# Longitudinal functional connectivity during rest and task is differentially related to Alzheimer’s pathology and episodic memory in older adults

## TL;DR

Changes in brain connectivity during rest and memory tasks are linked to Alzheimer’s pathology and memory decline in older adults, with differences based on APOE4 gene status.

## Contribution

The study reveals how longitudinal functional connectivity changes during rest and memory tasks are differentially associated with Alzheimer’s pathology and memory performance.

## Key findings

- Decreasing PMC connectivity during rest in APOE4 carriers correlates with higher amyloid and tau levels.
- Increasing MTL connectivity during encoding in APOE4 carriers is linked to higher tau burden.
- MTL-PMC connectivity during rest improves episodic memory, unlike during encoding.

## Abstract

Changes in functional connectivity (FC) strength involving the medial temporal lobe (MTL) and posteromedial cortex (PMC) are related to early Alzheimer’s pathology and alterations in episodic memory performance in cognitively unimpaired older adults, but their dynamics remain unclear. We examined how longitudinal changes in FC involving MTL and PMC during resting-state, episodic memory encoding, and retrieval relate to subsequent amyloid- and tau-PET burden, longitudinal episodic memory performance, and the APOE4 genotype in 152 cognitively unimpaired older adults from the PREVENT-AD cohort. We found APOE4- and fMRI paradigm-dependent associations of change in FC strength with pathology burden and change in episodic memory performance. Decreasing FC over time, or “hypoconnectivity”, within PMC during rest in APOE4 carriers and during retrieval in APOE4 non-carriers was related to more amyloid and tau, respectively. Conversely, increasing FC over time, or “hyperconnectivity”, within MTL during encoding in APOE4 carriers and between MTL and PMC during retrieval independent of APOE4 status was related to more tau. Further, increasing FC between MTL and PMC during rest, unlike during encoding, was beneficial for episodic memory. Our study highlights that pathology-related episodic memory network changes manifest differently during rest and task and have differential implications for episodic memory trajectories.

The online version contains supplementary material available at 10.1038/s41598-025-21596-0.