Alzheimer’s Disease: The Winds of Progress

Recently, I had the privilege of interviewing Peter St George-Hyslop –  one of the most cited authors in the field of Alzheimer’s disease – about the many challenges faced by researchers and the disappointments tied to treatment outcomes. However, drug development for Alzheimer’s seems to be bursting with renewed life (a resurgence largely attributed to lecanemab and donanemab). Is the future bright for Alzheimer’s disease? I spoke with Howard Fillit, Co-Founder and Chief Science Officer of the Alzheimer's Drug Discovery Foundation (ADDF) to get his view. 

What inspired your focus on geriatric medicine and the neurobiology of Alzheimer's?
 

My career started with neuroscience; I wrote my first paper on the cholinergic system back in 1965 while doing an internship at a medical research foundation near my home in New York. Soon after, I majored in neurobiology and behavior at Cornell University, publishing my first research paper in 1971 based on the work I did as an undergraduate student.

I was then fortunate enough to go to medical school, and subsequently became an internist. Around 1980, I was invited to a large nursing home in New York. The building was fairly modern and housed roughly 300 people. I didn’t realize it at the time, but this experience would go on to shape my professional career. When touring the facility, I became aware that these were severely impaired people – many of which were either wheelchair bound, bed bound, and unable to speak – who were suffering from the end stages of Alzheimer’s disease. Up until that point, I hadn’t heard of the condition.

Although Alois Alzheimer described the disease in 1906, not much was done until around 1968 when three investigators working in London – Blessed, Tomlinson and Roth – published a paper that looked at the brains of deceased people who had been diagnosed as senile. At the time, senility was thought to be a normal part of aging, but the three investigators reported that many of the older people diagnosed as senile had Alzheimer’s pathology, with plaques and tangles of misfolded proteins accumulating on their brains. 

Thus, it was during my university years that senility transitioned from being thought of as a normal part of aging to being understood as Alzheimer’s disease. At this point, there was limited medical information as very little research was being done on the disease. I believed that Alzheimer’s was going to be an important part of our world – it already was, but we needed to begin research and also educate people that cognitive decline is not a normal part of the aging body.  

 In 1981, I opened my first Alzheimer’s clinic devoted to the immunology of the disease at The Rockefeller University. It was the perfect opportunity to combine my skills as a physician, geriatrician, and neuroscientist to engage in a global issue.

Why is drug development for Alzheimer’s disease so difficult? 
 

I’m not sure if “difficult” is the right word; we suffer from a historical lag in research. The Imperial Cancer Trust was founded in 1902, almost 80 years before Alzheimer's was recognized as an important global problem. If you consider how long it has taken cancer therapies to get to the point they are today (roughly 120 years), it’s not unreasonable to afford Alzheimer’s research more time.

Basic Alzheimer’s research didn’t start until about 1980. Now, 40 years later, we are focused on exploring the underlying disease biology and translating that knowledge into clinical trials with new drugs. Various studies suggest it takes about 35 years from the start of basic research to the development of the first effective drug regardless of its target.

A strong example of this is statins – cholesterol was discovered as a risk factor and biomarker for coronary artery disease in the 1950s, but the first statins didn’t come to market until 30 years later in the 1980s. In my opinion, we are right on time in translating about 35-40 years of Alzheimer’s research into the first approvals of disease-modifying therapies. This reflects the time needed to develop the field, and to build clinical trial infrastructure.

A recent development of note is our ability to test drugs more efficiently. Today, we have as much knowledge about the basic biology of Alzheimer’s disease as we do for cancer, but because of this historical lag we’re just starting to test these new pathways guided by the biology of aging in clinical trials. Novel biomarkers have played a critical role. I predict we’ll see a lot of accelerated progress in the coming years.

We’re now seeing a number of clinical trial readouts and approvals for Alzheimer’s treatments; which results excite you the most and why?
 

For the first time, there are about 140 new drugs in the pipeline, with over 75 percent of them targeting pathways beyond amyloid and tau. This highlights the diversification of the drug pipeline and the industry’s shift toward developing drugs guided by the biology of aging. Inflammation is an interesting and promising drug target, and I believe the recognition that inflammation plays a critical role in the progression – and perhaps onset – of Alzheimer's will be a major focus for the ADDF and the field moving forward. 

One of the most exciting developments is the potential to combine treatments. For example, researchers are now considering how combination therapy leveraging anti-amyloid drugs and therapeutics that reduce neuroinflammation can slow cognitive decline.

There are several other pathways that are of interest to the research community, including mitochondrial and metabolic dysfunction. Currently, Novo Nordisk is exploring the use of the diabetes drug semaglutide to address the insulin resistance that occurs in the aging brain. We're also seeing drugs that are looking into  disorders of autophagy that occur with aging – when the cells that serve as the brain’s trash system for removing misfolded proteins become dysfunctional, resulting in plaque buildup. We now know that there are many misfolded proteins in the aging brain, with co-morbid pathology beyond beta-amyloid and phospho-tau, such as alpha-synuclein and TDP-43. We will need holistic, precision approaches to manage this array of misfolded proteins to address each patient’s individual biomarker profile.

