Differential effects of aging, Alzheimer’s pathology, andAPOE4on longitudinal functional connectivity and episodic memory in older adults

INTRODUCTION Both aging and Alzheimer’s disease (AD) affect episodic memory networks. How this relates to region-specific early differences in functional connectivity (FC), however, remains unclear. METHODS We assessed resting-state FC strength in the medial temporal lobe (MTL) - posteromedial cortex (PMC) - prefrontal network and cognition over two years in cognitively normal older adults from the PREVENT-AD cohort. RESULTS FC strength within PMC and between posterior hippocampus and inferomedial precuneus decreased in “normal” aging (amyloid- and tau-negative adults). Lower FC strength within PMC was associated with poorer longitudinal episodic memory performance. Increasing FC between anterior hippocampus and superior precuneus was related to higher baseline AD pathology. Higher FC strength was differentially associated with memory trajectories depending on APOE4 genotype. DISCUSSION Findings suggest differential effects of aging and AD pathology on longitudinal FC. MTL-PMC hypoconnectivity was related to aging and cognitive decline. Furthermore, MTL-PMC hyperconnectivity was related to early AD pathology and cognitive decline in APOE4 carriers. Graphical abstract. A) “Normal aging” is characterized by a longitudinal decrease in functional connectivity. B) Cognitively unimpaired older adults with more Alzheimer’s pathology at baseline (measured via cerebrospinal fluid) exhibit a longitudinal increase in functional connectivity.