Two novel loci, COBL and SLC10A2, for Alzheimer's disease in African Americans.

INTRODUCTION: African Americans' (AAs) late-onset Alzheimer's disease (LOAD) genetic risk profile is incompletely understood. Including clinical covariates in genetic analyses using informed conditioning might improve study power. METHODS: We conducted a genome-wide association study (GWAS) in AAs employing informed conditioning in 1825 LOAD cases and 3784 cognitively normal controls. We derived a posterior liability conditioned on age, sex, diabetes status, current smoking status, educational attainment, and affection status, with parameters informed by external prevalence information. We assessed association between the posterior liability and a genome-wide set of single-nucleotide polymorphisms (SNPs), controlling for APOE and ABCA7, identified previously in a LOAD GWAS of AAs. RESULTS: Two SNPs at novel loci, rs112404845 (P = 3.8 × 10-8), upstream of COBL, and rs16961023 (P = 4.6 × 10-8), downstream of SLC10A2, obtained genome-wide significant evidence of association with the posterior liability. DISCUSSION: An informed conditioning approach can detect LOAD genetic associations in AAs not identified by traditional GWAS.

Genetic Influences on Plasma Homocysteine Levels in African Americans and Yoruba Nigerians.

Plasma homocysteine, a metabolite involved in key cellular methylation processes seems to be implicated in cognitive functions and cardiovascular health with its high levels representing a potential modifiable risk factor for Alzheimer's disease (AD) and other dementias. A better understanding of the genetic factors regulating homocysteine levels, particularly in non-white populations, may help in risk stratification analyses of existing clinical trials and may point to novel targets for homocysteine-lowering therapy. To identify genetic influences on plasma homocysteine levels in individuals with African ancestry, we performed a targeted gene and pathway-based analysis using a priori biological information and then to identify new association performed a genome-wide association study. All analyses used combined data from the African American and Yoruba cohorts from the Indianapolis-Ibadan Dementia Project. Targeted analyses demonstrated significant associations of homocysteine and variants within the CBS (Cystathionine beta-Synthase) gene. We identified a novel genome-wide significant association of the AD risk gene CD2AP (CD2-associated protein) with plasma homocysteine levels in both cohorts. Minor allele (T) carriers of identified CD2AP variant (rs6940729) exhibited decreased homocysteine level. Pathway enrichment analysis identified several interesting pathways including the GABA receptor activation pathway. This is noteworthy given the known antagonistic effect of homocysteine on GABA receptors. These findings identify several new targets warranting further investigation in relation to the role of homocysteine in neurodegeneration.

Optimal blood pressure for cognitive function: findings from an elderly African-American cohort study.

OBJECTIVES: To report the results from a prospective cohort study on the association between blood pressure (BP) and cognitive function in elderly African Americans. DESIGN: Prospective cohort study conducted from 1997 to 2009. SETTING: Community-based study in Indianapolis. PARTICIPANTS: African Americans aged 65 years or older (N = 3,145). MEASUREMENTS: At each assessment, participant cognitive function was measured using the Community Screening Interview for Dementia. Other measurements included BP, height, weight, education level, antihypertensive medication use, alcohol use, smoking, and history of chronic medical conditions. RESULTS: Longitudinal assessments (n = 5,995) contributed by 2,721 participants with complete independent variables were analyzed using a semiparametric mixed-effects model. Systolic BP (SBP) of approximately 135 mmHg and diastolic BP (DBP) of approximately 80 mmHg were associated with optimal cognitive function after adjusting for other variables (P = .02). Weight loss with body mass index < 30.0 kg/m(2) was significantly related to poorer cognitive performance (P < .001). Older age at first assessment, lower education level; smoking; and history of depression, stroke, and diabetes mellitus were related to worse cognitive function; taking antihypertensive medication and drinking alcohol were associated with better cognitive function. CONCLUSION: High and low BP were associated with poorer cognitive performance. A joint optimal region of SBP and DBP for cognitive function has been identified, which may provide useful clinical information on optimal BP control in cognitive health and lead to better quality of life for elderly adults.

