Distinctive associations between plasma p-tau181 levels and hippocampal subfield volume across the Alzheimer's disease continuum.

Plasma p-tau181 is a promising diagnostic marker of Alzheimer's disease (AD) pathology, reflecting amyloid accumulation, tau deposition, and downstream neurodegeneration that leads to cognitive impairment. However, the specificity of plasma p-tau181 to AD-related tau pathology remains unclear. To assess whether plasma p-tau181 is differentially associated with volumetric changes in distinct hippocampal subfields and whether they mediate the relationship between plasma p-tau181 and cognition across the AD continuum. 213 participants with normal cognition (N=57), mild cognitive impairment (N=109), and AD (N=47) from the Alzheimer's Disease Neuroimaging Initiative (ADNI) were included for cross-sectional analyses of hippocampal subfield volume that was quantified using the Automatic Segmentation of Hippocampal Subfields (ASHS) software. A subset (n=89) was evaluated for one-year longitudinal changes in hippocampal subfield volume. Higher plasma p-tau181 levels (pg/mL) were associated with decreased volumes in the CA1 and dentate gyrus, bilaterally, and right entorhinal cortex ( ps < 0.05). Additionally, volumes of these subfields partially mediated the relationship between plasma p-tau181 and ADNI memory and executive function composite scores. Baseline plasma p-tau181, however, did not predict longitudinal atrophy of hippocampal subfields across diagnostic groups. Plasma p-tau181 is differentially associated with hippocampal subfields that are closely related to both age- and AD-related neurodegeneration. Elevated plasma p-tau181 levels may reflect tau accumulation, and volumetric changes in CA1 and DG may mediate the detrimental effect of tau pathology on cognition.