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1.  Alcohol intake and brain structure in a multiethnic elderly cohort 
Background & Aims
Evidence suggests that consuming light-to-moderate amounts of alcohol reduces the risk of dementia and is associated better cognitive function and less cardiovascular disease, relative to those consuming no or heavy alcohol. There are only minimal data on the association between alcohol and brain magnetic resonance imaging (MRI) markers. This study aimed to examine the association between alcohol and brain structure measured with MRI.
In this cross-sectional study, high-resolution structural MRI was collected on 589 multi-ethnic community residents of New York aged ≥65 with available alcohol intake assessments via a food frequency questionnaire. Total brain volume (TBV), white matter hyperintensity volume (WMHV), and presence of infarcts were derived from MRI scans with established methods. We examined the association of alcohol intake with these imaging markers using regression models adjusted for demographic, clinical, and vascular risk factors.
Compared to non-drinking, light-to-moderate total alcohol (b=0.007, p=0.04) or wine (b= 0.008, p=0.05) intake, but not beer or liquor intake, was associated with larger TBV. Further analysis showed a dose-response association between alcohol (p-trend=0.03) or wine (p-trend=0.006)) and TBV. Overall, alcohol intake was not associated with WMHV or brain infarcts.
Our study suggests that among older adults in the community, light-to-moderate alcohol intake, in particular wine, is associated with larger TBV. These findings suggest that light to moderate alcohol consumption is potentially beneficial for brain aging, but replication is needed.
PMCID: PMC4048329  PMID: 24011900
Alcohol; nutrition; magnetic resonance imaging (MRI); brain atrophy; cerebrovascular disease; neuroepidemiology
2.  Brain Amyloid Deposition and Longitudinal Cognitive Decline in Nondemented Older Subjects: Results from a Multi-Ethnic Population 
PLoS ONE  2015;10(7):e0123743.
We aimed to whether the abnormally high amyloid-β (Aβ) level in the brain among apparently healthy elders is related with subtle cognitive deficits and/or accelerated cognitive decline.
A total of 116 dementia-free participants (mean age 84.5 years) of the Washington Heights Inwood Columbia Aging Project completed 18F-Florbetaben PET imaging. Positive or negative cerebral Aβ deposition was assessed visually. Quantitative cerebral Aβ burden was calculated as the standardized uptake value ratio in pre-established regions of interest using cerebellar cortex as the reference region. Cognition was determined using a neuropsychological battery and selected tests scores were combined into four composite scores (memory, language, executive/speed, and visuospatial) using exploratory factor analysis. We examined the relationship between cerebral Aβ level and longitudinal cognition change up to 20 years before the PET scan using latent growth curve models, controlling for age, education, ethnicity, and Apolipoprotein E (APOE) genotype.
Positive reading of Aβ was found in 41 of 116 (35%) individuals. Cognitive scores at scan time was not related with Aβ. All cognitive scores declined over time. Aβ positive reading (B = -0.034, p = 0.02) and higher Aβ burden in temporal region (B = -0.080, p = 0.02) were associated with faster decline in executive/speed. Stratified analyses showed that higher Aβ deposition was associated with faster longitudinal declines in mean cognition, language, and executive/speed in African-Americans or in APOE ε4 carriers, and with faster memory decline in APOE ε4 carriers. The associations remained significant after excluding mild cognitive impairment participants.
High Aβ deposition in healthy elders was associated with decline in executive/speed in the decade before neuroimaging, and the association was observed primarily in African-Americans and APOE ε4 carriers. Our results suggest that measuring cerebral Aβ may give us important insights into the cognitive profile in the years prior to the scan in cognitively normal elders.
PMCID: PMC4519341  PMID: 26221954
3.  Morphometric variability of neuroimaging features in Children with Agenesis of the Corpus Callosum 
BMC Neurology  2015;15:116.
Agenesis of the corpus callosum (ACC) is a developmental brain malformation associated with a wide spectrum of structural brain abnormalities and genetic loci. To characterize the diverse callosal morphologies and malformations of brain development associated with ACC, we report on the neuroimaging findings of 201 individuals diagnosed with corpus callosal abnormalities.
We searched through medical records of individuals seen at New York Presbyterian Hospital between 2002 and 2013 and thought to have ACC. We confirmed 201 individuals meeting criteria and used magnetic resonance imaging to characterize morphological variants of the corpus callosum and associated brain malformations.
The majority of individuals displayed hypoplasia or dysplasia of the corpus callosum (N = 160, 80 %). Forty-one (20 %) displayed complete agenesis of the corpus callosum with other abnormalities, while only 18 (9 %) displayed complete agenesis without associated brain abnormalities. White matter abnormalities were more frequent in hypoplasia or dysplasia group than complete agenesis (28.2 % vs 9.8 %, p < 0.05). In contrast, hippocampal abnormalities, colpocephaly, and Probst bundles were significantly more frequent in complete agenesis compared to hypoplasia or dysplasia group.
Collectively, our results underscore the broad diversity of morphological variants of the corpus callosum and associated brain abnormalities in individuals with ACC.
PMCID: PMC4515020  PMID: 26209096
Agenesis; Dysplasia; Corpus callosum; Brain development; Neuroradiology
4.  F-box/LRR-repeat protein 7 is genetically associated with Alzheimer’s disease 
In the context of late-onset Alzheimer’s disease (LOAD) over 20 genes have been identified but, aside APOE, all show small effect sizes, leaving a large part of the genetic component unexplained. Admixed populations, such as Caribbean Hispanics, can provide a valuable contribution because of their unique genetic profile and higher incidence of the disease. We aimed to identify novel loci associated with LOAD.
