Opinion: It’s time to move past Aduhelm and focus on a broader Alzheimer’s drug pipeline

When Alzheimer’s disease was believed to be caused solely by the accumulation of amyloid protein in the brain, pinning all hopes on an amyloid-targeting drug like Aduhelm — the first drug approved to treat Alzheimer’s in 17 years — made sense. But newer knowledge that ties Alzheimer’s to the biology of aging indicates the disease is caused by a combination of age-related changes in the brain that affect different people in different ways.

That means neither Aduhelm nor any anti-amyloid drug on its own will be a cure for the estimated 6.2 million Americans living with Alzheimer’s. The next phase of research must focus on promising drugs that target a host of underlying pathologies that contribute to Alzheimer’s.

Today more than ever, research is embracing this new understanding, taking a more diversified “multiple shots on goal” approach to new drug targets. More than three in four treatments currently in clinical development work against non-amyloid targets. These include drugs to reduce inflammation in the brain, improve blood flow, clear misfolded proteins, improve how the brain metabolizes energy, and more.


To complement these pathways, new biomarkers are needed that will give physicians like me the tools needed to zero in on the causes of each patient’s Alzheimer’s and tailor combinations to provide precision personalized medicine.

Alzheimer’s research is notoriously challenging and expensive, outstripping cost estimates for research in most other therapeutic areas. The brain is incredibly complex, and while Alzheimer’s is the most common cause of dementia, it is not the only one. But I’m more optimistic than ever about what’s coming down the pipeline because Alzheimer’s research has moved into a modern era, not only in the breadth of its targets but in its ability to implement more rigorous clinical trials that track and determine the relationship between biomarker and clinical outcomes.


If Aduhelm and other anti-amyloid antibodies that follow it are, at best, just one incremental piece of the puzzle, how do the blanks get filled in? For a start, it is time for everyone in the Alzheimer’s ecosphere to look toward a broader and more diverse approach to curing this devastating disease and speed the development of new, effective therapies to treat and prevent Alzheimer’s disease and related dementias.

More — and better — biomarkers

A critical driver of better and faster clinical trials are biomarkers — objectively measurable biological and behavioral characteristics that correlate with Alzheimer’s disease — that are essential for improving trial design and quickly advancing the current pipeline of novel targets.

Biomarkers are already being used to great effect in early-stage trials, quickly telling researchers whether an experimental drug is engaging with its intended target in the brain. They are also playing a larger role in later-stage trials, providing better and quicker ways to screen and enroll patients whose Alzheimer’s disease profile includes the characteristic the experimental drug is meant to work on, and then by providing an easy means for tracking the effects of treatment. Biomarker data from brain amyloid PET scans, for example, provided the primary data for Aduhelm’s Food and Drug Administration accelerated approval.

Biomarkers are also making their way into clinical practice. Physicians can now use tests of blood and cerebrospinal fluid to measure brain amyloid levels in people experiencing early signs of mild cognitive impairment or dementia. The day will soon come when a simple blood sample, retina scan, or even a smartphone app will be able to identify underlying causes of Alzheimer’s during a doctor visit, allowing for treatment to be matched to a patient’s unique pathology.

As more drugs are developed against a wide range of targets, biomarkers must play a bigger role than ever in clinical trials. Researchers worldwide are working toward validating additional blood and other non-invasive tests that can measure brain levels of everything from tau and other toxic proteins to biological indicators of neuroinflammation, synaptic malfunction, and changes in metabolism. These new biomarker tests will be essential for both clinical trials and clinical practice.

Value-generating exploratory trials

Alzheimer’s researchers need to work together to conduct more biomarker-powered exploratory trials to more quickly and effectively assess whether a drug has promise. By adopting best practices in designing exploratory trials, researchers and companies can be more confident in using their results to make the all-important go/no-go decisions about advancing drugs to larger, later-stage trials.

In 2019, the Alzheimer’s Drug Discovery Foundation (which I co-founded) and the Association for Frontotemporal Degeneration convened an advisory panel of experts to provide recommendations on ways to optimize the design and application of exploratory trials. The panel’s recommendations, published last year in the journal Neurology, are designed to improve trial designs and engage patients more efficiently. When it comes to clinical trials, participants are a limited resource, so it is vitally important, especially for rarer forms of dementia, that they are matched to the right trials and that these trials run as efficiently as possible so each patient’s involvement is valued and maximized.

Repurposed drugs

Policies that support efforts to bring repurposed drugs to the market are also urgently needed. Repurposed drugs start with an advantage because some of the research, including essential information about safety in humans, has already been done. But they are hampered by the economic disadvantage of limited returns on investment.

The pressure from patient advocacy groups for the FDA to approve and for Medicare to cover Aduhelm — a drug that was at best only going to have a modest incremental benefit — reflects the understandable public hunger for new Alzheimer’s treatments. It also underscores the urgent need for better ways to get effective drugs to market for the millions living with Alzheimer’s.

It’s encouraging to see broader consensus in the research community for the need to take fresh looks at the biology of aging. In a 2021 Alzheimer’s Clinical Trials report, the Alzheimer’s Drug Discovery Foundation analyzed the approximately 120 clinical trials underway that are tackling a variety of age-related pathways.

These efforts will open the doors to new breakthroughs and the kinds of combination therapies that have changed the lives of people with cancer, diabetes, HIV, and other diseases. At this pivotal moment, academia, industry, regulatory agencies, patient advocates, venture philanthropists, and others need to work together as a community to accelerate the move into this new era of treatment possibilities for people with Alzheimer’s.

Howard M. Fillit is a neuroscientist and geriatrician, the co-founder and chief science officer of the Alzheimer’s Drug Discovery Foundation, and a clinical professor of geriatric medicine and palliative care, medicine, and neuroscience at the Icahn School of Medicine at Mount Sinai. He reports having consulted for various pharmaceutical companies, including Alector, LifeWorx, Eli Lilly, Otsuka Pharmaceuticals, and others. 

Source: STAT