{"doi":"10.1002/alz.70668","title":"Neurodevelopment and neural environment inform Alzheimer's disease age at onset and phenotype","abstract":"INTRODUCTION: Risk factors associated with sporadic non-amnestic and early-onset Alzheimer's disease (AD) remain underexamined. METHODS: We investigated a large, clinically heterogeneous, AD cohort for frequencies of established risk factors (hypertension, hypercholesterolemia, diabetes mellitus) alongside novel factors (non-right-handedness, learning disability, seizures, autoimmune disease). RESULTS: Early-onset AD possessed lower frequencies of established risk factors (hypertension, hypercholesterolemia, diabetes mellitus, all p < 0.001) and higher frequencies of novel factors (non-right-handedness, learning disability, active seizure, all p < 0.001; remote seizure, p = 0.002; and autoimmune disease, p = 0.007). An age at onset < 70 maximally distinguished novel from typical factors. Principal component analysis loaded novel factors into two components, non-right-handedness and learning disability versus seizure and autoimmune disease, which combined, resulted in an exponential decrease in age at onset from one factor alone. DISCUSSION: Identifying novel factors enriched in early-onset and non-amnestic AD introduces new theories of AD susceptibility and phenotypic heterogeneity, with significant implications for disease prediction and treatment. HIGHLIGHTS: We identified a suite of novel factors overrepresented in early-onset and non-amnestic AD. These factors can be broadly conceptualized as neurodevelopmental (non-right-handedness and learning disability) and neural environmental (seizure and autoimmunity). The combination of these factors produced exponential decreases in AD age at onset, compared to each alone, supporting a new theoretical framework for understanding AD risk with implications for disease prediction, prevention, and therapeutic intervention.","journal":"Alzheimer s & Dementia","year":2025,"id":522070,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":5,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.8503,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":230944,"name":"Rik Ossenkoppele","orcid":"0000-0003-1584-7477","position":1,"is_corresponding":false},{"id":230889,"name":"Neill R. 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