jingchuan Guo, M.D., Ph.D., an assistant professor of pharmaceutical outcomes and policy and the study’s senior author, said these findings may point to new therapeutic uses for drugs commonly used to treat Type 2 diabetes and obesity.

“It’s exciting that these diabetes medications may offer additional benefits, such as protecting brain health,” Guo said. “Based on our research, there is promising potential for GLP-1RAs and SGLT2is to be considered for Alzheimer’s disease prevention in the future. As use of these drugs continues to expand, it becomes increasingly important to understand their real-world benefits and risks across populations.”

Guo conducted this research in collaboration with William Donahoo, M.D., clinical professor and chief of the UF Health Division of Endocrinology, Diabetes and Metabolism, and Steven T DeKosky, M.D., deputy director of the McKnight Brain Institute and professor of Alzheimer’s research, neurology and neuroscience in the UF Department of Neurology. As the study only included patients with Type 2 diabetes, Guo said next steps include evaluating the effects of the two drugs in broader populations by using recent, real-world data that captures their growing use in clinical settings.

“Future research should focus on identifying heterogeneous treatment effects — specifically, determining which patients are most likely to benefit and who may be at greater risk for safety concerns,” Guo said.

Researchers from Drexel University’s College of Nursing and Health Professions recently published a study in Biological Research For Nursing examining symptoms, health outcomes and physical function over time in older adults with and without Alzheimer’s disease and related dementias and polypharmacy.

Led by Martha Coates, PhD, a postdoctoral research fellow in the College, the research team found that individuals who experiencing polypharmacy and have Alzheimer’s disease and related dementias experience more symptoms, falls, hospitalizations, mortality and had lower physical function – indicating that polypharmacy can also negatively impact quality of life for older adults with Alzheimer’s disease and related dementias.

“The cut-off of point of five or more medications daily has been associated with adverse health outcomes in previous research, and as the number of medications increase the risk of adverse drug events and harm increases,” said Coates.

The research team used a publicly available dataset from the National Health and Aging Trends Study – a nationally representative sample of Medicare beneficiaries in the United States from Johns Hopkins University. Since 2011, data is collected yearly to examine social, physical, technological and functional domains that are important in aging.

For this study, the research team used data from 2016 through 2019 to compare changes in symptoms, health outcomes and physical function among four groups: 1) those with Alzheimer’s disease and related dementias and polypharmacy; 2) those with Alzheimer’s disease and related dementias only; 3) those with polypharmacy only; and 4) those without either Alzheimer’s disease and related dementias or polypharmacy.

Coates explained that the researchers used analytic weights to analyze the data, which generates national estimates, making the sample of 2,052 individuals representative of 12 million Medicare beneficiaries in the U.S., increasing the generalizability of the findings.

“We found that older adults with Alzheimer’s disease and related dementias and polypharmacy experienced more unpleasant symptoms, increased odds of falling, being hospitalized and mortality compared to those without Alzheimer’s disease and related dementias and polypharmacy,” said Coates. “They also experienced more functional decline, required more assistance with activities of daily living like eating, bathing and dressing, and were more likely to need an assistive device like a cane or walker.”

Coates noted that there are tools available to help health care providers review and manage medication regimens for older adults experiencing polypharmacy and possibly taking medications that are potentially inappropriate or no longer provide benefit. However, currently there are no specific tools like that for older adults with Alzheimer’s disease and related dementias.

The findings from this research shed light on the negative impact polypharmacy can have on older adults with Alzheimer’s disease and related dementias. But Coates added that further research is needed to develop strategies to reduce the occurrence of polypharmacy in people with Alzheimer’s disease and related dementias.

“The older adult population is growing in the U.S., with an estimated 80 million individuals over the age of 65 by 2040,” said Coates. “This means that the number of older adults diagnosed with Alzheimer’s disease and related dementias will also increase, and currently there is no cure. Avoiding adverse outcomes related to polypharmacy can improve quality of life and prevent excess disability for older adults with Alzheimer’s disease and related dementias.”