Lecanemab or donanemab… Does one of these interest you more than the other?
 

I don't have a bias. The trials were conducted differently, so there is different information to analyze. For instance, the donanemab trial enrolled a very specific group of people based on their tau imaging. Both the drugs had similar entry criteria (e.g., a positive amyloid scan), which is a sign of using modern biomarkers to enhance our ability to ensure we enroll the right patients and then monitor the therapeutic efficacy of drugs intending to remove plaques.

It's too early to tell what the clinical benefit these drugs will have once in the real world, but there may be potential issues around the frequency of administration that will impact uptake, as leqembi requires a bi-monthly infusion, whereas donanemab is a once-monthly infusion. There may also be concerns around safety, pricing, availability, and accessibility. It appears the safety monitoring for the two drugs is very similar, if not identical. We’ll have to see how the drugs play out in the marketplace before pre-empting any preference for one or the other.

Have lessons been learned from Aduhelm?
 

What happened with Aduhelm was unfortunate, but looking back, the drug probably had a similar efficacy profile to lecanemab and donanemab. However, its efficacy was not clearly demonstrated because of a futility analysis performed in the middle of one of the studies. Nevertheless, from every trial we learn more about the disease and how to conduct more effective and rigorous trials, so like all trials, we learned from Aduhelm and used those learnings to drive more progress.

There is an overwhelming disparity between the number of women and men diagnosed with Alzheimer's. Do we know why?
 

In 1981, when I opened the first Alzheimer’s clinic at Rockefeller University, one of the first things I did was establish a collaboration with a lab that specialized in the neurobiology of gonadal hormones. We decided to conduct a clinical trial of estrogen replacement therapy for postmenopausal women with Alzheimer’s disease. This was a catalyst for the broader field to begin studying the role of the menopause as a risk factor for late-life Alzheimer’s disease.

This was over 40 years ago, so I’ve had a long-standing interest in the matter. Since then, the field has really matured: we now know that the activational effects of gonadal hormones – such as estrogen – are very important. Indeed, there are estrogen receptors and parts of the brain that are affected by Alzheimer’s disease, including the hippocampus. So perhaps, as with osteoporosis, the dramatic and relatively sudden loss of estrogen during the menopause begins the process of neurodegeneration.

Today, there are programs exploring how gonadal hormones – particularly 17 beta-estradiol – play an important role in the onset of the disease at menopause. 

This may open the field of Alzheimer’s prevention for women. Neuroimaging studies have shown that women who take 17 beta-estradiol at the time of menopause have a reduced accumulation of beta-amyloid as seen through PET beta-amyloid imaging. 

The window of menopause – and the neuronal dysfunction that occurs with the abrupt loss of estrogen – could mark the beginnings of amyloid deposition, which we can detect on PET amyloid imaging. Recent studies suggest that beta-amyloid deposition that may occur during the menopause can be prevented by taking the natural hormone 17 beta-estradiol. However, when patients are not taking any hormone replacement therapies, or replacement therapy with hormones like Premarin, the deposition of beta-amyloid is not prevented. 

For prevention studies, neuroimaging is a useful way to do studies without having to follow individual women in longitudinal studies for 30–40 years. If we can put off the effect of the menopause on a woman's brain, looking at these various biomarkers, including neuroimaging, we'll likely see progress in reducing the increased Alzheimer’s risk among women.

What other drug development initiatives have caught your eye?
 

The ADDF and I are very interested in the research shift towards novel approaches guided by the biology of aging. More specifically, we are interested in reducing inflammation in the brain and addressing metabolic disturbances that occur with aging, as well as the integrated stress response and mitochondrial response to oxidative damage. 

Neuroprotection is another interesting approach. Neurons sustain a range of injuries with age, and there is a neuroprotective drug going into late phase II trials now from an ADDF-funded company called PharmarophiX. Other promising companies addressing neuroprotection and inflammation include Alector and Denali Therapeutics, which both have drugs targeting progranulin as a neuroprotective approach. They are also studying TREM2 antibody agonists to promote microglial phagocytic function and reduce cytokine inflammatory damage that produces neuronal damage in the brain.

For the first time, there is an array of therapeutic avenues across multiple target pathways being researched for Alzheimer’s disease. Let’s not forget the increasing sophistication of biomarkers too. At the ADDF, we’re leading the development of novel biomarkers, which we are funding through our Diagnostics Accelerator (DxA). This $100-million program – co-funded by Bill Gates, Leonard Lauder, Jeff Bezos, the Dolby family, and several other philanthropists – intends to revolutionize Alzheimer’s biomarkers and diagnostics, which is necessary for the next stage of drug development and treatment. 

So, with all these advances, it’s fair to say the future of Alzheimer’s treatment looks promising!