About 4514 unrelated Caribbean Hispanics (2451 cases and 2063 controls) were selected for genome-wide association analysis. Significant loci were further tested in the expanded cohort that also included related family members (n = 5300). Two AD-like transgenic mice models (J20 and rTg4510) were used to study gene expression. Independent data sets of non-Hispanic Whites and African Americans were used to further validate findings, along with publicly available brain expression data sets.
A novel locus, rs75002042 in FBXL7 (5p15.1), was found genome-wide significant in the case–control cohort (odd ratio [OR] = 0.61, P = 6.19E-09) and confirmed in the related members cohorts (OR = 0.63, P = 4.7E-08). Fbxl7 protein was overexpressed in both AD-like transgenic mice compared to wild-type littermates. Publicly available microarray studies also showed significant overexpression of Fbxl7 in LOAD brains compared to nondemented controls. single-nucleotide polymorphism (SNP) rs75002042 was in complete linkage disequilibrium with other variants in two independent non-Hispanic White and African American data sets (0.0005 < P < 0.02) used for replication.
FBXL7, encodes a subcellular protein involved in phosphorylation-dependent ubiquitination processes and displays proapoptotic activity. F-box proteins also modulate inflammation and innate immunity, which may be important in LOAD pathogenesis. Further investigations are needed to validate and understand its role in this and other populations.
PMCID: PMC4554442  PMID: 26339675
5.  Missense variant in TREML2 protects against Alzheimer’s Disease 
Neurobiology of aging  2013;35(6):1510.e19-1510.e26.
TREM and TREM-like receptors are a structurally similar protein family encoded by genes clustered on chromosome 6p21.11. Recent studies have identified a rare coding variant (p.R47H) in TREM2 that confers a high risk for Alzheimer’s disease (AD). In addition, common SNPs in this genomic region are associated with cerebrospinal fluid (CSF) biomarkers for AD and a common intergenic variant found near the TREML2 gene has been identified to be protective for AD. However, little is known about the functional variant underlying the latter association or its relationship with the p.R47H. Here, we report comprehensive analyses using whole-exome sequencing data, CSF biomarker analyses, meta-analyses (16,254 cases and 20,052 controls) and cell-based functional studies to support the role of the TREML2 coding missense variant p.S144G (rs3747742) as a potential driver of the meta-analysis AD-associated GWAS signal. Additionally, we demonstrate that the protective role of TREML2 in AD is independent of the role of TREM2 gene as a risk factor for AD.
PMCID: PMC3961557  PMID: 24439484
6.  ABCC9 gene polymorphism is associated with hippocampal sclerosis of aging pathology 
Acta neuropathologica  2014;127(6):825-843.
Hippocampal sclerosis of aging (HS-Aging) is a high-morbidity brain disease in the elderly but risk factors are largely unknown. We report the first genome-wide association study (GWAS) with HS-Aging pathology as an endophenotype. In collaboration with the Alzheimer’s Disease Genetics Consortium, data were analyzed from large autopsy cohorts: (#1) National Alzheimer’s Coordinating Center (NACC); (#2) Rush University Religious Orders Study and Memory and Aging Project; (#3) Group Health Research Institute Adult Changes in Thought study; (#4) University of California at Irvine 90+ Study; and (#5) University of Kentucky Alzheimer’s Disease Center. Altogether, 363 HS-Aging cases and 2,303 controls, all pathologically confirmed, provided statistical power to test for risk alleles with large effect size. A two-tier study design included GWAS from cohorts #1–3 (Stage I) to identify promising SNP candidates, followed by focused evaluation of particular SNPs in cohorts #4–5 (Stage II). Polymorphism in the ATP-binding cassette, sub-family C member 9 (ABCC9) gene, also known as sulfonylurea receptor 2, was associated with HS-Aging pathology. In the meta-analyzed Stage I GWAS, ABCC9 polymorphisms yielded the lowest p values, and factoring in the Stage II results, the meta-analyzed risk SNP (rs704178:G) attained genome-wide statistical significance (p = 1.4 × 10−9), with odds ratio (OR) of 2.13 (recessive mode of inheritance). For SNPs previously linked to hippocampal sclerosis, meta-analyses of Stage I results show OR = 1.16 for rs5848 (GRN) and OR = 1.22 rs1990622 (TMEM106B), with the risk alleles as previously described. Sulfonylureas, a widely prescribed drug class used to treat diabetes, also modify human ABCC9 protein function. A subsample of patients from the NACC database (n = 624) were identified who were older than age 85 at death with known drug history. Controlling for important confounders such as diabetes itself, exposure to a sulfonylurea drug was associated with risk for HS-Aging pathology (p = 0.03). Thus, we describe a novel and targetable dementia risk factor.
PMCID: PMC4113197  PMID: 24770881
Oldest old; Neuropathology; KATP; CTAGE5; ADGC; Potassium channel
7.  Association of C-Reactive Protein to Cognitive Impairment 
Archives of neurology  2010;67(1):87-92.
High sensitivity C-reactive protein (hsCRP) is a biomarker of cardiovascular risk suggested as a biomarker for cognitive impairment.
