Heart problems can increase dementia risk, but a new study suggests that heparin, a common anticoagulant administered via injection, may help delay Alzheimer’s onset. Image credit: wang mengmeng/Getty Images.

• A new scientific statement from the American Heart Association (AHA) reveals a strong link between cardiovascular diseases — such as heart failure, atrial fibrillation and coronary heart disease — and an increased risk of cognitive impairment and dementia.
• The research explains how heart health directly impacts brain function, with conditions like high blood pressure and type 2 diabetes therefore contributing to cognitive decline.
• In another new study, researchers suggest that the blood thinner heparin may delay the onset of Alzheimer’s disease by interfering with harmful protein interactions in the brain; however, more research is needed.

A new expert report, published in the journal Stroke, reviews the latest research and explains that three common cardiovascular diseases in adults — heart failure, atrial fibrillation (AFib), and coronary heart disease — are linked to cognitive impairment and an increased risk of dementia.

The authors point out that stroke and cognitive decline, two significant factors in brain health, are chronic and disabling conditions that greatly impact individuals and society.

Maintaining heart health from a young age is essential to prevent cardiovascular diseases, protect brain function and lower the risk of cognitive decline later in life.

While dementia is often seen as an untreatable and progressive condition, evidence suggests that leading a healthy lifestyle and addressing vascular risk factors early on may help preserve cognitive function.

Heart problems contribute to cognitive decline

According to the studies highlighted in the AHA report, heart failure affects around 50% of people with cognitive issues, such as memory and language difficulties.

AFib, the most common heart rhythm disorder, is linked to a 39% increased risk of cognitive impairment, while coronary heart disease increases the risk of dementia by 27%, with up to 50% of heart attack survivors experiencing cognitive decline.

Previous research showed that people with AFib who were treated with direct oral anticoagulants (DOACs) had a 12% lower risk of developing dementia compared to those treated with the traditional blood thinner warfarin.

Could the anticoagulant heparin lower dementia risk?

Now, in a new study whose results appeared in Molecular Psychiatry, researchers found that people undergoing heparin treatment developed Alzheimer’s symptoms up to 2 years later than the typical timeframe, also indicating a potential protective benefit of this common anticoagulant.

Previous demonstrated that the risk of developing Alzheimer’s may be linked to a protein called Apolipoprotein E (ApoE), which interacts with cell surface molecules known as heparan sulfate proteoglycans (HSPGs).

The ApoE4 genetic variant is associated with the highest risk, while a rare form, ApoE Christchurch, binds weakly to HSPGs and appears to reduce the risk of Alzheimer’s in genetically predisposed individuals.

HSPGs also contribute to the buildup of tau protein, another key factor in Alzheimer’s brain damage.

Proteins that bind to HSPGs may accumulate in the brain long before symptoms appear and a gene involved in heparan sulfate production has been identified as an Alzheimer’s risk factor.

Heparin, a form of heparan sulfate used since the 1930s to prevent blood clots, does not enter the brain, but researchers speculate it could delay Alzheimer’s by disrupting ApoE-HSPG interactions.

What is the link between heparin and delay in Alzheimer’s onset?

In this new study, researchers analyzed medical records from two large health systems, Mount Sinai Health System (MSHS) and Columbia University Medical Center (CUMC).

Using a retrospective, longitudinal design, they compared patients who had received heparin to those who had not.

In the MSHS cohort, 24.7% of the 15,183 patients had received heparin, while 51.5% of the 6,207 CUMC patients had undergone heparin treatment.

While all the study participants eventually received an Alzheimer’s diagnosis, on average, patients in either cohort who received heparin got an Alzheimer’s diagnosis about 1 year later than those who did not.

The study’s first author, Benjamin Readhead, PhD, a research associate professor at the ASU-Banner Neurodegenerative Disease Research Center, explained the key findings to Medical News Today.

“Some of our co-authors had previously shown that a rare genetic mutation in the APOE gene is actually very protective against Alzheimer’s disease, and that this had something to do with disrupting how that version of the APOE protein binds to heparin-like molecules within the body,” Readhead told us.

“We wondered whether there might be a way of studying this by looking at the anticoagulant medicine heparin, and whether its usage seems to offer any protection against Alzheimer’s disease. When we looked at electronic health records (EHR) from two large health systems, we found that in both EHR, heparin therapy was associated with a significant delay of about 1 year in the clinical diagnosis of [Alzheimer’s disease] dementia.”

