Distinctive volumetric associations between plasma p-tau181 and hippocampal formation structures across the Alzheimer's disease continuum.

BackgroundPlasma 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.ObjectiveTo assess whether plasma p-tau181 is differentially associated with volumetric changes in distinct structures of the hippocampal formation and whether these structures mediate the relationship between plasma p-tau181 and cognition across the AD continuum.Methods213 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 formation 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 formation volume.ResultsHigher plasma p-tau181 levels (pg/mL) were associated with decreased volumes in the CA1 and dentate gyrus, bilaterally, and right entorhinal cortex ( < 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 formation structures across diagnostic groups.ConclusionsPlasma p-tau181 is differentially associated with regions of the hippocampal formation that are closely related to both age- and AD-related neurodegeneration. Elevated plasma p-tau181 levels may reflect tau pathology, and volumetric changes in CA1 and DG may mediate the detrimental effect of tau pathology on cognition.