To explore the association between hsCRP and cognitive impairment
Cross-sectional analysis of a population-based community aging study
Northern Manhattan, New York
1331 participants from a longitudinal study of aging without dementia and available hsCRP and neuropsychological testing at baseline.
Main Outcome Measures
Four cognitive scores (memory, visuospatial, executive, language) derived from a neuropsychological battery. Cognitive impairment was defined by scores below 1.5 SD of demographically corrected means.
Participants with the highest hsCRP tertile had higher adjusted odds of impaired memory (OR=1.5, 95%CI: 1.0–2.1; p for trend = 0.03) than participants with the lowest tertile Subjects in the highest hsCRP tertile also had greater odds of visuospatial impairment (OR=1.6, 95% CI: 1.0–2.3; p for trend-0.03). Higher hsCRP was not associated with executive or language impairment. Persons with at least one APOE-ε4 allele and hsCRP in the highest tertile had the greatest odds of impaired memory (OR=2.7, 95% CI: 1.6–4.4).
High hsCRP may be a marker of memory and visuspatial impairment in the elderly. The role of APOE-ε4 requires further exploration.
PMCID: PMC4426905  PMID: 20065134
8.  Gene-Wise Association of Variants in Four Lysosomal Storage Disorder Genes in Neuropathologically Confirmed Lewy Body Disease 
PLoS ONE  2015;10(5):e0125204.
Variants in GBA are associated with Lewy Body (LB) pathology. We investigated whether variants in other lysosomal storage disorder (LSD) genes also contribute to disease pathogenesis.
We performed a genetic analysis of four LSD genes including GBA, HEXA, SMPD1, and MCOLN1 in 231 brain autopsies. Brain autopsies included neuropathologically defined LBD without Alzheimer Disease (AD) changes (n = 59), AD without significant LB pathology (n = 71), Alzheimer disease and lewy body variant (ADLBV) (n = 68), and control brains without LB or AD neuropathology (n = 33). Sequencing of HEXA, SMPD1, MCOLN1 and GBA followed by ‘gene wise’ genetic association analysis was performed. To determine the functional effect, a biochemical analysis of GBA in a subset of brains was also performed. GCase activity was measured in a subset of brain samples (n = 64) that included LBD brains, with or without GBA mutations, and control brains. A lipidomic analysis was also performed in brain autopsies (n = 67) which included LBD (n = 34), ADLBV (n = 3), AD (n = 4), PD (n = 9) and control brains (n = 17), comparing GBA mutation carriers to non-carriers.
In a ‘gene-wise’ analysis, variants in GBA, SMPD1 and MCOLN1 were significantly associated with LB pathology (p range: 0.03–4.14 x10-5). Overall, the mean levels of GCase activity were significantly lower in GBA mutation carriers compared to non-carriers (p<0.001). A significant increase and accumulation of several species for the lipid classes, ceramides and sphingolipids, was observed in LBD brains carrying GBA mutations compared to controls (p range: p<0.05-p<0.01).
Our study indicates that variants in GBA, SMPD1 and MCOLN1 are associated with LB pathology. Biochemical data comparing GBA mutation carrier to non-carriers support these findings, which have important implications for biomarker development and therapeutic strategies.
PMCID: PMC4416714  PMID: 25933391
9.  Alzheimer disease: Epidemiology, Diagnostic Criteria, Risk Factors and Biomarkers 
Biochemical pharmacology  2014;88(4):640-651.
The global prevalence of dementia is as high as 24 million, and has been predicted to quadruple by the year 2050. In the US alone, Alzheimer disease (AD) – the most frequent cause of dementia characterized by a progressive decline in cognitive function in particular the memory domain -causes estimated health-care costs of $172 billion per year. Key neuropathological hallmarks of the AD brain are diffuse and neuritic extracellular amyloid plaques—often surrounded by dystrophic neurites—and intracellular neurofibrillary tangles. These pathological changes are frequently accompanied by reactive microgliosis and loss of neurons, white matter and synapses. The etiological mechanisms underlying these neuropathological changes remain unclear, but are probably caused by both environmental and genetic factors. In this review article, we provide an overview of the epidemiology of AD, review the biomarkers that may be used for risk assessment and in diagnosis, and give suggestions for future research
PMCID: PMC3992261  PMID: 24398425
10.  TREM2 is associated with increased risk for Alzheimer’s disease in African Americans 
TREM2 encodes for triggering receptor expressed on myeloid cells 2 and has rare, coding variants that associate with risk for late-onset Alzheimer’s disease (LOAD) in Caucasians of European and North-American origin. This study evaluated the role of TREM2 in LOAD risk in African-American (AA) subjects. We performed exonic sequencing and validation in two independent cohorts of >800 subjects. We selected six coding variants (p.R47H, p.R62H, p.D87N, p.E151K, p.W191X, and p.L211P) for case–control analyses in a total of 906 LOAD cases vs. 2,487 controls.
We identified significant LOAD risk association with p.L211P (p = 0.01, OR = 1.27, 95%CI = 1.05-1.54) and suggestive association with p.W191X (p = 0.08, OR = 1.35, 95%CI = 0.97-1.87). Conditional analysis suggests that p.L211P, which is in linkage disequilibrium with p.W191X, may be the stronger variant of the two, but does not rule out independent contribution of the latter. TREM2 p.L211P resides within the cytoplasmic domain and p.W191X is a stop-gain mutation within the shorter TREM-2V transcript. The coding variants within the extracellular domain of TREM2 previously shown to confer LOAD risk in Caucasians were extremely rare in our AA cohort and did not associate with LOAD risk.