– Benjamin Readhead, PhD

Eric M. Reiman, MD, the study’s senior author, told MNT that “while the findings have no implications for the use of current heparin formulations in the treatment and prevention of Alzheimer’s disease, the study could help inform the development of new disease-modifying treatments for Alzheimer’s disease, including in carriers of the APOE4 gene, the major genetic risk factor for [Alzheimer’s].”

Reiman pointed out that the study looked at a specific group of people who have a higher risk of developing Alzheimer’s due to their genetics.

The findings, that a rare version of APOE might help protect against the symptoms of Alzheimer’s, led the researchers to think that if they could block APOE from sticking to HSPG, it might be possible to create a treatment or even prevent Alzheimer’s.

Study may inform new treatments for Alzheimer’s

Clifford Segil, DO, a neurologist at Providence Saint John’s Health Center in Santa Monica, CA, not involved in this research, said that although “it is challenging to claim a ‘blood-thinning’ medication could affect [Alzheimer’s disease development], […] when it would be more likely this family of medications would protect against a certain type of dementia from recurrent strokes caused [by] multi-infarct dementia or vascular dementia.”

He cautioned that: “After reviewing this paper, I would think heparin use should not be assumed to prevent Alzheimer’s [disease], and I would like a follow-up study to determine if, in hospital, heparin use can cause a decrease in stroke dementias or vascular dementia, which may also be called multi-infarct dementia.”

Reiman added that this study “illustrates the opportunity to use large EHR data sets to evaluate the effects of different drugs in the treatment and prevention of [Alzheimer’s disease].”

“This information could be used to support further assessments of potentially repurposed drugs in the treatment and prevention of [Alzheimer’s disease] or, as illustrated in this particular case, provide new information about the biological changes that could be targeted in the development of new drug therapies.”

– Eric M. Reiman, MD

The researchers also considered whether heparin could help protect brain health, more generically.

However, because most forms of heparin do not easily reach the brain and are only used for short periods, it was uncertain if it would be effective as a brain-health-protective drug.

While more research is needed, the findings from analysing large sets of patient data suggest that it may be possible to develop drugs targeting this process.

These potential new treatments could be tested in experimental models in the future.

ADVERTISEMENT

• Heart Disease
• Alzheimer’s / Dementia
• Neurology / Neuroscience
• Drugs

Share this article

Written by Paul Ian Cross, PhD on October 16, 2024 — Fact checked by Jill Seladi-Schulman, Ph.D.

Was this article helpful?

Alzheimer’s: Are newly approved drugs making a real-life difference?

After a lull of nearly 2 decades, the Food and Drug Administration (FDA) has approved some novel drugs for the treatment of Alzheimer’s disease since 2021. Most of these drugs are antibody therapies targeting toxic protein aggregates in the brain. Their approval has sparked enthusiasm and controversy in equal measure. The core question remains: Are these drugs making a real difference? In this Special Feature, we investigate.

How are the newly approved Alzheimer’s drugs stacking up against expectations? Image credit: Katiuscia Noseda/Getty Images.

Alzheimer’s disease is a neurodegenerative disease that involves a gradual and irreversible decline in memory, thinking, and, eventually, the ability to perform daily activities. Aging is the leading risk factor for Alzheimer’s disease, and a rapidly aging population has made it a public health crisis.

In 2019, 57 million individuals around the globe had Alzheimer’s disease, and this number is expected to reach 153 million by 2050. This underscores the need for disease-modifying treatments that produce a lasting change in the trajectory of this disease, slowing its progression.

However, until recently, efforts to develop disease-modifying therapies for Alzheimer’s disease have not been successful.

Most of the clinical research to develop disease-modifying therapies for Alzheimer’s has focused on targeting the beta-amyloid protein, whose abnormal accumulation is generally considered to lead to the development of this neurodegenerative disorder.

Newly approved Alzheimer’s drugs: Breakthrough or slow start?

Aducanumab, an antibody-targeting amyloid-beta protein deposits, received Food and Drug Administration (FDA) approval  for the treatment of Alzheimer’s disease in 2021, and was considered the first disease-modifying therapy for this condition.

However, the clinical trials involving aducanumab failed to produce consistent improvements in cognitive function, which led Biogen, the company that produces it, to announce that it will eventually suspend its sales.

Since then, two other anti-amyloid antibodies, Biogen’s lecanemab and Eli Lily’s donanemab, have demonstrated an ability to slow cognitive decline in individuals with early Alzheimer’s disease in phase 3 clinical trials, and have received FDA approval.

