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1.  Age-at-Onset in Late Onset Alzheimer Disease is Modified by Multiple Genetic Loci 
JAMA neurology  2014;71(11):1394-1404.
Importance
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.
Objectives
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.
Results
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.
doi:10.1001/jamaneurol.2014.1491
PMCID: PMC4314944  PMID: 25199842
Alzheimer Disease; Alzheimer Disease Genetics; Alzheimer’s Disease - Pathophysiology; Genetics of Alzheimer Disease; Aging
2.  Symptom onset in autosomal dominant Alzheimer disease 
Neurology  2014;83(3):253-260.
Objective:
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.
Methods:
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.
Results:
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.
Conclusions:
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.
doi:10.1212/WNL.0000000000000596
PMCID: PMC4117367  PMID: 24928124
3.  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.
doi:10.1016/j.neurobiolaging.2014.06.024
PMCID: PMC4253058  PMID: 25150575
histone metabolism; meta-analysis; episodic memory performance
4.  Functional Connectivity in Autosomal Dominant and Late-Onset Alzheimer Disease 
JAMA neurology  2014;71(9):1111-1122.
Importance
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.
Results
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.
doi:10.1001/jamaneurol.2014.1654
PMCID: PMC4240274  PMID: 25069482
Resting-state functional connectivity; autosomal dominant Alzheimer's disease; late-onset Alzheimer's disease; default mode network; apolipoprotein E (APOE)
5.  Course and etiology of dysexecutive MCI in a community sample 
Background
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.
Methods
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.
Results
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.
Conclusions
DMCI appears to follow a different course, and be less associated with AD and more associated with stroke, than aMCI.
doi:10.1016/j.jalz.2012.10.014
PMCID: PMC3933297  PMID: 23452959
6.  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.
doi:10.1371/journal.pgen.1004606
PMCID: PMC4154667  PMID: 25188341
7.  Reduced Prevalence of Cognitive impairment in families with exceptional longevity 
JAMA neurology  2013;70(7):867-874.
Objective
To determine if families with exceptional longevity are protected against cognitive impairment consistent with Alzheimer’s disease (AD).
Design
Cross-sectional analysis.
Setting
Multi-site study in NY, MA, PA, and Denmark.
Participants
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.
Results
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).
Conclusions
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.
doi:10.1001/jamaneurol.2013.1959
PMCID: PMC4151346  PMID: 23649824
8.  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.
doi:10.1002/mgg3.85
PMCID: PMC4190878  PMID: 25333068
Alzheimer's disease; Caribbean Hispanics; familial dementia; mutations; next-generation sequencing
9.  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.
doi:10.3233/JAD-2012-129041
PMCID: PMC4149254  PMID: 22836187
Alzheimer’s disease; conversion; diet; cognitive reserve; epidemiology; genes; mild cognitive impairment; predictors; progression; risk factors
10.  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.
doi:10.1101/cshperspect.a006239
PMCID: PMC3405821  PMID: 22908189
11.  Dysexecutive versus amnestic Alzheimer’s disease subgroups: Analysis of demographic, genetic, and vascular factors 
The objective of this study was to compare demographic and vascular characteristics and APOE genotypes of a dysexecutive subgroup of Alzheimer’s disease (AD) with an amnestic subgroup of AD early in the disease course. 2,224 participants from the National Alzheimer’s Coordinating Center (NACC) database who carried a diagnosis of MCI (n=1,188) or mild AD (clinical dementia rating ≤1) (n=1,036) were included in this study. A subset of the MCI (n=61) and mild AD (n=79) participants underwent autopsy. A dysexecutive subgroup (n=587) was defined as having executive performance >1 SD worse than memory performance and an amnestic subgroup (n=549) was defined conversely. Among the autopsy subset, the likelihood of an AD pathologic diagnosis was compared in the two subgroups. Demographics, APOEε4 status, and vascular risk factors were compared in the two subgroups. Among the autopsy subset, the likelihood of having an AD pathologic diagnosis did not differ between the dysexecutive and amnestic subgroups. Under an additive model, participants in the dysexecutive subgroup possessed the APOEε4 allele less frequently than those in the amnestic subgroup. The dysexecutive subgroup had a history of hypertension less frequently than the amnestic subgroup. These distinct characteristics add to accumulating evidence that a dysexecutive subgroup of AD may have a unique underlying pathophysiology.
doi:10.1097/WAD.0b013e31826a94bd
PMCID: PMC3748394  PMID: 23954887
12.  Association of MAPT haplotypes with Alzheimer’s disease risk and MAPT brain gene expression levels 
Introduction
MAPT encodes for tau, the predominant component of neurofibrillary tangles that are neuropathological hallmarks of Alzheimer’s disease (AD). Genetic association of MAPT variants with late-onset AD (LOAD) risk has been inconsistent, although insufficient power and incomplete assessment of MAPT haplotypes may account for this.
