The rocky road of 55 years of change in the relationship of cardiovascular risk factors to cognition.

The mixed evidence that high levels of cardiovascular risk factors (CVRF) are associated with lower cognitive test scores of may be due to confounding of age across studies. We pooled and harmonized individual-level data (30,967 persons, age range 42-96y) from five prospective cohorts to examine the trajectories of betas estimating 1-year-age associations of a cognitive outcome (Digit Symbol Substitution Test; DSST) to five CVRF: systolic and e blood pressure, total cholesterol, fasting glucose and body mass index. Linear and quadratic piecewise regression models were fit to the trajectory patterns of these betas. The trajectories showed with each 1-year age increment, higher CVRF were associated with lower DSST, but associations attenuated toward zero as age increased. In addition, the pattern across age of each CVRF-DSST trajectory ranged from linear to non-liner. Without accounting for participant age in cohort comparisons, conclusions about the potential benefit on cognitive function of modifiable CVRF control will continue to be mixed and lead to delays in developing prevention programs.

Dynamics between psychological distress and body mass index throughout adult life; evidence from 3 large cohort studies.

BACKGROUND: Associations between body mass index (BMI) and psychological distress (PD) have been reported; however, few longitudinal studies have accounted for likely life-course differences in BMI and PD stability, consistency, and their interplay across time. METHODS: Via random intercepts cross-lagged panel models, we assessed the predictive effects (from BMI to PD or vice-versa) across the last two centuries in the Coronary Artery Risk Development in Young Adults [CARDIA, beginning in 1985-6] study using the Center for Epidemiological Studies-Depression Scale [CES-D], and in the National Child Development Study [NCDS, beginning in 1958] and British Cohort Study [BCS, beginning in 1970] using the Malaise Inventory [MI]), assessed at least 4 times in adult life. FINDINGS: In CARDIA (n = 4724), NCDS58 (n = 7149) and BCS70 (n = 5967), autoregressive effects were stronger for BMI than for PD, meaning that carry-over effects from one occasion to the next were larger for BMI than for PD. Small interindividual correlations between traits of higher BMI and higher PD were identified among females (rfemale<|0·2|) but not males (rmale<|0·03|) in CARDIA and NCDS. Cross-lagged effects were very weak or close to zero (standardized effects η<|0·1|). INTERPRETATION: In the United States, depressive symptoms and BMI were positively correlated at the trait level among females. In the United Kingdom, relationships between PD and BMI were inconsistent between generations, with effect sizes of unlikely clinical importance, indicating negligible dominance of an intraindividual effect of BMI on PD or vice versa.

Diffuse idiopathic skeletal hyperostosis in elderly Icelanders and its association with the metabolic syndrome: the AGES-Reykjavik Study.

Objective: To describe the prevalence of diffuse idiopathic skeletal hyperostosis (DISH) in a large population-based study of elderly Icelanders, with particular reference to weight-related factors and the metabolic syndrome.Method: The study population comprised 5321 participants aged 68-96 years (2276 males, mean ± sd age 76 ± 5 , and 3045 females, age 77 ± 6) from the AGES-Reykjavik Study. DISH diagnosis was based on computed tomography (CT) scans, and interpreted strictly by the Resnick criteria and additional suggestions for CT interpretation by Oudkerk et al. Radiology readings were taken by a radiology resident and sample readings by two experienced radiologists.Results: A diagnosis of DISH was made in 13.7% of males and 2.8% of females. There was no association with age, but a strong association was seen with the metabolic syndrome [odds ratio (OR) 2.12, 95% confidence interval (CI) 1.69-2.64, p = 3.9 × 10-11]. Among the components of the metabolic syndrome, the association with DISH was significant for the insulin resistance criterion (OR 1.66, 95% CI 1.32-2.01, p < 0.001) and the body mass index (BMI) criterion (OR 2.16, 95% CI 1.70-2.74, p < 0.001). Other weight-related variables (midlife BMI, weight, and abdominal circumference) showed similar associations.Conclusions: This study, which to our knowledge is the largest published study on the prevalence of DISH, shows an association with the metabolic syndrome, particularly with the insulin resistance and BMI criteria. This is analogous with previous reports linking DISH with metabolic causes. In this age category, we did not observe any increase in prevalence with age.

Characteristics of incidence hip fracture cases in older adults participating in the longitudinal AGES-Reykjavik study.