The research team anticipates this study will help guide future analysis of the impact of specific medications on health outcomes in individuals with Alzheimer’s disease and related dementias and that it provides a foundation to support intervention development for medication optimization in older adults with Alzheimer’s disease and related dementias and polypharmacy.

Read the full study here: https://journals.sagepub.com/doi/10.1177/10998004241289942.

The findings were published on Oct. 24, 2024 in Alzheimer’s and Dementia.

“This new study provides real-world evidence for its impact on Alzheimer’s disease, even though preclinical research has suggested that semaglutide may protect against neurodegeneration and neuroinflammation,” said Rong Xu, PhD, Professor of Biomedical Informatics and Director of the Center for AI in Drug Discovery at Case Western Reserve University School of Medicine in Cleveland, Ohio.

As background, the investigators noted that semaglutide, a glucagon-like peptide receptor (GLP-1R) molecule is also the active component in the diabetes and weight-loss drugs Wegovy and Ozempic.

The investigators conducted emulation target trials, a statistical approach that mimics a randomized clinical trial. They used data from a nationwide database of electronic health records of 116 million US patients.

Comparing semaglutide with seven other antidiabetic medications, they emulated seven target trials with a total of 1,094,761 eligible subjects who had been diagnosed with type 2 diabetes and who had no prior Alzheimer’s disease diagnosis.

They reported that semaglutide was associated with significantly reduced risk for first-time Alzheimer’s disease diagnosis when compared to insulin and with other GLP-1Ras.

“Our results indicate that further research into semaglutide’s use will need to be further investigated through randomized clinical trials so alternative drugs can be tested as potential treatment for this debilitating illness,” Xu said.

The disease-modifying drugs, lecanemab and donanemab, slow cognitive decline in people with early stage Alzheimer’s disease. And they have been granted ‘breakthrough therapy’ status in the UK because of their ability to remove beta amyloid protein in the brain, build-up of which is thought to have a key role in the development of the disease.

Already licensed for the treatment of Alzheimer’s disease in the US in 2023, regulatory approval of these drugs for use in the UK is expected shortly. But to maximise their effectiveness, a raft of clinical staff and diagnostic and monitoring tests and scans will be required, point out the researchers.

To gauge the potential level of healthcare demand, the researchers retrospectively evaluated patients attending 5 community memory services across North and East London and a national specialist cognitive disorders service between January and June in 2022.

They wanted to find out the proportion of patients who would likely be referred for triaging from the memory services for these new drugs as well as those from the specialist service who would potentially be suitable for treatment with them.

In all, the anonymised case files of 1017 patients were included, 517 of whom were seen in community memory services and 500 in specialist clinics.

Just over 40% of the memory service patients were men; their average age was 79, with just 14% (72) under the age of 70. After exclusions due to incomplete data and factors, such as symptom severity, frailty, and other coexisting conditions, nearly 1 in 3 (163; 31.5%) were potentially eligible for treatment with the new drugs.

Of these,161 had undergone neuroimaging; but fluid biomarker tests were carried out in only 2 patients. This is equivalent to less than 1% of the memory clinic patients included in the study, “making this an urgent area of need for service development to enable identification of suitable patients,” emphasise the researchers.

Based on these figures, they suggest: “With an average memory clinic caseload of 815 and 80 nationally accredited memory clinics in England and Northern Ireland, potentially over 20,000 people per year will need access to such confirmatory investigations.”

More of the specialist clinic patients were men (53%) and they tended to be younger. Their average age was 66, but well over half (58%; 290) were under the age of 70. Alzheimer’s disease was the most common diagnosis (177;35.5%), followed by frontotemporal dementia (72;14.5%).

Most of them (492) had been given diagnostic scans: computed tomography or magnetic resonance imaging. And fluid biomarker tests were performed in nearly two thirds (62%;109/177) of those with Alzheimer’s disease.