Our findings suggest that TREM2 coding variants also confer LOAD risk in AA, but implicate variants within different regions of the gene than those identified for Caucasian subjects. These results underscore the importance of investigating different ethnic populations for disease risk variant discovery, which may uncover allelic heterogeneity with potentially diverse mechanisms of action.
Electronic supplementary material
The online version of this article (doi:10.1186/s13024-015-0016-9) contains supplementary material, which is available to authorized users.
PMCID: PMC4426167  PMID: 25886450
LOAD; African-American; TREM2; Coding variants; Case–control
11.  Genetics of Alzheimer’s disease in Caribbean Hispanic and African American Populations 
Biological psychiatry  2013;75(7):534-541.
Late-onset Alzheimer’s disease, which is characterized by progressive deterioration in cognition, function and behavior, is the most common cause of dementia and the sixth leading cause of all deaths placing a considerable burden on western societies. Most studies aiming to identify genetic susceptibility factors for LOAD have focused on non-Hispanic white populations. This is, in part related to differences in linkage disequilibrium and allele frequencies between ethnic groups that could lead to confounding. However, in addition, non-Hispanic white populations are simply more widely studied. As a consequence, minorities are genetically under-represented despite the fact that in several minority populations living in the same community as Whites (including African American and Caribbean Hispanics) LOAD incidence is higher. This review summarizes the current knowledge on genetic risk factors associated with LOAD risk in Caribbean Hispanics and African Americans and provides suggestions for future research. We focus on Caribbean Hispanics and African Americans as they have a high LOAD incidence and a body of genetic studies on LOAD that is based on samples with GWAS data and reasonable large effect sizes to yield generalizable results.
PMCID: PMC3902050  PMID: 23890735
Alzheimer’s disease; genetics; gene; Caribbean Hispanic; African American; minorities
12.  Genome-wide association study identifies common loci influencing circulating glycated hemoglobin (HbA1c) levels in non-diabetic subjects: the Long Life Family Study (LLFS) 
Glycated hemoglobin (HbA1c) is a stable index of chronic glycemic status and hyperglycemia associated with progressive development of insulin resistance and frank diabetes. It is also associated with premature aging and increased mortality. To uncover novel loci for HbA1c that are associated with healthy aging, we conducted a genome-wide association study (GWAS) using non-diabetic participants in the Long Life Family Study (LLFS), a study with familial clustering of exceptional longevity in the US and Denmark.
A total of 4,088 non-diabetic subjects from the LLFS were used for GWAS discoveries, and a total of 8,231 non-diabetic subjects from the Atherosclerosis Risk in Communities Study (ARIC, in the MAGIC Consortium) and the Health, Aging, and Body Composition Study (HABC) were used for GWAS replications. HbA1c was adjusted for age, sex, centers, 20 principal components, without and with BMI. A linear mixed effects model was used for association testing.
Two known loci at GCK rs730497 (or rs2908282) and HK1 rs17476364 were confirmed (p < 5e–8). Of 25 suggestive (5e–8 < p < 1e–5) loci, one known (G6PC2 rs560887, replication p = 5e–5) and one novel (OR10R3P/SPTA1- rs12041363, replication p = 1e–17) loci were replicated (p < 0.0019). Similar findings resulted when HbA1c was further adjusted for BMI. Further validations are crucial for the remaining suggestive loci including the emerged variant near OR10R3P/SPTA1.
The analysis reconfirmed two known GWAS loci (GCK, HK1) and identified 25 suggestive loci including one reconfirmed variant in G6PC2 and one replicated variant near OR10R3P/SPTA1. Future focused survey of sequence elements containing mainly functional and regulatory variants may yield additional findings.
PMCID: PMC3965585  PMID: 24405752
Genome-wide association study; Non-enzymatic glycation; Glucose, insulin resistance and diabetes; Premature aging processes
13.  Heritability of and Mortality Prediction With a Longevity Phenotype: The Healthy Aging Index 
Longevity-associated genes may modulate risk for age-related diseases and survival. The Healthy Aging Index (HAI) may be a subphenotype of longevity, which can be constructed in many studies for genetic analysis. We investigated the HAI’s association with survival in the Cardiovascular Health Study and heritability in the Long Life Family Study.
The HAI includes systolic blood pressure, pulmonary vital capacity, creatinine, fasting glucose, and Modified Mini-Mental Status Examination score, each scored 0, 1, or 2 using approximate tertiles and summed from 0 (healthy) to 10 (unhealthy). In Cardiovascular Health Study, the association with mortality and accuracy predicting death were determined with Cox proportional hazards analysis and c-statistics, respectively. In Long Life Family Study, heritability was determined with a variance component–based family analysis using a polygenic model.
Cardiovascular Health Study participants with unhealthier index scores (7–10) had 2.62-fold (95% confidence interval: 2.22, 3.10) greater mortality than participants with healthier scores (0–2). The HAI alone predicted death moderately well (c-statistic = 0.643, 95% confidence interval: 0.626, 0.661, p < .0001) and slightly worse than age alone (c-statistic = 0.700, 95% confidence interval: 0.684, 0.717, p < .0001; p < .0001 for comparison of c-statistics). Prediction increased significantly with adjustment for demographics, health behaviors, and clinical comorbidities (c-statistic = 0.780, 95% confidence interval: 0.765, 0.794, p < .0001). In Long Life Family Study, the heritability of the HAI was 0.295 (p < .0001) overall, 0.387 (p < .0001) in probands, and 0.238 (p = .0004) in offspring.