Poor physical function and body composition my partly predict the risk of falls leading to fracture regardless of bone mineral density. INTRODUCTION: To examine the relationship between body composition, physical function, and other markers of health with hip fractures in older community-dwelling Icelandic adults. METHODS: A prospective cohort of 4782 older adults from the AGES-Reykjavik study. Baseline recruitment took place between 2002 and 2006, and information on hip fractures occurring through 2012 was extracted from clinical records. Using multivariate regression analyses, baseline measures of bone health, physical function, and body composition were compared between those who later experienced hip fractures and to those who did not. Associations with the risk of fractures were quantified using Cox regression. RESULTS: Mean age was 76.3 years at baseline. After adjustment for age, regression showed that male hip fracture cases compared with non-cases had (mean (95% confidence interval)) significantly lower thigh muscle cross-sectional area - 5.6 cm2 (- 10.2, - 1.1), poorer leg strength - 28 N (- 49, - 7), and decreased physical function as measured by longer timed up and go test 1.1 s (0.5, 1.7). After adjustment for age, female cases had, compared with non-cases, lower body mass index - 1.5 kg/m2 (- 2.1, - 0.9), less lean mass - 1.6 kg (- 2.5, - 0.8), thigh muscle cross-sectional area - 4.4 cm2 (- 6.5, - 2.3), and worse leg strength - 16 N (- 25, - 6). These differences largely persisted after further adjustment for bone mineral density (BMD), suggesting that body composition may contribute to the risk of fracture independent of bone health. When examining the association between these same factors and hip fractures using Cox regression, the same conclusions were reached. CONCLUSIONS: After accounting for age and BMD, older adults who later experienced a hip fracture had poorer baseline measures of physical function and/or body composition, which may at least partly contribute to the risk of falls leading to fracture.

Correction to: Characteristics of incidence hip fracture cases in older adults participating in the longitudinal AGES-Reykjavik study.

The original version of this article, published on 18 august 2020 contained a mistake. An author's name was misspelled.

Lifestyle and 25-hydroxy-vitamin D among community-dwelling old adults with dementia, mild cognitive impairment, or normal cognitive function.

BACKGROUND: Several studies have indicated that older adults with cognitive impairment have a poorer lifestyle than their healthy peers including lower 25-hydroxy-vitamin D levels (25OHD). AIM: To investigate the associations between lifestyle and 25OHD depending on cognitive status among old adults. METHODS: Community-dwelling old adults (65-96 years) participated in this cross-sectional study based on the Age-Gene/Environment-Susceptibility-Reykjavik-Study. The analytical sample included 5162 subjects who were stratified by cognitive status, i.e., dementia (n = 307), mild cognitive impairment (MCI, n = 492), and normal cognitive status (NCS, n = 4363). Lifestyle variables were assessed and 25OHD was measured. The associations between lifestyle and 25OHD were calculated using linear models correcting for potential confounders. RESULTS: According to linear regression models, 25OHD was significantly lower in older people with dementia (53.8 ± 19.6 nmol/L) than in NCS participants (57.6 ± 17.7 nmol/L). Cod liver oil (7.1-9.2 nmol/L, P < 0.001) and dietary supplements (4.4-11.5 nmol/L, P < 0.001) were associated with higher 25OHD in all three groups. However, physical activity ≥ 3 h/week (2.82 nmol/L, P < 0.001), BMI < 30 kg/m2 (5.2 nmol/L, P < 0.001), non-smoking (4.8 nmol/L, P < 0.001), alcohol consumption (2.7 nmol/L, P < 0.001), and fatty fish consumption ≥ 3x/week (2.6 nmol/L, P < 0.001) were related to higher 25OHD in NCS only, but not in participants with dementia or MCI. DISCUSSION: Older people living in Iceland with dementia are at higher risk for 25OHD deficiency when compared to healthy individuals. Physical activity reported among participants with dementia, and MCI is low and is not significantly associated with 25OHD. CONCLUSIONS: Lifestyle factors among NCS participants are associated with 25OHD levels. Importantly, healthy lifestyle should be promoted among individuals with MCI and dementia.

Genome-wide meta-analysis of variant-by-diuretic interactions as modulators of lipid traits in persons of European and African ancestry.

