Tau PET Burden Is Associated With Hippocampal Microstructure and Episodic Memory in Amyloid Positive Older Adults

ABSTRACT Growing evidence suggests that hippocampal gray matter microstructure, assessed through diffusion‐weighted imaging (DWI), is a sensitive marker of neurodegeneration in Alzheimer's disease (AD). While hippocampal atrophy is a characteristic feature of AD, microstructural changes likely precede macrostructural changes such as volumetric loss, offering important insights into the early phases of the disease. This study assessed the relationships between hippocampal microstructure (assessed with mean diffusivity MD from DWI) and Braak‐staged tau burden (measured by positron emission tomography PET) with performance on an episodic memory composite score, among individuals with and without amyloid burden, assessed by PET imaging. The study included 192 participants without dementia (14 with mild cognitive impairment MCI) from the BIOCARD cohort (mean age = 68), of which 52 (27%) were amyloid positive. In multiple linear regression analyses, increased hippocampal MD was associated with worse memory and greater tau PET burden in Braak stages II–IV, but only in individuals who were amyloid positive (e.g., significant amyloid × hippocampal MD interactions). Building on prior findings linking early Braak‐staged tau to memory, we further assessed whether tau PET burden statistically mediated the relationship between elevated hippocampal MD and poorer memory performance. Tau PET burden in Braak stages II–IV was found to statistically mediate the relationship between elevated hippocampal MD and poorer memory performance, independent of hippocampal volume, but only in amyloid‐positive participants. These associations were only significant when MCI participants were included in the analysis. These findings suggest hippocampal microstructure may be sensitive to AD‐related pathological burden and associated neurodegeneration, particularly in the early symptomatic phase, and is associated with tau PET and cognitive decline, even after accounting for hippocampal volume.