SUMMARY: PROJECT 2- MODULATING FACTORS Disappointing results from recent trials targeting b-amyloid alone underscore it is critical that we identify, measure, and better understand factors outside of canonical Alzheimer’s pathology that influence the emergence of late-life cognitive decline. This need is particularly acute for potentially-modifiable risk factors for decline that can be targeted for intervention, either alone or in combination with therapies directed at b-amyloid or tau. In this context, this new project will leverage several core strengths of the Harvard Aging Brain Study (HABS) to assess the extent to which physical activity, inflammatory, and vascular factors modify longitudinal cognitive decline, MRI-based measures of neurodegeneration, and whether these potentially-modifiable risk factors interact with Alzheimer’s disease pathological cascades to cause accelerated neurodegeneration and cognitive decline. Aims 1 and 2: Building on cross-sectional and longitudinal PET, MRI, and cognitive data available in HABS, we will add objective, longitudinal assessments of vascular risk, white matter disruption due to putative cerebrovascular injury, and assessment of day and night activity patterns. Primary analyses for these aims will assess whether individual variations in vascular and activity parameters presage longitudinal changes in cognition (jointly with Project 4), changes in hippocampal volume, and in the accumulation of tau pathology as measured by PET (jointly with Project 1). Secondary analyses will assess regional variations in brain atrophy, examine the interplay of activity patterns with functional network integrity (jointly with Project 3), and identify cognitive domains which may be differentially impacted by these modulating factors. Together with the Analytic Core, we will employ causal models to examine the directionality of vascular and activity effects on cognitive and neurodegenerative trajectories and examine whether activity effects can be ascribed to reverse causation. Aim 3: In this exploratory aim, we will use a focused set of biofluid markers of vascular, inflammatory, and neurodegenerative processes to elucidate the mechanisms underlying the modulating factors we examine here. Together, these studies will allow us to develop a broader understanding of how these potentially-modifiable factors may interact with b-amyloid to modulate cognitive decline and neurodegeneration, and to go deeper by using newly-available, high-sensitivity immunoassays to identify biologic pathways underlying the effects of these potentially-modifiable risk factors.