Association between cerebrospinal fluid tau and brain atrophy is not related to clinical severity in the Alzheimer's disease continuum

We aimed to assess the association between core cerebrospinal fluid (CSF) biomarkers, regional brain atrophy and clinical severity in the Alzheimer's disease (AD) continuum, as well as to investigate how cognitive reserve (CR) may modulate these putative associations. Forty-nine subjects (11 controls, 10 patients with subjective memory complaints, 19 with mild cognitive impairment and 9 mild AD) underwent lumbar puncture and high-resolution magnetic resonance imaging (MRI). CSF amyloid-β_1-42 (Aβ_1-42), total tau (t-tau) and phosphorylated tau (p-tau₁₈₁) were determined. Voxel-based morphometry (VBM) was applied and multiple regression analyses for the whole sample were carried out. Clinical severity was adjusted using the Clinical Dementia Rating Sum of Boxes score (CDR-SB). A negative correlation between t-tau levels and grey matter (GM) volume in temporo-parietal regions was found, regardless of CDR-SB score. In contrast, the negative correlation between p-tau₁₈₁ and GM volume was largely explained by clinical severity, except in the posterior cingulate cortex. CR did not significantly modify these correlations. Aβ_1-42 levels were not related to GM volume but were related to clinical severity, an association that was attenuated when CR was considered. In conclusion, the present findings reflect that t-tau CSF concentrations are associated with GM atrophy in neuropathologically relevant areas across the AD continuum, whereas the p-tau₁₈₁ association is largely dependent on the degree of clinical severity. The relationship between CSF Aβ_1-42 and clinical severity seems to be modulated by CR, suggesting that there may be subjects with pathological levels of Aβ_1-42 and high CR estimates who remain clinically asymptomatic.