Cumulative Use of Proton Pump Inhibitors and Risk of Dementia: The Atherosclerosis Risk in Communities Study.

BACKGROUND AND OBJECTIVES: Studies on the association between proton pump inhibitor (PPI) use and dementia report mixed results and do not examine the impact of cumulative PPI use. We evaluated the associations between current and cumulative PPI use and risk of incident dementia in the Atherosclerosis Risk in Communities (ARIC) Study. METHODS: These analyses used participants from a community-based cohort (ARIC) from the time of enrollment (1987-1989) through 2017. PPI use was assessed through visual medication inventory at clinic visits 1 (1987-1989) to 5 (2011-2013) and reported annually in study phone calls (2006-2011). This study uses ARIC visit 5 as baseline because this was the first visit in which PPI use was common. PPI use was examined 2 ways: current use at visit 5 and duration of use before visit 5 (from visit 1 to 2011, exposure categories: 0 day, 1 day-2.8 years, 2.8-4.4 years, >4.4 years). The outcome was incident dementia after visit 5. Cox proportional hazard models were used, adjusted for demographics, comorbid conditions, and other medication use. RESULTS: A total of 5,712 dementia-free participants at visit 5 (mean age 75.4 ± 5.1 years; 22% Black race; 58% female) were included in our analysis. The median follow-up was 5.5 years. The minimum cumulative PPI use was 112 days, and the maximum use was 20.3 years. There were 585 cases of incident dementia identified during follow-up. Participants using PPIs at visit 5 were not at a significantly higher risk of developing dementia during subsequent follow-up than those not using PPIs (hazard ratio (HR): 1.1 [95% confidence interval (CI) 0.9-1.3]). Those who used PPIs for >4.4 cumulative years before visit 5 were at 33% higher risk of developing dementia during follow-up (HR: 1.3 [95% CI 1.0-1.8]) than those reporting no use. Associations were not significant for lesser durations of PPI use. DISCUSSION: Future studies are needed to understand possible pathways between cumulative PPI use and the development of dementia. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that the use of prescribed PPIs for >4.4 years by individuals aged 45 years and older is associated with a higher incidence of newly diagnosed dementia.

Association of Plasma Aß42/Aß40 Ratio and Late-Onset Epilepsy: Results From the Atherosclerosis Risk in Communities Study.

BACKGROUND AND OBJECTIVES: The objective of this study was to determine the relationship between plasma ß-amyloid (Aß), specifically the ratio of 2 Aß peptides (the Aß42/Aß40 ratio, which correlates with increased accumulation of Aß in the CNS), and late-onset epilepsy (LOE). METHODS: We used Medicare fee-for-service claims codes from 1991 to 2018 to identify cases of LOE among 1,424 Black and White men and women enrolled in the Atherosclerosis Risk in Communities (ARIC) study cohort. The Aß42/Aß40 ratio was calculated from plasma samples collected from ARIC participants in 1993-1995 (age 50-71 years) and 2011-2013 (age 67-90 years). We used survival analysis accounting for the competing risk of death to determine the relationship between late-life plasma Aß42/Aß40, and its change from midlife to late life, and the subsequent development of epilepsy. We adjusted for demographics, the apolipoprotein e4 genotype, and comorbidities, including stroke, dementia, and head injury. A low plasma ratio of 2 Aß peptides, the Aß42/Aß40 ratio, correlates with low CSF Aß42/Aß40 and with increased accumulation of Aß in the CNS. RESULTS: Decrease in plasma Aß42/Aß40 ratio from midlife to late life, but not an isolated measurement of Aß42/Aß40, was associated with development of epilepsy in later life. For every 50% reduction in Aß42/Aß40, there was a 2-fold increase in risk of epilepsy (adjusted subhazard ratio 2.30, 95% CI 1.27-4.17). DISCUSSION: A reduction in plasma Aß42/Aß40 is associated with an increased risk of subsequent epilepsy. Our observations provide a further validation of the link between Aß, hyperexcitable states, and LOE.

Genetic Risk, Midlife Life's Simple 7, and Incident Dementia in the Atherosclerosis Risk in Communities Study.