But after exclusions due to frailty and contraindications for treatment, etc, only 40% (70) of the Alzheimer’s disease patients were potentially eligible for treatment with the new drugs, equivalent to just 14% of all the cases reviewed at the specialist cognitive clinics.

“Systems need to be set up to deal with this potential large mismatch between referral and ultimate eligibility in order to avoid overwhelming services,” highlight the researchers.

They add: “A significant issue is that due to the lack of biomarker testing in community memory clinics, the clinical suspicion of [Alzheimer’s disease] is likely to be incorrect in at least 30% of cases.”

Accurate diagnosis would reduce the number of patients ultimately eligible for the new therapies. But that would only be possible with confirmatory fluid biomarkers or brain (PET) scans, which aren’t usually available to memory services in the UK, they point out.

“While there are limitations on the accuracy of our estimates, given current barriers to early clinical presentations and referral, our study provides predicted numbers based on real-world community cohorts,” they write.

Demand for diagnostic services among those with early cognitive concerns is only likely to grow once the new drugs have been licensed and formally appraised by the National Institute for Health and Care Excellence, “placing further demands on already overstretched services,” they warn.

“While a sizeable proportion of patients attending memory clinics may be referred for triaging for [disease modifying drugs for Alzheimer’s disease], only a minority are likely to be suitable for these, as demonstrated in patients seen in specialist cognitive services. This will need to be considered when designing pathways for delivery [of these drugs],” they conclude.

In a linked editorial, Dr Benjamin Underwood, of Fulbourn Hospital, Cambridge, highlights the study limitations. “It is retrospective and several ‘unknowns’ remain, including how many people would choose to have treatment if eligible, how many would meet criteria for ‘amyloid positivity,’ and  whether the advent of treatment might encourage more people to present,” he writes.

“Nevertheless, if these treatments are approved for use, the work presented here will help plan services. It also provides a reminder that only a minority of people will be appropriate to receive these treatments. It is essential that services retain focus on the majority of people who will need other forms of treatment and care,” he concludes.

“Although we’re making progress with the new treatments for Alzheimer’s disease that work to clear amyloid plaques in the brain for people with early stages of the disease, we desperately need treatments that can prevent or delay the development of Alzheimer’s disease,” said author Ruth Brauer, PhD, of the University College in London, UK. “These results are encouraging and warrant further research.”

The authors analyzed retrospectively health records from IQVIA Medical Research Data UK (formerly known as the THIN database). They identified men aged 40 and older who received a new diagnosis of erectile dysfunction between 2000 and 2017.

They excluded men with a prior diagnosis of dementia, cognitive impairment, confusion or prescriptions for treatment of dementia symptoms.

The study included 269,725 subjects. There were 1,119 newly diagnosed subjects with Alzheimer’s disease during a median follow-up of 5.1 years.

Among the subjects treated with erectile dysfunction drugs, 749 developed Alzheimer’s disease, which is a rate of 8.1 cases per 10,000 person-years.

Among those who did not take Alzheimer’s disease drugs, 370 developed Alzheimer’s disease, which is a rate of 9.7 cases per 10,000 person-years.

When the investigators adjusted the findings for other factors that could affect the rate of Alzheimer’s disease onset (age, smoking and alcohol consumption), they noted that users of erectile dysfunction drugs were 18% less likely to develop Alzheimer’s than non-users.

Also, the reduction in Alzheimer’s risk was greatest among subjects issued the most prescriptions for erectile dysfunction drugs during of the study.

“More research is needed to confirm these findings, learn more about the potential benefits and mechanisms of these drugs and look into the optimal dosage,” Brauer said. “A randomized, controlled trial with both male and female participants is warranted to determine whether these findings would apply to women as well.”

An interdisciplinary study led by University of California, Riverside, computer scientists found that both internet information gathering services have strengths and weaknesses for people seeking information about Alzheimer’s disease and other forms of dementia. The team included clinical scientists from the University of Alabama and Florida International University.

