Muehlboeck, J‐Sebastian

AbstractBackgroundPure Alzheimer’s disease (AD), characterized by combined amyloid and tau pathology, is not the most prevalent form of the disease as non‐AD pathologies (e.g., alpha‐synuclein and TDP‐43) are commonly observed postmortem. The role of AD and non‐AD pathologies is unclear in relation to disease heterogeneity. Therefore, we investigated whether antemortem MRI‐based atrophy subtypes of AD differ in postmortem neuropathological features and comorbid non‐AD pathologies.MethodsWe selected individuals from the ADNI with antemortem MRI evaluating brain atrophy within 2 years before death; antemortem diagnosis of AD dementia/mild cognitive impairment; and a postmortem‐confirmed AD neuropathologic change. Antemortem atrophy subtypes were modeled as continuous phenomena using a recent conceptual framework: typicality (spanning limbic predominant AD to hippocampal sparing AD) and severity (spanning typical AD to minimal atrophy AD). Postmortem neuropathological evaluation included AD hallmarks (amyloid‐beta, tau), non‐AD pathologies (alpha‐synuclein, TDP‐43) and concomitant pathological burden. Partial correlations assessed the associations between antemortem atrophy subtype dimensions and postmortem neuropathological outcomes.ResultsIn 31 individuals (mean age = 80y, 26% females), antemortem typicality was significantly associated with neuropathological features: amyloid‐beta (rho = ‐0.39 overall), tau (rho = ‐0.38 regionally), neuritic plaque density (rho = ‐0.4 overall), alpha‐synuclein (rho = ‐0.39 regionally), TDP‐43 (rho = ‐0.49 overall), and concomitance pathological burden (rho = ‐0.59 regionally). This suggests that limbic predominant AD was associated with higher burden of these pathologies compared to hippocampal sparing AD. Antemortem severity was significantly associated with concomitant pathological burden (rho = ‐0.43 regionally), such that typical AD showed higher burden than minimal atrophy AD.ConclusionsBased on our direct antemortem‐to‐postmortem validation, we hypothesize that: (a) typicality and severity in atrophy reflect differential aspects of susceptibility of the brain to AD and non‐AD pathologies; (b) limbic predominant AD and typical AD subtypes may share similar biological pathways, making them more vulnerable to the investigated AD and non‐AD pathologies compared to hippocampal sparing AD, which may follow a different biological pathway. Our findings provide a deeper understanding of associations of atrophy subtypes in AD with different pathologies, enhancing prevailing knowledge of biological heterogeneity in AD.

AbstractBackgroundBiological heterogeneity in Alzheimer’s disease (AD) has been observed and described as subtypes in measures of neurodegeneration (e.g., hypometabolism and atrophy). However, the relationship between these AD subtypes have not been studied. Thus, we aimed to compare and identify pathways associated with hypometabolism‐based and atrophy‐based subtypes.MethodCross‐sectional FDG‐PET and MRI scans from 173 amyloid‐positive AD individuals and 120 amyloid‐negative cognitively normal control individuals from the ADNI were included. Subtypes were identified in each neuroimaging modality by random forest hierarchical clustering using FDG‐PET uptake (measuring hypometabolism) and MRI volumes (measuring atrophy) in cortical and subcortical regions. We performed cross‐modal comparisons of atrophy patterns in hypometabolism‐based subtypes and hypometabolism patterns in atrophy‐based subtypes. To identify neurodegenerative pathways corresponding to each subtype, we used event‐based modelling to predict sequential progression of abnormality in hypometabolism and atrophy across brain regions (hippocampus, AD signature, frontal, posterior areas).ResultClustering revealed four hypometabolism‐based (two relatively limbic‐predominant: 25.7%, 19.8% and two relatively cortical‐predominant: 25.7%, 28.6%) and three atrophy‐based (diffuse: 18.7%, relatively limbic‐predominant: 28.6%, minimal: 52.6%) subtypes of AD with distinct spatial patterns and demographic and clinical characteristics. Cross‐modally, we found comparable AD‐typical atrophy patterns (involving the hippocampus and temporal regions) across the four hypometabolism‐based subtypes and comparable AD‐typical hypometabolism patterns (involving the retrosplenial cortex) across the three atrophy‐based subtypes. Event‐based modelling showed that each hypometabolism‐based subtype was associated with a unique sequential progression of regional hypometabolism, but not regional atrophy (sequence always initiated with frontal atrophy across all subtypes). Similarly, each atrophy‐based subtype was associated with a unique sequential progression of regional atrophy, but not regional hypometabolism (sequence always initiated with hypometabolism in AD signature areas across all subtypes).ConclusionOur findings suggest that hypometabolism‐based and atrophy‐based AD subtypes are not interchangeable. We identified unique metabolic and atrophy pathways specific to each subtype, which supports the notion that neurodegeneration manifests and progresses differentially across subtypes of AD. Despite being measures of neurodegeneration, hypometabolism and atrophy may not share the same extent of heterogeneity, bearing a complex multimodal relationship. Disentangling such relationships and combining complementary biomarkers to investigate heterogeneity could aid personalized treatment of AD.