AbstractBackgroundThe timing of AD biomarker positivity may be important for defining optimal anti‐amyloid therapy windows for secondary prevention. This work characterizes the AD biological cascade and investigates biomarker onset timing and associations of timing with preclinical cognitive decline and tau PET accumulation using data from the Wisconsin Registry for Alzheimer’s Prevention (WRAP).MethodWRAP participants (N = 172; mean(SD) age at last plasma = 69.4(6.6) years; 159 unimpaired, 9 MCI, 3 dementia, 1 impaired non‐AD) with available plasma pTau217, amyloid PET, and longitudinal cognitive assessments were included. Plasma pTau217 was quantified using an immunoassay on the Meso Scale Discovery platform (Lilly Research Laboratories). Amyloid burden was quantified using cortical 11C‐PiB DVR (cerebellum GM reference region). Positivity thresholds were defined using group‐based trajectory modeling applied to participants with longitudinal (≥2) biomarker observations (Ptau217, n = 162; PiB, n = 155). Sampled iterative local approximation (SILA) was used to model longitudinal PiB and pTau217 trajectories and estimate biomarker onset ages. Biomarker timing groups were defined as: PiB(‐)/pTau217(‐); coincident (PiB(+) and pTau217(+) onsets within 2 years of each other); PiB(+) first; or pTau217(+) first. We used a linear mixed effects model (random intercept and age‐related slope; unstructured covariance) to investigate the impact of biomarker timing group on cognitive decline measured by a three‐test Preclinical Alzheimer’s Cognitive Composite (PACC‐3). In a subset with tau PET (n = 120), we assessed regional tau burden (18F‐MK‐6240 SUVRs; 70‐90min, inferior cerebellar GM reference region) relative to plasma pTau217(+) and PiB(+) timing.ResultIn the PiB(+)/pTau217(+) subset (n = 60; 35%), PiB(+) onset generally preceded pTau217(+), but with considerable heterogeneity in this timing (Figure 1A‐H). Older age at PiB(+) onset was associated with shorter time to pTau217(+) onset (Figure 1G‐H). In PACC‐3 analyses, post‐hoc analyses of the significant biomarker timing group*age interaction showed fastest decline in the pTau217(+) first group (Figure 2). Both PiB(+) and pTau217(+) durations predicted MK‐6240 accumulation; ∆AICc indicated better fit with pTau217(+) time (Figure 3).ConclusionIn this mostly preclinical sample, the timing of PiB(+) and plasma pTau217(+) were differentially associated with cognitive decline and tau PET accumulation. These preliminary findings suggest secondary AD prevention with anti‐amyloid therapy may be most beneficial before pTau217 onset.