To evaluate the association of risk and age at onset (AAO) of Alzheimer disease (AD) with single-nucleotide polymorphisms (SNPs) in the chromosome 19 region including apolipoprotein E (APOE) and a repeat-length polymorphism in TOMM40 (poly-T, rs10524523).
Conditional logistic regression models and survival analysis.
Fifteen genome-wide association study data sets assembled by the Alzheimer's Disease Genetics Consortium.
Eleven thousand eight hundred forty AD cases and 10 931 cognitively normal elderly controls.
Main Outcome Measures
Association of AD risk and AAO with genotyped and imputed SNPs located in an 800-Mb region including APOE in the entire Alzheimer's Disease Genetics Consortium data set and with the TOMM40 poly-T marker genotyped in a subset of 1256 cases and 1605 controls.
In models adjusting for APOE ε4, no SNPs in the entire region were significantly associated with AAO at P<.001. Rs10524523 was not significantly associated with AD or AAO in models adjusting for APOE genotype or within the subset of ε3/ε3 subjects.
APOE alleles ε2, ε3, and ε4 account for essentially all the inherited risk of AD associated with this region. Other variants including a poly-T track in TOMM40 are not independent risk or AAO loci.
To explore the role of leucine-rich repeat transmembrane 3 (LRRTM3) in late-onset Alzheimer disease (AD) by independent genetic epidemiologic and functional studies.
First, we explored associations between LRRTM3 single-nucleotide polymorphisms and AD in the National Institute on Aging Late-Onset Alzheimer’s Disease case-control data set (993 patients and 884 control subjects) and a cohort of Caribbean Hispanics (549 patients and 544 controls) using single-marker and haplo-type analyses. Then we explored the effect of LRRTM3 small-hairpin RNAs on amyloid precursor protein processing.
One single-nucleotide polymorphism in the promoter region (rs16923760; C allele: odds ratio,−0.74, P=.03), and a block of 4 single-nucleotide polymorphisms in intron 2 (rs1925608, C allele: 0.84, P=.04; rs7082306, A allele: 0.75, P=.04; rs1925609, T allele: 1.2, P=.03; and rs10997477, T allele: 0.88, P=.05) were associated with AD in the National Institute on Aging Late-Onset Alzheimer’s Disease data set or the Caribbean His-panic data set. The corresponding haplotypes were also associated with AD risk (.01< P<.05). In addition, LRRTM3 knockdown with small-hairpin RNAs caused a significant decrease in amyloid precursor protein processing (P<.05 to P<.01) compared with the scrambled small-hairpin RNA condition.
These complementary findings support the notions that genetic variation in LRRTM3 is associated with AD risk and that LRRTM3 may modulate γ-secretase processing of amyloid precursor protein. Additional studies are needed to determine whether the specific alleles associated with differential risk for AD indeed confer this risk through an effect of LRRTM3 expression levels that in turn modulates amyloid precursor protein processing.
Familial aggregation of dementia with Lewy bodies (DLB) remains unclear.
To determine the degree of family aggregation of DLB by comparing DLB risk between siblings of probands with clinically diagnosed DLB and siblings of probands with clinically diagnosed Alzheimer disease in a cohort of Caribbean Hispanic families and to explore the degree of aggregation of specific clinical manifestations (ie, cognitive fluctuations, visual hallucinations, and parkinsonism) in DLB.
Familial cohort study.
We separately compared risks of possible DLB, probable DLB, and clinical core features of DLB (cognitive fluctuations, visual hallucinations, and parkinsonism) between siblings of probands with clinically diagnosed DLB (n=344) and siblings of probands with clinically diagnosed Alzheimer disease (n=280) in 214 Caribbean Hispanic families with extended neurologic and neuropsychological assessment.
Main Outcome Measures
We applied general estimating equations to adjust for clustering within families. In these models, age and proband disease status were independent variables, and disease status of siblings was the measure of disease risk and the dependent variable.
Compared with siblings of probands having clinically diagnosed Alzheimer disease, siblings of probands having clinically diagnosed DLB had higher risks of probable DLB (odds ratio [OR], 2.29; 95% confidence interval [CI], 1.04–5.04) and visual hallucinations (2.32; 1.16–4.64). They also had increased risks of possible DLB (OR, 1.51; 95% CI, 0.97–2.34) and cognitive fluctuations (1.55; 0.95–2.53).
Dementia with Lewy bodies and core features of DLB aggregate in families. Compared with siblings of probands having clinically diagnosed AD, siblings of probands having clinically diagnosed DLB are at increased risks of DLB and visual hallucinations. These findings are an important step in elucidating the genetic risk factors underlying DLB and in delineating DLB from other neurodegenerative diseases, such as Alzheimer disease.
