Biomarkers.

Background: The medial temporal lobe's (MTL) early involvement in tau pathology makes it a key focus in the development of preclinical Alzheimer's disease (AD) biomarkers. ROI analyses in prior studies reported significant MTL structural differences in cognitively normal individuals with and without β-amyloid (A+/-CN). Pointwise analysis, offering spatial information of early neurodegeneration, has potential to pinpoint "signature regions" of pathological change, but has been underexplored in the MTL. This study employs a specialized pointwise analysis pipeline to examine the spatial pattern of MTL structural change in subgroups dichotomized by both β-amyloid and tau status in a large cohort of CN individuals.

Methods: A dataset of 3036 CN (A-/A+: 1270/1558, Table 1) individuals from ADNI, HABS, A4 and ABC were analyzed. We extracted MTL regional thickness maps from MRI using tailored pipelines, ASHS-T1 and CRASHS. For participants with prospective longitudinal MRI (five years follow-up), regional maps of longitudinal atrophy rate were extracted using SkelDBM. Subjects with cross-sectional tau PET available (N=563) were further divided into A and T subgroups by tracer uptake. General linear modeling was performed on each surface point to investigate cross-sectional and longitudinal MTL structural group differences (detailed in Figure 1) and their correlation with MTL tau burden in All/A+/A- CN. Age and sex were covariates and cluster-level multiple comparison correction was performed.

Results: A+CN demonstrated a significantly faster atrophy rate than A-CN across the whole MTL, primarily driven by A+T+CN individuals (Figure 1-b). Notably, A-T+CN showed significantly faster atrophy rate in the entorhinal cortex (ERC) and Brodmann area 35 (BA35), the earliest sites of tau pathology (Figure 1-b, second column). Figure 2-b displays an MTL-wise significant correlation between atrophy rate and tau in All/A+/A- CN. In both analyses, cross-sectional effects are consistently weaker than longitudinal ones, but have some significant clusters in ERC and BA35.

Conclusions: Pointwise analysis revealed extensive tau-associated accelerated neurodegeneration in the MTL in preclinical AD. Furthermore, accelerated atrophy was observed in early Braak regions in A-CN with evidence of tau pathology, potentially driven by primary age-related tauopathy (PART). These pointwise longitudinal MTL measures provide sensitive measures that may allow for disease monitoring in preclinical AD.