After decades of clinical research failing to produce effective disease-modifying therapies, the approval of lecanemab and donanemab has been viewed as a breakthrough and met with enthusiasm by clinicians and researchers.

However, some researchers have raised concerns about the modest clinical benefits conferred by these anti-amyloid therapies, citing safety risks and a lack of cost-effectiveness.

Dag Aarsland, MD, professor of old age psychiatry at King’s College London in the United Kingdom, told Medical News Today that, “[w]hile there are indeed challenges both at the clinical, societal, and healthcare levels, we should not forget the opportunities and the breakthrough that after decades of very costly negative trials, we finally have unequivocal evidence that it is possible to reduce the disease progression.”

Similarly, Paresh Malhotra, PhD, professor of clinical neurology at Imperial College London in the U.K., noted that despite the modest efficacy of these anti-amyloid therapies, “it is important to recognize that these drugs are the first to have clinical effects which appear to relate to a key mechanism of disease progression, and their introduction may accelerate treatment development and transform clinical services for Alzheimer’s disease, the most common cause of dementia worldwide.”

Amyloid cascade hypothesis and Alzheimer’s research

The development of anti-amyloid antibody treatments such as donanemab and lecanemab is based on the amyloid cascade hypothesis.

According to this hypothesis, the accumulation of the beta-amyloid protein triggers other changes in the brain, leading to the development of Alzheimer’s disease.

Specifically, the formation of beta-amyloid aggregates is considered to lead to inflammation, oxidative stress, damage to neurons, loss of synapses — the “links” between neurons that allow them to “communicate” — and, ultimately, cognitive decline.

Consistent with this, the accumulation of the beta-amyloid protein precedes the decline in cognitive function, including memory and decision-making, by several years.

The beta-amyloid protein is formed after the cleavage of a larger amyloid precursor protein by secretase enzymes. Each unit of the beta-amyloid protein is referred to as a monomer, and these monomers can aggregate to form short chains called oligomers, which consist of two to over 50 monomers and are soluble.

Beta-amyloid monomers can also aggregate to form larger, soluble protofibrils and insoluble fibrils. The insoluble fibrils then assemble to form plaques in the extracellular space between neurons.

Previously, the amyloid plaques were thought to be toxic and responsible for the development of Alzheimer’s disease. However, in the past two decades, studies have suggested that beta-amyloid oligomers are more toxic than amyloid plaques, and oligomers could play a larger role in the development of Alzheimer’s disease.

Targeting beta-amyloid aggregates to treat Alzheimer’s

The accumulation of beta-amyloid aggregates is thought to occur due to the impaired production or clearance of beta-amyloid protein.

In the past two decades, several drugs have been developed that either target the enzymes involved in the production of beta-amyloid or facilitate the clearance of beta-amyloid aggregates. However, these drugs have been unsuccessful in receiving FDA approval due to their severe adverse effects or failure to produce the desired clinical effects.

The anti-amyloid antibodies donanemab, aducanumab, and lecanemab are the only therapies targeting beta-amyloid aggregates to gain FDA approval. These antibodies differ in their affinity for the various types of aggregates of the beta-amyloid protein.

Donanemab binds to a specific form of beta-amyloid that is only found in plaques, whereas aducanumab and lecanemab bind to beta-amyloid oligomers, protofibrils, and plaques.

Lecanemab shows the highest affinity for beta-amyloid protofibrils, whereas aducanumab has a higher affinity for insoluble fibrils.

One of the supposed mechanisms through which anti-amyloid antibodies produce their therapeutic effects is activating an immune response against the beta-amyloid aggregates, resulting in their removal. Anti-amyloid antibodies can also potentially destabilize the plaques or bind to oligomers to neutralize them.

Impact of anti-amyloid antibodies on cognitive function

The FDA granted accelerated approval to aducanumab for the treatment of Alzheimer’s disease in 2021 based on its ability to clear amyloid plaques. While aducanumab was successful in clearing amyloid plaques in the brain, its effects on cognitive function were inconsistent across clinical trials.

The approval of aducanumab, despite the lack of evidence to support its therapeutic effects, led to controversy about the FDA’s approval process and a reluctance to prescribe the drug. And, as previously mentioned, as of 2024, Biogen has suspended aducanumab’s sales and development.

