L. J. Launer

Association between blood pressure, white matter lesions, and atrophy of the medial temporal lobe

Background: Blood pressure level is associated with the risk of clinical Alzheimer disease (AD), yet the underlying mechanisms are unclear. High blood pressure levels may cause cerebral small-vessel pathology, which contributes to cognitive decline in patients with AD. Alternatively, in persons with high blood pressure, increased numbers of neurofibrillary tangles and amyloid plaques at autopsy have also been observed, suggesting direct links between blood pressure and AD. Objective: To investigate the association of blood pressure and markers of small-vessel disease (white matter lesions [WMLs] on MRI) with hippocampal and amygdalar atrophy on MRI—potential in vivo indicators of Alzheimer pathology. Methods: In 1995 to 1996, 511 nondemented elderly subjects (age 60 to 90) underwent MRI. The extent of WMLs was assessed, and volumes of the hippocampus and amygdala were measured. Blood pressure levels were assessed at the time of MRI and 5 years before the MRI. Results: Higher diastolic blood pressure 5 years before MRI predicted more hippocampal atrophy in persons untreated for hypertension (per SD increase −0.10 mL [95% CI −0.19 to −0.02, p = 0.02]). Conversely, in persons treated for hypertension, a low diastolic blood pressure was associated with more severe atrophy. Persons with more WMLs on MRI more often had severe atrophy of the hippocampus and amygdala. Conclusion: Blood pressure and indicators of small-vessel disease in the brain may be associated with atrophy of structures affected by Alzheimer pathology.

Cerebral microbleeds in the population based AGES-Reykjavik study: prevalence and location

Background and purpose: Incidental foci of signal loss suggestive of cerebral microbleeds (CMBs) are frequent findings on gradient echo T2* weighted MRI (T2* MRI) of patients with haemorrhagic or ischaemic stroke. There are few prevalence data on older populations. This paper reports on the prevalence and location of CMBs in a community based cohort of older men and women (born 1907–1935) who participated in the Age Gene/Environment Susceptibility (AGES)-Reykjavik Study, a population based cohort study that followed the Reykjavik Study Methods: As part of the examination, all eligible and consenting cohort members underwent a full brain MRI, and blood was drawn for genotyping. Results are based on the first 1962 men (n = 820) and women (n = 1142), mean age 76 years, with complete MRI and demographic information available. Results: Evidence of CMBs was found in 218 participants (11.1% (95% CI 9.8% to 12.6%)); men had significantly more CMBs than women (14.4% vs 8.8%; p = 0.0002, age adjusted). The prevalence of CMBs increased with age (p = 0.0001) in both men (p = 0.006) and women (p = 0.007). CMBs were located in the cerebral lobes (70%), the basal ganglia region (10.5%) and infratentorium (18.6%). Having a CMB was significantly associated with a homozygote Apo E 44 genotype (p = 0.01). Conclusion: Cerebral microbleeds are common in older persons. The association with homozygote Apo E 4 genotype and finding a relative predominance in the parietal lobes might indicate an association with amyloid angiopathy.

Hippocampal, amygdalar, and global brain atrophy in different apolipoprotein E genotypes

The &egr;4 allele of the APOE gene increases the risk for AD, whereas the &egr;2 allele may be protective. The authors assessed the impact of APOE genotype on hippocampal, amygdalar, and global brain atrophy as putative markers of preclinical AD in a nondemented population. Carriers of &egr;4 had significantly more hippocampal and amygdalar atrophy than &egr;3&egr;3 subjects, but not more global brain atrophy. Carriers of &egr;2 did not have less brain atrophy than &egr;3&egr;3 subjects.

