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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:Severe infections, often requiring ICU admission, have been associated with persistent cognitive dysfunction. Less severe infections are more common and whether they are associated with an increased risk of dementia is unclear. We determined the association of pneumonia hospitalization with risk of dementia in well-functioning older adults.Secondary analysis of a randomized multicenter trial to determine the effect of Gingko biloba on incident dementia.Five academic medical centers in the United States.Healthy community volunteers (n = 3,069) with a median follow-up of 6.1 years.None.We identified pneumonia hospitalizations using International Classification of Diseases, 9th Edition-Coding Manual codes and validated them in a subset. Less than 3% of pneumonia cases necessitated ICU admission, mechanical ventilation, or vasopressor support. Dementia was adjudicated based on neuropsychological evaluation, neurological examination, and MRI. Two hundred twenty-one participants (7.2%) incurred at least one hospitalization with pneumonia (mean time to pneumonia = 3.5 yr). Of these, dementia was developed in 38 (17%) after pneumonia, with half of these cases occurring 2 years after the pneumonia hospitalization. Hospitalization with pneumonia was associated with increased risk of time to dementia diagnosis (unadjusted hazard ratio = 2.3; CI, 1.6-3.2; p < 0.0001). The association remained significant when adjusted for age, sex, race, study site, education, and baseline mini-mental status examination (hazard ratio = 1.9; CI, 1.4-2.8; p < 0.0001). Results were unchanged when additionally adjusted for smoking, hypertension, diabetes, heart disease, and preinfection functional status. Results were similar using propensity analysis where participants with pneumonia were matched to those without pneumonia based on age, probability of developing pneumonia, and similar trajectories of cognitive and physical function prior to pneumonia (adjusted prevalence rates, 91.7 vs 65 cases per 1,000 person-years; adjusted prevalence rate ratio = 1.6; CI, 1.06-2.7; p = 0.03). Sensitivity analyses showed that the higher risk also occurred among those hospitalized with other infections.Hospitalization with pneumonia is associated with increased risk of dementia.

Project description:Great heterogeneity exists in survival and the interval between onset of motor symptoms and dementia symptoms across synucleinopathies. We aimed to identify genetic and pathological markers that have the strongest association with these features of clinical heterogeneity in synucleinopathies.In this retrospective study, we examined symptom onset, and genetic and neuropathological data from a cohort of patients with Lewy body disorders with autopsy-confirmed ? synucleinopathy (as of Oct 1, 2015) who were previously included in other studies from five academic institutions in five cities in the USA. We used histopathology techniques and markers to assess the burden of tau neurofibrillary tangles, neuritic plaques, ?-synuclein inclusions, and other pathological changes in cortical regions. These samples were graded on an ordinal scale and genotyped for variants associated with synucleinopathies. We assessed the interval from onset of motor symptoms to onset of dementia, and overall survival in groups with varying levels of comorbid Alzheimer's disease pathology according to US National Institute on Aging-Alzheimer's Association neuropathological criteria, and used multivariate regression to control for age at death and sex.On the basis of data from 213 patients who had been followed up to autopsy and met inclusion criteria of Lewy body disorder with autopsy-confirmed ? synucleinopathy, we identified 49 (23%) patients with no Alzheimer's disease neuropathology, 56 (26%) with low-level Alzheimer's disease neuropathology, 45 (21%) with intermediate-level Alzheimer's disease neuropathology, and 63 (30%) with high-level Alzheimer's disease neuropathology. As levels of Alzheimer's disease neuropathology increased, cerebral ?-synuclein scores were higher, and the interval between onset of motor and dementia symptoms and disease duration was shorter (p<0·0001 for all comparisons). Multivariate regression showed independent negative associations of cerebral tau neurofibrillary tangles score with the interval between onset of motor and dementia symptoms (? -4·0, 95% CI -5·5 to -2·6; p<0·0001; R2 0·22, p<0·0001) and with survival (-2·0, -3·2 to -0·8; 0·003; 0·15, <0·0001) in models that included age at death, sex, cerebral neuritic plaque scores, cerebral ?-synuclein scores, presence of cerebrovascular disease, MAPT haplotype, and APOE genotype as covariates.Alzheimer's disease neuropathology is common in synucleinopathies and confers a worse prognosis for each increasing level of neuropathological change. Cerebral neurofibrillary tangles burden, in addition to ?-synuclein pathology and amyloid plaque pathology, are the strongest pathological predictors of a shorter interval between onset of motor and dementia symptoms and survival. Diagnostic criteria based on reliable biomarkers for Alzheimer's disease neuropathology in synucleinopathies should help to identify the most appropriate patients for clinical trials of emerging therapies targeting tau, amyloid-? or ? synuclein, and to stratify them by level of Alzheimer's disease neuropathology.US National Institutes of Health (National Institute on Aging and National Institute of Neurological Disorders and Stroke).

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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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