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[Background and Objectives] To investigate whether antemortem MRI-based atrophy subtypes of Alzheimer's disease (AD) differ in neuropathological features and comorbid non-AD pathologies at postmortem., [Methods] From the Alzheimer's Disease Neuroimaging Initiative cohort, we included individuals with antemortem MRI evaluating brain atrophy within 2 years before death, antemortem diagnosis of AD dementia/mild cognitive impairment, and postmortem-confirmed AD neuropathologic change. Antemortem atrophy subtypes were modeled as continuous phenomena based on a recent conceptual framework: typicality (spanning limbic-predominant AD to hippocampal-sparing AD) and severity (spanning typical AD to minimal atrophy AD). Postmortem neuropathologic evaluation included AD hallmarks, β-amyloid, and tau as well as non-AD pathologies, alpha-synuclein and TAR DNA-binding protein 43 (TDP-43). We also investigated the overall concomitance across these pathologies. Partial correlations assessed the associations between antemortem atrophy subtypes and postmortem neuropathologic outcomes., [Results] In 31 individuals (26 AD dementia/5 mild cognitive impairment, mean age = 80 years, 26% females), antemortem typicality was significantly negatively associated with neuropathologic features, including β-amyloid (rho = −0.39 overall), tau (rho = −0.38 regionally), alpha-synuclein (rho = −0.39 regionally), TDP-43 (rho = −0.49 overall), and concomitance of pathologies (rho = −0.59 regionally). Limbic-predominant AD was associated with higher Thal phase, neuritic plaque density, and presence of TDP-43 compared with hippocampal-sparing AD. Regionally, limbic-predominant AD showed a higher presence of tau and alpha-synuclein pathologies in medial temporal structures, a higher presence of TDP-43, and concomitance of pathologies subcortically/cortically compared with hippocampal-sparing AD. Antemortem severity was significantly negatively associated with concomitance of pathologies (rho = −0.43 regionally), such that typical AD showed higher concomitance of pathologies than minimal atrophy AD., [Discussion] We provide a direct antemortem-to-postmortem validation, highlighting the importance of understanding atrophy-based heterogeneity in AD relative to AD and non-AD pathologies. We suggest that (1) typicality and severity in atrophy reflect differential aspects of susceptibility of the brain to AD and non-AD pathologies; and (2) limbic-predominant AD and typical AD subtypes share similar biological pathways, making them more vulnerable to AD and non-AD pathologies compared with 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 the prevailing knowledge of biological heterogeneity in AD and could contribute toward tracking disease progression and designing clinical trials in the future., This study was funded by the Swedish Foundation for Strategic Research (SSF); the Strategic Research Programme in Neuroscience at Karolinska Institutet (StratNeuro); the Swedish Research Council (VR); the regional agreement on medical training and clinical research (ALF) between Stockholm County Council and Karolinska Institutet; Center for Innovative Medicine (CIMED); the Swedish Alzheimer Foundation; the Swedish Brain Foundation; the Åke Wiberg Foundation; Demensfonden; Stiftelsen Olle Engkvist Byggmästare; Birgitta och Sten Westerberg; Foundation for Geriatric Diseases at Karolinska Institutet; Loo och Hans Ostermans stiftelse för medicinsk forskning; Stiftelsen För Gamla Tjänarinnor; and Gun and Bertil Stohne Stiftelse. M.J.G. is supported by the “Miguel Servet” program [CP19/00031] and a research grant [PI20/00613] of the Instituto de Salud Carlos III-Fondo Europeo de Desarrollo Regional (ISCIII-FEDER).