Cerebral microbleeds, retinopathy, and dementia The AGES-Reykjavik Study

Objective: To determine whether microvascular damage, indicated by cerebral microbleeds (CMBs) and retinal microvascular signs, is associated with cognitive function and dementia in older persons. Methods: This is a cross-sectional study of 3,906 participants (mean age 76 years; 58% women) in the AGES-Reykjavik Study (2002–2006). We assessed CMBs on MRI and retinal microvascular signs on digital retinal images. Composite Z scores of memory, processing speed, and executive function were derived from a battery of neurocognitive tests. Dementia and subtypes were diagnosed following international criteria. Regression models were used to relate cognitive Z scores and dementia to CMBs and retinal microvascular signs, adjusting for demographics, cardiovascular factors, and brain ischemic lesions. Results: People with multiple (≥2) CMBs had lower Z scores on tests of processing speed (β-coefficient −0.16; 95% confidence interval −0.26 to −0.05) and executive function (−0.14; −0.24 to −0.04); results were strongest for having multiple CMBs located in the deep hemispheric or infratentorial areas. The odds ratio of vascular dementia was 2.32 (95% confidence interval 1.02 to 5.25) for multiple CMBs and 1.95 (1.04 to 3.62) for retinopathy. Having both CMBs and retinopathy, compared to having neither, was significantly associated with markedly slower processing speed (−0.25; −0.37 to −0.12), poorer executive function (−0.19; −0.31 to −0.07), and an increased odds ratio of vascular dementia (3.10; 1.11 to 8.62). Conclusion: Having multiple CMBs or concomitant CMBs and retinopathy is associated with a profile of vascular cognitive impairment. These findings suggest that microvascular damage, as indicated by CMBs and retinopathy lesions, has functional consequences in older men and women living in the community.

ATP5H/KCTD2 locus is associated with Alzheimer's disease risk

To identify loci associated with Alzheimer disease, we conducted a three-stage analysis using existing genome-wide association studies (GWAS) and genotyping in a new sample. In Stage I, all suggestive single-nucleotide polymorphisms (at P<0.001) in a previously reported GWAS of seven independent studies (8082 Alzheimer’s disease (AD) cases; 12 040 controls) were selected, and in Stage II these were examined in an in silico analysis within the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium GWAS (1367 cases and 12904 controls). Six novel signals reaching P<5 × 10−6 were genotyped in an independent Stage III sample (the Fundació ACE data set) of 2200 sporadic AD patients and 2301 controls. We identified a novel association with AD in the adenosine triphosphate (ATP) synthase, H+ transporting, mitochondrial F0 (ATP5H)/Potassium channel tetramerization domain-containing protein 2 (KCTD2) locus, which reached genome-wide significance in the combined discovery and genotyping sample (rs11870474, odds ratio (OR)=1.58, P=2.6 × 10−7 in discovery and OR=1.43, P=0.004 in Fundació ACE data set; combined OR=1.53, P=4.7 × 10−9). This ATP5H/KCTD2 locus has an important function in mitochondrial energy production and neuronal hyperpolarization during cellular stress conditions, such as hypoxia or glucose deprivation.

The interaction of adiposity with the CRP gene affects CRP levels: age, gene/environment susceptibilty-Reykjavik study.

Objective:Common diseases often have an inflammatory component reflected by associated markers such as serum C-reactive protein (CRP) levels. Circulating CRP levels have also been associated with adipose tissue as well as with specific CRP genotypes. We examined the interaction between measures of body mass index (BMI), waist circumference and fat percent (total fat measured by bioimpedance) with genotypes of the CRP gene in the determination of CRP levels.Methods:The first 2296 participants (mean age 76±6 years, 42% men) in the Age, Gene/Environment Susceptibility-Reykjavik Study, a multidisciplinary epidemiological study to determine risk factors in aging, were genotyped for 10 single nucleotide polymorphisms (SNPs) in the CRP gene. General linear models with age and terms for interaction of CRP genotypes with BMI, waist circumference and percent fat were used to evaluate the association of genotypes to CRP levels (high-sensitivity method, range 0–10 mg l−1) in men and women separately.Results:We focused on the SNP rs1205 that represents the allele that captures the strongest effects of the gene on CRP levels. Carriers of the rs1205 G allele had significantly higher CRP levels than noncarriers in a dose-dependent manner. Compared to the AA genotype, the slope of the increase in CRP with increasing BMI (P=0.045) and waist circumference (P=0.014) was different for the G allele carriers and of similar magnitude in both men and women. The rs1205 interactions were not significant for fat mass percent, suggesting a possible association with fat localization.Conclusions:This study further illuminates the known association between measures of adiposity and CRP levels and is shown to be dependent on variation in the rs1205 SNP of the CRP gene. The correlated increase in CRP levels with adiposity is accentuated by presence of the G allele.