To identify novel loci for late-onset Alzheimer disease (LOAD) in Caribbean Hispanic individuals and to replicate the findings in a publicly available data set from the National Institute on Aging Late-Onset Alzheimer’s Disease Family Study.
Nested case-control genome-wide association study.
The Washington Heights–Inwood Columbia Aging Project and the Estudio Familiar de Influencia Genetica de Alzheimer study.
Five hundred forty-nine affected and 544 unaffected individuals of Caribbean Hispanic ancestry.
The Illumina HumanHap 650Y chip for genotyping.
Main Outcome Measure
Clinical diagnosis or pathologically confirmed diagnosis of LOAD.
The strongest support for allelic association was for rs9945493 on 18q23 (P=1.7 × 10−7), but 22 additional single-nucleotide polymorphisms (SNPs) had a P value less than 9 × 10−6 under 3 different analyses: unadjusted and stratified by the presence or absence of the APOE ε4 allele. Of these SNPs, 5 SNPs (rs4669573 and rs10197851 on 2p25.1; rs11711889 on 3q25.2; rs1117750 on 7p21.1; and rs7908652 on 10q23.1) were associated with LOAD in an independent cohort from the National Institute on Aging Late-Onset Alzheimer’s Disease Family Study. We also replicated genetic associations for CLU, PICALM, and BIN1.
Our genome-wide search of Caribbean Hispanic individuals identified several novel genetic variants associated with LOAD and replicated these associations in a white cohort. We also replicated associations in CLU, PICALM, and BIN1 in the Caribbean Hispanic cohort.
To determine whether genotypes at CLU,
PICALM, and CR1 confer risk for
Alzheimer’s disease (AD) and whether risk for AD associated with
these genes is influenced by APOE genotypes.
Association study of AD and CLU,
PICALM, CR1 and APOE
Academic research institutions in the United States, Canada, and
7,070 AD cases, 3,055 with autopsies, and 8,169 elderly cognitively
normal controls, 1,092 with autopsies from 12 different studies, including
Caucasians, African Americans, Israeli-Arabs, and Caribbean Hispanics.
Unadjusted, CLU [odds ratio (OR) =
0.91, 95% confidence interval (CI) = 0.85 – 0.96 for
single nucleotide polymorphism (SNP) rs11136000],
CR1 (OR = 1.14, CI = 1.07 –
1.22, SNP rs3818361), and PICALM (OR = 0.89, CI
= 0.84 – 0.94, SNP rs3851179) were associated with AD in
Caucasians. None were significantly associated with AD in the other ethnic
groups. APOE ε4 was significantly associated with
AD (ORs from 1.80 to 9.05) in all but one small Caucasian cohort and in the
Arab cohort. Adjusting for age, sex, and the presence of at least one
APOE ε4 allele greatly reduced evidence for
association with PICALM but not CR1 or
CLU. Models with the main SNP effect,
APOE ε4 (+/−), and an
interaction term showed significant interaction between
APOE ε4 (+/−) and
We confirm in a completely independent dataset that CR1,
CLU, and PICALM are AD susceptibility loci in
European ancestry populations. Genotypes at PICALM confer risk predominantly
in APOE ε4-positive subject. Thus, APOE and PICALM synergistically
Administration of cognitive test batteries by telephone has been shown to be a valid and cost-effective means of assessing cognition, but it remains relatively uncommon in epidemiological research.
To develop composite cognitive measures and assess how much of the variability in their scores is associated with mode of test administration (i.e., in person or by telephone).
Cross-sectional cohort study
Late Onset of Alzheimer’s Disease Family Study conducted at 18 centers across the United States.
A total of 1,584 persons, 368 with dementia, from 646 families.
Main Outcome Measures
Scores on composite measures of memory and cognitive function derived from a battery of 7 performance tests administered in person (69%) or by telephone (31%) by examiners who underwent a structured performance-based training program with annual recertification.
Based in part on the results of a factor analysis of the 7 tests, we developed summary measures of working memory, declarative memory, episodic memory, semantic memory, and global cognition. In linear regression analyses, mode of test administration accounted for less than 2% of the variance in the measures. In mixed-effects models, variability in cognitive scores due to center was small relative to variability due to differences between individuals and families.
In epidemiologic research on aging and AD, assessment of cognition by telephone has little effect on performance and provides operational flexibility and a means of reducing costs and missing data.
