Characterizing the onset and progression of Alzheimer's pathologies using amyloid and tau PET imaging and plasma p-tau217.
Level 3 - non-randomized controlled study
Prospective longitudinal observational cohort study evaluating biomarker trajectory timelines
PubMed 41322203 · doi:10.1093/braincomms/fcaf449
What was done
Researchers evaluated 172 participants from the Wisconsin Registry for Alzheimer's Prevention (mean age 63.2 ± 6.3 years at baseline plasma; 149 cognitively unimpaired at last assessment) who had amyloid PET imaging and plasma p-tau217 measurements from two platforms (Lilly Meso Scale Discovery and Quanterix Alzpath). Within-person onset times for detectable amyloid PET and plasma p-tau217 positivity were estimated using sampled iterative local approximation modeling. Linear mixed-effects models then assessed how the timing of biomarker onsets related to downstream tau PET accumulation and cognitive decline.
What was found
Longitudinal modeling indicated that amyloid PET positivity preceded plasma p-tau217 positivity on average, and both preceded detectable brain tau PET accumulation. In participants positive for both markers, the interval between amyloid PET and p-tau217 onset ranged from -5.5 to 24.6 years. Time from p-tau217 onset accounted for more variance in tau PET accumulation and cognitive decline than time from amyloid PET onset when using the Lilly assay, but showed no difference when using the Alzpath assay.
Why it matters
These findings delineate the temporal sequence of fluid and imaging biomarkers in preclinical Alzheimer's disease, suggesting that plasma p-tau217 may serve as an accessible tool for biological disease staging and help define therapeutic windows for secondary prevention trials.
Limits
The study is limited to a single regional cohort with predominantly cognitively unimpaired participants, restricting generalizability to more diverse or clinically impaired populations. The interval between amyloid PET and p-tau217 onset showed wide interindividual variability (-5.5 to 24.6 years), and platform-dependent discrepancies between the Lilly and Alzpath assays were observed.
Cited by
- supports Amyloid and tau pathology can accumulate in the brain 10 to 15 years before clinical cognitive complaints appear in Alzheimer's disease.