The HAI should be investigated further as a candidate phenotype for uncovering longevity-associated genes in humans.
PMCID: PMC3968826  PMID: 23913930
Epidemiology; Genetics; Longevity; Successful aging.
14.  Common Genetic Variants on 6q24 Associated With Exceptional Episodic Memory Performance in the Elderly 
JAMA neurology  2014;71(12):1514-1519.
There aregenetic influences on memory ability as we age. but no specific genes have been identified.
To use a cognitive endophenotype. exceptional episodic memory(EEM) performance. derived from nondemented offspring from the Long Life FamilyStudy(LLFS) to identify genetic variants that may be responsible for the high cognitive performance of LLFS participants and further replicate these variants using an additional 4006 nondemented individuals from 4 independent elderly cohorts
A total of 467 LLFS participants from 18 families with 2 or more offspring that exhibited exceptional memory performance were used for genome-wide linkage analysis Adjusted multivariate linear analyses in the 40-megabase region encompassing the linkage peak were conducted using 4 independent replication data sets that included 4006 nondemented elderly individuals. Results of the individual replication cohorts were combined by meta-analysis
Episodic memory scores computed as the mean of the 2 standardized measures of Logical Memory IA and IIA
Heritability estimates indicated a significant genetic component for E EM (h2 = 0.21; SE = 0.09) Genome-wide linkage analysis revealed that EEM was linked to the 6q24 region (maximum logarithm of odds score, 3.64) Association analysis in LLFS families identified single-nucleotide polymorphisms (SNPs) nominally associated with EEM in the 40-megabase window encompassing the linkage peak Replication in one cohort identified a set of 26 SNPs associated with episodic memory (P ≤ 05) Meta-analysis of the 26 SNPs using the 4 independent replication cohorts found SN Ps rs9321334 and rs6902875 to be nominally significantly associated with episodic memory (P= .009 and P = .013. respectively). With meta-analysis restricted to individuals lacking an APOE ε4 allele. SNP rs6902875 became statistically significant (meta-analysis. P = 6.7 × 10−5) Haplotypeanalysis incorporating the 2 SNPs flanking rs6902875 (rs9321334 and rs48975 74) revealed that the A-A-Chap lotype was significantly associated with episodic memory performance (P = 2.4 × 10−5). This genomic region harbors monooxygenase dopamine β-hydroxylase-1ike 1gene (MOXD1). implicated in the biosynthesis of norepinephrine. which is prominently involved in cognitive functions.
The results provide strong evidence for potential candidate genes related to EE Mon 6q24 Identifying the genes will help in understanding the biological basis of memory performance and allow interventions for enhancement of cognitive function.
PMCID: PMC4355405  PMID: 25317765
15.  Longitudinal change in CSF biomarkers in autosomal-dominant Alzheimer disease 
Science translational medicine  2014;6(226):226ra30.
Clinicopathologic evidence suggests the pathology of Alzheimer disease (AD) begins many years prior to cognitive symptoms. Biomarkers are required to identify affected individuals during this asymptomatic (“pre-clinical”) stage to permit intervention with potential disease-modifying therapies designed to preserve normal brain function. Studies of families with autosomal-dominant AD (ADAD) mutations provide a unique and powerful means to investigate AD biomarker changes during the asymptomatic period. In this biomarker study comparing cerebrospinal fluid (CSF), plasma and in vivo amyloid imaging, cross-sectional data obtained at baseline in individuals from ADAD families enrolled in the Dominantly Inherited Alzheimer Network (DIAN) demonstrate reduced concentrations of CSF amyloid-β1-42 (Aβ1–42) associated with the presence of β-amyloid plaques, and elevated concentrations of CSF tau, ptau181 and VILIP-1, markers of neurofibrillary tangles and/or neuronal injury/death, in asymptomatic mutation carriers 10-20 years prior to their estimated age at symptom onset (EAO), and prior to detection of cognitive deficits. When compared longitudinally, however, the concentrations of CSF biomarkers of neuronal injury/death within-individuals decrease after their EAO, suggesting a slowing of acute neurodegenerative processes with symptomatic disease progression. These results emphasize the importance of longitudinal, within-person assessment when modeling biomarker trajectories across the course of the disease. If corroborated, this pattern may influence the definition of a positive neurodegenerative biomarker outcome in clinical trials.
PMCID: PMC4038930  PMID: 24598588
16.  Age-at-Onset in Late Onset Alzheimer Disease is Modified by Multiple Genetic Loci 
JAMA neurology  2014;71(11):1394-1404.
As APOE locus variants contribute to both risk of late-onset Alzheimer disease and differences in age-at-onset, it is important to know if other established late-onset Alzheimer disease risk loci also affect age-at-onset in cases.
To investigate the effects of known Alzheimer disease risk loci in modifying age-at-onset, and to estimate their cumulative effect on age-at-onset variation, using data from genome-wide association studies in the Alzheimer’s Disease Genetics Consortium (ADGC).