Alzheimer’s disease; dementia; memory; cognition
Telephone-based interviews can be used for screening and to obtain key study outcomes when participants in longitudinal studies die or cannot be seen in person, but must be validated among ethnically and educationally diverse people.
The sample consisted of 377 (31% non-Hispanic white, 35% non-Hispanic black, and 34% Caribbean Hispanic) older adults. The validation standard was diagnosis of dementia and mild cognitive impairment (MCI) based on in-person evaluation. The Telephone Interview for Cognitive Status (TICS) and the Dementia Questionnaire (DQ) were administered within the same assessment wave.
The sample included 256 (68%) people with normal cognition, 68 (18%) with MCI, and 53 (14%) with dementia. Validity of the TICS was comparable among non-Hispanic whites, non-Hispanic blacks, and Hispanics, but the DQ had better discrimination of dementia from those without dementia and with MCI among Whites than other groups. Telephone measures discriminated best when used to differentiate demented from nondemented participants (sensitivity/specificity for the TICS = 88%/87%; DQ = 66%/89%) and when used to differentiate cognitively normal participants from those with cognitive impairment (i.e., MCI and demented combined; sensitivity/specificity for the TICS = 73%/77%; DQ = 49%/82%). When demographics and prior memory test performance were used to calculate pre-test probability, consideration of the telephone measures significantly improved diagnostic validity.
The TICS has high diagnostic validity for identification of dementia among ethnically diverse older adults, especially when supported by the DQ and prior visit data. However, telephone interview data were unable to reliably distinguish MCI from normal cognition.
To reexamine the association between the neuronal sortilin-related receptor gene (SORL1) and Alzheimer disease (AD).
Comprehensive and unbiased meta-analysis of all published and unpublished data from case-control studies for the SORL1 single-nucleotide polymorphisms (SNPs) that had been repeatedly assessed across studies.
Academic research institutions in the United States, the Netherlands, Canada, Belgium, the United Kingdom, Singapore, Japan, Sweden, Germany, France, and Italy.
All published white and Asian case-control data sets, which included a total of 12 464 cases and 17 929 controls.
Main Outcome Measures
Alzheimer disease according to the Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition) and the National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer’s Disease and Related Disorders Association (now known as the Alzheimer’s Association).
In the white data sets, several markers were associated with AD after correction for multiple testing, including previously reported SNPs 8, 9, and 10 (P<.001). In addition, the C-G-C haplotype at SNPs 8 through 10 was associated with AD risk (P<.001). In the combined Asian data sets, SNPs 19 and 23 through 25 were associated with AD risk (P<.001). The disease-associated alleles at SNPs 8, 9, and 10 (120 873 131-120 886 175 base pairs [bp]; C-G-C alleles), at SNP 19 (120 953 300 bp; G allele), and at SNPs 24 through 25 (120 988 611 bp; T and C alleles) were the same previously reported alleles. The SNPs 4 through 5, 8 through 10, 12, and 19 through 25 belong to distinct linkage disequilibrium blocks. The same alleles at SNPs 8 through 10 (C-G-C), 19 (G), and 24 and 25 (T and C) have also been associated with AD endophenotypes, including white matter hyperintensities and hippocampal atrophy on magnetic resonance imaging, cerebrospinal fluid measures of amyloid β-peptide 42, and full-length SORL1 expression in the human brain.
This comprehensive meta-analysis provides confirmatory evidence that multiple SORL1 variants in distinct linkage disequilibrium blocks are associated with AD.
To determine the association of blood pressure (BP) level and longterm fluctuation in BP with cerebrovascular disease.
Participants received structural MRI and BP measurements in 3, 24 month intervals prior to scanning. We derived the mean and standard deviation (SD) of the mean BP for each participant over the 3 intervals and divided them into four groups defined as above and below the group median (≤ 96.48 mmHg or >96.48mmHg) and further subdivided by the median standard deviation (below SD ≤ 7.21 mmHg or above SD > 7.21 mmHg). This scheme yielded four groups representing the full range of BP and fluctuations in BP. We examined differences in white matter hyperintensity (WMH) volume and brain infarctions across these groups.
The Washington Heights-Inwood Columbia Aging Project, a community-based epidemiological study of older adults from northern Manhattan.
686 non-demented older adults who received structural MRI and had BP measurements over three study visits.
WMH volume increased across the four groups in a linear fashion with the lowest WMH volume in the lowest mean/lowest SD group and the highest in the highest mean/highest SD group (F(3,610)=27.43, p=0.0017). Frequency of infarction also increased monotonically across groups (from 22% to 41%; p-for-trend=0.004).
