CSF biomarker associations with change in hippocampal volume and precuneus thickness: implications for the Alzheimer’s pathological cascade

Neurofibrillary tangles (NFT) and amyloid plaques are hallmark neuropathological features of Alzheimer’s disease (AD). There is some debate as to which neuropathological feature comes first in the disease process, with early autopsy studies suggesting that NFT develop first, and more recent neuroimaging studies supporting the early role of amyloid beta (Aβ) deposition. Cerebrospinal fluid (CSF) biomarkers of Aβ 42 and hyperphosphorylated tau (p-tau) have been shown to serve as in vivo proxy measures of amyloid plaques and NFT, respectively. The aim of this study was to examine the association between CSF biomarkers and rate of atrophy in the precuneus and hippocampus. These regions were selected because the precuneus appears to be affected early and severely by Aβ deposition, and the hippocampus similarly by NFT pathology. We predicted (1) baseline Aβ 42 would be related to accelerated rate of cortical thinning in the precuneus and volume loss in the hippocampus, with the latter relationship expected to be weaker, (2) baseline p-tau 181p would be related to accelerated rate of hippocampal atrophy and cortical thinning in the precuneus, with the latter relationship expected to be weaker. Using all ADNI cohorts, we fitted separate linear mixed-effects models for changes in hippocampus and precuneus longitudinal outcome measures with baseline CSF biomarkers modeled as predictors. Results partially supported our hypotheses: Both baseline p-tau 181p and Aβ 42 were associated with hippocampal atrophy over time. Neither p-tau 181p nor Aβ 42 were significantly related to cortical thinning in the precuneus over time. However, follow-up analyses demonstrated that having abnormal levels of both Aβ 42 and p-tau 181p was associated with an accelerated rate of atrophy in both the hippocampus and precuneus. Results support early effects of Aβ in the Alzheimer’s disease process, which are less apparent than and perhaps dependent on p-tau effects as the disease progresses. However, amyloid deposition alone may be insufficient for emergence of significant morphometric changes and clinical symptoms.