Background: Alzheimer’s disease (AD) and cerebrovascular disease (CeVD) are common causes of cognitive decline and often co-evolve. The concurrent temporal evolution of these pathologies and contributions to cognitive decline are not well understood. We evaluated the temporal association of AD and CeVD biomarkers with memory decline in a population-based sample.

 

Methods: We included Mayo Clinic Study of Aging participants with amyloid PET, MRI and serial cognitive assessments. Non-linear mixed effects (NLME) models were fit with AD biomarkers (amyloid PET, tau PET, plasma p-tau217), CeVD biomarkers (WMH volume, ARTS - ARTerioloSclerosis, PSMD- marker of early white-matter disease) and memory scores (AVLT sum of trials) as outcomes and sex, APOE ε4, education, and cardiovascular metabolic conditions (CMC) score as covariates. Model output included a per-participant adjustment (time-shift) for each biomarker indicating how much earlier or later the biomarker was estimated to progress relative to the population mean, correlation between adjustments for each pair of biomarkers, and covariate effects on each biomarker’s timing. By applying cutpoints to model output, we generated curves of the percentage of individuals with abnormal biomarker values versus age.

 

Results: The study included 630 participants, age 78(±10) years, 46% female, 84% cognitively unimpaired. Correlations of individuals’ adjustments between AD biomarkers and AVLT were 0.46 (95%CI: 0.34, 0.57) for amyloid PET, 0.44 (0.30, 0.58) for p-tau217, and 0.33 (0.21, 0.44) for tau PET (Figure 1). Correlations of the timing of CeVD biomarker progression with AVLT decline was lower: 0.26 (0.12, 0.38) for PSMD, 0.16 (0.04, 0.29) for WMH%, and 0.09 (-0.04, 0.22) for ARTS. Male sex was associated with earlier progression on PSMD, APOE ε4 carriership with earlier progression on amyloid PET and p-tau217, and CMC with earlier progression on AD and CeVD biomarkers (Figure 2). Figure 3 shows the order in which biomarkers were estimated to become abnormal in the population.

 

Conclusion: Progression of AD biomarkers more closely tracked with memory decline than progression of CeVD biomarkers. The CMC score was associated with earlier progression on tau and amyloid PET, in addition to CeVD biomarkers. Future work will investigate temporal associations of these biomarkers with other cognitive domains.