Polygenic variation accounts for a substantial portion of the risk of Alzheimer's disease (AD), but its effect on the rate of fibrillar-tau accumulation as a key driver of dementia symptoms is unclear.We combined the to-date largest number of genetic risk variants of AD (n = 85 lead single-nucleotide polymorphisms [SNPs]) from recent genome-wide association studies (GWAS) to generate a polygenic score (PGS). We assessed longitudinal tau-positron emission tomography (PET), amyloid-PET, and cognition in 231 participants from the Alzheimer's Disease Neuroimaging Initiative (ADNI). Using the PGS, together with global amyloid-PET, we predicted the rate of tau-PET increases in Braak-stage regions-of-interest and cognitive decline. We also assessed PGS-risk enrichment effects on the required sample size in clinical trials targeting tau pathology.We found that a higher PGS was associated with higher rates of tau-PET accumulation, in particular at elevated amyloid-PET levels. The tau-PET increases mediated the association between PGS and faster cognitive decline. Risk enrichment through high PGS afforded sample size savings by 34%.Our results demonstrate that the PGS predicts faster tau progression and thus cognitive decline, showing utility to enhance statistical power in clinical trials. ANN NEUROL 2023.

Ischemic stroke etiology remains undetermined in 30% of cases. We explored the genetic architecture of stroke classified as undetermined to test if mechanisms and risk factors underlying large-artery atherosclerotic (LAAS), cardioembolic (CES), and small-vessel stroke (SVS) contribute to its pathogenesis.We analyzed genome-wide data from 16,851 ischemic stroke cases and 32,473 controls. Using polygenic risk scores for LAAS, CES, and SVS, we assessed the genetic overlap with stroke of undetermined source and used pairwise genomewide association study (GWAS-PW) to search for shared loci. We then applied Mendelian randomization (MR) to identify potentially causal risk factors of stroke of undetermined source.Genetic risk for LAS, CES, and SVS was associated with stroke of undetermined source pointing to overlap in their genetic architecture. Pairwise analyses revealed 19 shared loci with LAAS, 2 with CES, and 5 with SVS that have been implicated in atherosclerosis-related phenotypes. Genetic liability to both carotid atherosclerosis and atrial fibrillation was associated with stroke of undetermined source, but the association with atrial fibrillation was attenuated after excluding cases with incomplete diagnostic workup. MR analyses showed effects of genetically determinants of blood pressure, diabetes, waist-to-hip ratio, inflammatory pathways (IL-6 signaling, MCP-1/CCL2 levels), and factor XI levels on stroke of undetermined source.Stroke of undetermined source shares genetic and vascular risk factors with other stroke subtypes, especially LAAS, thus highlighting the diagnostic limitations of current subtyping approaches. The potentially causal associations with carotid atherosclerosis and atherosclerotic risk factors might have implications for prevention strategies targeting these mechanisms. ANN NEUROL 2022;91:640-651.

OBJECTIVE: Ischemic stroke etiology remains undetermined in 30% of cases. We explored the genetic architecture of stroke classified as undetermined to test if mechanisms and risk factors underlying large-artery atherosclerotic (LAAS), cardioembolic (CES), and small-vessel stroke (SVS) contribute to its pathogenesis. METHODS: We analyzed genome-wide data from 16,851 ischemic stroke cases and 32,473 controls. Using polygenic risk scores for LAAS, CES, and SVS, we assessed the genetic overlap with stroke of undetermined source and used pairwise genomewide association study (GWAS-PW) to search for shared loci. We then applied Mendelian randomization (MR) to identify potentially causal risk factors of stroke of undetermined source. RESULTS: Genetic risk for LAS, CES, and SVS was associated with stroke of undetermined source pointing to overlap in their genetic architecture. Pairwise analyses revealed 19 shared loci with LAAS, 2 with CES, and 5 with SVS that have been implicated in atherosclerosis-related phenotypes. Genetic liability to both carotid atherosclerosis and atrial fibrillation was associated with stroke of undetermined source, but the association with atrial fibrillation was attenuated after excluding cases with incomplete diagnostic workup. MR analyses showed effects of genetically determinants of blood pressure, diabetes, waist-to-hip ratio, inflammatory pathways (IL-6 signaling, MCP-1/CCL2 levels), and factor XI levels on stroke of undetermined source. INTERPRETATION: Stroke of undetermined source shares genetic and vascular risk factors with other stroke subtypes, especially LAAS, thus highlighting the diagnostic limitations of current subtyping approaches. The potentially causal associations with carotid atherosclerosis and atherosclerotic risk factors might have implications for prevention strategies targeting these mechanisms. ANN NEUROL 2022.