Hypertension (HTN) is a significant risk factor for cardiovascular morbidity and mortality. Metabolic abnormalities, including adverse cholesterol and triglycerides (TG) profiles, are frequent comorbid findings with HTN and contribute to cardiovascular disease. Diuretics, which are used to treat HTN and heart failure, have been associated with worsening of fasting lipid concentrations. Genome-wide meta-analyses with 39,710 European-ancestry (EA) individuals and 9925 African-ancestry (AA) individuals were performed to identify genetic variants that modify the effect of loop or thiazide diuretic use on blood lipid concentrations. Both longitudinal and cross sectional data were used to compute cohort-specific interaction results, which were then combined through meta-analysis in each ancestry. These ancestry-specific results were further combined through trans-ancestry meta-analysis. Analysis of EA data identified two genome-wide significant (p < 5 × 10-8) loci with single nucleotide variant (SNV)-loop diuretic interaction on TG concentrations (including COL11A1). Analysis of AA data identified one genome-wide significant locus adjacent to BMP2 with SNV-loop diuretic interaction on TG concentrations. Trans-ancestry analysis strengthened evidence of association for SNV-loop diuretic interaction at two loci (KIAA1217 and BAALC). There were few significant SNV-thiazide diuretic interaction associations on TG concentrations and for either diuretic on cholesterol concentrations. Several promising loci were identified that may implicate biologic pathways that contribute to adverse metabolic side effects from diuretic therapy.

White Matter Lesion Penumbra Shows Abnormalities on Structural and Physiologic MRIs in the Coronary Artery Risk Development in Young Adults Cohort.

BACKGROUND AND PURPOSE: White matter lesions are 1 age-related manifestation of cerebrovascular disease, but subthreshold abnormalities have been identified in nonlesional WM. We hypothesized that structural and physiologic MR imaging findings of early cerebrovascular disease can be measured in middle-aged subjects in tissue adjacent to WM lesions, termed "penumbra." MATERIALS AND METHODS: WM lesions were defined using automated segmentation in 463 subjects, 43-56 years of age, from the Coronary Artery Risk Development in Young Adults (CARDIA) longitudinal observational cohort study. We described 0- to 2-mm and 2- to 4-mm-thick spatially defined penumbral WM tissue ROIs as rings surrounding WM lesions. The remaining WM was defined as distant normal-appearing WM. Mean signal intensities were measured for FLAIR, T1-, and T2-weighted images, and from fractional anisotropy, mean diffusivity, CBF, and vascular reactivity maps. Group comparisons were made using Kruskal-Wallis and pair-wise t tests. RESULTS: Lesion volumes averaged 0.738 ± 0.842 cm3 (range, 0.005-7.27 cm3). Mean signal intensity for FLAIR, T2, and mean diffusivity was increased, while T1, fractional anisotropy, and CBF were decreased in white matter lesions versus distant normal-appearing WM, with penumbral tissues showing graded intermediate values (corrected P < .001 for all group/parameter comparisons). Vascular reactivity was significantly elevated in white matter lesions and penumbral tissue compared with distant normal-appearing white matter (corrected P ≤ .001). CONCLUSIONS: Even in relatively healthy 43- to 56-year-old subjects with small white matter lesion burden, structural and functional MR imaging in penumbral tissue reveals significant signal abnormalities versus white matter lesions and other normal WM. Findings suggest that the onset of WM injury starts by middle age and involves substantially more tissue than evident from focal white matter lesions visualized on structural imaging.

Associations between Proportion of Plasma Phospholipid Fatty Acids, Depressive Symptoms and Major Depressive Disorder. Cross-Sectional Analyses from the AGES Reykjavik Study.

