Person:

Blacker, Deborah

Background: Alzheimer's disease is a common debilitating dementia with known heritability, for which 20 late onset susceptibility loci have been identified, but more remain to be discovered. This study sought to identify new susceptibility genes, using an alternative gene-wide analytical approach which tests for patterns of association within genes, in the powerful genome-wide association dataset of the International Genomics of Alzheimer's Project Consortium, comprising over 7 m genotypes from 25,580 Alzheimer's cases and 48,466 controls. Principal Findings In addition to earlier reported genes, we detected genome-wide significant loci on chromosomes 8 (TP53INP1, p = 1.4×10−6) and 14 (IGHV1-67 p = 7.9×10−8) which indexed novel susceptibility loci. Significance The additional genes identified in this study, have an array of functions previously implicated in Alzheimer's disease, including aspects of energy metabolism, protein degradation and the immune system and add further weight to these pathways as potential therapeutic targets in Alzheimer's disease.

Background: With the onset of prevention trials for individuals at high risk for Alzheimer disease, there is increasing need for accurate risk prediction to inform study design and enrollment, but available risk estimates are limited. We developed risk estimates for the incidence of mild cognitive impairment (MCI) or dementia among cognitively unimpaired individuals by APOE-e4 dose for the genetic disclosure process of the Alzheimer’s Prevention Initiative Generation Study, a prevention trial in cognitively unimpaired APOE-e4/e4 homozygote individuals. Methods and findings We included cognitively unimpaired individuals aged 60–75 y, consistent with Generation Study eligibility criteria, from the National Alzheimer’s Coordinating Center (NACC) (n = 5,073, 158 APOE-e4/e4), the Rotterdam Study (n = 6,399, 156 APOE-e4/e4), the Framingham Heart Study (n = 4,078, 67 APOE-e4/e4), and the Sacramento Area Latino Study on Aging (SALSA) (n = 1,294, 11 APOE-e4/e4). We computed stratified cumulative incidence curves by age (60–64, 65–69, 70–75 y) and APOE-e4 dose, adjusting for the competing risk of mortality, and determined risk of MCI and/or dementia by genotype and baseline age. We also used subdistribution hazard regression to model relative hazard based on age, APOE genotype, sex, education, family history of dementia, vascular risk, subjective memory concerns, and baseline cognitive performance. The four cohorts varied considerably in age, education, ethnicity/race, and APOE-e4 allele frequency. Overall, cumulative incidence was uniformly higher in NACC than in the population-based cohorts. Among APOE-e4/e4 individuals, 5-y cumulative incidence was as follows: in the 60–64-y age stratum, it ranged from 0% to 5.88% in the three population-based cohorts versus 23.06% in NACC; in the 65–69-y age stratum, from 9.42% to 10.39% versus 34.62%; and in the 70–75-y age stratum, from 18.64% to 33.33% versus 38.34%. Five-year incidence of dementia was negligible except for APOE-e4/e4 individuals and those over 70 y. Lifetime incidence (to age 80–85 y) of MCI or dementia for the APOE-e4/e4 individuals in the long-term Framingham and Rotterdam cohorts was 34.69%–38.45% at age 60–64 y, 30.76%–40.26% at 65–69 y, and 33.3%–35.17% at 70–75 y. Confidence limits for these estimates are often wide, particularly for APOE-e4/e4 individuals and for the dementia outcome at 5 y. In regression models, APOE-e4 dose and age both consistently increased risk, as did lower education, subjective memory concerns, poorer baseline cognitive performance, and family history of dementia. We discuss several limitations of the study, including the small numbers of APOE-e4/e4 individuals, missing data and differential dropout, limited ethnic and racial diversity, and differences in definitions of exposure and outcome variables. Conclusions: Estimates of the absolute risk of MCI or dementia, particularly over short time intervals, are sensitive to sampling and a variety of methodological factors. Nonetheless, such estimates were fairly consistent across the population-based cohorts, and lower than those from a convenience cohort and those estimated in prior studies—with implications for informed consent and design for clinical trials targeting high-risk individuals.

Background: Hypertension is the strongest modifiable risk factor for subcortical ischemic changes and is also a risk factor for Alzheimer’s dementia. We used neuroimaging to investigate the pathological basis of early cognitive symptoms in patients with hypertension. Methods: In this cross-sectional cohort study 67 patients age >60 years with hypertension and Clinical Dementia Rating scale score of 0.5 without dementia, and without history of symptomatic stroke, underwent MRI for measurement of subcortical vascular changes and positron emission tomography (PET) scan with Pittsburgh Compound B (PiB-PET) to detect beta-amyloid deposition. These imaging measures were related to neuropsychological tests of memory, executive function and processing speed. Results: Mean age was 75.0 (standard deviation, SD, 7.3). Mean neuropsychological Z scores were: episodic memory -0.63 (SD 1.23), executive function -0.40 (SD 1.10), processing speed -0.24 (SD 0.88); 22 of the 67 subjects met criteria for mild cognitive impairment (MCI) and the remaining 45 subjects had subjective cognitive concerns only. In multivariable models adjusting for age and years of education, each 0.1 unit increase in mean cortical PiB-PET binding was associated with 0.14 lower mean Z score for episodic memory (95% CI -0.28 to -0.01). This means that for every 0.1 unit increase in mean cortical PiB-PET, episodic memory was 0.14 standard deviations lower. White matter hyperintensity volume, silent brain infarcts and microbleeds were not associated with neuropsychological test scores. Conclusions: Episodic memory was prominently affected in hypertensive participants with MCI or subjective cognitive concerns, and was associated with PiB-PET binding. This suggests a prominent role for Alzheimer pathology in cognitive impairment even in hypertensive participants at elevated risk for vascular cognitive impairment.