Project Summary The goal of the proposed research is to investigate a potential mechanism by which the accumulation of beta amyloid (Aβ) plaques and tau tangles could lead to episodic memory impairments. A loss of episodic memory is one of the hallmarks of age-related cognitive decline and is a major risk factor for dementia. Before the symptoms of dementia occur in Alzheimer’s disease (AD), Aβ plaques and neurofibrillary tau tangles begin to appear in the brain. This process typically starts in the neural systems associated with episodic memory and tracks closely with age-related memory impairments. An important open question is how Aβ and tau accumulation lead to memory decline. One possibility is that Aβ and tau may lead to memory loss through the disruption, or ‘dedifferentiation’, of episodic memory networks. For example, large-scale canonical networks, such as the default mode, salience, and attention networks, have been reported to be less segregated in older vs. younger adults, and such dedifferentiation has been associated with impaired performance on a variety of tasks. However, the molecular and pathological substrate of these observations is unknown. I propose to test whether the accumulation of Aβ and tau is associated with network segregation in the episodic memory system and whether network segregation mediates the association between neuropathology and memory decline. In preliminary analyses, I used resting state fMRI to measure functional network segregation in the neural systems most associated with episodic memory (the anterior temporal (AT) and posteromedial (PM) networks) in older and younger adults. I found that the AT and PM networks were significantly less segregated in older relative to younger adults. Building on these findings, I will study older adults with Aβ and tau PET at baseline, and memory performance at three time points over a period of about 6 years. My proposed research will test the following hypotheses: (1) Increased Aβ/tau will be associated with less segregated AT/PM networks, (2) less segregated AT/PM networks will predict worse episodic memory performance at baseline as well as change in performance over time, and (3) more Aβ/tau will predict worse memory performance (at baseline and change in performance over time), and network segregation will mediate the relationship between Aβ/tau and performance. Together, the proposed experiments will test a model in which age-related increases in Aβ and tau lead to neural dedifferentiation of intrinsic functional memory networks, which in turn leads to memory deficits. By studying this episodic memory system in healthy older adults, we can advance our understanding of healthy aging and its similarities to and differences from pathological aging, which could serve as a crucial building block for the early detection of AD.