BACKGROUND: Deficits in n-3 fatty acids may be associated with depression. However, data are scarce from older adults who are at greater risk of poor dietary intake and of developing depression. OBJECTIVE: To investigate proportion of plasma phospholipid fatty acids with respect to depressive symptoms and major depressive disorder in community dwelling older adults. METHODS: Cross-sectional analyses of 1571 participants in the Age, Gene/Environment Susceptibility (AGES)-Reykjavik Study aged 67-93 years. Depressive symptoms were measured using the 15-item Geriatric Depression Scale (GDS-15). Major depressive disorder was assessed according to Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) criteria using the Mini-International Neuropsychiatric Interview (MINI). RESULTS: Depressive symptoms were observed in 195 (12.4%) subjects and there were 27 (1.7%) cases of major depressive disorder. Participants with depressive symptoms were less educated, more likely to be smokers, less physically active and consumed cod liver oil less frequently. Difference in GDS-15 scores by tertiles of n-3 fatty acid proportion was not significant. Proportion of long chain n-3 fatty acids (Eicosapentaenoic- + Docosahexaenoic acid) were inversely related to major depressive disorder, (tertile 2 vs. tertile 1) OR: 0.31 (95% CI: 0.11, 0.86); tertile 3 vs. tertile 1, OR: 0.45 (95% CI: 0.17, 1.21). CONCLUSION: In our cross sectional analyses low proportions of long chain n-3 fatty acids in plasma phospholipids appear to be associated with increased risk of major depressive disorder. However, the results from this study warrant further investigation in prospective setting with sufficiently long follow-up.

Large-scale pharmacogenomic study of sulfonylureas and the QT, JT and QRS intervals: CHARGE Pharmacogenomics Working Group.

Sulfonylureas, a commonly used class of medication used to treat type 2 diabetes, have been associated with an increased risk of cardiovascular disease. Their effects on QT interval duration and related electrocardiographic phenotypes are potential mechanisms for this adverse effect. In 11 ethnically diverse cohorts that included 71 857 European, African-American and Hispanic/Latino ancestry individuals with repeated measures of medication use and electrocardiogram (ECG) measurements, we conducted a pharmacogenomic genome-wide association study of sulfonylurea use and three ECG phenotypes: QT, JT and QRS intervals. In ancestry-specific meta-analyses, eight novel pharmacogenomic loci met the threshold for genome-wide significance (P<5 × 10-8), and a pharmacokinetic variant in CYP2C9 (rs1057910) that has been associated with sulfonylurea-related treatment effects and other adverse drug reactions in previous studies was replicated. Additional research is needed to replicate the novel findings and to understand their biological basis.

Pharmacogenomics study of thiazide diuretics and QT interval in multi-ethnic populations: the cohorts for heart and aging research in genomic epidemiology.

Thiazide diuretics, commonly used antihypertensives, may cause QT interval (QT) prolongation, a risk factor for highly fatal and difficult to predict ventricular arrhythmias. We examined whether common single-nucleotide polymorphisms (SNPs) modified the association between thiazide use and QT or its component parts (QRS interval, JT interval) by performing ancestry-specific, trans-ethnic and cross-phenotype genome-wide analyses of European (66%), African American (15%) and Hispanic (19%) populations (N=78 199), leveraging longitudinal data, incorporating corrected standard errors to account for underestimation of interaction estimate variances and evaluating evidence for pathway enrichment. Although no loci achieved genome-wide significance (P<5 × 10-8), we found suggestive evidence (P<5 × 10-6) for SNPs modifying the thiazide-QT association at 22 loci, including ion transport loci (for example, NELL1, KCNQ3). The biologic plausibility of our suggestive results and simulations demonstrating modest power to detect interaction effects at genome-wide significant levels indicate that larger studies and innovative statistical methods are warranted in future efforts evaluating thiazide-SNP interactions.

Marinesco bodies and substantia nigra neuron density in Parkinson's disease.

AIM: Marinesco bodies (MB) are intranuclear inclusions in pigmented neurons of the substantia nigra (SN). While rare in children, frequency increases with normal ageing and is high in Alzheimer's disease, dementia with Lewy bodies and other neurodegenerative disorders. Coinciding with the age-related rise in MB frequency is initiation of cell death among SN neurons. Whether MB have a role in this process is unknown. Our aim is to examine the association of MB with SN neuron density in Parkinson's disease (PD) in the Honolulu-Asia Aging Study. METHODS: Data on MB and neuron density were measured in SN transverse sections in 131 autopsied men aged 73-99 years at the time of death from 1992 to 2007. RESULTS: Marinesco body frequency was low in the presence vs. absence of PD (2.3% vs. 6.6%, P < 0.001). After PD onset, MB frequency declined as duration of PD increased (P = 0.006). Similar patterns were observed for SN neuron density. When MB frequency was low, neuron density was noticeably reduced in the SN ventrolateral quadrant, the region most vulnerable to PD neurodegeneration. Low MB frequency was unique to PD as its high frequency in non-PD cases was unrelated to parkinsonian signs and incidental Lewy bodies. Frequency was high in the presence of Alzheimer's disease and apolipoprotein ε4 alleles. CONCLUSIONS: While findings confirm that MB frequency is low in PD, declines in MB frequency continue with PD duration. The extent to which MB have a distinct relationship with PD warrants clarification. Further studies of MB could be important in understanding PD processes.