Trends in the incidence and prevalence of Alzheimer's disease, dementia, and cognitive impairment in the United States.

Declines in heart disease and stroke mortality rates are conventionally attributed to reductions in cigarette smoking, recognition and treatment of hypertension and diabetes, effective medications to improve serum lipid levels and to reduce clot formation, and general lifestyle improvements. Recent evidence implicates these and other cerebrovascular factors in the development of a substantial proportion of dementia cases. Analyses were undertaken to determine whether corresponding declines in age-specific prevalence and incidence rates for dementia and cognitive impairment have occurred in recent years. Data spanning 1 or 2 decades were examined from community-based epidemiological studies in Minnesota, Illinois, and Indiana, and from the Health and Retirement Study, which is a national survey. Although some decline was observed in the Minnesota cohort, no statistically significant trends were apparent in the community studies. A significant reduction in cognitive impairment measured by neuropsychological testing was identified in the national survey. Cautious optimism appears justified.

Weight loss and incident dementia in elderly Yoruba Nigerians: a 10-year follow-up study.

BACKGROUND: The relationship between weight and dementia risk has not been investigated in populations with relatively low body mass index (BMI) such as the Yoruba. This study set out to achieve this objective using a prospective observational design. METHODS: The setting was Idikan Ward in Ibadan City, Nigeria. The participants were all aged 65 years or older and were enrolled in the Indianapolis-Ibadan Dementia Project. Repeated cognitive assessments and clinical evaluations were conducted to identify participants with dementia or MCI during 10 years of follow-up (mean duration: 5.97 years). BMI measures, information on alcohol, smoking history, cancer, hypertension, diabetes, heart attack, stroke and depression were collected at each follow-up evaluation. Mixed effect models adjusted for covariates were used to examine the differences in BMI among participants who developed dementia or MCI and those who remained cognitively normal during the follow-up. RESULTS: This analysis included 1559 participants who had no dementia at their first BMI measurements. There were 136 subjects with incident dementia, 255 with MCI and 1168 with normal cognition by the end of the study. The mean BMI at baseline was higher for female participants (22.31; SD = 4.39) than for male (21.09; SD = 3.61, p < 0.001). A significantly greater decline in BMI was found in those with either incident dementia (p < 0.001) or incident MCI (p < 0.001) compared to normal subjects. CONCLUSION: Decline in BMI is associated with incident MCI and dementia in elderly Yoruba. This observation calls for close monitoring of weight loss in elderly individuals which may indicate future cognitive impairment for timely detection and tailored interventions.

Prevalence rates for dementia and Alzheimer's disease in African Americans: 1992 versus 2001.

BACKGROUND: This study compares age-specific and overall prevalence rates for dementia and Alzheimer's disease (AD) in two nonoverlapping, population-based cohorts of elderly African Americans in Indianapolis in 2001 and 1992. METHODS: We used a two-stage design. The first stage involves the Community Screening Interview for Dementia (CSI-D). The CSI-D scores are grouped into good, intermediate, and poor performance before selection for clinical assessment. Diagnoses were performed using standard criteria in a consensus diagnosis conference; clinicians were blind to performance groups. In 1992, interviewers visited randomly sampled addresses to enroll self-identified African Americans aged > or =65 years. Of 2582 eligible, 2212 enrolled (9.6% refused, and 4.7% were too sick). In 2001, Medicare rolls were used for African Americans aged >70 years. Of 4260 eligible, 1892 (44%) enrolled, 1999 (47%) refused, and the remainder did not participate for other reasons. RESULTS: The overall age-adjusted prevalence rate for dementia at age > or =70 years in 2001 was 7.45% (95 confidence interval [CI], 4.27-10.64), and in the 1992 cohort, this prevalence rate was 6.75% (95% CI, 5.77-7.74). The overall age-adjusted prevalence rate at age > or =70 years for AD in the 2001 cohort was 6.77% (95% CI, 3.65-9.90), and for the 1992 cohort, it was 5.47% (95% CI, 4.51-6.42). Rates for dementia and AD were not significantly different in the two cohorts (dementia, P = .3534; AD, P = .2649). CONCLUSIONS: We found no differences in the prevalence rates of dementia and AD between 1992 and 2001, despite significant differences in medical history and medical treatment within these population-based cohorts of African American elderly.