Compared to individuals with low BP with low fluctuations in BP, the risk of cerebrovascular disease increases with increasing BP and BP fluctuation. Given that cerebrovascular disease is associated with disability, findings suggest that interventions should focus on longterm fluctuating BP as well as elevated BP.
blood pressure; cerebrovascular disease; white matter hyperintensities
To develop a simple summary risk score for the prediction of Alzheimer disease in elderly persons based on their vascular risk profiles.
A longitudinal, community-based study.
New York, New York.
One thousand fifty-one Medicare recipients aged 65 years or older and residing in New York who were free of dementia or cognitive impairment at baseline.
Main Outcome Measures
We separately explored the associations of several vascular risk factors with late-onset Alzheimer disease (LOAD) using Cox proportional hazards models to identify factors that would contribute to the risk score. Then we estimated the score values of each factor based on their βcoefficients and created the LOAD vascular risk score by summing these individual scores.
Risk factors contributing to the risk score were age, sex, education, ethnicity, APOE ε4 genotype, history of diabetes, hypertension or smoking, high-density lipoprotein levels, and waist to hip ratio. The resulting risk score predicted dementia well. According to the vascular risk score quintiles, the risk to develop probable LOAD was 1.0 for persons with a score of 0 to 14 and increased 3.7-fold for persons with a score of 15 to 18, 3.6-fold for persons with a score of 19 to 22, 12.6-fold for persons with a score of 23 to 28, and 20.5-fold for persons with a score higher than 28.
While additional studies in other populations are needed to validate and further develop the score, our study suggests that this vascular risk score could be a valuable tool to identify elderly individuals who might be at risk of LOAD. This risk score could be used to identify persons at risk of LOAD, but can also be used to adjust for confounders in epidemiologic studies.
To reexamine the association of lipid levels with Alzheimer disease (AD) using Cox proportional hazards models.
Prospective cohort study.
Northern Manhattan, New York.
One thousand one hundred thirty elderly individuals free of cognitive impairment at baseline.
Main Outcome Measure
High-density lipoprotein cholesterol (HDL-C) levels.
Higher levels of HDL-C (>55 mg/dL) were associated with a decreased risk of both probable and possible AD and probable AD compared with lower HDL-C levels (hazard ratio, 0.4; 95% confidence interval, 0.2–0.9; P=.03 and hazard ratio, 0.4; 95% confidence interval, 0.2–0.9; P=.03). In addition, higher levels of total and non–HDL-C were associated with a decreased risk of AD in analyses adjusting for age, sex, education, ethnic group, and APOEe4 genotype.
High HDL-C levels in elderly individuals may be associated with a decreased risk of AD.
To examine the association between the Mediterranean diet (MeDi) and Alzheimer disease (AD) in a different AD population and to investigate possible mediation by vascular pathways.
Design, Setting, Patients, and Main Outcome Measures
A case-control study nested within a community-based cohort in New York, NY. Adherence to the MeDi (0- to 9-point scale with higher scores indicating higher adherence) was the main predictor of AD status (194 patients with AD vs 1790 nondemented subjects) in logistic regression models that were adjusted for cohort, age, sex, ethnicity, education, apolipoprotein E genotype, caloric intake, smoking, medical comorbidity index, and body mass index (calculated as weight in kilograms divided by height in meters squared). We investigated whether there was attenuation of the association between MeDi and AD when vascular variables (stroke, diabetes mellitus, hypertension, heart disease, lipid levels) were simultaneously introduced in the models (which would constitute evidence of mediation).
Higher adherence to the MeDi was associated with lower risk for AD (odds ratio, 0.76; 95% confidence interval, 0.67–0.87; P<.001). Compared with subjects in the lowest MeDi tertile, subjects in the middle MeDi tertile had an odds ratio of 0.47 (95% confidence interval, 0.29–0.76) and those at the highest tertile an odds ratio of 0.32 (95% confidence interval, 0.17–0.59) for AD (P for trend <.001). Introduction of the vascular variables in the model did not change the magnitude of the association.
We note once more that higher adherence to the MeDi is associated with a reduced risk for AD. The association does not seem to be mediated by vascular comorbidity. This could be the result of either other biological mechanisms (oxidative or inflammatory) being implicated or measurement error of the vascular variables.
Background and Objective
The validity of a self-reported stroke remains inconclusive. The objective of the present study was to validate the diagnosis of self-reported stroke using stroke identified by magnetic resonance imaging (MRI) as the standard.
Design and Setting
Community-based cohort study of non-demented, ethnically diverse elderly in northern Manhattan.
