Hippocampal atrophy is a core marker of neurodegeneration in dementia, particularly in Alzheimer’s disease (AD). However, most studies focus on total hippocampal volume loss and overlook hemispheric asymmetry, which may reflect distinct biological processes. While tau pathology is closely linked to medial temporal lobe degeneration, it remains unclear whether tau is associated with asymmetric patterns of hippocampal atrophy.

We analyzed 483 cognitively unimpaired participants from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) with baseline cerebrospinal fluid (CSF) phosphorylated tau (pTau181) and amyloid-β (Aβ42) measurements and longitudinal structural MRI data over 10 years of follow-up. Total hippocampal volume and hemispheric asymmetry, defined as the absolute difference between left and right hippocampal volumes (|L−R|), were quantified at each visit. Linear mixed-effects models assessed associations between baseline CSF biomarkers and longitudinal changes in hippocampal asymmetry, adjusting for demographic factors, APOE ε4 status, and baseline hippocampal volume.

Higher baseline CSF pTau181 was associated with greater increases in hippocampal asymmetry over time (β = 1.20, SE = 0.43, p = 0.006). This association remained significant after additional adjustment for total hippocampal volume and baseline CSF Aβ42. CSF total tau was highly correlated with pTau181 (Spearman’s ρ =0.98, p < 0.001) and showed comparable associations with hippocampal measures. In contrast, baseline Aβ42 was not associated with subsequent changes in hippocampal asymmetry. Both pTau181 and Aβ42 were associated with faster decline in total hippocampal volume. In amyloid-stratified analyses, pTau181 was associated with increasing hippocampal asymmetry only among amyloid-negative individuals, whereas its association with total hippocampal atrophy was observed primarily in amyloid-positive individuals.

CSF pTau181 is associated not only with overall hippocampal atrophy but also with progressive hippocampal asymmetry, suggesting that tau-related neurodegeneration may manifest as both magnitude and imbalance of tissue loss. These findings support hippocampal asymmetry as a complementary neuroimaging marker that may capture medial temporal lobe neurodegeneration in cognitively unimpaired older adults, with potential applications in early disease risk stratification, longitudinal disease monitoring, and the identification of biologically distinct participants for future clinical trials.