Google provides the most current information, but query results are skewed by service and product providers seeking customers, the researchers found. ChatGPT, meanwhile, provides more objective information, but it can be outdated and lacks the sources of its information in its narrative responses.

“If you pick the best features of both, you can build a better system, and I think that this is what will happen in the next couple of years,” said Vagelis Hristidis, a professor of computer science and engineering in UCR’s Bourns College of Engineering.

In their study, Hristidis and his co-authors submitted 60 queries to both Google and ChatGPT that would be typical submissions from people living with dementia and their families.

The researchers focused on dementia because more than 6 million Americans are impacted by Alzheimer’s disease or a related condition, said study co-author Nicole Ruggiano, a professor of social work at the University of Alabama.

“Research also shows that caregivers of people living with dementia are among the most engaged stakeholders in pursuing health information, since they often are tasked with making decisions for their loved one’s care,” Ruggiano said.

Half of the queries submitted by the researchers sought information about the disease processes, while the other half sought information on services that could assist patients and their families.

The results were mixed.

“Google has more up-to-date information, and covers everything,” Hristidis said. “Whereas ChatGPT is trained every few months. So, it is behind. Let’s say there’s some new medicine that just came out last week, you will not find it on ChatGPT.”

While dated, ChatGPT provided more reliable and accurate information than Google. This is because the ChatGPT creators at OpenAI choose the most reliable websites when they train ChatGPT through computationally intensive machine learning. Yet, users are left in dark about specific sources of information because the resulting narratives are void of references.

Google, however, has a reliability problem because it essentially “covers everything from the reliable sources to advertisements,” Hristidis said.

In fact, advertisers pay Google for their website links to appear at the top of search result pages. So, users often first see links to websites of for-profit companies trying to sell them care-related services and products. Finding reliable information from Google searches thus requires a level of user skill and experience, Hristidis said.

Co-author Ellen Brown, an associate professor of nursing at the Florida International University, pointed out that families need timely information about Alzheimer’s.

“Although there is no cure for the disease, many clinical trials are underway and recently a promising treatment for early stage Alzheimer’s disease was approved by the FDA,” Brown said. “Therefore, up-to-date information is important for families looking to learn about recent discoveries and available treatments.”

The authors of the study write that “the addition of both the source and the date of health-related information and availability in other languages may increase the value of these platforms for both non-medical and medical professionals.” It was published in the Journal of Medical Internet Research under the title “ChatGPT vs Google for Queries Related to Dementia and Other Cognitive Decline: Comparison of Results.”

Google and ChatGPT both scored low for readability scores, which makes it difficult for people with lower levels of education and low health literacy skills.

“My prediction is that the readability is the easier thing to improve because there are already some tools, some AI methods, that can read and paraphrase text,” Hristidis said. “In terms of improving reliability, accuracy, and so on, that’s much harder. Don’t forget that it took scientists many decades of AI research to build ChatGPT. It is going to be slow improvements from where we are now.”

Currently, over 55 million people are living with dementia around the world, with that number set to increase to 78 million by 2030, and the focus on dementia research increasingly shifting towards prevention.

The online tool takes approximately 20 minutes to complete and provides a personalised dementia risk report that patients can discuss with their doctor.

Since developing the risk tool – known as CogDRisk – in 2022, the team has been evaluating the success of the tool, by trialling it on four existing datasets, with the results published recently in The Journal of Prevention of Alzheimer’s Disease.

On their analysis, they found that CogDrisk is effective at predicting dementia.

“There’s lots of information about the risk factors for dementia in the academic literature,” says Professor Kaarin Anstey from UNSW’s School of Psychology and NeuRA.

“But there’s a gap between just knowing the risks and actually being able to assess whether or not you have the risk, and then knowing what to do about it. CogDrisk was developed to address this.”