Methods
We examined the association of MAPT haplotypes with LOAD risk in more than 20,000 subjects (n-cases = 9,814, n-controls = 11,550) from Mayo Clinic (n-cases = 2,052, n-controls = 3,406) and the Alzheimer’s Disease Genetics Consortium (ADGC, n-cases = 7,762, n-controls = 8,144). We also assessed associations with brain MAPT gene expression levels measured in the cerebellum (n = 197) and temporal cortex (n = 202) of LOAD subjects. Six single nucleotide polymorphisms (SNPs) which tag MAPT haplotypes with frequencies greater than 1% were evaluated.
Results
H2-haplotype tagging rs8070723-G allele associated with reduced risk of LOAD (odds ratio, OR = 0.90, 95% confidence interval, CI = 0.85-0.95, p = 5.2E-05) with consistent results in the Mayo (OR = 0.81, p = 7.0E-04) and ADGC (OR = 0.89, p = 1.26E-04) cohorts. rs3785883-A allele was also nominally significantly associated with LOAD risk (OR = 1.06, 95% CI = 1.01-1.13, p = 0.034). Haplotype analysis revealed significant global association with LOAD risk in the combined cohort (p = 0.033), with significant association of the H2 haplotype with reduced risk of LOAD as expected (p = 1.53E-04) and suggestive association with additional haplotypes. MAPT SNPs and haplotypes also associated with brain MAPT levels in the cerebellum and temporal cortex of AD subjects with the strongest associations observed for the H2 haplotype and reduced brain MAPT levels (β = -0.16 to -0.20, p = 1.0E-03 to 3.0E-03).
Conclusions
These results confirm the previously reported MAPT H2 associations with LOAD risk in two large series, that this haplotype has the strongest effect on brain MAPT expression amongst those tested and identify additional haplotypes with suggestive associations, which require replication in independent series. These biologically congruent results provide compelling evidence to screen the MAPT region for regulatory variants which confer LOAD risk by influencing its brain gene expression.
doi:10.1186/alzrt268
PMCID: PMC4198935  PMID: 25324900
13.  Gene-Wide Analysis Detects Two New Susceptibility Genes for Alzheimer's Disease 
Escott-Price, Valentina | Bellenguez, Céline | Wang, Li-San | Choi, Seung-Hoan | Harold, Denise | Jones, Lesley | Holmans, Peter | Gerrish, Amy | Vedernikov, Alexey | Richards, Alexander | DeStefano, Anita L. | Lambert, Jean-Charles | Ibrahim-Verbaas, Carla A. | Naj, Adam C. | Sims, Rebecca | Jun, Gyungah | Bis, Joshua C. | Beecham, Gary W. | Grenier-Boley, Benjamin | Russo, Giancarlo | Thornton-Wells, Tricia A. | Denning, Nicola | Smith, Albert V. | Chouraki, Vincent | Thomas, Charlene | Ikram, M. Arfan | Zelenika, Diana | Vardarajan, Badri N. | Kamatani, Yoichiro | Lin, Chiao-Feng | Schmidt, Helena | Kunkle, Brian | Dunstan, Melanie L. | Vronskaya, Maria | Johnson, Andrew D. | Ruiz, Agustin | Bihoreau, Marie-Thérèse | Reitz, Christiane | Pasquier, Florence | Hollingworth, Paul | Hanon, Olivier | Fitzpatrick, Annette L. | Buxbaum, Joseph D. | Campion, Dominique | Crane, Paul K. | Baldwin, Clinton | Becker, Tim | Gudnason, Vilmundur | Cruchaga, Carlos | Craig, David | Amin, Najaf | Berr, Claudine | Lopez, Oscar L. | De Jager, Philip L. | Deramecourt, Vincent | Johnston, Janet A. | Evans, Denis | Lovestone, Simon | Letenneur, Luc | Hernández, Isabel | Rubinsztein, David C. | Eiriksdottir, Gudny | Sleegers, Kristel | Goate, Alison M. | Fiévet, Nathalie | Huentelman, Matthew J. | Gill, Michael | Brown, Kristelle | Kamboh, M. Ilyas | Keller, Lina | Barberger-Gateau, Pascale | McGuinness, Bernadette | Larson, Eric B. | Myers, Amanda J. | Dufouil, Carole | Todd, Stephen | Wallon, David | Love, Seth | Rogaeva, Ekaterina | Gallacher, John | George-Hyslop, Peter St | Clarimon, Jordi | Lleo, Alberto | Bayer, Anthony | Tsuang, Debby W. | Yu, Lei | Tsolaki, Magda | Bossù, Paola | Spalletta, Gianfranco | Proitsi, Petra | Collinge, John | Sorbi, Sandro | Garcia, Florentino Sanchez | Fox, Nick C. | Hardy, John | Naranjo, Maria Candida Deniz | Bosco, Paolo | Clarke, Robert | Brayne, Carol | Galimberti, Daniela | Scarpini, Elio | Bonuccelli, Ubaldo | Mancuso, Michelangelo | Siciliano, Gabriele | Moebus, Susanne | Mecocci, Patrizia | Zompo, Maria Del | Maier, Wolfgang | Hampel, Harald | Pilotto, Alberto | Frank-García, Ana | Panza, Francesco | Solfrizzi, Vincenzo | Caffarra, Paolo | Nacmias, Benedetta | Perry, William | Mayhaus, Manuel | Lannfelt, Lars | Hakonarson, Hakon | Pichler, Sabrina | Carrasquillo, Minerva M. | Ingelsson, Martin | Beekly, Duane | Alvarez, Victoria | Zou, Fanggeng | Valladares, Otto | Younkin, Steven G. | Coto, Eliecer | Hamilton-Nelson, Kara L. | Gu, Wei | Razquin, Cristina | Pastor, Pau | Mateo, Ignacio | Owen, Michael J. | Faber, Kelley M. | Jonsson, Palmi V. | Combarros, Onofre | O'Donovan, Michael C. | Cantwell, Laura B. | Soininen, Hilkka | Blacker, Deborah | Mead, Simon | Mosley, Thomas H. | Bennett, David A. | Harris, Tamara B. | Fratiglioni, Laura | Holmes, Clive | de Bruijn, Renee F. A. G. | Passmore, Peter | Montine, Thomas J. | Bettens, Karolien | Rotter, Jerome I. | Brice, Alexis | Morgan, Kevin | Foroud, Tatiana M. | Kukull, Walter A. | Hannequin, Didier | Powell, John F. | Nalls, Michael A. | Ritchie, Karen | Lunetta, Kathryn L. | Kauwe, John S. K. | Boerwinkle, Eric | Riemenschneider, Matthias | Boada, Mercè | Hiltunen, Mikko | Martin, Eden R. | Schmidt, Reinhold | Rujescu, Dan | Dartigues, Jean-François | Mayeux, Richard | Tzourio, Christophe | Hofman, Albert | Nöthen, Markus M. | Graff, Caroline | Psaty, Bruce M. | Haines, Jonathan L. | Lathrop, Mark | Pericak-Vance, Margaret A. | Launer, Lenore J. | Van Broeckhoven, Christine | Farrer, Lindsay A. | van Duijn, Cornelia M. | Ramirez, Alfredo | Seshadri, Sudha | Schellenberg, Gerard D. | Amouyel, Philippe | Williams, Julie
PLoS ONE  2014;9(6):e94661.
Background
Alzheimer's disease is a common debilitating dementia with known heritability, for which 20 late onset susceptibility loci have been identified, but more remain to be discovered. This study sought to identify new susceptibility genes, using an alternative gene-wide analytical approach which tests for patterns of association within genes, in the powerful genome-wide association dataset of the International Genomics of Alzheimer's Project Consortium, comprising over 7 m genotypes from 25,580 Alzheimer's cases and 48,466 controls.
Principal Findings
In addition to earlier reported genes, we detected genome-wide significant loci on chromosomes 8 (TP53INP1, p = 1.4×10−6) and 14 (IGHV1-67 p = 7.9×10−8) which indexed novel susceptibility loci.