High-resolution quantitative MRI was acquired on 717 participants without dementia. Sensitivity and specificity of stroke by self-report were examined using cross-sectional analyses and the χ2-test. Putative relations between factors potentially influencing the reporting of stroke, including memory performance, cognitive function and vascular risk factors were assessed using logistic regression models. Subsequently all analyses were repeated stratified by age, sex, ethnic group and level of education.
In analyses for the whole sample, sensitivity of stroke self-report for a diagnosis of stroke on MRI was 32.4% and specificity was 78.9%. In analyses stratified by median of age (80.1 years), the validity between reported stroke and detection of stroke on MRI was significantly better in the younger than the older age group (for all vascular territories: sensitivity: 36.7% (specificity 81.3%) vs. sensitivity 27.6% (specificity: 26.2%), p=0.02). Impaired memory, cognitive or language ability, and the presence of hypertension or myocardial infarction were associated with higher false-negatives.
Using brain MRI as the standard, specificity and sensitivity of stroke self-report are low. Accuracy of self-report is influenced by age, presence of vascular disease and cognitive function. In stroke research, sensitive neuroimaging techniques rather than stroke self-report should be used to determine stroke history.
Hippocampal atrophy and reductions in basal cerebral blood volume (CBV), a hemodynamic correlate of brain function, occur with cognitive impairment in Alzheimer's disease but whether these are early or late changes remains unclear. Magnetic resonance imaging (MRI) assesses structure and function in the hippocampal formation. The objective of the present study was to estimate differences in the associations of hippocampus and entorhinal cortex volumes and CBV with memory function in early and late stages of cognitive impairment by relating these measures with memory function in demented and nondemented persons with detailed brain imaging and neuropsychological assessment.
Design and Setting
Multivariate regression analyses were used to relate entorhinal cortex volume, entorhinal cortex CBV, hippocampus volume and hippocampus-CBV with measures of memory performance in 231 elderly persons from a community-based cohort. The same measures were related with language function as a reference cognitive domain.
There was no association between entorhinal cortex volume or hippocampus-CBV and memory. Decreased hippocampus volume was strongly associated with worse performance in total recall, while lower entorhinal cortex CBV was significantly associated with lower performance in delayed recall. Excluding persons with Alzheimer's disease (AD), the associations of entorhinal cortex CBV with memory measures was stronger, while the association between hippocampus volume and total recall became non-significant.
These finding suggest that in the early stages of AD or in nondemented persons with worse memory ability functional/metabolic hippocampal hypofunction contribute to memory impairment, while in the later stages both functional and structural changes play a role.
entorhinal cortex cerebral blood volume; hippocampus volume; memory performance
Mutations in the glucocerebrosidase (GBA) gene are associated with Lewy body (LB) disorders.
To determine the relationship of GBA mutations and APOE4 genotype to LB and Alzheimer disease (AD) pathological findings.
The 187 subjects included patients with primary neuropathological diagnoses of LB disorders with or without AD changes (95 cases), randomly selected patients with AD (without significant LB pathological findings; 60 cases), and controls with neither LB nor AD pathological findings (32 cases).
Main Outcome Measures
GBA mutation status, APOE4 genotype, LB pathological findings (assessed according to the third report of the Dementia With Lewy Body Consortium), and Alzheimer plaque and tangle pathological findings (rated by criteria of Braak and Braak, the Consortium to Establish a Registry for Alzheimer Disease, and the National Institute on Aging–Reagan Institute).
GBA mutations were found in 18% (34 of 187) of all subjects, including 28% (27 of 95) of those with primary LB pathological findings compared with 10% (6 of 60) of those with AD pathological findings and 3% (1 of 32) of those without AD or LB pathological findings (P=.001). GBA mutation status was significantly associated with the presence of cortical LBs (odds ratio, 6.48; 95% confidence interval, 2.45–17.16; P<.001), after adjusting for sex, age at death, and presence of APOE4. GBA mutation carriers were significantly less likely to meet AD pathological diagnostic (National Institute on Aging–Reagan Institute intermediate or high likelihood) criteria (odds ratio, 0.35; 95% confidence interval, 0.15–0.79; P=.01) after adjustment for sex, age at death, and APOE4.
GBA mutations may be associated with pathologically “purer” LB disorders, characterized by more extensive (cortical) LB, and less severe AD pathological findings and may be a useful marker for LB disorders.
To examine the impact of age, sex, ethnicity, and vascular disease on measures of brain morphology, including relative brain volume, ventricle volume, hippocampus and entorhinal cortex volume, and white matter hyperintensity (WMH) burden in a large community-based cohort of non-demented, ethnically diverse older adults.