Collating the risk factors for dementia

Unsuccessful clinical trials for dementia treatment have led to urgent calls for dementia prevention.

“Prevention is now recognized by the World Health Organization as one of the key areas of research. Alzheimer’s Disease International and most of the National Dementia action plans include dementia risk reduction,” says Prof. Anstey.

But while there are a lot of different studies on risk factors for dementia across the world, there’s not necessarily always agreement on what the risk factors are. To address this problem, the team used statistical methods to combine all the risk factors cited in the existing literature.

“So we did a systematic review, to get all the different risk factors for dementia – those which were robust, and those which were modifiable and could be assessed through a self-report instrument,” says Prof. Anstey.

Some of the key modifiable risk factors that increase someone’s risk of dementia include insufficient physical activity, obesity in middle age, high blood pressure in middle age, smoking, and poor diet. “That whole process took several years, we published the review, and then we had to develop the risk assessment tool itself.”

Assessing the tool on different cohorts

Often risk assessment tools are developed on a single cohort and therefore fit a particular dataset and population, which doesn’t work well when applied to other populations.

This study analysed four different cohorts from existing medical studies, with varying demographics and a total of over 9500 participants.

The cohort data was matched against the key risk and protective factors assessed in the CogDrisk tool, including whether individuals have diabetes, depression and insomnia, information on their diet and eating habits and how much they engaged in physical activity.

The team were then able to match these to a record of dementia cases that developed within the same cohort.

“Our statistical analysis shows it’s a very robust and generalisable tool,” says Prof. Anstey. “It works across different countries and different data sets. And it’s also quite comprehensive, it includes a lot of the newer risk factors that weren’t previously included.”

Challenge with predicting dementia and future uses of CogDrisk

Predicting dementia is more difficult than predicting some other diseases, partly because it progresses over two or three decades and there can be a strong genetic component.

“It’s a multi-causal disease. But there are some modifiable risk factors. Most people want to know what their risk factors are and want to do something about them once they know,” says Prof Anstey. The team who developed the tool are hoping that in can be used in healthcare settings to make it easier for GPs and patients to get information on risk reduction.

“Not only are there lots of risk factors, but dementia itself is very complex, and GPs are very busy. So we’re trying to develop ways of making it easier for the public and GPs to get the right information.”

Next, Prof. Anstey is looking to translate the online tool into different languages, so it’s accessible to more people. “And we’re also looking at developing a short form of the tool. So there’s a lot of happening in the research translation, as well as language translation space that we’re working on.”

The findings were recently published in Alzheimer’s & Dementia: The Journal of the Alzheimer’s Association.

According to the Alzheimer’s Association, more than 6.5 million Americans are living with Alzheimer’s disease, and 1 in 3 seniors die with the disease or another form of dementia.

“There’s an urgent need for safe and affordable interventions to protect cognition against decline in older adults,” said Laura D. Baker, Ph.D., professor of gerontology and geriatric medicine at Wake Forest University School of Medicine and co-principal investigator of the trial, along with Mark Espeland, Ph.D., professor of gerontology and geriatric medicine at Wake Forest University School of Medicine.

The COcoa Supplement and Multivitamin Outcomes Study for the Mind (COSMOS-Mind), funded by the National Institute on Aging of the National Institutes of Health, was an ancillary study to the COSMOS trial led by Brigham and Women’s Hospital that randomized 21,442 men and women across the U.S. The study investigated whether taking a daily cocoa extract supplement or a daily multivitamin-mineral supplement reduces the risk of developing heart disease, stroke, cancer and other health outcomes.

According to Baker, cocoa extract is rich in compounds called flavanols, and past research suggests that these compounds may positively impact cognition. Baker also said that several micronutrients and minerals are needed to support normal body and brain function, and deficiencies in older adults may increase the risk for cognitive decline and dementia.