Significance
The additional genes identified in this study, have an array of functions previously implicated in Alzheimer's disease, including aspects of energy metabolism, protein degradation and the immune system and add further weight to these pathways as potential therapeutic targets in Alzheimer's disease.
doi:10.1371/journal.pone.0094661
PMCID: PMC4055488  PMID: 24922517
14.  Molecular drivers and cortical spread of lateral entorhinal cortex dysfunction in preclinical Alzheimer’s disease 
Nature neuroscience  2013;17(2):304-311.
The entorhinal cortex has been implicated in the early stages of Alzheimer’s disease, which is characterized by changes in the tau protein and in the cleaved fragments of the amyloid precursor protein (APP). We used a high-resolution functional magnetic resonance imaging (fMRI) variant that can map metabolic defects in patients and mouse models to address basic questions about entorhinal cortex pathophysiology. The entorhinal cortex is divided into functionally distinct regions, the medial entorhinal cortex (MEC) and the lateral entorhinal cortex (LEC), and we exploited the high-resolution capabilities of the fMRI variant to ask whether either of them was affected in patients with preclinical Alzheimer’s disease. Next, we imaged three mouse models of disease to clarify how tau and APP relate to entorhinal cortex dysfunction and to determine whether the entorhinal cortex can act as a source of dysfunction observed in other cortical areas. We found that the LEC was affected in preclinical disease, that LEC dysfunction could spread to the parietal cortex during preclinical disease and that APP expression potentiated tau toxicity in driving LEC dysfunction, thereby helping to explain regional vulnerability in the disease.
doi:10.1038/nn.3606
PMCID: PMC4044925  PMID: 24362760
15.  Meta-analysis of 74,046 individuals identifies 11 new susceptibility loci for Alzheimer’s disease 
Lambert, Jean-Charles | Ibrahim-Verbaas, Carla A | Harold, Denise | Naj, Adam C | Sims, Rebecca | Bellenguez, Céline | Jun, Gyungah | DeStefano, Anita L | Bis, Joshua C | Beecham, Gary W | Grenier-Boley, Benjamin | Russo, Giancarlo | Thornton-Wells, Tricia A | Jones, Nicola | Smith, Albert V | Chouraki, Vincent | Thomas, Charlene | Ikram, M Arfan | Zelenika, Diana | Vardarajan, Badri N | Kamatani, Yoichiro | Lin, Chiao-Feng | Gerrish, Amy | Schmidt, Helena | Kunkle, Brian | Dunstan, Melanie L | Ruiz, Agustin | Bihoreau, Marie-Thérèse | Choi, Seung-Hoan | Reitz, Christiane | Pasquier, Florence | Hollingworth, Paul | Ramirez, Alfredo | Hanon, Olivier | Fitzpatrick, Annette L | Buxbaum, Joseph D | Campion, Dominique | Crane, Paul K | Baldwin, Clinton | Becker, Tim | Gudnason, Vilmundur | Cruchaga, Carlos | Craig, David | Amin, Najaf | Berr, Claudine | Lopez, Oscar L | De Jager, Philip L | Deramecourt, Vincent | Johnston, Janet A | Evans, Denis | Lovestone, Simon | Letenneur, Luc | Morón, Francisco J | Rubinsztein, David C | Eiriksdottir, Gudny | Sleegers, Kristel | Goate, Alison M | Fiévet, Nathalie | Huentelman, Matthew J | Gill, Michael | Brown, Kristelle | Kamboh, M Ilyas | Keller, Lina | Barberger-Gateau, Pascale | McGuinness, Bernadette | Larson, Eric B | Green, Robert | Myers, Amanda J | Dufouil, Carole | Todd, Stephen | Wallon, David | Love, Seth | Rogaeva, Ekaterina | Gallacher, John | St George-Hyslop, Peter | Clarimon, Jordi | Lleo, Alberto | Bayer, Anthony | Tsuang, Debby W | Yu, Lei | Tsolaki, Magda | Bossù, Paola | Spalletta, Gianfranco | Proitsi, Petroula | Collinge, John | Sorbi, Sandro | Sanchez-Garcia, Florentino | Fox, Nick C | Hardy, John | Deniz Naranjo, Maria Candida | Bosco, Paolo | Clarke, Robert | Brayne, Carol | Galimberti, Daniela | Mancuso, Michelangelo | Matthews, Fiona | Moebus, Susanne | Mecocci, Patrizia | Zompo, Maria Del | Maier, Wolfgang | Hampel, Harald | Pilotto, Alberto | Bullido, Maria | Panza, Francesco | Caffarra, Paolo | Nacmias, Benedetta | Gilbert, John R | Mayhaus, Manuel | Lannfelt, Lars | Hakonarson, Hakon | Pichler, Sabrina | Carrasquillo, Minerva M | Ingelsson, Martin | Beekly, Duane | Alvarez, Victoria | Zou, Fanggeng | Valladares, Otto | Younkin, Steven G | Coto, Eliecer | Hamilton-Nelson, Kara L | Gu, Wei | Razquin, Cristina | Pastor, Pau | Mateo, Ignacio | Owen, Michael J | Faber, Kelley M | Jonsson, Palmi V | Combarros, Onofre | O’Donovan, Michael C | Cantwell, Laura B | Soininen, Hilkka | Blacker, Deborah | Mead, Simon | Mosley, Thomas H | Bennett, David A | Harris, Tamara B | Fratiglioni, Laura | Holmes, Clive | de Bruijn, Renee F A G | Passmore, Peter | Montine, Thomas J | Bettens, Karolien | Rotter, Jerome I | Brice, Alexis | Morgan, Kevin | Foroud, Tatiana M | Kukull, Walter A | Hannequin, Didier | Powell, John F | Nalls, Michael A | Ritchie, Karen | Lunetta, Kathryn L | Kauwe, John S K | Boerwinkle, Eric | Riemenschneider, Matthias | Boada, Mercè | Hiltunen, Mikko | Martin, Eden R | Schmidt, Reinhold | Rujescu, Dan | Wang, Li-san | Dartigues, Jean-François | Mayeux, Richard | Tzourio, Christophe | Hofman, Albert | Nöthen, Markus M | Graff, Caroline | Psaty, Bruce M | Jones, Lesley | Haines, Jonathan L | Holmans, Peter A | Lathrop, Mark | Pericak-Vance, Margaret A | Launer, Lenore J | Farrer, Lindsay A | van Duijn, Cornelia M | Van Broeckhoven, Christine | Moskvina, Valentina | Seshadri, Sudha | Williams, Julie | Schellenberg, Gerard D | Amouyel, Philippe
Nature genetics  2013;45(12):1452-1458.
Eleven susceptibility loci for late-onset Alzheimer’s disease (LOAD) were identified by previous studies; however, a large portion of the genetic risk for this disease remains unexplained. We conducted a large, two-stage meta-analysis of genome-wide association studies (GWAS) in individuals of European ancestry. In stage 1, we used genotyped and imputed data (7,055,881 SNPs) to perform meta-analysis on 4 previously published GWAS data sets consisting of 17,008 Alzheimer’s disease cases and 37,154 controls. In stage 2,11,632 SNPs were genotyped and tested for association in an independent set of 8,572 Alzheimer’s disease cases and 11,312 controls. In addition to the APOE locus (encoding apolipoprotein E), 19 loci reached genome-wide significance (P < 5 × 10−8) in the combined stage 1 and stage 2 analysis, of which 11 are newly associated with Alzheimer’s disease.
doi:10.1038/ng.2802
PMCID: PMC3896259  PMID: 24162737
16.  Epidemiology of Alzheimer Disease 
Cold Spring Harbor perspectives in medicine  2012;2(8):10.1101/cshperspect.a006239 a006239.
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 intra-neuronal 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.
doi:10.1101/cshperspect.a006239
PMCID: PMC3405821  PMID: 22908189
17.  Investigation of C9orf72 in 4 Neurodegenerative Disorders 
Archives of neurology  2012;69(12):1583-1590.
Objective
To estimate the allele frequency of C9orf72 (G4C2) repeats in amyotrophic lateral sclerosis (ALS), frontotemporal lobar degeneration (FTLD), Alzheimer disease (AD), and Parkinson disease (PD).
Design
The number of repeats was estimated by a 2-step genotyping strategy. For expansion carriers, we sequenced the repeat flanking regions and obtained APOE genotypes and MAPT H1/H2 haplotypes.
Setting
Hospitals specializing in neurodegenerative disorders.
Subjects
We analyzed 520 patients with FTLD, 389 patients with ALS, 424 patients with AD, 289 patients with PD, 602 controls, 18 families, and 29 patients with PD with the LRRK2 G2019S mutation.
