Top-down attention and Alzheimer's pathology affect cortical selectivity during learning, influencing episodic memory in older adults

Effective memory formation declines in human aging. Diminished neural selectivity-reduced differential responses to preferred versus nonpreferred stimuli-may contribute to memory decline, but its drivers remain unclear. We investigated the effects of top-down attention and preclinical Alzheimer's disease (AD) pathology on neural selectivity in 166 cognitively unimpaired older participants using functional magnetic resonance imaging during a word-face/word-place associative memory task. During learning, neural selectivity in place- and, to a lesser extent, face-selective regions was greater for subsequently remembered than forgotten events; positively scaled with variability in dorsal attention network activity, within and across individuals; and negatively related to AD pathology, evidenced by elevated plasma phosphorylated Tau₁₈₁ (pTau₁₈₁). Path analysis revealed that neural selectivity mediated the effects of age, attention, and pTau₁₈₁ on memory. These data reveal multiple pathways that contribute to memory differences among older adults-AD-independent reductions in top-down attention and AD-related pathology alter the precision of cortical representations of events during experience, with consequences for remembering.