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

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 Tau ₁₈₁ (pTau ₁₈₁ ). Path analysis revealed that neural selectivity mediated the effects of age, attention, and pTau ₁₈₁ 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.