Investigation of the independent role of a rare APOE variant (L28P; APOE*4Pittsburgh) in late-onset Alzheimer disease
Year: 2022
Type: article
Study design: Observational Study
Abstract: A rare missense APOE variant (L28P; APOE*4Pittsburgh), which is present only in populations with European ancestry, has been reported to be a risk factor for late-onset Alzheimer's disease (LOAD). However, due to the complete linkage disequilibrium of L28P with APOE*4 (C112R), its independent genetic association is uncertain. The original association study implicating L28P with LOAD risk was carried out in a relatively small sample size. In the current study, we have re-evaluated this association in a large case-control sample of 15,762 White U.S. subjects and investigated its independent effect in APOE 3/4 subjects, as L28P has been observed only in the heterozygous state of APOE*4 carriers and 3/4 is the most common genotype containing the APOE*4 allele. The heterozygous carrier frequency of L28P, all with APOE*4, was about 3-fold higher in AD cases than in cognitively intact controls (0.845% vs. 0.277%). The age- and sex-adjusted meta-analysis odds ratio (OR) was 2.87 (95% CI: 1.34 - 6.13; = 0.0066). Among APOE 3/4 subjects, age- and sex-adjusted meta-analysis OR was 1.53 (95% CI: 0.70 - 3.36; p = 0.28), indicating its effect was independent of APOE*4. The lack of statistical significance appears mainly due to the low power of 4138 subjects with the 3/4 genotype (12% power at α= 0.05) compared to the required sample of 139,088 subjects with the 3/4 genotype to detect an OR of 1.5 at α= 0.05 and 80% power. Our data suggesting that L28P has an independent genetic effect on AD risk is reinforced by earlier experimental findings showing that this mutation leads to significant structural and conformational changes in the ApoE4 molecule and can induce functional defects associated with neuronal Aβ42 accumulation and oxidative stress. Additional functional studies in cell-based systems and animal models will help to delineate its functional significance in the etiology of AD.
Source: Neurobiology of Aging
Institutions: University of Pittsburgh, University of Florida
Language: English
Subfield: Physiology (medical)
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
Estimated APC paid: $3,200
Funders: U.S. Department of Health and Human Services, University of Pennsylvania, Broad Institute, European Commission, ZonMw, Russian Foundation for Basic Research, Erasmus Medisch Centrum, Nederlandse Organisatie voor Wetenschappelijk Onderzoek, National Institutes of Health, Uniformed Services University of the Health Sciences, National Institute on Aging, National Heart, Lung, and Blood Institute, National Institute of Mental Health, National Human Genome Research Institute, National Center for Complementary and Alternative Medicine, National Institute of Neurological Disorders and Stroke, U.S. National Library of Medicine, National Center for Complementary and Integrative Health
Awards: G1052397333, G1058046096, G1077033501, G1135917780, G1220223050, G1230194470, G1243299691, G1246907430, Genetic Architecture of Alzheimer’s disease Proteinopathies, CORONARY HEART DISEASE AND STROKE, CORONARY HEART DISEASE &STROKE IN PEOPLE AGED 65-84, G1295759896, G1495020029, G1527150935, G1589312473, CORONARY HEART DISEASE AND STROKE, G1691174148, Mild Cognitive Impairment: a Prospective Community Study, G173303992, G1801104442, G1859875883, G1941623656, CHARGE: Identifying Risk & Protective SNV for AD in ADSP Case-control Sample, Large Scale Sequencing and Analysis of Genomes, G2194386449, CORONARY HEART DISEASE &STROKE IN PEOPLE AGED 65-84, G2391884931, G2439406834, G2442294994, G2614709755, Deep Resequencing of Candidate Gene Regions in Late-onset Alzheimer's Disease, CORONARY HEART DISEASE &STROKE IN THE ELDERLY, G278200998, G2818629771, A Platform for Large-Scale Genomic Discovery, G2990051238, G300339986, G3045517347, Alzheimer's Disease Research Center, G3114902838, G3220743633, National Alzheimer's Coordinating Center, G3405256882, G3410686264, G3462919067, G3483586962, CHS research resources for the cardiovascular health of older adults, G3540777072, G3552494845, ADSP Follow-up in Multi-Ethnic Cohorts via Endophenotypes, Omics & Model Systems, G3834732120, G3839646794, G384457986, CENTRAL BLOOD ANALYSIS LABORATORY FOR CHS, Predictors of Alheimers Disease in Mild Cognitive Impairment, EPIDEMIOLOGY OF DEMENTIA: A PROSPECTIVE COMMUNITY STUDY, G4258630424, Replication and Extension of ADSP Discoveries in African-Americans, The Human Genome Sequencing Center, G457330776, ARIC Neurocognitive Study (ARIC-NCS) Renewal UNC 4 of 5, European Network for Genetic and Genomic Epidemiology, Search for the Alzheimers Genes, G4775840120, G494123624, ARIC Neurocognitive Study (ARIC-NCS) Renewal 4 of 5, Temporal Trends, Novel Imaging and Molecular Characterization of Preclinical and Clinical Alzheimer's Disease in the Framingham Cohorts, G5164707915, Whole Genome Sequencing in Ethnically Diverse Cohorts for the ADSP Follow-Up Study (FUS), Alzheimer's Disease Genetics Consortium, G5364873420, G5457026379, G5479317095, Preclinical AD: Correlates of Amyloid, Tau PET and fcMRI in Framingham Gen 3 Young Adults, G5558075022, G5588026468, G5652732059, MRI, Cognitive, Genetic and Biomarker Precursors of AD & Dementia in Young Adults, G567847597, G5789161078, G581887176, G583528397, G5874676332, CHARGE consortium: omics discovery for CVD and aging phenotypes, CHS Events Follow-up Study, G6091493096, Consortium for Alzheimers Sequence Analysis (CASA), Sequence-based Discovery of AD Risk & Protective Alleles, G6226795708, Ginkgo Biloba Prevention Trial in Older Individuals, The Framingham Heart Study, G6548750934, G6568533755, G6648385527, CHS-Transition Phase, ARIC Neurocognitive Study (ARIC-NCS) Renewal 2 of 5, ARIC Neurocognitive Study (ARIC-NCS), G6994344002, G7176672723, G7431531211, Exceptional Survival: Trajectories to Functional Aging (CHS All Stars), G770899802, The ARIC and Neurocognitive Longitudinal Study, Sequence-based Discovery of AD Risk & Protective Alleles, Genetic Architecture of Alzheimer's disease Proteinopathies, Modifier Genes that Influence Age at Onset or Protect Against Development of Alzheimer's Disease (AD), AD Gene Discovery: Exome Chip, New Endophenotypes & Functional Studies in CHARGE, G8506111834, G8506930532, COGNITIVE TESTS, APOE, BRAIN MRI AND RISKS OF DEMENTIA, Identification and characterization of AD risk networks using multi-dimensional "omics" data, G8821835834, Building on GWAS for NHLBI-disease: the CHARGE consortium, G890705022, G8927421343, G9000216768, G9000257646, G9000331231, Genome Center for Alzheimer's Disease (GCAD), Mild Cognitive Impairment: A Prospective Community Study, Alzheimer Disease Research Center, THE NIA GENETICS OF ALZHEIMER'S DISEASE DATA STORAGE SITE, ARIC Neurocognitive Study (ARIC-NCS) Renewal 2023-2028, Precursors of Stroke Incidence and Prognosis, Clinical and Translational Research Training in Geriatric Mental Health, National Centralized Repository for Alzheimer's Disease and Related Dementias (NCRAD), G931319380
OpenAlex ID: W4309477414