BACKGROUND: and ObjectivesHigher scores in Life's Simple 7 (LS7), a metric for cardiovascular and brain health, have been associated with lower risk of dementia. It is uncertain whether this association holds among those with high genetic risk of dementia. Our objective is to evaluate the extent that LS7 may offset dementia risk across the range of genetic risk.Methods PARTICIPANTS: in the Atherosclerosis Risk in Communities (ARIC) Study were followed from 1987-89 to 2019. We derived midlife LS7 scores and generated genetic risk scores (GRS) using genome-wide summary statistics of Alzheimer's Disease, which have been used to study the genetic risk for dementia. Incident dementia was ascertained based on the criteria of the National Institute on Aging-Alzheimer's Association workgroups and Diagnostic and Statistical Manual of Mental Disorders. The associations of the GRS and LS7 with incident dementia were evaluated using Cox regression. RESULTS: This study included 8,823 European Americans (EA) and 2,738 African Americans (AA) (mean age at baseline: 54). We observed 1,603 cases of dementia among EA and 631 among AA (median follow-up: 26.2 years). Higher GRS were associated with higher risk of dementia (EA, hazard ratio [HR] per standard deviation [SD] 1.44, 95% confidence interval [CI]: 1.37, 1.51; AA, HR 1.26, 95% CI: 1.16, 1.36). Among EA, higher LS7 scores were consistently associated with lower risk of dementia across quintiles of GRS, including the highest quintile (HR per point 0.91, 95% CI: 0.87, 0.96). Among AA, the associations between LS7 and incident dementia within stratum of GRS had the same direction as among EA, though wide confidence intervals and smaller sample sizes limited reliable inferences. CONCLUSIONS: Across strata of GRS, higher midlife LS7 scores were associated with lower risk of dementia. Larger sample sizes from diverse populations are needed to obtain more reliable estimates of the effects of modifiable health factors on dementia risk within genetic risk stratum in each ancestry group.

Plasma phospholipid very-long-chain SFAs in midlife and 20-year cognitive change in the Atherosclerosis Risk in Communities (ARIC): a cohort study.

BACKGROUND: Very-long-chain SFAs (VLSFAs) have recently gained considerable attention as having beneficial effects on health and aging. OBJECTIVES: The objective of this study was to assess the associations of plasma phospholipid VLSFAs [arachidic acid (20:0), behenic acid (22:0), tricosanoic acid (23:0), and lignoceric acid (24:0)] with 20-y cognitive decline in the Atherosclerosis Risk in Communities (ARIC) participants. Furthermore, this study compared the associations of plasma phospholipid VLSFAs with 5 common groups of fatty acids [i.e., total SFAs, total MUFAs, total ω-3 (n-3) PUFAs, total marine-derived ω-3 PUFAs, total ω-6 PUFAs]. METHODS: This study used a cohort study design of 3229 ARIC participants enrolled at the Minnesota field center. Fatty acids were measured at visit 1 (1987-1989); and cognition was assessed at visits 2 (1990-1992), 4 (1996-1998), and 5 (2011-2013) using 3 tests: the Delayed Word Recall Test (DWRT), the Digit-Symbol Substitution Test (DSST), and the Word Fluency Test (WFT). RESULTS: Higher proportions of plasma phospholipid total VLSFAs and each individual VLSFA were associated with less decline in WFT, a test of verbal fluency. For example, 1 SD higher in total VLSFAs at baseline was associated with 0.057 SD (95% CI: 0.018, 0.096, P = 0.004) less cognitive decline over 20 y as measured by WFT score. None of the 5 common fatty acid groups were associated with change in WFT, but a higher proportion of plasma phospholipid total MUFAs was associated with greater decline in DWRT; higher total ω-6 PUFAs with less decline in DWRT; and higher total ω-3 and total marine-derived ω-3 PUFAs with less decline in DSST. CONCLUSIONS: This study suggests that higher proportions of plasma phospholipid VLSFAs in midlife may be associated with less 20-y cognitive decline.

Factors Related to Differences in Retention among African American and White Participants in the Atherosclerosis Risk in Communities Study (ARIC) Prospective Cohort: 1987-2013.