Main Outcome Measure
The expansion frequency.
Results
Based on a prior cutoff (>30 repeats), the expansion was detected in 9.3% of patients with ALS, 5.2% of patients with FTLD, and 0.7% of patients with PD but not in controls or patients with AD. It was significantly associated with family history of ALS or FTLD and age at onset of FTLD. Phenotype variation (ALS vs FTLD) was not associated with MAPT, APOE, or variability in the repeat flanking regions. Two patients with PD were carriers of 39 and 32 repeats with questionable pathological significance, since the 39-repeat allele does not segregate with PD. No expansion or intermediate alleles (20–29 repeats) were found among the G2019S carriers and AD cases with TAR DNA-binding protein 43–positive inclusions. Surprisingly, the frequency of the 10-repeat allele was marginally increased in all 4 neurodegenerative diseases compared with controls, indicating the presence of an unknown risk variation in the C9orf72 locus.
Conclusions
The C9orf72 expansion is a common cause of ALS and FTLD, but not of AD or PD. Our study raises concern about a reliable cutoff for the pathological repeat number, which is important in the utility of genetic screening.
doi:10.1001/archneurol.2012.2016
PMCID: PMC4005900  PMID: 22964832
18.  Age-Specific Incidence Rates for Dementia and Alzheimer Disease in NIA-LOAD/NCRAD and EFIGA Families 
JAMA neurology  2014;71(3):315-323.
IMPORTANCE
Late-onset Alzheimer disease (LOAD), defined as onset of symptoms after age 65 years, is the most common form of dementia. Few reports investigate incidence rates in large family-based studies in which the participants were selected for family history of LOAD.
OBJECTIVE
To determine the incidence rates of dementia and LOAD in unaffected members in the National Institute on Aging Genetics Initiative for Late-Onset Alzheimer Disease/National Cell Repository for Alzheimer Disease (NIA-LOAD/NCRAD) and Estudio Familiar de Influencia Genetica en Alzheimer (EFIGA) family studies.
DESIGN, SETTING, AND PARTICIPANTS
Families with 2 or more affected siblings who had a clinical or pathological diagnosis of LOAD were recruited as a part of the NIA-LOAD/NCRAD Family Study. A cohort of Caribbean Hispanics with familial LOAD was recruited in a different study at the Taub Institute for Research on Alzheimer’s Disease and the Aging Brain in New York and from clinics in the Dominican Republic as part of the EFIGA study.
MAIN OUTCOMES AND MEASURES
Age-specific incidence rates of LOAD were estimated in the unaffected family members in the NIA-LOAD/NCRAD and EFIGA data sets. We restricted analyses to families with follow-up and complete phenotype information, including 396 NIA-LOAD/NCRAD and 242 EFIGA families. Among the 943 at-risk family members in the NIA-LOAD/NCRAD families, 126 (13.4%) developed dementia, of whom 109 (86.5%) met criteria for LOAD. Among 683 at-risk family members in the EFIGA families, 174 (25.5%) developed dementia during the study period, of whom 145 (83.3%) had LOAD.
RESULTS
The annual incidence rates of dementia and LOAD in the NIA-LOAD/NCRAD families per person-year were 0.03 and 0.03, respectively, in participants aged 65 to 74 years; 0.07 and 0.06, respectively, in those aged 75 to 84 years; and 0.08 and 0.07, respectively, in those 85 years or older. Incidence rates in the EFIGA families were slightly higher, at 0.03 and 0.02, 0.06 and 0.05, 0.10 and 0.08, and 0.10 and 0.07, respectively, in the same age groups. Contrasting these results with the population-based estimates, the incidence was increased by 3-fold for NIA-LOAD/NCRAD families (standardized incidence ratio, 3.44) and 2-fold among the EFIGA compared with the NIA-LOAD/NCRAD families (1.71).
CONCLUSIONS AND RELEVANCE
The incidence rates for familial dementia and LOAD in the NIA-LOAD/NCRAD and EFIGA families are significantly higher than population-based estimates. The incidence rates in all groups increase with age. The higher incidence of LOAD can be explained by segregation of Alzheimer disease–related genes in these families or shared environmental risks.
doi:10.1001/jamaneurol.2013.5570
PMCID: PMC4000602  PMID: 24425039
19.  GWAS of cerebrospinal fluid tau levels identifies novel risk variants for Alzheimer’s disease 
Neuron  2013;78(2):256-268.