Beginning in 2003, high-resolution quantitative magnetic resonance imaging (MRI) was acquired on 769 participants without dementia. The relations of age, sex, self reported vascular disease history, and ethnicity, with brain morphology was examined in a cross-sectional study using multiple linear regression analyses. Sex and ethnicity interactions were also considered.
The Washington Heights/Hamilton Heights Aging Project (WHICAP), a community-based epidemiological study of older adults from three ethnic groups (i.e., Caucasian, Hispanic, African American) from northern Manhattan.
Main outcome measures
Relative brain volume (absolute brain volume/cranial volume), ventricular volume, hippocampus and entorhinal cortex volumes were derived manually on high-resolution MRI scans. White matter hyperintensities were quantified semi-automatically on FLAIR-weighted MRI.
Increased age was associated with decreased relative brain volume and increased ventricular and WMH volume. Hispanic and African American participants had larger relative brain volumes and more severe WMH burden than Caucasians, but their associations with age were similar across ethnic groups. Compared with men, women had larger relative brain volumes. Vascular disease was associated with smaller relative brain volume and higher WMH burden, particularly among African Americans.
Increased age and vascular disease particularly among African Americans are associated with increased brain atrophy and WMH burden. African American and Hispanic participants have larger relative brain volumes and more WMH than Caucasians. Ethnic group differences in WMH severity appear to be partially attributable to differences in vascular disease. Future work will focus on the determinants and cognitive correlates of these differences.
The relation between plasma lipid levels and Alzheimer disease (AD) and vascular dementia (VaD), and the impact of drugs to lower lipid levels remains unclear.
To investigate the relation between plasma lipid levels and the risk of AD and VaD and the impact of drugs to lower lipid levels on this relationship.
Design and Setting
Cross-sectional and prospective community-based cohort studies.
Random sample of 4316 Medicare recipients, 65 years and older, residing in northern Manhattan, NY.
Main Outcome Measures
Vascular dementia and AD according to standard criteria.
Elevated levels of non–high-density lipoprotein (HDL-C) and low-density lipoprotein cholesterol (LDL-C) and decreased levels of HDL-C were weak risk factors for VaD in either cross-sectional or prospective analyses. Higher levels of total cholesterol were associated with a decreased risk of incident AD after adjustment for demographics, apolipoprotein E genotype, and cardiovascular risk factors. Treatment with drugs to lower lipid levels did not change the disease risk of either disorder.
We found a weak relation between non–HDL-C, LDL-C, and HDL-C levels and the risk of VaD. Lipid levels and the use of agents to lower them do not seem to be associated with the risk of AD.
To identify putative genetic loci related to the risk of late-onset Alzheimer disease (LOAD).
Linkage analysis and family-based and case-control association analyses from a genomewide scan using approximately 6000 single-nucleotide polymorphic markers at an average intermarker distance of 0.65 cM.
The National Institute on Aging Genetics Initiative for Late-Onset Alzheimer's Disease (NIA-LOAD) was created to expand the resources for studies to identify additional genes contributing to the risk for LOAD.
We investigated 1902 individuals from 328 families with LOAD and 236 unrelated control subjects.
Main Outcome Measures
Clinical diagnosis of LOAD.
The strongest overall finding was at chromosome 19q13.32, confirming the effect of the apolipoprotein E gene on LOAD risk in the family-based and case-control analyses. However, single-nucleotide polymorphisms at the following loci were also statistically significant in 1 or more of the analyses performed: 7p22.2, 7p21.3, and 16q21 in the linkage analyses; 17q21.31 and 22q11.21 in the family-based association analysis; and 7q31.1 and 22q12.3 in the case-control analysis. Positive associations at 7q31.1 and 20q13.33 were also significant in the meta-analysis results in a publicly available database.
Several additional loci may harbor genetic variants associated with LOAD. This data set provides a wealth of phenotypic and genotypic information for use as a resource in discovery and confirmatory research.
Background and Objective
There are conflicting data relating hypertension to the risk of Alzheime's disease (AD). We sought to explore whether hypertension is associated with the risk of mild cognitive impairment (MCI), an intermediate stage to dementia.
Design and Setting
Prospective community-based cohort study conducted in northern Manhattan.
Multivariate proportional hazards regression analyses, relating hypertension to incident all-cause MCI, amnestic MCI, and non-amnestic MCI in 918 persons without prevalent MCI at baseline followed for a mean of 4.7 years.
