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Title | APOE ε4 increases risk for dementia in pure synucleinopathies. |
Publication Type | Journal Article |
Year of Publication | 2013 |
Authors | Tsuang D, Leverenz JB, Lopez OL, Hamilton RL, Bennett DA, Schneider JA, Buchman AS, Larson EB, Crane PK, Kaye JA, Kramer P, Woltjer R, Trojanowski JQ, Weintraub D, Chen-Plotkin AS, Irwin DJ, Rick J, Schellenberg GD, G Watson S, Kukull W, Nelson PT, Jicha GA, Neltner JH, Galasko D, Masliah E, Quinn JF, Chung KA, Yearout D, Mata IF, Wan JY, Edwards KL, Montine TJ, Zabetian CP |
Journal | JAMA Neurol |
Volume | 70 |
Issue | 2 |
Pagination | 223-8 |
Date Published | 2013 Feb |
ISSN | 2168-6157 |
Keywords | Aged, Aged, 80 and over, Alzheimer Disease, Apolipoprotein E4, Case-Control Studies, Dementia, Female, Gene Frequency, Humans, Lewy Body Disease, Longitudinal Studies, Male, Middle Aged, Parkinson Disease, Retrospective Studies, Risk Factors, Synucleins, Up-Regulation |
Abstract | OBJECTIVE: To test for an association between the apolipoprotein E (APOE) ϵ4 allele and dementias with synucleinopathy. DESIGN: Genetic case-control association study. SETTING: Academic research. PATIENTS: Autopsied subjects were classified into 5 categories: dementia with high-level Alzheimer disease (AD) neuropathologic changes (NCs) but without Lewy body disease (LBD) NCs (AD group; n=244), dementia with LBDNCs and high-level ADNCs (LBD-AD group; n=224), dementia with LBDNCs and no or low levels of ADNCs (pure DLB [pDLB] group; n=91), Parkinson disease dementia (PDD) with no or low levels of ADNCs (n=81), and control group (n=269). MAIN OUTCOME MEASURE The APOE allele frequencies. RESULTS The APOE ϵ4 allele frequency was significantly higher in the AD (38.1%), LBD-AD (40.6%), pDLB (31.9%), and PDD (19.1%) groups compared with the control group (7.2%; overall χ(2)(4)=185.25; P=5.56 × 10(-39)), and it was higher in the pDLB group than the PDD group (P= .01). In an age-adjusted and sex-adjusted dominant model, ϵ4 was strongly associated with AD (odds ratio, 9.9; 95% CI, 6.4-15.3), LBD-AD (odds ratio, 12.6; 95% CI, 8.1-19.8), pDLB (odds ratio, 6.1; 95% CI, 3.5-10.5), and PDD (odds ratio, 3.1; 95% CI, 1.7-5.6). CONCLUSIONS The APOE ϵ4 allele is a strong risk factor across the LBD spectrum and occurs at an increased frequency in pDLB relative to PDD. This suggests that ϵ4 increases the likelihood of presenting with dementia in the context of a pure synucleinopathy. The elevated ϵ4 frequency in the pDLB and PDD groups, in which the overall brain neuritic plaque burden was low, indicates that apoE might contribute to neurodegeneration through mechanisms unrelated to amyloid processing. |
DOI | 10.1001/jamaneurol.2013.600 |
Alternate Journal | JAMA Neurol |
PubMed ID | 23407718 |
PubMed Central ID | PMC3580799 |
Grant List | R01 CA149051 / CA / NCI NIH HHS / United States P30 AG010124 / AG / NIA NIH HHS / United States P50 AG005131 / AG / NIA NIH HHS / United States I01 BX000531 / BX / BLRD VA / United States T32 AG000255 / AG / NIA NIH HHS / United States R01 NS065070 / NS / NINDS NIH HHS / United States U01 AG016976 / AG / NIA NIH HHS / United States P50 NS053488 / NS / NINDS NIH HHS / United States P50 AG005136 / AG / NIA NIH HHS / United States P30 AG008017 / AG / NIA NIH HHS / United States P30 AG010161 / AG / NIA NIH HHS / United States R37 AG018440 / AG / NIA NIH HHS / United States P50 AG005133 / AG / NIA NIH HHS / United States P50 NS062684 / NS / NINDS NIH HHS / United States U01 AG006781 / AG / NIA NIH HHS / United States R01 AG010845 / AG / NIA NIH HHS / United States P01 AG022074 / AG / NIA NIH HHS / United States R01 NS048595 / NS / NINDS NIH HHS / United States P30 AG028383 / AG / NIA NIH HHS / United States R01 AG015819 / AG / NIA NIH HHS / United States |