Dataset Information

Association of Cortical ?-Amyloid Protein in the Absence of Insoluble Deposits With Alzheimer Disease.

ABSTRACT: Importance:?-Amyloid deposits are a pathologic hallmark of Alzheimer disease (AD). However, the extent to which cortical ?-amyloid protein in the absence of insoluble deposits is associated with classic features of AD appear to be unknown. Objective:To examine the associations of cortical ?-amyloid protein in the absence of insoluble deposits with cognitive decline, neurofibrillary tangles, other age-associated neuropathologic conditions, and APOE. Design, Setting, and Participants:This analysis combines data from 2 community-based clinicopathologic cohort studies of aging. The Religious Orders Study started in 1994, and the Rush Memory and Aging Project started in 1997. Both studies are ongoing. Participants without known dementia were enrolled and agreed to annual clinical evaluations and brain donation after death. Primary analyses focused on individuals without ?-amyloid deposits. Data analyses occurred in mid-September 2018. Main Outcomes and Measures:?-Amyloid protein abundance was measured by targeted proteomics using selected reaction monitoring. ?-Amyloid deposits were detected using immunohistochemistry. Other neuropathologic indices were quantified via uniform structured evaluation. Linear mixed models were used to examine the association of ?-amyloid protein with cognitive decline. Regression models examined the protein associations with neuropathologic outcomes and the APOE genotype. Results:By mid-September 2018, 3575 older persons were enrolled, and 1559 had died and undergone brain autopsy. Proteomic data were collected in 1208 individuals, and 5 with missing cognitive scores were excluded. Of the remaining 1203, primary analyses focused on 148 individuals (12.3%) without ?-amyloid deposits. In this group, the mean (SD) age at death was 87.0 (7.0) years, and 84 individuals (56.8%) were women. In the absence of ?-amyloid deposits, we did not observe an association of ?-amyloid protein with decline in episodic memory, but the protein was associated with faster rates of decline in processing speed (mean [SE] change, -0.014 [0.005]; P?=?.008) and visuospatial abilities (mean [SE] change, -0.013 [0.005]; P?=?.006). We did not observe protein association with paired helical filament tau tangle density. The protein was associated with amyloid angiopathy (odds ratio, 1.38 [95% CI, 1.15-1.67]; P?

SUBMITTER: Yu L

PROVIDER: S-EPMC6583061 | biostudies-literature | 2019 Jul

REPOSITORIES: biostudies-literature

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Association of Cortical β-Amyloid Protein in the Absence of Insoluble Deposits With Alzheimer Disease.

Yu Lei L Petyuk Vladislav A VA Tasaki Shinya S Boyle Patricia A PA Gaiteri Chris C Schneider Julie A JA De Jager Philip L PL Bennett David A DA

JAMA neurology 20190701 7

<h4>Importance</h4>β-Amyloid deposits are a pathologic hallmark of Alzheimer disease (AD). However, the extent to which cortical β-amyloid protein in the absence of insoluble deposits is associated with classic features of AD appear to be unknown.<h4>Objective</h4>To examine the associations of cortical β-amyloid protein in the absence of insoluble deposits with cognitive decline, neurofibrillary tangles, other age-associated neuropathologic conditions, and APOE.<h4>Design, setting, and particip ...[more]

PMID: 31009033

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Project description:Background and objectivesThere is considerable heterogeneity in the association between increasing β-amyloid (Aβ) pathology and early cognitive dysfunction in preclinical Alzheimer disease (AD). At this stage, some individuals show no signs of cognitive dysfunction, while others show clear signs of decline. The factors explaining this heterogeneity are particularly important for understanding progression in AD but remain largely unknown. In this study, we examined an array of genetic variants that may influence the relationships among Aβ, brain structure, and cognitive performance in 2 large cohorts.MethodsIn 2,953 cognitively unimpaired participants from the Anti-Amyloid Treatment in Asymptomatic Alzheimer disease (A4) study, interactions between genetic variants and 18F-Florbetapir PET standardized uptake value ratio (SUVR) to predict the Preclinical Alzheimer Cognitive Composite (PACC) were assessed. Genetic variants identified in the A4 study were evaluated in the Alzheimer Disease Neuroimaging Initiative (ADNI, N = 527) for their association with longitudinal cognition and brain atrophy in both cognitively unimpaired participants and those with mild cognitive impairment.ResultsIn the A4 study, 4 genetic variants significantly moderated the association between Aβ load and cognition. Minor alleles of 3 variants were associated with additional decreases in PACC scores with increasing Aβ SUVR (rs78021285, β = -2.29, SE = 0.40, p FDR = 0.02, nearest gene ARPP21; rs71567499, β = -2.16, SE = 0.38, p FDR = 0.02, nearest gene PPARD; and rs10974405, β = -1.68, SE = 0.29, p FDR = 0.02, nearest gene GLIS3). The minor allele of rs7825645 was associated with less decrease in PACC scores with increasing Aβ SUVR (β = 0.71, SE = 0.13, p FDR = 0.04, nearest gene FGF20). The genetic variant rs76366637, in linkage disequilibrium with rs78021285, was available in both the A4 and ADNI. In the A4, rs76366637 was strongly associated with reduced PACC scores with increasing Aβ SUVR (β = -1.01, SE = 0.21, t = -4.90, p < 0.001). In the ADNI, rs76366637 was associated with accelerated cognitive decline (χ2 = 15.3, p = 0.004) and atrophy over time (χ2 = 26.8, p < 0.001), with increasing Aβ SUVR.DiscussionPatterns of increased cognitive dysfunction and accelerated atrophy due to specific genetic variation may explain some of the heterogeneity in cognition in preclinical and prodromal AD. The genetic variant near ARPP21 associated with lower cognitive scores in the A4 and accelerated cognitive decline and brain atrophy in the ADNI may help to identify those at the highest risk of accelerated progression of AD.

Dataset Information

Association of Cortical ?-Amyloid Protein in the Absence of Insoluble Deposits With Alzheimer Disease.

Publications

Association of Cortical β-Amyloid Protein in the Absence of Insoluble Deposits With Alzheimer Disease.

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