There were 334 cases of incident MCI, 160 cases of amnestic MCI and 174 cases of non-amnestic MCI during 4337 person years of follow-up. Hypertension was associated with an increased risk of all-cause MCI (HR 1.4, 95% CI 1.06-1.77, p=0.02) and non-amnestic MCI (HR 1.7, 95% CI 1.13-2.42, p=0.009) after adjusting for age and gender. Both associations were slightly attenuated in models additionally adjusting for stroke and other vascular risk factors. There was no association between hypertension and the risk of amnestic MCI (HR 1.1, 95% CI 0.79-1.63, p=0.49). Consistent with this association, hypertension was related with the slope of change in an executive ability score, but not with memory or language scores. There was no effect modification of the association between hypertension and MCI by APOEε4 genotype or use of antihypertensive medication.
A history of hypertension is related to a higher risk of MCI. The association seems to be stronger with the non-amnestic than the amnestic component of MCI. These findings suggest that prevention and treatment of hypertension may have an important impact in lowering the risk of cognitive impairment.
blood pressure; hypertension; mild cognitive impairment
There is conflicting data showing that stroke is associated with a higher risk of dementia and a more severe decline in persons with cognitive impairment. However, if cerebrovascular disease is directly related to cognitive decline in the absence of cognitive impairment or dementia remains unclear.
To examine the association between stroke and changes in cognitive function over time in elderly persons without dementia at baseline.
The results of neuropsychological tests from several intervals over a five-year-period were clustered into domains of memory, abstract/visuospatial and language in 1271 elderly without dementia or cognitive decline. Stroke was related to the slope of performance in each cognitive domain using generalized estimating equations.
Memory performance declined over time while abstract/visuospatial and language performance remained stable over the study period. Stroke was associated with a more rapid decline in memory performance, while there was no association between stroke and decline in abstract/visuospatial or language performance. The association between stroke and decline in memory performance was strongest for men and for persons without an APOE4 allele. A significant association between stroke and decline in abstract/visuospatial performance was also observed for persons without the APOE-e4 allele.
A history of stroke is related to a progressive decline in memory and abstract/visuospatial performance especially among men and those without an APOE-e4 allele.
stroke; memory performance; cognitive performance
Higher adherence to the Mediterranean diet (MeDi) may protect from Alzheimer’s disease (AD) but its association with Mild Cognitive Impairment (MCI) has not been explored.
To investigate the association between MeDi and MCI.
Design, Setting, Patients, Outcomes
In a multiethnic community study in New York, we used Cox proportional hazards to investigate the association between adherence to the MeDi (0 – 9 scale; higher scores higher adherence) and (1) incidence of MCI and (2) progression from MCI to AD. All models were adjusted for cohort, age, gender, ethnicity, education, APOE genotype, caloric intake, body mass index and time duration between baseline dietary assessment and baseline diagnosis.
There were 1393 cognitively normal participants, 275 of whom developed MCI during 4.5 (± 2.7, 0.9–16.4) years of follow-up. Compared to subjects in the lowest MeDi adherence tertile, subjects in the middle MeDi tertile had 17 % (HR, 0.83; 95% CI, 0.62 – 1.12; p=0.24) less risk of developing MCI, while those at the highest MeDi adherence tertile had 28 % (HR, 0.72; 95% CI, 0.52 – 1.00; p=0.05) less risk of developing MCI (trend HR, 0.85; 95% CI, 0.72 – 1.00; p for trend= 0.05). There were 482 subjects with MCI, 106 of whom developed AD during 4.3 (± 2.7, 1.0 – 13.8) years of follow-up. Compared to subjects in the lowest MeDi adherence tertile, subjects in the middle MeDi adherence tertile had 45 % (HR, 0.55; 95% CI, 0.34 – 0.90; p=0.01) less risk of developing AD, while those at the highest MeDi adherence tertile had 48 % (HR, 0.52; 95% CI, 0.30 – 0.91; p=0.02) less risk of developing AD (trend HR, 0.71; 95% CI, 0.53 – 0.95; p for trend= 0.02).
Higher adherence to the MeDi is associated with a trend for reduced risk for developing MCI and with reduced risk for MCI conversion to AD.
Variants in 3′ and 5′ regions of SORL1, the neuronal sorting protein-related receptor, were recently found to be associated with late onset familial and sporadic Alzheimer’s disease in several datasets that were selected for familial aggregation or were ethnically diverse or clinic-based selected series.
To investigate the association between Alzheimer’s disease and variant alleles in SORL1 using a series of single nucleotide polymorphisms (SNPs) in an urban, multiethnic community-based population.