Association of bone turnover markers with volumetric bone loss, periosteal apposition, and fracture risk in older men and women: the AGES-Reykjavik longitudinal study.

Association between serum bone formation and resorption markers and cortical and trabecular bone loss and the concurrent periosteal apposition in a population-based cohort of 1069 older adults was assessed. BTM levels moderately reflect the cellular events at the endosteal and periosteal surfaces but are not associated with fracture risk. INTRODUCTION: We assessed whether circulating bone formation and resorption markers (BTM) were individual predictors for trabecular and cortical bone loss, periosteal expansion, and fracture risk in older adults aged 66 to 93 years from the AGES-Reykjavik study. METHODS: The sample for the quantitative computed tomography (QCT)-derived cortical and trabecular BMD and periosteal expansion analysis consisted of 1069 participants (474 men and 595 women) who had complete baseline (2002 to 2006) and follow-up (2007 to 2011) hip QCT scans and serum baseline BTM. During the median follow-up of 11.7 years (range 5.4-12.5), 54 (11.4 %) men and 182 (30.6 %) women sustained at least one fracture of any type. RESULTS: Increase in BTM levels was associated with faster cortical and trabecular bone loss at the femoral neck and proximal femur in men and women. Higher BTM levels were positively related with periosteal expansion rate at the femoral neck in men. Markers were not associated with fracture risk. CONCLUSION: This data corroborates the notion from few previous studies that both envelopes are metabolically active and that BTM levels may moderately reflect the cellular events at the endosteal and periosteal surfaces. However, our results do not support the routine use of BTM to assess fracture risk in older men and women. In light of these findings, further studies are justified to examine whether systemic markers of bone turnover might prove useful in monitoring skeletal remodeling events and the effects of current osteoporosis drugs at the periosteum.

Are bone turnover markers associated with volumetric bone density, size, and strength in older men and women? The AGES-Reykjavik study.

UNLABELLED: Association between serum bone formation and resorption markers and bone mineral, structural, and strength variables derived from quantitative computed tomography (QCT) in a population-based cohort of 1745 older adults was assessed. The association was weak for lumbar spine and femoral neck areal and volumetric bone mineral density. INTRODUCTION: The aim of this study was to examine the relationship between levels of bone turnover markers (BTMs; osteocalcin (OC), C-terminal cross-linking telopeptide of type I collagen (CTX), and procollagen type 1N propeptide (P1NP)) and quantitative computed tomography (QCT)-derived bone density, geometry, and strength indices in the lumbar spine and femoral neck (FN). METHODS: A total of 1745 older individuals (773 men and 972 women, aged 66-92 years) from the Age, Gene/Environment Susceptibility (AGES)-Reykjavik cohort were studied. QCT was performed in the lumbar spine and hip to estimate volumetric trabecular, cortical, and integral bone mineral density (BMD), areal BMD, bone geometry, and bone strength indices. Association between BTMs and QCT variables were explored using multivariable linear regression. RESULTS: Major findings showed that all BMD measures, FN cortical index, and compressive strength had a low negative correlation with the BTM levels in both men and women. Correlations between BTMs and bone size parameters were minimal or not significant. No associations were found between BTMs and vertebral cross-sectional area in women. BTMs alone accounted for only a relatively small percentage of the bone parameter variance (1-10 %). CONCLUSION: Serum CTX, OC, and P1NP were weakly correlated with lumbar spine and FN areal and volumetric BMD and strength measures. Most of the bone size indices were not associated with BTMs; thus, the selected bone remodeling markers do not reflect periosteal bone formation. These results confirmed the limited ability of the most sensitive established BTMs to predict bone structural integrity in older adults.

Genetic overlap between Alzheimer's disease and Parkinson's disease at the MAPT locus.