BACKGROUND: Few studies have addressed retention of minorities, particularly African Americans, in longitudinal research. Our aim was to determine whether there was differential retention between African Americans and Whites in the ARIC cohort and identify cardiovascular disease (CVD) risk factors and indicators of socioeconomic status (SES) associated with these retention differences. METHODS: 15,688 participants, 27% African American and 73% White, were included from baseline, 1987-1989, and classified as having died, lost or withdrew from study contact, or remained active in study calls through 2013. Life tables were created illustrating retention patterns stratified by race, from baseline through visit 5, 2011-2013. Prevalence tables stratified by race, participation status, and center were created to examine CVD risk factors and SES at baseline and visit 5. RESULTS: 54% of African Americans compared with 62% of Whites were still in follow-up by 2013. This difference was due to an 8% higher cumulative incidence of death among African Americans. Those who remained in follow-up had the lowest baseline CVD risk factors and better SES, followed by those who were lost/withdrew, then those who died. Whites had lower levels of most CVD risk factors and higher SES than African Americans overall at baseline and visit 5; though, the magnitude of visit 5 differences was less. CONCLUSIONS: In the ARIC cohort, retention differed among African Americans and Whites, but related more to mortality differences than dropping-out. Additional research is needed to better characterize the factors contributing to minority participants' recruitment and retention in longitudinal research.

Genome-wide association study of coronary heart disease and its risk factors in 8,090 African Americans: the NHLBI CARe Project.

Coronary heart disease (CHD) is the leading cause of mortality in African Americans. To identify common genetic polymorphisms associated with CHD and its risk factors (LDL- and HDL-cholesterol (LDL-C and HDL-C), hypertension, smoking, and type-2 diabetes) in individuals of African ancestry, we performed a genome-wide association study (GWAS) in 8,090 African Americans from five population-based cohorts. We replicated 17 loci previously associated with CHD or its risk factors in Caucasians. For five of these regions (CHD: CDKN2A/CDKN2B; HDL-C: FADS1-3, PLTP, LPL, and ABCA1), we could leverage the distinct linkage disequilibrium (LD) patterns in African Americans to identify DNA polymorphisms more strongly associated with the phenotypes than the previously reported index SNPs found in Caucasian populations. We also developed a new approach for association testing in admixed populations that uses allelic and local ancestry variation. Using this method, we discovered several loci that would have been missed using the basic allelic and global ancestry information only. Our conclusions suggest that no major loci uniquely explain the high prevalence of CHD in African Americans. Our project has developed resources and methods that address both admixture- and SNP-association to maximize power for genetic discovery in even larger African-American consortia.

Association between SLC2A9 transporter gene variants and uric acid phenotypes in African American and white families.

OBJECTIVES: SLC2A9 gene variants associate with serum uric acid in white populations, but little is known about African American populations. Since SLC2A9 is a transporter, gene variants may be expected to associate more closely with the fractional excretion of urate, a measure of renal tubular transport, than with serum uric acid, which is influenced by production and extrarenal clearance. METHODS: Genotypes of single nucleotide polymorphisms (SNPs) distributed across the SLC2A9 gene were obtained in the Genetic Epidemiology Network of Arteriopathy cohorts. The associations of SNPs with serum uric acid, fractional excretion of urate and urine urate-to-creatinine ratio were assessed with adjustments for age, sex, diuretic use, BMI, homocysteine and triglycerides. RESULTS: We identified SLC2A9 gene variants that were associated with serum uric acid in 1155 African American subjects (53 SNPs) and 1132 white subjects (63 SNPs). The most statistically significant SNPs in African American subjects (rs13113918) and white subjects (rs11723439) were in the latter half of the gene and explained 2.7 and 2.8% of the variation in serum uric acid, respectively. After adjustment for this SNP in African Americans, 0.9% of the variation in serum uric acid was explained by an SNP (rs1568318) in the first half of the gene. Unexpectedly, SLC2A9 gene variants had stronger associations with serum uric acid than with fractional excretion of urate. CONCLUSIONS: These findings support two different loci by which SLC2A9 variants affect uric acid levels in African Americans and suggest SLC2A9 variants affect serum uric acid level via renal and extrarenal clearance.