Cerebrospinal fluid (CSF) tau, tau phosphorylated at threonine 181 (ptau) and Aβ42 are established biomarkers for Alzheimer’s Disease (AD), and have been used as quantitative traits for genetic analyses. We performed the largest genome-wide association study for cerebrospinal fluid (CSF) tau/ptau levels published to date (n=1,269), identifying three novel genome-wide significant loci for CSF tau and ptau: rs9877502 (P=4.89×10−9 for tau) located at 3q28 between GEMC1 and OSTN, rs514716 (P=1.07×10−8 and P=3.22×10−9 for tau and ptau respectively), located at 9p24.2 within GLIS3 and rs6922617 (P = 3.58×10−8 for CSF ptau) at 6p21.1 within the TREM gene cluster, a region recently reported to harbor rare variants that increase AD risk. In independent datasets rs9877502 showed a strong association with risk for AD, tangle pathology and global cognitive decline (P=2.67×10−4, 0.039, 4.86×10−5 respectively) illustrating how this endophenotype-based approach can be used to identify new AD risk loci.
doi:10.1016/j.neuron.2013.02.026
PMCID: PMC3664945  PMID: 23562540
20.  Evidence of Recessive Alzheimer Disease Loci in a Caribbean Hispanic Data Set 
JAMA neurology  2013;70(10):1261-1267.
IMPORTANCE
The search for novel Alzheimer disease (AD) genes or pathologic mutations within known AD loci is ongoing. The development of array technologies has helped to identify rare recessive mutations among long runs of homozygosity (ROHs), in which both parental alleles are identical. Caribbean Hispanics are known to have an elevated risk for AD and tend to have large families with evidence of inbreeding.
OBJECTIVE
To test the hypothesis that the late-onset AD in a Caribbean Hispanic population might be explained in part by the homozygosity of unknown loci that could harbor recessive AD risk haplotypes or pathologic mutations.
DESIGN
We used genome-wide array data to identify ROHs (>1 megabase) and conducted global burden and locus-specific ROH analyses.
SETTING
A whole-genome case-control ROH study.
PARTICIPANTS
A Caribbean Hispanic data set of 547 unrelated cases (48.8% with familial AD) and 542 controls collected from a population known to have a 3-fold higher risk of AD vs non-Hispanics in the same community. Based on a Structure program analysis, our data set consisted of African Hispanic (207 cases and 192 controls) and European Hispanic (329 cases and 326 controls) participants.
EXPOSURE
Alzheimer disease risk genes.
MAIN OUTCOMES AND MEASURES
We calculated the total and mean lengths of the ROHs per sample. Global burden measurements among autosomal chromosomes were investigated in cases vs controls. Pools of overlapping ROH segments (consensus regions) were identified, and the case to control ratio was calculated for each consensus region. We formulated the tested hypothesis before data collection.
RESULTS
In total, we identified 17 137 autosomal regions with ROHs. The mean length of the ROH per person was significantly greater in cases vs controls (P = .0039), and this association was stronger with familial AD (P = .0005). Among the European Hispanics, a consensus region at the EXOC4 locus was significantly associated with AD even after correction for multiple testing (empirical P value 1 [EMP1], .0001; EMP2, .002; 21 AD cases vs 2 controls). Among the African Hispanic subset, the most significant but nominal association was observed for CTNNA3, a well-known AD gene candidate (EMP1, .002; 10 AD cases vs 0 controls).
CONCLUSIONS AND RELEVANCE
Our results show that ROHs could significantly contribute to the etiology of AD. Future studies would require the analysis of larger, relatively inbred data sets that might reveal novel recessive AD genes. The next step is to conduct sequencing of top significant loci in a subset of samples with overlapping ROHs.
doi:10.1001/jamaneurol.2013.3545
PMCID: PMC3991012  PMID: 23978990
21.  TREM2 and Neurodegenerative Disease 
The New England journal of medicine  2013;369(16):1564-1565.
doi:10.1056/NEJMc1306509#SA1
PMCID: PMC3980568  PMID: 24131184
22.  Apolipoprotein E and Familial Longevity 
Neurobiology of aging  2012;34(4):1287-1291.
