A Closer Look at the Evolution and Emerging Insights with Amyloid and Tau PET for Dementia and Alzheimer’s Disease
In an address at the recent SNMMI conference, neuroradiologist Tammie Benzinger, MD, PhD, discussed key studies in the evolution of amyloid and tau PET, and their continued emergence in detection, staging and monitoring of people with dementia.
At the recent Society of Nuclear Medicine and Molecular Imaging (SNMMI) conference, Tammie Benzinger, MD, PhD, was honored by the SNMMI Brain Imaging Council with the Kuhl-Lassen Award, which annually recognizes outstanding research contributions to the field of functional neuroimaging.
In a subsequent lecture at the
Here are nine takeaways from Dr. Benzinger’s address at the SNMMI conference.
Why Conventional Imaging Falls Short in Differentiating Dementia
- Structural imaging alone cannot distinguish dementia subtypes. Benzinger noted that dementia encompasses multiple overlapping pathologies that structural imaging cannot reliably separate.
"Dementia is a lot of different diseases, and it's a lot of different mixed pathologies. When you take almost anyone at autopsy and look at the brain, you see a lot of atrophy, and maybe this looks like an Alzheimer's pattern, but this could be a lot of different dementias to be honest with you,” posited Dr. Benzinger, the Hugh Monroe Wilson Professor of Radiology, a professor of neurosurgery and chief of the MRI service with the Mallinckrodt Institute of Radiology at the Washington University School of Medicine in St. Louis, Mo. She added that structural MRIs "don't have that molecular specificity" needed to make that distinction.
How Far in Advance Can PET Imaging Detect Signs of Alzheimer’s Disease and Dementia?
2. Amyloid PET can detect pathology roughly 15 years before symptom onset. Using data from autosomal dominant Alzheimer's disease (ADAD) families in which genetic mutations produce predictable ages of onset, Dr. Benzinger noted the first documented in vivo evidence in 2012 showing amyloid accumulation beginning in the frontal lobe and precuneus well over a decade before clinical symptoms appear.1
3. FDG PET hypometabolism precedes structural atrophy. In the same ADAD cohort, Dr. Benzinger said statistically detectable hypometabolism emerged roughly 10 years before dementia onset, preceding measurable brain atrophy on structural imaging.
Pertinent Considerations with Tau PET Findings
4. Tau pathology correlates with cognitive decline even in asymptomatic individuals. Braak-based tau PET staging in cognitively normal subjects showed measurable correlation with cognitive composite scores, suggesting no amount of tau pathology should be considered clinically benign, according to Dr. Benzinger.2
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5. Tau PET behaves differently than amyloid PET in genetic Alzheimer's disease. Unlike the gradual, diffuse spread seen with amyloid PET, tau positivity in carriers of autosomal dominant Alzheimer’s disease (ADAD) carriers appeared as a step function tied closely to the estimated year of symptom onset, a pattern Dr. Benzinger said her group is still working to understand.3
“It gives us hope that there is something that connects the amyloid stage of disease to the tau disease that maybe we could prevent,” posited Dr. Benzinger.
Assessing Post-Treatment Response
6. Post-treatment amyloid PET is now a standard clinical request. With anti-amyloid therapies approved based on demonstrated target engagement, clinicians are increasingly ordering follow-up amyloid PET at 12 to 18 months to assess plaque clearance. Dr. Benzinger noted these scans are visually challenging due to patchy removal patterns and continued atrophy.
7. Amyloid clearance alone isn't the clinical endpoint that matters most. Benzinger drew a distinction between imaging biomarkers and what patients and regulators ultimately care about.
“If you're a patient with Alzheimer's disease, you don't care if someone's removed amyloid from your brain. You'd be happy to have that, but what you really care about is, are your symptoms progressing? That's what the FDA cares about as well,” noted Dr. Benzinger.
She noted that current approved therapies are, on average, slowing — not stopping — progression, potentially delaying the need for assisted living or nursing care by several months.
What Donanemab Trial Data Revealed About Tau Burden
8. Tau burden, not just positivity, predicts treatment response. In donanemab trial data, patients with low tau burden showed 35 percent slowing of decline compared with 22 percent overall.4 "It's really important not just to say positive or negative, but to comment on how much of the brain is involved with it," emphasized Dr. Benzinger.
She also pointed out that timing is critical given how quickly tau pathology spreads.
"If we make somebody wait three months before we can get the PET scan, we're undoing a lot of the potential benefit that someone might get on therapy,” noted Dr. Benzinger.
What is a Key Limitation with Tau PET?
9. Access is the primary barrier to tau PET in the United States. "I think our main barriers right now to tau PET in the US are not whether it impacts the clinical care or the prognosis. It's really: is it accessible? Do we have (the) tracer available? Is it paid for?,” noted Dr. Benzinger. She framed this as a systems problem rather than a scientific one, noting that the clinical rationale for tau PET is already well established.
Dr. Benzinger emphasized that timely tau PET access matters clinically, since delays allow pathology to continue spreading before treatment decisions are made. Pointing to a small subgroup of ADAD patients who began treatment on gantenerumab while tau PET-negative and have remained so, Dr. Benzinger commented: “We have people that are now 10 years past that age of onset — not very many, it's a small sample size — but they're beating the genetics, which is incredible.”
Final Notes
She also called for continued development of additional PET tracers targeting alpha-synuclein, TDP-43, and neuroinflammation to address the mixed pathologies common in dementia patients, describing current diagnostic and monitoring approaches as increasingly parallel to established practices in oncologic imaging.
References
- Bateman RJ, Xiong C, Benzinger TLS, et al. Clinical and biomarker changes in dominantly inherited Alzheimer’s disease. N Engl J Med. 2012;367(9):795-804.
2. Mishra S, Gordon BA, Su Y. AV-1451 PET imaging of tau pathology in preclinical Alzheimer disease: defining a summary measure. Neuroimage. 2017;161:171-178.
3. Gordon BA, Blazey TM, Christensen J, et al. Tau PET in autosomal dominant Alzheimer’s disease: relationship with cognition, dementia and other biomarkers. Brain. 2019;142(4):1063-1076.
4. Sims JR, Zimmer JA, Evans CD, et al. Donanemab in early symptomatic Alzheimer disease: the TRALBLAZER-ALZ 2 randomized clinical trial. JAMA. 2023;330(6):512-527.
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