Correlates of depressive symptoms in rural elderly Chinese.

OBJECTIVE: Late life depression has been studied in many populations around the world. However, findings on risk factors for late life depression have remained inconsistent. METHODS: A cross-sectional survey of 1737 rural Chinese age 65 and over from two provinces in China was conducted assessing cognitive functions using various cognitive instruments and collecting information on demographic characteristics and medical history. Depressive symptoms were assessed using the Geriatric Depression Scale (GDS). Analysis of covariance and logistic regression models were used to identify factors associated with the continuous GDS score, mild or severe depression. RESULTS: In this cohort, 26.5% (95% CI: 24.4-28.6%) met the criteria for mild depression and 4.3% (95% CI: 3.4-5.4%) for severely depression. Living alone, history of heart attack, head injury, and fracture were associated with higher depressive symptoms. Alcohol consumption and higher cognitive function were associated with lower depressive symptoms. Living alone, not attended school, history of head injury, fracture, and low cognitive function were associated with increased probability of mild depression. Living alone, history of stroke or heart attack, and low cognitive function were associated with severe depression. CONCLUSIONS: Depression, particularly mild depression, is common in rural elderly Chinese. Among a number of factors identified in this cohort as being significantly associated with depressive symptoms, living alone and lower cognitive function were the most consistent factors associated with depressive symptoms, mild and severe depression. History of stroke, heart attack, and fracture were also risk factors for depressive symptoms.

APOE epsilon4 is not associated with Alzheimer's disease in elderly Nigerians.

Since 1992, research teams from Indiana University and the University of Ibadan have been collecting and comparing data from two diverse, elderly populations to identify risk factors for dementia and Alzheimer's disease. Apolipoprotein E (APOE) was genotyped in 2,245 Nigerian samples. Of these, 830 had a diagnosis: 459 were normal, and 140 had dementia including 123 diagnosed with Alzheimer's disease. In contrast with other populations, the APOE epsilon4 allele was not significantly associated with Alzheimer's disease or dementia. This lack of association in the Yoruba might reflect genetic variation, environmental factors, as well as genetic/environmental interactions.

Apolipoprotein E and mortality in African-Americans and Yoruba.

The literature on the association between apolipoprotein E (ApoE) and mortality across ethnic and age groups has been inconsistent. No studies have looked at this association in developing countries. We used data from the Indianapolis-Ibadan Dementia study to examine this association between APOE and mortality in 354 African-Americans from Indianapolis and 968 Yoruba from Ibadan, Nigeria. Participants were followed up to 9.5 years for Indianapolis and 8.7 years for Ibadan. Subjects from both sites were divided into 2 groups based upon age at baseline. A Cox proportional hazards regression model adjusting for age at baseline, education, hypertension, smoking history and gender in addition to time-dependent covariates of cancer, diabetes, heart disease, stroke, and dementia was fit for each cohort and age group. Having ApoE epsilon4 alleles significantly increased mortality risk in Indianapolis subjects under age 75 (hazard ratio: 2.00; 95% CI: 1.19-3.35; p = 0.0089). No association was found in Indianapolis subjects 75 and older (hazard ratio: 0.71; 95% CI: 0.45-1.10; p = 0.1238), Ibadan subjects under 75 (hazard ratio: 1.04; 95% CI: 0.78 to 1.40; p = 0.7782), or Ibadan subjects over 75 (hazard ratio: 1.21; 95% CI: 0.83 to 1.75; p = 0.3274).