Background
Exceptional longevity is associated with substantial heritability. The ε4 allele in Apolipoprotein E and the linked G allele in rs2075650 of TOMM40 have been associated with increased mortality and the ε2 allele with decreased mortality, although inconsistently.
Methods
Offspring from long lived families and spouse controls were recruited at three sites in the US and in Denmark. We used Generalized Estimating Equations to compare the likelihood of carrying risk alleles in offspring (n=2,307) and spouse controls (n=764), adjusting for age, sex, level of education and family membership.
Results
The likelihood of carrying an APOE ε4 allele or a G allele in rs2075650 was lower (OR=0.75, p =.005 and OR=0.70, p = .002) and the likelihood of carrying an APOE ε2 allele was higher (OR= 1.5, p = .007) among family members in the offspring generation than among their spouse controls.
Conclusions
Our findings support the hypothesis that both reduction in the frequency of the ε4 allele and increase in the frequency of the ε2 allele contribute to longevity.
doi:10.1016/j.neurobiolaging.2012.08.019
PMCID: PMC3545094  PMID: 23040522
Exceptional longevity; familial longevity; offspring; APOE; TOMM40
23.  C9ORF72 repeat expansions not detected in a group of patients with schizophrenia 
Neurobiology of aging  2012;34(4):1309.e9-1309.10.
A hexanucleotide repeat expansion in C9ORF72 was recently found to cause some cases of FTLD, FTD-ALS, and ALS. FTLD patients with the C9ORF72 repeat expansion are more likely than those without to present with psychosis. In this study, we screened DNA samples from 192 unrelated subjects with schizophrenia for the C9ORF72 repeat expansion. None of the subjects with schizophrenia had the pathogenic expansion. C9ORF72 repeat expansions either do not cause schizophrenia, or do so rarely (less than 1% of cases).
doi:10.1016/j.neurobiolaging.2012.08.011
PMCID: PMC3584690  PMID: 23036583
FTLD; Schizophrenia; C9ORF72 repeat expansion; psychosis
24.  Initial Assessment of the Pathogenic Mechanisms of the recently identified Alzheimer Risk Loci 
Annals of human genetics  2013;77(2):85-105.
SUMMARY
Recent genome wide association studies have identified CLU, CR1, ABCA7 BIN1, PICALM and MS4A6A/MS4A6E in addition to the long established APOE, as loci for Alzheimer’s disease. We have systematically examined each of these loci to assess whether common coding variability contributes to the risk of disease. We have also assessed the regional expression of all the genes in the brain and whether there is evidence of an eQTL explaining the risk. In agreement with other studies we find that coding variability may explain the ABCA7 association, but common coding variability does not explain any of the other loci. We were not able to show that any of the loci had eQTLs within the power of this study. Furthermore the regional expression of each of the loci did not match the pattern of brain regional distribution in Alzheimer pathology.
Although these results are mainly negative, they allow us to start defining more realistic alternative approaches to determine the role of all the genetic loci involved in Alzheimer’s disease.
doi:10.1111/ahg.12000
PMCID: PMC3578142  PMID: 23360175
Alzheimer’s disease; genetic risk; GWAS
25.  White matter hyperintensity volume and impaired mobility among older adults 
Journal of neurology  2012;260(3):884-890.
Gait speed is associated with multiple adverse outcomes of aging. White matter hyperintensities (WMH) on magnetic resonance imaging (MRI) have been associated with gait speed, though few studies have examined changes in gait speed over time in population-based studies comprising participants from diverse cultural backgrounds. The purpose of this study was to examine the association between a decline in gait speed and total and regional WMH volumes in a community-based study of aging. Participants (n=701) in a community-based study of older adults underwent gait speed measurement via a 4-meter walk test at the time of initial enrollment and MRI at a second time interval (mean 4.7[SD=0.5] years apart). Logistic regression was used to examine the association between large WMH volume and regional WMH volume with gait speed < 0.5 m/s (abnormal speed), and a transition to abnormal gait speed. Analyses were adjusted for demographic and clinical factors. Large WMH volume was associated with a transition to abnormal gait speed between the two visits, but not after adjustment for modifiable vascular disease risk factors. In adjusted models increased frontal lobe WMH volume was not associated with a transition to abnormal gait speed.
WMH are associated with slowing of gait over time. Prevention of WMH presents a potential strategy for the prevention of gait speed decline.
doi:10.1007/s00415-012-6731-z
PMCID: PMC3594567  PMID: 23128969

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