We investigated the genetic overlap between Alzheimer's disease (AD) and Parkinson's disease (PD). Using summary statistics (P-values) from large recent genome-wide association studies (GWAS) (total n=89 904 individuals), we sought to identify single nucleotide polymorphisms (SNPs) associating with both AD and PD. We found and replicated association of both AD and PD with the A allele of rs393152 within the extended MAPT region on chromosome 17 (meta analysis P-value across five independent AD cohorts=1.65 × 10(-7)). In independent datasets, we found a dose-dependent effect of the A allele of rs393152 on intra-cerebral MAPT transcript levels and volume loss within the entorhinal cortex and hippocampus. Our findings identify the tau-associated MAPT locus as a site of genetic overlap between AD and PD, and extending prior work, we show that the MAPT region increases risk of Alzheimer's neurodegeneration.

Cognitive function in a middle aged cohort is related to higher quality dietary pattern 5 and 25 years earlier: the CARDIA study.

BACKGROUND: Preserving cognitive function is an important public health issue. We investigated whether dietary pattern associates with cognitive function in middle-age. METHODS: We studied 2435 participants in the community-based Coronary Artery Risk Development in Young Adults (CARDIA) study of black and white men and women aged 18-30 in 1985-86 (year 0, Y0). We hypothesized that a higher A Priori Diet Quality Score, measured at Y0 and Y20, is associated with better cognitive function measured at Y25. The diet score incorporated 46 food groups (each in servings/day) as the sum of quintile ranks of food groups rated beneficial, 0 for food groups rated neutral, and reversed quintile ranks for food groups rated adverse; higher score indicated better diet quality. Y25 cognitive testing included verbal memory (Rey Auditory-Verbal Learning Test (RAVLT)), psychomotor speed (Digit Symbol Substitution Test (DSST)) and executive function (Stroop). RESULTS: Per 10-unit higher diet score at Y20, the RAVLT was 0.32 words recalled higher, the DSST was 1.76 digits higher, and the Stroop was 1.00 seconds+errors lower (better performance) after adjusting for race, sex, age, clinic, and energy intake. Further adjustment for physical activity, smoking, education, and body mass index attenuated the association slightly. Diet score at Y0 and increase in diet score over 20 years were also positively associated with each cognitive test. CONCLUSIONS: A higher quality dietary pattern was associated with better cognitive function 5 years and even 25 years later in apparently healthy middle-aged adults.

Polyunsaturated fatty acids in relation to incident mobility disability and decline in gait speed; the Age, Gene/Environment Susceptibility-Reykjavik Study.

BACKGROUND/OBJECTIVES: Low intake of long chain polyunsaturated fatty acids (PUFAs) are associated with physical disability; however, prospective studies of circulating PUFAs are scarce. We examined associations between plasma phospholipid n-3 and n-6 PUFAs with risk of incident mobility disability and gait speed decline. SUBJECTS/METHODS: Data are from a subgroup of the Age, Gene/Environment Susceptibility-Reykjavik Study, a population-based study of risk factors for disease and disability in old age. In this subgroup (n = 556, mean age 75.1 ± 5.0 years, 47.5% men), plasma phospholipid PUFAs were assessed at baseline using gas chromatography. Mobility disability and usual gait speed were assessed at baseline and after 5.2 ± 0.2 years. Mobility disability was defined as the following: having much difficulty, or being unable to walk 500 m or climb up 10 steps; decline in gait speed was defined as change ⩾ 0.10 m/s. Logistic regression analyses were performed to determine associations between sex-specific s.d. increments in PUFAs with risk of incident mobility disability and gait speed decline. Odds ratios (95% confidence intervals) adjusted for demographics, follow-up time, risk factors and serum vitamin D were reported. RESULTS: In women, but not men, every s.d. increment increase of total n-3 PUFAs and docosahexaenoic acid (DHA) was associated with lower mobility disability risk, odds ratio 0.48 (0.25; 0.93) and odds ratio 0.45 (0.24; 0.83), respectively. There was no association between n-6 PUFAs and the risk of incident mobility disability or gait speed decline. CONCLUSIONS: Higher concentrations of n-3 PUFAs and, particularly, DHA may protect women from impaired mobility but does not appear to have such an effect in men.

Co-Presence of Multimorbidity and Disability with Frailty: An Examination of Heterogeneity in the Frail Older Population.

