Distribution of pathological hallmarks and association with post-mortem MRI cortical thickness in typical and atypical Alzheimer’s disease.

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Alzheimer’s disease (AD) may present with typical amnestic symptoms (70%) as well as atypical non-amnestic symptoms such as spatial disorientation, aphasia, or behavioural change. This heterogeneity in clinical symptoms is reflected by pathology and neuroimaging, showing different patterns of protein aggregation, inflammation and atrophy. In this study we aimed to assess the within-subject regional pathological abnormalities and association with MRI cortical atrophy in clinical phenotypes, using a post-mortem MRI-pathology pipeline.

16 clinically confirmed AD donors, eight typical (4F, 73y±9) and eight atypical (3F, 63y±11), and 11 non-neurological donors (6F, 70y±7) underwent post-mortem in-situ 3T MRI. Upon subsequent autopsy, eight cortical regions were selected for paraffin embedding and Aβ, (p-)tau and CD68 (clone KP1) immunohistochemistry, which was quantitatively analysed as area %-load with ImageJ. Freesurfer was used on T1 images to calculate regional cortical thickness. Outcome measures were compared across groups using non-parametric tests. In a linear mixed model we related regional pathology with cortical thickness, adjusting for age and post-mortem delay.

Across all regions, Aβ, (p-)tau and CD68 load differed between groups; more pathology in (a)typical AD than controls (all p< 0.001), and more (p-)tau and CD68 in atypical versus typical AD (p<0.001 and p<0.01). Cortical thickness differed between (a)typical AD and controls (p<0.001) and between atypical and typical AD (p<0.01).

Within regions, no difference in Aβ load or cortical thickness was found, but there was more (p-)tau in the precuneus (p=0.04) and more CD68 in the middle (p=0.03) and superior frontal cortex (p=0.028) in atypical AD compared to typical AD.

Across all groups and regions, there was a negative association between cortical thickness and Aβ (p<0.05), (p-)tau (p<0.001) and CD68 load (p<0.001). Within AD groups, cortical thickness showed a negative association with Aβ for atypical AD, with (p-)tau for both phenotypes. Within regions, associations with (p-)tau and CD68 were found for frontal and parietal thickness in (a)typical AD, but none survived Bonferroni correction.
Our results show regional differences in (p-)tau, CD68 and cortical thickness between typical and atypical AD. Aβ pathology may play a differential role in atrophy between typical and atypical AD.

Original languageEnglish
JournalAlzheimer's & dementia : the journal of the Alzheimer's Association
Publication statusPublished - 1 Dec 2020
Eventalzheimer's association international conference 2020 - virtual
Duration: 27 Jul 2020 → …


  • Alzheimer's Disease
  • pathology
  • postmortem MRI

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