Ventral striatal volume is associated with cognitive decline in older people: a population based MR-study

Striatal degeneration may contribute to cognitive impairment in older people. Here, we examine the relation of degeneration of the striatum and substructures to cognitive decline and dementia in subjects with a wide range of cognitive function. Data are from the prospective community-based Honolulu Asia Aging Study of Japanese American men born 1900-1919. Brain magnetic resonance imaging (MRI) (1.5 T) was acquired on a stratified subsample (n = 477) that included four groups defined by cognitive status relative to the scan date: subjects without dementia (n = 347), subjects identified as demented 2-3 years before brain scanning (n = 30), at the time of scanning (n = 58), and 3-5 years after scanning (n = 42). Volumes of the striatum, including the accumbens, putamen, and caudate nucleus were automatically estimated from T1 MR images. Global cognitive function was measured with the cognitive ability screening instrument (CASI), at four examinations spanning an 8-year interval. Trajectories of cognitive decline were estimated for each quartile of striatal volume using mixed models, controlling for demographic variables, measures of cerebro-vascular damage, global brain atrophy, and hippocampal volume. Diagnosis of dementia before, during, and after brain scanning was associated with smaller volumes of n. accumbens and putamen, but not with caudate nucleus volume. Subjects in the lowest quartile of n. accumbens volume, both in the total sample and in the subjects not diagnosed with dementia during the study, had a significantly (p < 0.0001) steeper decline in cognitive performance compared with those in the highest quartile. In conclusion, volumes of the n. accumbens and putamen are closely associated with the occurrence of dementia and n. accumbens volume predicts cognitive decline in older people. These associations were found independent of the magnitude of other pivotal markers of cognitive decline, i.e. cerebro-vascular damage and hippocampal volume. The present study suggests a role for the ventral striatum in the development of clinical dementia.

IGF2BP1, IGF2BP2 and IGF2BP3 genotype, haplotype and genetic model studies in metabolic syndrome traits and diabetes

OBJECTIVE Genetic variation at the insulin-like binding protein 2 (IGF2BP2) gene has been associated with type 2 diabetes (T2D) by genome-wide association studies and by replication analyses. Our aim was to explore the underlying genetic model and mechanism of action, factors accounting for non-replications of the associations, and the effect of variation from pathway-related genes IGF2BP1 and IGF2BP3. METHOD We analysed here the association between T2D (and related traits) and rs4402960 and rs1470579 in IGF2BP2, and rs46522 and rs6949019 (marking IGF2BP1 and IGF2BP3 respectively) from the Age, Gene/Environment Susceptibility (AGES)-Reykjavik Study (N approximately 2500 aged 65-96 years). We undertook a retrospective analysis of the deviations from the multiplicative model in previous studies and the present study. RESULTS We replicated an association between rs4402960 and T2D status, and reported significant associations with anthropometric traits, fasting insulin, HOMA-IR and HOMA-%B. These associations were also observed for rs1470579, but not for the SNPs marking IGF2BP1 and IGF2BP3. CONCLUSIONS The lower fasting insulin levels and the impaired beta-cell function associated with IGF2BP2 SNPs are independent of obesity phenotypes. The action of these SNPs on T2D may result from an effect on beta-cell function. This could lead to lower insulin levels, the association with anthropometric traits being secondary. We discuss possible mechanisms of action relating IGF2BP2 with T2D traits. The occurrence of null alleles, the inclusion of T2D patients in analyses of metabolic syndrome risk traits and the genetic model, are possible factors accounting for non-replications of IGF2BP2 associations with T2D.

Meta-analysis of genome-wide association studies of HDL cholesterol response to statins.

Background In addition to lowering low density lipoprotein cholesterol (LDL-C), statin therapy also raises high density lipoprotein cholesterol (HDL-C) levels. Inter-individual variation in HDL-C response to statins may be partially explained by genetic variation. Methods and results We performed a meta-analysis of genome-wide association studies (GWAS) to identify variants with an effect on statin-induced high density lipoprotein cholesterol (HDL-C) changes. The 123 most promising signals with p<1×10−4 from the 16 769 statin-treated participants in the first analysis stage were followed up in an independent group of 10 951 statin-treated individuals, providing a total sample size of 27 720 individuals. The only associations of genome-wide significance (p<5×10−8) were between minor alleles at the CETP locus and greater HDL-C response to statin treatment. Conclusions Based on results from this study that included a relatively large sample size, we suggest that CETP may be the only detectable locus with common genetic variants that influence HDL-C response to statins substantially in individuals of European descent. Although CETP is known to be associated with HDL-C, we provide evidence that this pharmacogenetic effect is independent of its association with baseline HDL-C levels.

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.