In contrast, both donanemab and lecanemab have shown an ability to clear amyloid plaques while slowing down disease progression. These therapeutics are more effective in individuals with early-stage Alzheimer’s disease and lower baseline beta-amyloid levels.

The FDA has granted lecanemab and donanemab approval for administration via intravenous infusion in individuals with early Alzheimer’s disease, which includes those with mild cognitive impairment or mild Alzheimer’s disease.

Lecanemab is indicated for administration every 2 weeks, whereas donanemab needs to be administered every 4 weeks.

One of the unique features of donanemab is that participants can discontinue treatment after achieving complete plaque clearance. The build-up of amyloid plaques takes several years, and it is assumed that individuals would potentially require minimal further treatment.

Participants in the phase 3 trials for lecanemab and donanemabTrusted Source showed a 27% and 36% slower decline in cognitive function compared with placebo, respectively.

However, some researchers have argued that these outcomes are modest and comparable to the effects of symptomatic treatments, such as acetylcholinesterase inhibitors that ameliorate symptoms without changing the trajectory of the disease.

Furthermore, the changes in cognition noted above were measured using the Clinical Dementia Rating Sum of Boxes (CDR-SB).

Researchers have also noted that the impact of these anti-amyloid therapies was not clinically meaningful when evaluated based on the absolute difference in decline in cognitive function — measured directly in terms of difference in scores on the CDR-SB scale — between the placebo and anti-amyloid antibody treatment groups.

More objective measures of cognition, such as the Mini-Mental State Examination [MMSE], reported only a 14.8% slower decline in cognitive function in individuals treated with donanemab. In other words, it has been argued that currently available evidence suggests that these anti-amyloid drugs may only provide a modest clinical benefit.

Alberto Espay, MD, a professor of neurology at the University of Cincinnati, told MNT that:

“The efficacy of these drugs is not translated into improvements, but they just mean a statistically significant but clinically meaningless slower decline.”

Dr. Espay further noted that the safety concerns, along with modest clinical benefits, “makes the case that the costs are not commensurate with the efficacy.” However, what constitutes a clinically meaningful effect remains a contentious.

How valid is the amyloid cascade hypothesis?

Some researchers have posited that the clinical benefits of anti-amyloid antibodies indicate the validity of the amyloid cascade hypothesis. However, others have argued that this conclusion is premature, with many questions yet to be answered.

According to the amyloid-beta hypothesis, the ability of aducanumab to clear plaques should have resulted in slower progression of Alzheimer’s disease. However, critics argue that trials involving aducanumab showed effective removal of amyloid plaques without consistently producing clinical benefits.

Similarly, donanemab removed about 85% of plaques in patients in the phase III trial but only resulted in a 14.8% slower decline in cognitive function, as measured using MMSE scores.

Importantly, the FDA’s decision to grant approval to aducanumab was grounded in the amyloid cascade hypothesis. Alzheimer’s disease also involves the accumulation of the tau protein inside neurons, and the extent of tau accumulation, rather than beta-amyloid, is associated with the magnitude of cognitive decline.

David Perlmutter, MD, a neurologist and fellow of the American College of Nutrition, commented that:

“Pharmaceutical interventions based on reducing beta-amyloid or reducing its production are leveraging the idea that beta-amyloid is playing a central role in the production and progression of Alzheimer’s disease. This hypothesis has been widely challenged. And the results of clinical trials of these medications reveal minimal efficacy and significant associated risk.”

As a result, some researchers argue that instead of indicating that the beta-amyloid pathway plays a focal the development of Alzheimer’s disease, the modest efficacy of the anti-amyloid antibodies suggests that the beta-amyloid pathway contributes to the development of Alzheimer’s disease along with other pathways.

According to this view, a complex network of factors, including those associated with the environment, oxidative stress, inflammation, metabolic factors, and genes unrelated to the amyloid pathway, also play a role in the development of Alzheimer’s disease.

Also according to this view, anti-amyloid therapies could have a role in the treatment of Alzheimer’s disease in combination with other therapies.

Alternatively, the aggregation of beta-amyloid could be a downstream phenomenon or symptom of other impaired biological pathways. Perlmutter explained, “[i]t is now clear that metabolic dysfunction upstream of amyloid plaque formation is central to the activation of the brain’s microglial cells, and this phenotypic change both enhances beta-amyloid formation while reducing its degradation.”

