Podcast recap: Suzanne Schindler on Alzheimer’s biomarkers

On the latest episode of The Genetics Podcast, Patrick Short speaks with Dr. Suzanne Schindler associate professor of neurology at Washington University in St. Louis, about how Alzheimer’s disease develops, why biomarkers like p-tau217 matter, and what new blood-based tools could mean for diagnosis, prognosis, and clinical trials.

A central theme of the conversation is that Alzheimer’s should be understood as a biological process long before it becomes a clinical diagnosis. Suzanne explains how amyloid and tau pathology unfold over many years, how APOE shapes risk, and why the next wave of progress may come from combining precise biomarkers with better models of timing and progression.

Alzheimer’s disease is not the same as dementia

Suzanne clarifies the difference between Alzheimer’s disease and dementia. Dementia describes a clinical syndrome involving declines in memory and thinking severe enough to affect daily life. Alzheimer’s disease, by contrast, is defined biologically by the presence of amyloid plaques and tau neurofibrillary tangles. That distinction matters because cognitive impairment can arise from many causes, including vascular disease, Lewy body pathology, medication effects, sleep disorders, and other neurodegenerative processes.

For researchers, clinicians, and trial designers, that framing is essential. It shifts attention away from symptoms alone and toward the underlying pathology that may be present years before symptoms appear.

As Suzanne puts it, “If you don’t have amyloid in the brain, you don’t have Alzheimer’s, period, regardless of what your symptoms are.”

Amyloid may start the process, but tau is more tightly linked to symptoms

Suzanne walks through the current view of the amyloid-tau axis in Alzheimer’s disease. Amyloid plaques begin accumulating early, often many years before symptom onset. The APOE4 risk gene is one of the factors that increases the likelihood that a person will begin accumulating amyloid and reach that tipping point earlier in life.

From there, tau appears to respond to amyloid-related changes. One early sign is phosphorylation at specific sites, including tau217, which can be measured in cerebrospinal fluid (CSF) and blood. Importantly, these changes show up well before substantial tau tangle pathology is visible on imaging.

That timing is what makes p-tau217 so compelling. It offers a window into disease biology long before the stage at which patients would typically be diagnosed.

At the same time, Suzanne is careful to emphasize that the process is not fully linear or fully understood. Age, sex, APOE status, inflammation, and co-pathologies all appear to influence how amyloid “bothers tau,” and why some people progress faster than others.

p-tau217 is helping turn Alzheimer’s risk into a timeline

One of the most interesting parts of the discussion focuses on Suzanne’s recent work using plasma p-tau217 to estimate when someone might develop symptoms of Alzheimer’s disease.

Rather than treating biomarker values as static readouts, her group has used what they call “clock models” to understand how biomarkers change over time. The key idea is that although people begin accumulating pathology at different ages, once they pass a certain threshold, the trajectories of change become surprisingly consistent across individuals.

That consistency makes it possible to estimate when someone likely became biomarker-positive and then relate that timing to future symptom onset. This indicates the field may be moving from asking whether someone is at risk to asking when symptoms are likely to emerge.

The current models are not yet precise enough for routine clinical prognosis, but they are already useful for research and may become increasingly relevant for trial design.

Why timing matters so much for clinical trials

On the topic of how these innovations can be integrated into clinical trials, Suzanne explains that one of the challenges is that many Alzheimer’s trials are short relative to the long biological course of the disease. If a trial enrolls a large number of people who are unlikely to progress during the study window, it becomes much harder to detect treatment effects. Biomarker-based timing models could help identify people more likely to progress within a given timeframe, making studies more efficient and potentially more informative.

One particularly interesting finding from her work is that the same p-tau217 level does not have consistent effects across age groups. Older individuals with a given level of p-tau217 are, on average, closer to symptom onset than younger individuals with the same biomarker value. That suggests age is capturing part of the burden of other co-pathologies and resilience factors not yet directly measured.

For trial design, that has practical implications. Enrollment criteria may need to reflect not just whether a participant is biomarker-positive, but where they are on a biologically informed timeline.

New biomarkers could sharpen diagnosis even further

Suzanne’s recent work highlighted a newer tau biomarker, MTBR-tau243, which appears to be more tightly linked to tau neurofibrillary tangles and cognitive symptoms than p-tau217 alone.

Suzanne explains that p-tau217 is extremely sensitive and very effective for detecting Alzheimer’s pathology, but that sensitivity can also mean it identifies many people who are biologically positive before they are symptomatic. MTBR-tau243 may add specificity by helping distinguish those who are more likely to have symptomatic Alzheimer’s disease.

That creates interesting possibilities for both clinical care and study design. Depending on the therapeutic strategy, researchers may want to identify people who are amyloid-positive and already showing stronger tau-related signals, or those who are earlier in the cascade and therefore better suited for prevention-focused interventions.

More broadly, Suzanne sees major opportunity in expanding biomarker discovery beyond classic Alzheimer’s pathology. The next frontier is blood-based detection of co-pathologies such as alpha-synuclein and TDP-43, which could help explain why patients with apparently similar Alzheimer’s biomarker profiles often differ so much in symptoms and progression.

The field is moving toward combination thinking

On therapeutics, Suzanne takes a pragmatic view. She believes amyloid-targeting therapies can help when used early enough, and she is particularly interested in what those approaches may achieve before symptom onset. She is also optimistic about tau-targeting therapies and combination approaches that address both amyloid and tau together.

At the same time, she highlights the complexity of inflammation, APOE biology, and mixed pathology in older patients. Alzheimer’s is unlikely to be solved through a single target alone. Progress will come from better biological measurement, better patient stratification, and better alignment between mechanism and stage of disease.

Listen to the full episode below.