BACKGROUND: Frailty is often associated with multimorbidity and disability. OBJECTIVES: We investigated heterogeneity in the frail older population by characterizing five subpopulations according to quantitative biological markers, multimorbidity and disability, and examined their association with mortality and nursing home admission. DESIGN: Observational study. PARTICIPANTS: Participants (n=4,414) were from the population-based Age Gene/Environment Susceptibility Reykjavik Study. MEASUREMENTS: Frailty was defined by ≥ 3 of five characteristics: weight loss, weakness, reduced energy levels, slowness and physical inactivity. Multimorbidity was assessed using a simple disease count, based on 13 prevalent conditions. Disability was assessed by five activities of daily living; participants who had difficulty with one or more tasks were considered disabled. Differences among frail subpopulations were based on the co-presence of multimorbidity and disability. Differences among the following subpopulations were examined: 1) Non-frail (reference group); 2) Frail only; 3) Frail with disability; 4) Frailty with multimorbidity; 5) Frail with disability and multimorbidity. RESULTS: Frailty was present in 10.7% (n=473). Frailty was associated with increased risk for mortality (OR 1.40; 95% CI 1.15-1.69) and nursing home admission (OR 1.50; 95% CI 1.16-1.93); risks differed by subpopulations. Compared to the non-frail, the frail only group had poorer cognition and increased inflammation levels but did not have increased risk for mortality (OR 1.40; 95% CI 0.84-2.33) or nursing home admission (OR 1.01; 95% CI 0.46-2.21). Compared to the non-frail, the other frail subpopulations had significantly poorer cognition, increased inflammation levels, more white matter lesions, higher levels of calcium, glucose and red cell distribution width and increased risk for mortality and nursing home admission. CONCLUSIONS: The adverse health risks associated with frailty in the general older adult population may primarily be driven by increased disease burden and disability.

Follow-up of loci from the International Genomics of Alzheimer's Disease Project identifies TRIP4 as a novel susceptibility gene.

To follow-up loci discovered by the International Genomics of Alzheimer's Disease Project, we attempted independent replication of 19 single nucleotide polymorphisms (SNPs) in a large Spanish sample (Fundació ACE data set; 1808 patients and 2564 controls). Our results corroborate association with four SNPs located in the genes INPP5D, MEF2C, ZCWPW1 and FERMT2, respectively. Of these, ZCWPW1 was the only SNP to withstand correction for multiple testing (P=0.000655). Furthermore, we identify TRIP4 (rs74615166) as a novel genome-wide significant locus for Alzheimer's disease risk (odds ratio=1.31; confidence interval 95% (1.19-1.44); P=9.74 × 10(-)(9)).

Allelic differences between Europeans and Chinese for CREB1 SNPs and their implications in gene expression regulation, hippocampal structure and function, and bipolar disorder susceptibility.

Bipolar disorder (BD) is a polygenic disorder that shares substantial genetic risk factors with major depressive disorder (MDD). Genetic analyses have reported numerous BD susceptibility genes, while some variants, such as single-nucleotide polymorphisms (SNPs) in CACNA1C have been successfully replicated, many others have not and subsequently their effects on the intermediate phenotypes cannot be verified. Here, we studied the MDD-related gene CREB1 in a set of independent BD sample groups of European ancestry (a total of 64,888 subjects) and identified multiple SNPs significantly associated with BD (the most significant being SNP rs6785[A], P=6.32 × 10(-5), odds ratio (OR)=1.090). Risk SNPs were then subjected to further analyses in healthy Europeans for intermediate phenotypes of BD, including hippocampal volume, hippocampal function and cognitive performance. Our results showed that the risk SNPs were significantly associated with hippocampal volume and hippocampal function, with the risk alleles showing a decreased hippocampal volume and diminished activation of the left hippocampus, adding further evidence for their involvement in BD susceptibility. We also found the risk SNPs were strongly associated with CREB1 expression in lymphoblastoid cells (P<0.005) and the prefrontal cortex (P<1.0 × 10(-6)). Remarkably, population genetic analysis indicated that CREB1 displayed striking differences in allele frequencies between continental populations, and the risk alleles were completely absent in East Asian populations. We demonstrated that the regional prevalence of the CREB1 risk alleles in Europeans is likely caused by genetic hitchhiking due to natural selection acting on a nearby gene. Our results suggest that differential population histories due to natural selection on regional populations may lead to genetic heterogeneity of susceptibility to complex diseases, such as BD, and explain inconsistencies in detecting the genetic markers of these diseases among different ethnic populations.