In COSMOS-Mind, researchers tested whether daily administration of cocoa extract versus placebo and a multivitamin-mineral versus placebo improved cognition in older adults. More than 2,200 participants, ages 65 and older, enrolled and were followed for three years. Participants completed tests over the telephone at baseline and annually to evaluate memory and other cognitive abilities.

“Our study showed that although cocoa extract did not affect cognition, daily multivitamin-mineral supplementation resulted in statistically significant cognitive improvement,” Baker said. “This is the first evidence of cognitive benefit in a large longer-term study of multivitamin supplementation in older adults.”

The researchers estimated that three years of multivitamin supplementation roughly translated to a 60% slowing of cognitive decline (about 1.8 years). The benefits were relatively more pronounced in participants with significant cardiovascular disease, which is important because these individuals are already at increased risk for cognitive impairment and decline.

“It’s too early to recommend daily multivitamin supplementation to prevent cognitive decline,” Baker said. “While these preliminary findings are promising, additional research is needed in a larger and more diverse group of people. Also, we still have work to do to better understand why the multivitamin might benefit cognition in older adults.”

The COcoa Supplement and Multivitamin Outcomes Study (COSMOS) is supported by an investigator-initiated grant from Mars Edge, a segment of Mars dedicated to nutrition research and products, which included infrastructure support and the donation of study pills and packaging. Haleon provided support through the partial provision of study pills and packaging. COSMOS is also supported in part by grants AG050657, AG071611, EY025623 and HL157665 from the National Institutes of Health, Bethesda, Md. The Women’s Health Initiative (WHI) program is funded by the National Heart, Lung, and Blood Institute, National Institutes of Health, U.S. Department of Health and Human Services through contracts 75N92021D00001, 75N92021D00002, 75N92021D00003, 75N92021D00004, 75N92021D00005. Neither Mars Edge nor Haleon provided input regarding data analyses, interpretation of results or manuscript development.

In a study published today in the Journal of Alzheimer’s Disease, researchers report that people 65 and older who contracted COVID-19 were more prone to developing Alzheimer’s disease in the year following their COVID diagnosis. And the highest risk was observed in women at least 85 years old.

The findings showed that the risk for developing Alzheimer’s disease in older people nearly doubled (0.35% to 0.68%) over a one-year period following infection with COVID. The researchers say it is unclear whether COVID-19 triggers new development of Alzheimer’s disease or accelerates its emergence.

“The factors that play into the development of Alzheimer’s disease have been poorly understood, but two pieces considered important are prior infections, especially viral infections, and inflammation,” said Pamela Davis, Distinguished University Professor and The Arline H. and Curtis F. Garvin Research Professor at the Case Western Reserve School of Medicine, the study’s coauthor.

“Since infection with SARS-CoV2 has been associated with central nervous system abnormalities including inflammation, we wanted to test whether, even in the short term, COVID could lead to increased diagnoses,” she said.

The research team analyzed the anonymous electronic health records of 6.2 million adults 65 and older in the United States who received medical treatment between February 2020 and May 2021 and had no prior diagnosis of Alzheimer’s disease.

They then divided this population two groups: one composed of people who contracted COVID-19 during that period, and another with people who had no documented cases of COVID-19. More than 400,000 people were enrolled in the COVID study group, while 5.8 million were in the non-infected group.

“If this increase in new diagnoses of Alzheimer’s disease is sustained, the wave of patients with a disease currently without a cure will be substantial, and could further strain our long-term care resources,” Davis said. “Alzheimer’s disease is a serious and challenging disease, and we thought we had turned some of the tide on it by reducing general risk factors such as hypertension, heart disease, obesity and a sedentary lifestyle. Now, so many people in the U.S. have had COVID and the long-term consequences of COVID are still emerging. It is important to continue to monitor the impact of this disease on future disability.”

Rong Xu, the study’s corresponding author, professor of Biomedical Informatics at the School of Medicine and director of the Center for AI in Drug Discovery, said the team plans to continue studying the effects of COVID-19 on Alzheimer’s disease and other neurodegenerative disorders—especially which subpopulations may be more vulnerable—and the potential to repurpose FDA-approved drugs to treat COVID’s long-term effects.

