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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\u2010staged 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\u2009=\u200968), 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\u2013IV, but only in individuals who were amyloid positive (e.g., significant amyloid\u2009\u00d7\u2009hippocampal MD interactions). Building on prior findings linking early Braak\u2010staged 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\u2013IV was found to statistically mediate the relationship between elevated hippocampal MD and poorer memory performance, independent of hippocampal volume, but only in amyloid\u2010positive participants. These associations were only significant when MCI participants were included in the analysis. These findings suggest hippocampal microstructure may be sensitive to AD\u2010related 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.<\/jats:p>","DOI":"10.1002\/hipo.70038","type":"journal-article","created":{"date-parts":[[2025,9,29]],"date-time":"2025-09-29T09:58:13Z","timestamp":1759139893000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Tau\n                    <scp>PET<\/scp>\n                    Burden Is Associated With Hippocampal Microstructure and Episodic Memory in Amyloid Positive\u00a0Older Adults"],"prefix":"10.1002","volume":"35","author":[{"given":"Daniel D.","family":"Callow","sequence":"first","affiliation":[{"name":"Department of Psychiatry and Behavioral Sciences Johns Hopkins University School of Medicine  Baltimore Maryland 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