Christiane Reitz

BACKGROUND: The prevalence of Alzheimer disease (AD) is increasing in the elderly, and vascular risk factors may increase its risk. OBJECTIVE: To explore the association of the aggregation of vascular risk factors with AD. METHODS: The authors followed 1,138 individuals without dementia at baseline (mean age 76.2) for a mean of 5.5 years. The presence of vascular risk factors was related to incident possible and probable AD. RESULTS: Four risk factors (diabetes, hypertension, heart disease, and current smoking) were associated with a higher risk of AD (p < 0.10) when analyzed individually. The risk of AD increased with the number of risk factors (diabetes + hypertension + heart disease + current smoking). The adjusted hazards ratio of probable AD for the presence of three or more risk factors was 3.4 (95% CI: 1.8, 6.3; p for trend < 0.0001) compared with no risk factors. Diabetes and current smoking were the strongest risk factors in isolation or in clusters, but hypertension and heart disease were also related to a higher risk of AD when clustered with diabetes, smoking, or each other. CONCLUSIONS: The risk of Alzheimer disease (AD) increased with the number of vascular risk factors. Diabetes and current smoking were the strongest risk factors, but clusters including hypertension and heart disease also increased the risk of AD. These associations are unlikely to be explained by misclassification of the outcome, given strong associations when only probable AD is considered.

BACKGROUND: Type 2 diabetes mellitus is an important risk factor for Alzheimer disease and is more prevalent in elderly minority persons compared with non-Hispanic white persons. OBJECTIVE: To determine whether diabetes is related to a higher risk of mild cognitive impairment (MCI), a transitional stage between normal cognition and Alzheimer disease, in a multiethnic cohort with a high prevalence of diabetes. DESIGN: Longitudinal cohort study. SETTING: Northern Manhattan in New York, NY. PARTICIPANTS: We studied persons without prevalent MCI or dementia at baseline and with at least 1 follow-up interval. Of 1772 participants with a complete neuropsychological evaluation, 339 (19.1%) were excluded because of prevalent dementia, 304 were excluded because of prevalent MCI (17.2%), and 211 were excluded because of loss to follow-up (11.9%), resulting in a final sample of 918 participants for longitudinal analyses. MAIN OUTCOME MEASURES: We related diabetes defined by self-report to incident all-cause MCI, amnestic MCI, and nonamnestic MCI. We conducted multivariate analyses with proportional hazards regression adjusting for age, sex, years of education, ethnic group, apolipoprotein E (APOE) epsilon4 allele, hypertension, low-density lipoprotein level, current smoking, heart disease, and stroke. RESULTS: A total of 334 persons had incident MCI, 160 (47.9%) had amnestic MCI, and 174 (52.1%) had nonamnestic MCI. Diabetes was related to a significantly higher risk of all-cause MCI and amnestic MCI after adjustment for all covariates. Diabetes was also related to a higher risk of nonamnestic MCI, but this association was appreciably attenuated after adjustment for socioeconomic variables and vascular risk factors. The risk of MCI attributable to diabetes was 8.8% for the whole sample and was higher for African American persons (8.4%) and Hispanic persons (11.0%) compared with non-Hispanic white persons (4.6%), reflecting the higher prevalence of diabetes in minority populations in the United States. CONCLUSION: Diabetes is related to a higher risk of amnestic MCI in a population with a high prevalence of this disorder.

IMPORTANCE: Genetic variants associated with susceptibility to late-onset Alzheimer disease are known for individuals of European ancestry, but whether the same or different variants account for the genetic risk of Alzheimer disease in African American individuals is unknown. Identification of disease-associated variants helps identify targets for genetic testing, prevention, and treatment. OBJECTIVE: To identify genetic loci associated with late-onset Alzheimer disease in African Americans. DESIGN, SETTING, AND PARTICIPANTS: The Alzheimer Disease Genetics Consortium (ADGC) assembled multiple data sets representing a total of 5896 African Americans (1968 case participants, 3928 control participants) 60 years or older that were collected between 1989 and 2011 at multiple sites. The association of Alzheimer disease with genotyped and imputed single-nucleotide polymorphisms (SNPs) was assessed in case-control and in family-based data sets. Results from individual data sets were combined to perform an inverse variance-weighted meta-analysis, first with genome-wide analyses and subsequently with gene-based tests for previously reported loci. MAIN OUTCOMES AND MEASURES: Presence of Alzheimer disease according to standardized criteria. RESULTS: Genome-wide significance in fully adjusted models (sex, age, APOE genotype, population stratification) was observed for a SNP in ABCA7 (rs115550680, allele = G; frequency, 0.09 cases and 0.06 controls; odds ratio [OR], 1.79 [95% CI, 1.47-2.12]; P = 2.2 × 10(-9)), which is in linkage disequilibrium with SNPs previously associated with Alzheimer disease in Europeans (0.8 < D' < 0.9). The effect size for the SNP in ABCA7 was comparable with that of the APOE ϵ4-determining SNP rs429358 (allele = C; frequency, 0.30 cases and 0.18 controls; OR, 2.31 [95% CI, 2.19-2.42]; P = 5.5 × 10(-47)). Several loci previously associated with Alzheimer disease but not reaching significance in genome-wide analyses were replicated in gene-based analyses accounting for linkage disequilibrium between markers and correcting for number of tests performed per gene (CR1, BIN1, EPHA1, CD33; 0.0005 < empirical P < .001). CONCLUSIONS AND RELEVANCE: In this meta-analysis of data from African American participants, Alzheimer disease was significantly associated with variants in ABCA7 and with other genes that have been associated with Alzheimer disease in individuals of European ancestry. Replication and functional validation of this finding is needed before this information is used in clinical settings.