Susceptibility to postmortem (co)-pathologies in antemortem atrophy-based subtypes of Alzheimer's disease

ObjectivesTo investigate whether antemortem atrophy-based subtypes of Alzheimers disease (AD) may be differentially susceptible to individual or concomitance of AD and non-AD (co)-pathologies, assessed neuropathologically at postmortem. MethodsWe selected 31 individuals from the AD neuroimaging initiative with: an antemortem magnetic resonance imaging scan evaluating brain atrophy available within two years before death; an antemortem diagnosis of AD dementia or prodromal AD; and postmortem neuropathological confirmation of AD. Antemortem atrophy-based subtypes was modeled as a continuous phenomenon in terms of two recently proposed dimensions: typicality (ranging from limbic-predominant AD to hippocampal-sparing AD subtypes) and severity (ranging from typical AD to minimal atrophy AD subtypes). Postmortem neuropathological evaluation included global and regional outcomes: AD hallmark pathologies of amyloid-beta and tau; non-AD co-pathologies of alpha-synuclein Lewy body and TDP-43; and the overall concomitance across these four (co)-pathologies. Partial correlation and linear regression models were used to assess the association between antemortem atrophy-based subtypes and postmortem neuropathological outcomes. ResultsWe observed significant global and regional associations between antemortem typicality and postmortem (co)-pathologies including tau, alpha-synuclein Lewy bodies and TDP-43. Antemortem typicality demonstrated stronger regional associations with concomitance of multiple postmortem (co)-pathologies in comparison to antemortem severity. Our findings suggest the following susceptibilities of atrophy-based subtypes: limbic-predominant AD towards higher burden of tau and TDP-43 pathologies while hippocampal-sparing AD towards lower burdens; limbic-predominant AD and typical AD towards higher burden of alpha-synuclein Lewy body pathology while hippocampal-sparing AD and minimal-atrophy AD towards lower burdens. DiscussionThrough a direct antemortem-to-postmortem validation, our study highlights the importance of understanding heterogeneity in AD in relation to concomitance of AD and non-AD pathologies. Our findings provide a deeper understanding of both global and regional vulnerabilities of the biological subtypes of AD brain towards (co)-pathologies. Relative involvement of both AD hallmark and non-AD (co)-pathologies will enhance prevailing knowledge of biological heterogeneity in AD and could thus, contribute towards tracking disease progression and designing clinical trials in the future.