“In addition, microglial activation threatens the viability of neurons and leads to synaptic degradation, both central features of Alzheimer’s disease. As such, therapies targeting brain metabolism will likely provide substantial benefit for Alzheimer’s disease as has now been demonstrated in preliminary studies using GLP-1 agonists,” added Perlmutter.

Safety risks and accessibility of new Alzheimer’s drugs

The modest clinical benefits conferred by anti-amyloid antibody treatments need to be weighed against the risks, costs, and accessibility of these therapies. Adverse effects have been observed in a significant proportion of participants in the phase 3 clinical trials for lecanemab(45%) and donanemab(89%).

For instance, patients undergoing anti-amyloid antibody treatments often show changes in the brain known as amyloid-related imaging abnormalities (ARIA). These changes are observed during routine follow-up magnetic resonance imaging (MRI) scans and involve either brain swelling (edema) or small areas of bleeding due to the rupture of blood vessels (microhemorrhage).

For instance, 21% and 36.8% of individuals treated with lecanemab and donanemab, respectively, showed ARIA during the phase 3 trials. Most cases of ARIA are asymptomatic and resolve within 10 weeks.

While the symptomatic cases of ARIA are typically mild to moderate in severity, severe adverse effects, such as seizures and death, have also been reported. For instance, around 1.6% of participants in the phase III donanemab clinical trial experienced severe adverse effects related to ARIA, whereas the death rate in the donanemab group was 0.35%.

Besides concerns over these serious adverse effects, the long-term effects of amyloid-related imaging abnormalities, even when mild to moderate in severity, are not known. The infusion of these anti-amyloid antibodies is also associated with adverse effects, such as nausea, fever, rash, and dizziness.

Such infusion-related reactions were observed in 24.7% and 8.7% of patients treated with lecanemab and donanemab, respectively. These amyloid-related imaging abnormalities and other adverse effects necessitate frequent MRI scans and clinical follow-ups.

Individuals carrying at least one copy of the APOE4 gene, a gene linked to increased Alzheimer’s disease risk, were at higher risk of brain swelling in the phase III trials for donanemabTrusted Source and lecanemab.

Moreover, these drugs had lower efficacy in individuals with one or more copies of APOE4. Thus, individuals need to be genetically screened before the onset of anti-amyloid treatment.

Anti-amyloid immunotherapies are also associated with a reduction in the whole brain volume accompanied by an increase in the volume of ventricles, the fluid-filled spaces in the brain. An increase in the volume of ventricles and a decrease in whole brain volume are associated with reduced cognition.

However, whether a causal relationship exists between these changes in brain volume and cognitive function is unclear. Thus, there is a need to examine the impact of these changes in brain volume after anti-amyloid treatments. Interestingly, donanemab treatment resulted in a smaller reduction in the volume of the hippocampus, a brain region that plays a critical role in learning and memory.

Only a few individuals with Alzheimer’s disease in the population are likely to meet the criteria for inclusion in the clinical trials for lecanemab or donanemab.

The patients included in these studies were younger and had few co-occurring medical conditions. The treatment of a real-world population consisting of individuals with Alzheimer’s and co-occurring conditions is thus likely to lead to more adverse events or reduced efficacy.

Besides the management of adverse effects, the screening and diagnosis of individuals eligible for anti-amyloid therapies poses another challenge for the healthcare system.

Most individuals with Alzheimer’s disease are not diagnosed until later stages of the disease, and early diagnosis would require screening a large number of individuals using imaging scans or measuring cerebrospinal fluid biomarkers.

Thus, the broad availability would entail a substantial investment of resources for the screening and diagnosis of individuals with early Alzheimer’s disease, genetic testing for APOE4, and the monitoring and managing ARIAs and infusion-related reactions, regardless of their severity.

Jennifer Keen, Head of Policy at the Alzheimer’s Society in the U.K., told MNT:

“Confirming eligibility for new treatment requires specific diagnostic tests, and currently, a third of people living with dementia in the UK don’t get a diagnosis at all. We need to see investment into diagnostic infrastructure and workforce to ensure that people who are eligible for new treatments can access them when they’re most effective, which appears to be in the early stages of Alzheimer’s.”

The annual cost of receiving infusions of lecanemab and donanemab was around $26,000 and $32,000, respectively. However, this does not include the cost of screening and diagnosis, genetic testing, and monitoring and managing adverse effects.

Yet advances in diagnostic methods and the identification of novel biomarkers for monitoring treatment outcomes have the potential to reduce costs and improve the accessibility of anti-amyloid therapies.

ReplyReply to allForwardAI Reply