Previous COVID-related studies led by CWRU have found that people with dementia are twice as likely to contract COVID; those with substance abuse disorder orders are more likely to contract COVID; and that 5% of people who took Paxlovid for treatment of COVID symptoms experienced rebound infections within a month.

“In this population-based administrative register study of 1.7 million New Zealand citizens observed for 3 decades, people with early-life mental disorders were at elevated risk of subsequent dementia and younger dementia onset,” the authors said.  “Associations were evident across different psychiatric conditions, for Alzheimer disease and all other dementias, and after accounting for preexisting physical diseases and socioeconomic deprivation,” they added.

As background, the authors noted that discovering a potential link between mental disorders and dementia risk requires data that includes a full range of psychiatric conditions, data on mental disorders from early life and data that distinguishes between Alzheimer disease and related dementias.

This study included data on all persons born in New Zealand between 1928 and 1967 who resided in the country for any time during the 30-year observation period between July 1988 and June 2018.

The researchers gathered and analyzed data from the New Zealand Integrated Data Infrastructure, a group of sources linked at the individual level.

They determined diagnoses of dementia from public-hospital records, mortality records, and pharmaceutical records.

Of 1,711, 386 subjects included in the analyses, 866,301 (50.6%) were male and were aged 21 to 60 years at baseline.

The researchers reported that compared to subjects without a mental disorder, those previously diagnosed with a disorder were at 4.24-fold increased risk of developing dementia

Among subjects with dementia, those previously diagnosed with a mental disorder developed dementia 5.60 years (mean) sooner than those without a mental disorder.

After adjusting for preexisting chronic physical diseases and socioeconomic deprivation, the correlation held between mental disorder and subsequent dementia.

Compared to subjects without a mental disorder, increased risk of subsequent dementia ranged from 2.93-fold for prior neurotic disorders to 6.20-fold for prior psychotic disorders, and were evident for a subsequent diagnosis of Alzheimer disease (2.76-fold increased risk) and all other dementias (5.58-fold increased risk).

The authors concluded, “In this study, mental disorders were associated with the onset of dementia in the population. Ameliorating mental disorders in early life might also ameliorate neurodegenerative conditions and extend quality of life in old age.”

“There’s been a rapid development of different Alzheimer’s biomarkers in recent years, enabling us to measure and detect early signs of the disease in patients,” says the study’s first author Marco Bucci, researcher at the Center for Alzheimer Research, part of the Department of Neurobiology, Care Sciences and Society, Karolinska Institutet. “But we still need to find tests that can predict the development of the disease with greater specificity, so that we can improve not only its diagnosis but also its prognosis and treatment.”

Some biomarkers identify accumulations of A? or tau, while others are used to measure the loss of nerve function (neurodegeneration). Protein accumulation and neurodegeneration can be measured in the cerebrospinal fluid (CSF) and plasma, or through brain imaging using positron emission tomography (PET) and magnetic resonance imaging (MRI). Current guidelines for the early detection of Alzheimer’s disease with biomarkers endorse the interchangeability of brain imaging methods and analyses of CSF biomarkers (pTau and Ab), but this has been mooted. There is also a lack of longitudinal studies showing how the biomarkers are linked to gradual cognitive impairment.

“Our study shows that the presence of amyloid plaque in the brain and changes in concentrations of Ab and pTau in the CSF can be detected early during the course of the disease, but they do not seem to have any correlation with later memory loss,” says Dr Bucci. “However, our results show that the presence of tau in the brain measured by a PET scanner is linked to a rapid decline, especially of the episodic memory, which is often affected at an early stage of the disease. Our observation suggests that tau PET should be recommended for the clinical prognostic assessment of cognitive decline in Alzheimer’s patients.”

