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APOE ?4 increases risk for dementia in pure synucleinopathies.

ABSTRACT: To test for an association between the apolipoprotein E (APOE) ?4 allele and dementias with synucleinopathy.Genetic case-control association study.Academic research.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 ?4 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 ?(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, ?4 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 ?4 allele is a strong risk factor across the LBD spectrum and occurs at an increased frequency in pDLB relative to PDD. This suggests that ?4 increases the likelihood of presenting with dementia in the context of a pure synucleinopathy. The elevated ?4 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.

SUBMITTER: Tsuang D

PROVIDER: S-EPMC3580799 | biostudies-literature | 2013 Feb

REPOSITORIES: biostudies-literature

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APOE ε4 increases risk for dementia in pure synucleinopathies.

Tsuang Debby D Leverenz James B JB Lopez Oscar L OL Hamilton Ronald L RL Bennett David A DA Schneider Julie A JA Buchman Aron S AS Larson Eric B EB Crane Paul K PK Kaye Jeffrey A JA Kramer Patricia P Woltjer Randy R Trojanowski John Q JQ Weintraub Daniel D Chen-Plotkin Alice S AS Irwin David J DJ Rick Jacqueline J Schellenberg Gerard D GD Watson G Stennis GS Kukull Walter W Nelson Peter T PT Jicha Gregory A GA Neltner Janna H JH Galasko Doug D Masliah Eliezer E Quinn Joseph F JF Chung Kathryn A KA Yearout Dora D Mata Ignacio F IF Wan Jia Y JY Edwards Karen L KL Montine Thomas J TJ Zabetian Cyrus P CP

JAMA neurology 20130201 2

<h4>Objective</h4>To test for an association between the apolipoprotein E (APOE) ϵ4 allele and dementias with synucleinopathy.<h4>Design</h4>Genetic case-control association study.<h4>Setting</h4>Academic research.<h4>Patients</h4>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 ...[more]

PMID: 23407718

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Project description:BackgroundApolipoprotein E epsilon 4 (APOE-ε4) carrier status is an established risk factor for Alzheimer's disease (AD) dementia. It has also been linked with sleep disturbance in healthy older adults and increased insomnia risk. This association may be driven by the effect of APOE-ε4 on AD pathological change, itself associated with sleep abnormalities. To assess this relationship, we have evaluated post-mortem neuropathological findings in patients with and without cognitive impairment and AD pathology, who had extensive clinical assessment within 12 months of death.MethodsThis retrospective cohort study used UK Brain Banks Network data. Eligible subjects were aged over 50, with pre-mortem neuropsychiatry inventory scores of sleep disturbance (NPI-K), neurocognitive testing and functional cognitive status assessment (Clinical Dementia Rating scale). Neuropathological data included Thal phase, Braak stage and CERAD scores (measures of Aβ plaque distribution, tangle distribution and neuritic plaque density, respectively) combined to form the National Institute on Aging Alzheimer's Association (NIA-AA) ABC score reflecting AD neuropathology. Participants with other significant intracerebral pathology or pathological features of non-AD dementia were excluded. Multivariate linear regression was performed with NPIK Global Score (NPIK frequency score multiplied by severity score) as the dependent variable and APOE-ε4 heterozygosity or homozygosity as independent variables. Covariates included age, gender, APOE-ε2 status and ABC NPI measures reflecting depression and anxiety. Further models stratified by ABC score and functional cognitive status were also produced.ResultsSeven hundred twenty-eight records were identified. Two hundred two participants were included in the final analysis: mean (SD) age 84.0 (9.2) and MMSE 14.0 (11.8). Mean sleep disturbance scores were highest in ε4 homozygosity (n=11), 4.55 (5.4); intermediate in ε4 heterozygosity (n=95), 2.03 (4.0); and lowest in non-ε4 carriers (n=96), 1.36 (3.3). Within the full sample, controlling for pathological status, age, gender, depression, anxiety and CDR-SOB status, APOE-ε4 homozygosity was associated with sleep disturbance (β 2.53, p=0.034). APOE-ε4 heterozygosity was similarly associated in individuals without dementia (β 1.21, p=0.048).ConclusionThese findings lend weight to the hypothesis that APOE-ε4 affects sleep by mechanisms independent of AD pathological change. Evaluation of those mechanisms would enhance understanding of sleep disturbance pathways and potentially provide treatment targets.

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APOE ?4 increases risk for dementia in pure synucleinopathies.

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APOE ε4 increases risk for dementia in pure synucleinopathies.

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