Basic Science and Pathogenesis

Recently recognized syndromic variants in cases with AD pathology reflect regional differences in susceptibility to AD-tau pathology. We found systematic differences in sleep architectures between amnestic (amAD) and atypical AD (atypAD), including evidence of a more blunted circadian rhythm pattern in amAD compared to atypAD. However, the underlying neurobiological basis remains unknown. We hypothesize that amAD cases exhibit greater degeneration of the suprachiasmatic nucleus (SCN) than atypAD. The link between increased regional susceptibility in AD variant and sleep physiology may be involved in protein dysregulation, contributing to AD pathololgy.

We analyzed 27 postmortem SCN tissues from controls without neuropathological change and individuals with amnestic AD or atypical (logopenic) AD. We quantified arginine vasopressin (AVP+) and vasoactive intestinal peptide (VIP+) positive neurons and conducted semi-quantitative counts of neurofibrillary tau. Moreover, we applied in-situ proteomics using GeoMx Digital Spatial Profiler (DSP) to examine expression levels of 57 proteins commonly dysregulated in amnestic AD.

AtypAD exhibited lower tau burden and higher SCN neuronal counts. The differences between AD variants was more pronouced in AVP+ neurons. Amyloid pathology was absent in all cases. Spatial proteomics analyses revealed that AD-associated proteins showed more preserved pathoprotein expression in atypAD than amAD.

Our findings suggest that the SCN is more severely affected in amAD than in atypAD, exhibiting greater tau burden and neuronal loss, particularly in AVP+ neurons. This supports the hypothesis that differences in regional vulnerability to AD-tau pathology contribute to AD variant phenotypes and may underlie the blunted circadian rhythms observed in amAD. Additionally, spatial proteomics revealed more preserved pathoprotein expression in atypAD, suggesting distinct molecular dysfunctions across AD variants. These findings highlight the need for further investigation into molecular factors driving protein dysregulation, such as neuroinflammatory or lysosomal disruptions, as key contributors to differential susceptibility in AD pathology.