Design, Setting and Participants
The ADGC comprises 14 case-control, prospective, and family-based datasets with data on 9,162 Caucasian participants with Alzheimer’s occurring after age 60 who also had complete age-at-onset information, gathered between 1989 and 2011 at multiple sites by participating studies. Data on genotyped or imputed single nucleotide polymorphisms (SNPs) most significantly associated with risk at ten confirmed LOAD loci were examined in linear modeling of AAO, and individual dataset results were combined using a random effects, inverse variance-weighted meta-analysis approach to determine if they contribute to variation in age-at-onset. Aggregate effects of all risk loci on AAO were examined in a burden analysis using genotype scores weighted by risk effect sizes.
Main Outcomes and Measures
Age at disease onset abstracted from medical records among participants with late-onset Alzheimer disease diagnosed per standard criteria.
Analysis confirmed association of APOE with age-at-onset (rs6857, P=3.30×10−96), with associations in CR1 (rs6701713, P=7.17×10−4), BIN1 (rs7561528, P=4.78×10−4), and PICALM (rs561655, P=2.23×10−3) reaching statistical significance (P<0.005). Risk alleles individually reduced age-at-onset by 3-6 months. Burden analyses demonstrated that APOE contributes to 3.9% of variation in age-at-onset (R2=0.220) over baseline (R2=0.189) whereas the other nine loci together contribute to 1.1% of variation (R2=0.198).
Conclusions and Relevance
We confirmed association of APOE variants with age-at-onset among late-onset Alzheimer disease cases and observed novel associations with age-at-onset in CR1, BIN1, and PICALM. In contrast to earlier hypothetical modeling, we show that the combined effects of Alzheimer disease risk variants on age-at-onset are on the scale of, but do not exceed, the APOE effect. While the aggregate effects of risk loci on age-at-onset may be significant, additional genetic contributions to age-at-onset are individually likely to be small.
PMCID: PMC4314944  PMID: 25199842
Alzheimer Disease; Alzheimer Disease Genetics; Alzheimer’s Disease - Pathophysiology; Genetics of Alzheimer Disease; Aging
17.  Symptom onset in autosomal dominant Alzheimer disease 
Neurology  2014;83(3):253-260.
To identify factors influencing age at symptom onset and disease course in autosomal dominant Alzheimer disease (ADAD), and develop evidence-based criteria for predicting symptom onset in ADAD.
We have collected individual-level data on ages at symptom onset and death from 387 ADAD pedigrees, compiled from 137 peer-reviewed publications, the Dominantly Inherited Alzheimer Network (DIAN) database, and 2 large kindreds of Colombian (PSEN1 E280A) and Volga German (PSEN2 N141I) ancestry. Our combined dataset includes 3,275 individuals, of whom 1,307 were affected by ADAD with known age at symptom onset. We assessed the relative contributions of several factors in influencing age at onset, including parental age at onset, age at onset by mutation type and family, and APOE genotype and sex. We additionally performed survival analysis using data on symptom onset collected from 183 ADAD mutation carriers followed longitudinally in the DIAN Study.
We report summary statistics on age at onset and disease course for 174 ADAD mutations, and discover strong and highly significant (p < 10−16, r2 > 0.38) correlations between individual age at symptom onset and predicted values based on parental age at onset and mean ages at onset by mutation type and family, which persist after controlling for APOE genotype and sex.
Significant proportions of the observed variance in age at symptom onset in ADAD can be explained by family history and mutation type, providing empirical support for use of these data to estimate onset in clinical research.
PMCID: PMC4117367  PMID: 24928124
18.  Genetic variants in a ‘cAMP element binding protein’ (CREB)-dependent histone acetylation pathway influence memory performance in cognitively healthy elderly individuals 
Neurobiology of aging  2014;35(12):2881.e7-2881.e10.
The molecular pathways underlying age-related memory changes remain unclear. There is a substantial genetic contribution to memory performance though life span. A recent study has implicated RbAp48, which mediates its effect on age-related memory decline by interacting with CBP (CREB1 Binding Protein) and influencing this histone acetylation pathway. To validate these findings, we tested whether genetic variants in RbAp48, CREB1 and CREBBP are associated with memory performance in three independent datasets consisting of 2674 cognitively healthy elderly. Genetic variant rs2526690 in the CREBBP gene was significantly associated with episodic memory performance (Pmeta = 3.7 × 10-4) in a multivariate model adjusted for age, sex and APOE status. Identifying genetic variants that modulate mechanisms of cognitive aging will allow identifying valid targets for therapeutic intervention.
PMCID: PMC4253058  PMID: 25150575
histone metabolism; meta-analysis; episodic memory performance
19.  Functional Connectivity in Autosomal Dominant and Late-Onset Alzheimer Disease 
JAMA neurology  2014;71(9):1111-1122.
Autosomal dominant Alzheimer disease (ADAD) is caused by rare genetic mutations in three specific genes, in contrast to late-onset Alzheimer Disease (LOAD), which has a more polygenetic risk profile.
Design, Setting, and Participants
We analyzed functional connectivity in multiple brain resting state networks (RSNs) in a cross-sectional cohort of ADAD (N=79) and LOAD (N=444) human participants using resting state functional connectivity MRI (rs-fcMRI) at multiple international academic sites.
Main Outcomes and Measures
For both types of AD, we quantified and compared functional connectivity changes in RSNs as a function of dementia severity as measured by clinical dementia rating (CDR). In ADAD, we qualitatively investigated functional connectivity changes with respect to estimated years from onset of symptoms within five RSNs.
