Work

Tau PET Burden is Associated with Hippocampal Microstructure and Episodic Memory in Older Adults with Amyloid Burden

Year: 2025

Type: article

Abstract: BACKGROUND: 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 may precede macrostructural changes such as volumetric loss, offering important insights into the early phases of disease. METHOD: This study assessed the relationships between hippocampal microstructure (assessed with DWI) tau pathology [by positron emission tomography (PET)], and episodic memory performance, focusing on the moderating role of Aβ status 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 Aβ positive. Multiple linear regression analyses tested whether Aβ status moderated associations between hippocampal mean diffusivity (MD), Braak-staged tau accumulation on PET, and an episodic memory composite score. RESULT: Increased hippocampal MD was associated with worse memory (β = -0.24, SE = 0.12, p = 0.039) and greater tau PET burden in Braak stages II-IV (β = .29, SE = .08, p < 0.001; β = .26, SE = .08, p = 0.002; β = .19, SE = .08, p = 0.018 for Braak stages II-IV respectively), but only in individuals who were amyloid positive (e.g., significant amyloid x hippocampal MD interactions). Building on prior findings linking early Braak-staged tau to memory, we further assessed whether tau PET burden mediated the relationship between elevated hippocampal MD and poorer memory performance. Tau PET burden in Braak stages II-IV was found to fully mediate the relationship between elevated hippocampal MD and poorer memory performance (indirect effects with 95% CI: β = 0.25 [-0.47, -0.04]; β = 0.19 [-0.38, -0.01]; β = 0.22 [-0.43, -0.02]), but only in amyloid-positive participants and independent of hippocampal volume. These associations were not significant when excluding MCI participants from the analysis. CONCLUSION: 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 while accounting for hippocampal volume.

Source: Alzheimer s & Dementia

DOI: 10.1002/alz70862_110257