Clinical Phenotypes of Alzheimer’s Disease: Pathological Correlates of Regional Cortical Volume

AbstractBackgroundRecent studies highlight distinct patterns of cortical atrophy in amnestic (typical) and non‐amnestic (atypical – behavioural, dysexecutive and visuospatial) clinical phenotypes of Alzheimer’s disease (AD). The current study aimed to assess regional phenotypic MRI patterns of cortical atrophy, and their association with Amyloid‐beta (Aβ), phosphorylated Tau (pTau), and axonal degeneration (NfL).MethodPostmortem In‐situ 3DT1 3T‐MRI data were collected for 28 AD (14 typical, 14 atypical) and 10 control brain donors. Images were segmented using QyScore® and regional volumes according to the AAL3 atlas were obtained. At subsequent autopsy, Eight brain regions from the right hemisphere were selected and immunostained for Aβ (4G8), pTau (AT8), and Neurofilament light (NfL), and quantified for area% load. Group comparisons and MRI volume‐pathology associations were analyzed using linear models with covariates age, gender, postmortem delay, and intracranial volume when applicable.ResultsWhen assessing regional cortical volumes, compared to controls, typical AD showed a more parietal‐temporal, while atypical AD showed a more a frontal‐temporal atrophy pattern (fig1).Typical and atypical phenotypes showed different pathological load across all selected regions in both Aβ and NFL (p = 0.032,p = 0.0007, respectively). Subsequent explorative assessment indicates a difference in regional pTau distribution between behavioural, dysexecutive and visuospatial subtypes, specifically in the occipital region (fig2).Addressing MRI‐pathology associations across all selected regions, we observed a positive association between cortical volume and Aβ in typical AD (β = 1.98,p = 0.026), while both pTau and NFL showed a negative association (β = ‐0.26,p = 0.004; β = ‐2.00,p = 0.001, respectively). In atypical AD, only NFL showed a significant negative association (β = ‐2.27,p<0.001) with cortical volume. Regionally (fig3), only NfL associated with MRI volume; with the precuneus in both typical and atypical AD (β = ‐2.81,p = 0.044; β = ‐3.81,p = 0.011, respectively), and with posterior cingulate cortex volume in atypical AD (β = ‐3.24,p = 0.045).ConclusionThis study found varying atrophy patterns in AD phenotypes when compared to controls. Across all selected regions, typical AD showed volume‐pathology associations with Aβ, pTau and axonal damage, while atypical AD only showed associations with axonal damage, indicating a possible difference in volume‐pathology associations between phenotypes. Regionally, cortical volume was predominantly associated with axonal damage, rather than Aβ or pTau protein accumulation, in parietal regions.