Design & Setting
We used a nested case-control analysis in a population-based, prospective study of aging and dementia in Medicare recipients, 65 years and older, residing in northern Manhattan.
There were 296 patients with probable Alzheimer’s disease and 428 healthy elderly controls. The participants were of African American (34%), Caribbean Hispanic (51%) or non-Hispanic whites (15%).
Main Outcome Measures
We genotyped all 29 SNPs in SORL1 that were examined in the earlier report. We assessed allelic association with AD using standard case-control methods which included APOE genotype as a covariate.
Several individual SNPs and SNP haplotypes were significantly associated with AD in this prospectively collected community-based cohort, confirming the previously reported positive association of SORL1 with Alzheimer’s disease. SNP 12 near the 5′ region was associated with AD in African-Americans and Hispanics. Two SNPs in the 3′ region were also associated with AD in African-Americans (SNP 26) and Whites (SNP 20). A single haplotype in the 3′ region was associated with AD in Hispanics. However, several different haplotypes were associated with AD in the African-Americans and Whites, including the “TTC” haplotypes at SNPs 23–25 (p=0.035) that was significantly associated with AD in the North European Whites in the previous report.
This study confirms the association between genetic variants in SORL1 and AD. While the associations observed in these datasets overlap with those previously reported, the finding of novel SNP and haplotype associations suggest that there may be extensive allelic heterogeneity in SORL1. Broad regions of the SORL1 gene will therefore need to be scrutinized for functional pathogenic variants.
SORL1; Alzheimer’s disease; sporadic; African American; Caribbean Hispanic
The clinical delineation of Dementia with Lewy bodies (DLB) and Alzheimer's disease (AD) remains unclear.
To compare the neuropsychological profiles of patients with clinically diagnosed Dementia with Lewy bodies (DLB) and Alzheimer's disease (AD).
We first compared measures of memory, orientation, language, executive, visual perception and visual construction function between persons with DLB and AD in two Caribbean Hispanic cohorts, including a family dataset (DLB =89; AD: n=118) and an epidemiologic dataset (DLB: n=70; AD: n=157). DLB in the family sample was further divided into i) families with two or more affected family members (DLB), or ii) one affected family member (DLB). To determine whether observed differences in cognitive profiles were driven by heritable factors, we then repeated the analyses in the epidemiologic cohort excluding all familial cases. We applied general linear models adjusting for age, sex, education, disease duration, and APOE-ε4 genotype.
Persons with DLB were in both cohorts more severely impaired in orientation, visual construction and non verbal reasoning after controlling for potential confounders. Persons with 2 or more DLB cases per family had the most severe impairment in episodic and semantic memory, followed by those with one DLB case per family, then by those with AD. When familial AD and DLB cases were excluded from the analysis in the epidemiologic cohort, the differences between the AD and DLB groups persisted but were attenuated.
Compared to persons with AD, persons with DLB are more severely impaired in various cognitive domains, particularly orientation, visual perception and visual construction. The difference appears strong in familial rather than sporadic DLB. Whether this divergence in cognitive functions is caused by gene-gene or gene-environmental interactions remains unclear.
Deposition of the amyloid beta peptide, Aβ42, is thought to be an important initial step in the pathogenesis of Alzheimer’s disease. Individuals with Down syndrome have both increased levels of Aβ peptides and increased risk for Alzheimer’s disease.
To examine the relation of plasma levels of Aβ42 and Aβ40 to risk of dementia in nondemented participants and to all-cause mortality in adults with Down syndrome.
Prospective, community-based longitudinal cohort study.
State and voluntary service providers in New York State
Adults with Down syndrome (N=204).
MAIN OUTCOME MEASURE
Plasma Aβ42 and Aβ40 levels were measured at initial examination. Participants were assessed for cognitive and functional abilities, behavioral/psychiatric conditions, health and vital status at 14–18 month intervals over four cycles of data collection.
Among participants who were nondemented at baseline, those in the middle and highest tertiles of plasma Aβ42 levels were over 2 times as likely to develop AD as those in the lowest tertile. Compared with participants without AD, participants with prevalent AD had higher levels of plasma Aβ42 but not Aβ40. Among all participants, those in the highest tertile of plasma Aβ42 level at baseline were over twice as likely to die over the study period as those in the lowest tertile, while there was no difference in risk of death between those in the middle and lowest tertile of plasma Aβ42 level.
Elevations in plasma Aβ42 peptide are associated with earlier onset of AD and increased risk of death.
Beta amyloid 1–42; Down syndrome; Alzheimer’s disease; blood plasma