Functional connectivity decreases with increasing CDR were similar for both LOAD and ADAD in multiple RSNs. Ordinal logistic regression models constructed in each type of AD accurately predicted CDR stage in the other, further demonstrating similarity of functional connectivity loss in each disease type. Among ADAD participants, functional connectivity in multiple RSNs appeared qualitatively lower in asymptomatic mutation carriers near their anticipated age of symptom onset compared to asymptomatic mutation non-carriers.
Conclusions and Relevance
rs-fcMRI changes with progressing AD severity are similar between ADAD and LOAD. Rs-fcMRI may be a useful endpoint for LOAD and ADAD therapy trials. ADAD disease process may be an effective model for LOAD disease process.
PMCID: PMC4240274  PMID: 25069482
Resting-state functional connectivity; autosomal dominant Alzheimer's disease; late-onset Alzheimer's disease; default mode network; apolipoprotein E (APOE)
20.  Course and etiology of dysexecutive MCI in a community sample 
Amnestic MCI (aMCI) is associated with an elevated risk of progressing to Alzheimer’s disease. Much less is known about the course of dysexecutive MCI (dMCI). The goals of this study were to determine: How the profile of cognitive deficits differs over time between patients with dMCI, aMCI, and control subjects; if the type of dementia differs between dMCI and aMCI in patients who progress to dementia; and if dMCI is more associated with strokes and white matter hyperintensities on MRI than aMCI.
A prospective evaluation of an inception cohort of 1167 ethnically-diverse elders recruited from an urban community-based sample and followed with clinical and neuropsychological testing over an average of 4.5 years (SD=0.8). A subset of the subjects had MRI scans. We compared four groups of MCI patients: single domain amnestic and dysexecutive MCI and multiple domain MCI with and without executive dysfunction.
Compared with aMCI, dMCI was less likely to involve other areas of cognition over time and progress to dementia. None of the 33 single domain dMCI patients progressed to dementia. The presence of executive dysfunction in multiple domain MCI did not increase risk of progression to dementia. Patients with multiple domain MCI with executive dysfunction who progressed to dementia were less likely to have an Alzheimer’s type dementia than MCI patients without executive dysfunction. Patients with dMCI were more likely to have strokes, but not white matter hyperintensities, detected on MRI than patients with aMCI.
DMCI appears to follow a different course, and be less associated with AD and more associated with stroke, than aMCI.
PMCID: PMC3933297  PMID: 23452959
21.  Genome-Wide Association Meta-analysis of Neuropathologic Features of Alzheimer's Disease and Related Dementias 
PLoS Genetics  2014;10(9):e1004606.
Alzheimer's disease (AD) and related dementias are a major public health challenge and present a therapeutic imperative for which we need additional insight into molecular pathogenesis. We performed a genome-wide association study and analysis of known genetic risk loci for AD dementia using neuropathologic data from 4,914 brain autopsies. Neuropathologic data were used to define clinico-pathologic AD dementia or controls, assess core neuropathologic features of AD (neuritic plaques, NPs; neurofibrillary tangles, NFTs), and evaluate commonly co-morbid neuropathologic changes: cerebral amyloid angiopathy (CAA), Lewy body disease (LBD), hippocampal sclerosis of the elderly (HS), and vascular brain injury (VBI). Genome-wide significance was observed for clinico-pathologic AD dementia, NPs, NFTs, CAA, and LBD with a number of variants in and around the apolipoprotein E gene (APOE). GalNAc transferase 7 (GALNT7), ATP-Binding Cassette, Sub-Family G (WHITE), Member 1 (ABCG1), and an intergenic region on chromosome 9 were associated with NP score; and Potassium Large Conductance Calcium-Activated Channel, Subfamily M, Beta Member 2 (KCNMB2) was strongly associated with HS. Twelve of the 21 non-APOE genetic risk loci for clinically-defined AD dementia were confirmed in our clinico-pathologic sample: CR1, BIN1, CLU, MS4A6A, PICALM, ABCA7, CD33, PTK2B, SORL1, MEF2C, ZCWPW1, and CASS4 with 9 of these 12 loci showing larger odds ratio in the clinico-pathologic sample. Correlation of effect sizes for risk of AD dementia with effect size for NFTs or NPs showed positive correlation, while those for risk of VBI showed a moderate negative correlation. The other co-morbid neuropathologic features showed only nominal association with the known AD loci. Our results discovered new genetic associations with specific neuropathologic features and aligned known genetic risk for AD dementia with specific neuropathologic changes in the largest brain autopsy study of AD and related dementias.
Author Summary
Alzheimer's disease (AD) and related dementias are a major public health challenge and present a therapeutic imperative for which we need additional insight into molecular pathogenesis. We performed a genome-wide association study (GWAS), as well as an analysis of known genetic risk loci for AD dementia, using data from 4,914 brain autopsies. Genome-wide significance was observed for 7 genes and pathologic features of AD and related diseases. Twelve of the 22 genetic risk loci for clinically-defined AD dementia were confirmed in our pathologic sample. Correlation of effect sizes for risk of AD dementia with effect size for hallmark pathologic features of AD were strongly positive and linear. Our study discovered new genetic associations with specific pathologic features and aligned known genetic risk for AD dementia with specific pathologic changes in a large brain autopsy study of AD and related dementias.
PMCID: PMC4154667  PMID: 25188341
22.  Reduced Prevalence of Cognitive impairment in families with exceptional longevity 
JAMA neurology  2013;70(7):867-874.
