PROJECT SUMMARY / ABSTRACT This project conducts longitudinal Alzheimer’s Disease (AD) biomarker imaging on participants in the Wisconsin Registry for Alzheimer’s Prevention, a midlife observational cohort that is risk-enriched for AD due to parental history of AD dementia. We have been conducting longitudinal amyloid positron emission tomography (PET) with [11C]PiB since 2009 and tau PET with [18F]MK-6240 since 2017 together with advanced MRI, CSF and now longitudinal plasma biomarkers. In the prior funding period we demonstrated that non-demented persons who are Amyloid positive (A+), and tau+ (T+) have been exhibiting cognitive decline since midlife; we developed computational methods to construe amyloid from a temporal standpoint, including individual estimates of A+ onset age and its duration; we found that A+ chronicity predicts cognitive decline and time to dementia—which is ~23 years, giving empirical support to an oft-cited heuristic; we were an early adopter of [18F]MK-6240 for tau PET imaging and delineated its imaging characteristics; we developed and applied cutting edge measures of vascular compromise in the brain with dynamic 4D flow imaging including novel ways for assessing vessel stiffness that is associated with amyloid. The overarching hypothesis of this renewal is that recontextualizing PET amyloid burden along its temporal dimension and anchoring our analyses to A+ onset age and/or its duration will explain heterogeneity in the expression of other biomarkers and cognitive decline. A secondary goal is to determine what can be learned from serial plasma markers of A and T and N (relative to A+ chronology). In Aim 1, anchored to amyloid onset age we will examine factors related to progression of other biomarkers including tau, and examine cognitive decline over a 15 yr period of observation. We will determine the characteristics associated with T+ onset and rate of change (using MK6240 PET) relative to A+ chronicity; we will identify those who are exhibiting disease resistance (i.e., T- in the presence of more chronic A+) and identify the modifiable and genetic factors associated with this biomarker pattern; we will also examine plasma and CSF markers of AD and related disorders. In Aim 2: We will examine conditional processes regarding the added influence of vascular MRI measures on cognitive decline in the presence of progressing AD proteinopathy and patterns of neurodegeneration. Finally, Aim 3 employs computational algorithms to create a joint spatiotemporal profile of amyloid tau and neurodegeneration enabling a joint estimate of disease burden and progression. Significance: This work will fill in the biomarker timeline from late-middle age, providing clarity on the temporal span of preclinical AD proteinopathy anchored to amyloid onset. This project has the potential to greatly improve individualized prognostic precision in view of overall known disease burden, to shed insight on characteristics of disease resistance, and...