The results are based on brain imaging (PET and MRI) and CSF analyses in a group of 282 participants comprising people with mild cognitive impairment, people with Alzheimer’s dementia and healthy controls. 213 of the participants were also monitored for three years with tests of episodic memory (i.e. short term memory related to daily events).

“Our findings show that the concentration of tau in the brain in Alzheimer’s disease plays an important part in its pathological progression and may become a key target for future drug treatments,” says principal investigator Agneta Nordberg, professor at the Center for Alzheimer Research, Karolinska Institutet.

The study was financed by the Swedish Foundation for Strategic Research, the Swedish Research Council, Region Stockholm, the Swedish Brain Fund, the Swedish Alzheimer’s Foundation, the Centre for Innovative Medicine and the Swedish Society for Medical Research. There are no reported conflicts of interest.

Journal Reference:

1. Marco Bucci, Konstantinos Chiotis, Agneta Nordberg. Alzheimer’s disease profiled by fluid and imaging markers: tau PET best predicts cognitive decline. Molecular Psychiatry, 2021; DOI: 1038/s41380-021-01263-2

Developing effective treatment methods for Alzheimer’s disease has proved difficult. The most effective, which have just been approved, only provide marginal effects. There are several major reasons why they are not effective, one of which is that the antibodies used do not bind to all the types of toxic clumps that cause Alzheimer’s disease.

In Alzheimer’s disease, the amyloid-beta protein begins to form clumps. This process is called aggregation, and the clumps created are called aggregates. The research group has previously shown that treatment with the peptide somatostatin causes the body to begin breaking down building blocks of the aggregate. In the new study, the researchers use an antibody that can bind to the toxic aggregates to stop them from harming cells.

The problem with the treatment methods currently tested in patient studies is that the antibodies bind much more strongly to large clumps and hardly at all to small clumps. The small clumps are just as toxic as the large ones and many think that they are actually even more dangerous since they can move more.

The purpose of the current study was to develop an antibody format that can bind to both large and small clumps of amyloid-beta. Antibodies use the avidity effect to bind strongly to their targets. This requires the binding of both arms of the antibody to the same target at the same time.

The distance between the arms of the antibody is crucial for how small an aggregate the antibody can bind to strongly. If the aggregate is smaller than the distance between the arms, they do not bind to the aggregate strongly. If it is larger, they bind to the aggregate very strongly. In the new article, the researchers have developed a new antibody format with shorter distances between the arms so that they bind to smaller aggregates. The new format also has more binding sites to make the binding extra strong.

“Thanks to the avidity effect, the new antibody format is at least 40 times stronger in binding to the clumps. The new type of antibody can also bind to small aggregates with avidity, which we have not previously seen any other antibody do. That is fantastic,” says Greta Hultqvist, Senior lecturer and Associate Professor in Protein drug design at Uppsala University who led the study.

The effects of the antibodies were also tested in a cell culture experiment, which showed that the new antibody format could save cells from death caused by amyloid-beta aggregates. Although no pre-clinical experiments were included, the team thinks their results suggest that the new antibody design could be more effective than those trialled so far.

“The focus of the study was targeting the amyloid-beta protein in Alzheimer’s disease, but the new antibody design can be general and applicable to other disease-causing clumps. From a long-term perspective, we hope that the new format can open up new avenues for the generation of future treatments, not only in Alzheimer’s disease, but also other diseases where proteins start to form aggregates, like Parkinson’s disease,” says Fadi Rofo, doctoral student and first author of the study.

Journal Reference:

1. Fadi Rofo, Jos Buijs, Ronny Falk, Ken Honek, Lars Lannfelt, Anna M. Lilja, Nicole G. Metzendorf, Tobias Gustavsson, Dag Sehlin, Linda Söderberg, Greta Hultqvist. Novel multivalent design of a monoclonal antibody improves binding strength to soluble aggregates of amyloid beta. Translational Neurodegeneration, 2021; 10 (1) DOI: 1186/s40035-021-00258-x