Hippocampal microstructure as a measure of cognitive resilience to tau PET burden in older adults

Abstract

Background: Cognitive resilience, the ability to maintain better than expected cognitive function despite neuropathological burden, is a key contributor to clinical outcomes in Alzheimer's disease (AD), though the underlying neurobiological mechanisms remain poorly understood.

Objectives: To determine whether hippocampal volume and microstructure moderate the relationship between early tau pathology and cognitive performance, thereby serving as potential markers of cognitive resilience.

Design: Cross-sectional observational study.

Setting: Participant data was obtained from the longitudinal BIOCARD Study, a volunteer-based research cohort.

Participants: The sample included 190 dementia-free adults (mean age = 68 years), comprising 176 cognitively unimpaired individuals and 14 with mild cognitive impairment (MCI).

Measurements: Hippocampal volume and microstructure (mean diffusivity (MD)) were measured using structural magnetic resonance imaging (MRI) and diffusion-weighted imaging (DWI), respectively. Tau pathology was measured using FMK-6240 tau PET imaging across Braak stages I-III. Cognitive performance was indexed using global and domain-specific composite scores. Regression models tested the interactions between hippocampal volume or MD and tau burden, adjusting for demographics, APOE genotype, amyloid status, and diagnostic status.

Results: Lower hippocampal MD (indicative of better microstructural integrity) attenuated the negative association between tau burden in Braak stages II-III and both global cognition and episodic memory (ps < 0.010). Logistic regression models indicated that lower hippocampal MD was associated with a weaker relationship between tau burden in Braak stages II-III and the likelihood of MCI diagnosis (ps < 0.050). In contrast, hippocampal volume did not moderate the relationship between tau and any cognitive outcome (ps > 0.250).

Conclusions: Hippocampal MD may serve as a promising imaging marker of cognitive resilience to early tau pathology, with potential utility for risk stratification and as a target for preventive interventions in AD.

Keywords: Alzheimer’s disease; Braak stages; Hippocampal mean diffusivity; Neuroinflammation; Synaptic integrity.