To determine if families with exceptional longevity are protected against cognitive impairment consistent with Alzheimer’s disease (AD).
Cross-sectional analysis.
Multi-site study in NY, MA, PA, and Denmark.
1870 individuals (1510 family members and 360 spouse controls) recruited through the Long Life Family Study (LLFS).
Main Outcome Measures
Prevalence of cognitive impairment based on a diagnostic algorithm validated using the National Alzheimer’s Coordinating Center dataset.
The cognitive algorithm classified 546 (38.5%) individuals as having cognitive impairment consistent with AD. LLFS probands had a slightly but not statistically significant reduced risk of cognitive impairment compared with spouse controls (121/232 for probandsvs 45/103 for spouse controls: OR = 0.70; 95% CI (0.4–1.4)), whereas LLFS sons and daughters had a clearly reduced risk of cognitive impairment (11/213 for sons and daughters vs 28/216 for spouse controls: OR = 0.40; 95% CI (0.2–0.9)). Restriction to nieces and nephews in the offspring generation attenuated this effect (37/328 for nieces and nephews vs 28/216 for spouse controls OR = 0.70; 95% CI (0.4–1.4).
Rates of cognitive impairment characteristic of AD were relatively high. In the proband generation, rates were comparable across family members and spouse controls whereas sons and daughters of probands had significantly lower rates than spouse controls. Results suggest a delayed onset of cognitive impairment in families with exceptional longevity, but assessment of age-specific incidence rates is required to confirm this hypothesis.
PMCID: PMC4151346  PMID: 23649824
23.  Disease-related mutations among Caribbean Hispanics with familial dementia 
Pathogenic mutations in the three known genes – the amyloid precursor protein (APP), presenilin 1 (PSEN1), presenilin 2 (PSEN2) – are known to cause familial Alzheimer's disease (AD) and tend to be associated with early-onset AD. However, the frequency and risk associated with these mutations vary widely. In addition, mutations in the frontotemporal lobar degeneration (FTLD) genes – the microtubule-associated protein tau (MAPT), granulin (GRN) – have also been found to be associated with clinical AD. Here, we conducted targeted resequencing of the exons in genes encoding APP, PSEN1, PSEN2, GRN, and MAPT in 183 individuals from families with four or more affected relatives, presumed to be AD, and living in the Dominican Republic and Puerto Rico. We then performed linkage and family-based association analyses in carrier families, and genotyped 498 similarly aged unrelated controls from the same ethnic background. Twelve potentially pathogenic mutations were found to be associated with disease in 53 individuals in the five genes. The most frequently observed mutation was the p.Gly206Ala variant in PSEN1 present in 30 (57%) of those sequenced. In the combined linkage and association analyses several rare variants were associated with dementia. In Caribbean Hispanics with familial AD, potentially pathogenic variants were present in 29.2%, four were novel mutations, while eight had been previously observed. In addition, some family members carried variants in the GRN and MAPT genes which are associated with FTLD.
PMCID: PMC4190878  PMID: 25333068
Alzheimer's disease; Caribbean Hispanics; familial dementia; mutations; next-generation sequencing
24.  Lessons from Epidemiologic Research about Risk Factors, Modifiers, and Progression of Late Onset Alzheimer’s Disease in New York City at Columbia University Medical Center 
Journal of Alzheimer's disease : JAD  2013;33(0 1):S447-S455.
This review summarizes the findings and importance of 12 articles from research at Columbia University in New York City that were among the most cited in the literature between 2006 and 2011. The 12 articles summarized in this review made important contributions to the field of Alzheimer’s disease in the last 5 years. Four of the articles established the Mediterranean diet as a food consumption pattern that may prevent Alzheimer’s disease in addition to physical activity. Two of the articles advanced our knowledge of predictors of conversion from mild cognitive impairment to dementia. Four of the articles provided important knowledge of risk factors for the progression of Alzheimer’s disease and its complications. Lastly, one of the articles laid the theoretical framework for the study of cognitive reserve, an important modifier of the manifestation of Alzheimer’s disease. These studies have advanced our knowledge about risk factors, modifiers, and progression of late onset Alzheimer’s disease.
PMCID: PMC4149254  PMID: 22836187
Alzheimer’s disease; conversion; diet; cognitive reserve; epidemiology; genes; mild cognitive impairment; predictors; progression; risk factors
25.  Epidemiology of Alzheimer Disease 
The global prevalence of dementia has been estimated to be as high as 24 million, and is predicted to double every 20 years until at least 2040. As the population worldwide continues to age, the number of individuals at risk will also increase, particularly among the very old. Alzheimer disease is the leading cause of dementia beginning with impaired memory. The neuropathological hallmarks of Alzheimer disease include diffuse and neuritic extracellular amyloid plaques in brain that are frequently surrounded by dystrophic neurites and intraneuronal neurofibrillary tangles. The etiology of Alzheimer disease remains unclear, but it is likely to be the result of both genetic and environmental factors. In this review we discuss the prevalence and incidence rates, the established environmental risk factors, and the protective factors, and briefly review genetic variants predisposing to disease.
Alzheimer disease is the most frequent cause of dementia in Western societies. Advancing age and genetic and nongenetic antecedent factors (e.g., education and obesity) are thought to play important roles.
PMCID: PMC3405821  PMID: 22908189

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