ArticleActa neuropathologica2022
APOE4 exacerbates α-synuclein seeding activity and contributes to neurotoxicity in Alzheimer's disease with Lewy body pathology.
Article in Acta neuropathologica, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 52 papers, 1 of them a synthesis that pooled it.
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52 citing papers in PubMed, 1 synthesis or guideline pooled it, 66 citations in OpenAlex.
- Genome wide association study meta-analysis of neuropathologic lesions of Alzheimer's disease and related dementias in a multi-site autopsy cohort.PLoS genetics · 2026Pooled it
- TMEM106B is a selective modulator of TDP-43 pathology in Alzheimer's disease.Alzheimer's & dementia : the journal of the Alzheimer's Association · 2026Article
- APOE4 disrupts the central dogma by arresting neuronal proteome dynamics.bioRxiv : the preprint server for biology · 2026Article
- Understanding the genetic imperfections of Lewy body dementia.Molecular neurodegeneration · 2026Review
- Apolipoprotein E Deficiency Attenuates Neuroinflammatory Responses and Demyelination in Experimental Autoimmune Encephalomyelitis.Molecular neurobiology · 2026Article
- Molecular profiling of alpha-synuclein pathology and seeding activity in Parkinson's disease.Acta neuropathologica · 2026Article
- Amyloid-linked versus age-driven copathologies in Alzheimer's dementia: differential associations withResearch square · 2026Article
- Plasma Proteomic Analysis ofmedRxiv : the preprint server for health sciences · 2026Article
- Spatially resolved molecular signatures of Lewy body dementia.Acta neuropathologica · 2026Article
- Alpha-synuclein seeding activity in postmortem tissues from patients with diffuse and isolated Lewy bodies.Acta neuropathologica communications · 2026Article
- Autophagy and mitophagy at the synapse and beyond: implications for learning, memory and neurological disorders.Autophagy · 2026Review
- Alpha-Synuclein Neurobiology in Parkinson's Disease: A Comprehensive Review of Its Role, Mechanisms, and Therapeutic Perspectives.Brain sciences · 2025Review
- Correlation between ApoE gene polymorphisms and the prognosis of coronary artery disease in patients undergoing percutaneous coronary intervention.BMC cardiovascular disorders · 2025Article
- APOE ε4 linked effects on clinical features and neuropathology in dementia with Lewy bodies.Alzheimer's & dementia : the journal of the Alzheimer's Association · 2025Article
- Lewy body dementia: exploring biomarkers and pathogenic interactions of amyloid β, tau, and α-synuclein.Molecular neurodegeneration · 2025Review
- Genome-wide association study of neuropathological features in Lewy body disease.Brain : a journal of neurology · 2025Article
- Alpha-synuclein seeding amplification assays in Lewy body dementia: a brief review.Molecular neurodegeneration · 2025Review
- Genetic risk and plasma biomarkers of dementia with Lewy bodies in a Chinese population.NPJ Parkinson's disease · 2025Article
- Cortical microstructural abnormalities in dementia with Lewy bodies and their associations with Alzheimer's disease copathologies.NPJ Parkinson's disease · 2025Article
- Distinct patterns of cognitive traits in extreme old age and Alzheimer's disease.Alzheimer's & dementia : the journal of the Alzheimer's Association · 2025Article
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19 authors at 2 institutions in 1 country.
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Abstract
Approximately half of Alzheimer's disease (AD) brains have concomitant Lewy pathology at autopsy, suggesting that α-synuclein (α-SYN) aggregation is a regulated event in the pathogenesis of AD. Genome-wide association studies revealed that the ε4 allele of the apolipoprotein E (APOE4) gene, the strongest genetic risk factor for AD, is also the most replicated genetic risk factor for Lewy body dementia (LBD), signifying an important role of APOE4 in both amyloid-β (Aβ) and α-SYN pathogenesis. How APOE4 modulates α-SYN aggregation in AD is unclear. In this study, we aimed to determine how α-SYN is associated with AD-related pathology and how APOE4 impacts α-SYN seeding and toxicity. We measured α-SYN levels and their association with other established AD-related markers in brain samples from autopsy-confirmed AD patients (N = 469), where 54% had concomitant LB pathology (AD + LB). We found significant correlations between the levels of α-SYN and those of Aβ40, Aβ42, tau and APOE, particularly in insoluble fractions of AD + LB. Using a real-time quaking-induced conversion (RT-QuIC) assay, we measured the seeding activity of soluble α-SYN and found that α-SYN seeding was exacerbated by APOE4 in the AD cohort, as well as a small cohort of autopsy-confirmed LBD brains with minimal Alzheimer type pathology. We further fractionated the soluble AD brain lysates by size exclusion chromatography (SEC) ran on fast protein liquid chromatography (FPLC) and identified the α-SYN species (~ 96 kDa) that showed the strongest seeding activity. Finally, using human induced pluripotent stem cell (iPSC)-derived neurons, we showed that amplified α-SYN aggregates from AD + LB brain of patients with APOE4 were highly toxic to neurons, whereas the same amount of α-SYN monomer was not toxic. Our findings suggest that the presence of LB pathology correlates with AD-related pathologies and that APOE4 exacerbates α-SYN seeding activity and neurotoxicity, providing mechanistic insight into how APOE4 affects α-SYN pathogenesis in AD.
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