A Multiancestral Genome-Wide Exome Array Study of Alzheimer Disease, Frontotemporal Dementia, and Progressive Supranuclear Palsy

Importance Previous studies have indicated a heritable component of the etiology of neurodegenerative diseases such as Alzheimer disease (AD), frontotemporal dementia (FTD), and progressive supranuclear palsy (PSP). However, few have examined the contribution of low-frequency coding variants on a genome-wide level. Objective To identify low-frequency coding variants that affect susceptibility to AD, FTD, and PSP. Design, Setting, and Participants We used the Illumina HumanExome BeadChip array to genotype a large number of variants (most of which are low-frequency coding variants) in a cohort of patients with neurodegenerative disease (224 with AD, 168 with FTD, and 48 with PSP) and in 224 control individuals without dementia enrolled between 2005-2012 from multiple centers participating in the Genetic Investigation in Frontotemporal Dementia and Alzheimer’s Disease (GIFT) Study. An additional multiancestral replication cohort of 240 patients with AD and 240 controls without dementia was used to validate suggestive findings. Variant-level association testing and gene-based testing were performed. Main Outcomes and Measures Statistical association of genetic variants with clinical diagnosis of AD, FTD, and PSP. Results Genetic variants typed by the exome array explained 44%, 53%, and 57% of the total phenotypic variance of AD, FTD, and PSP, respectively. An association with the known AD gene ABCA7 was replicated in several ancestries (discovery P = .0049, European P = .041, African American P = .043, and Asian P = .027), suggesting that exonic variants within this gene modify AD susceptibility. In addition, 2 suggestive candidate genes, DYSF (P = 5.53 × 10−5) and PAXIP1 (P = 2.26 × 10−4), were highlighted in patients with AD and differentially expressed in AD brain. Corroborating evidence from other exome array studies and gene expression data points toward potential involvement of these genes in the pathogenesis of AD. Conclusions and Relevance Low-frequency coding variants with intermediate effect size may account for a significant fraction of the genetic susceptibility to AD and FTD. Furthermore, we found evidence that coding variants in the known susceptibility gene ABCA7, as well as candidate genes DYSF and PAXIP1, confer risk for AD

Correction to: A nonsynonymous mutation in PLCG2 reduces the risk of Alzheimer’s disease, dementia with Lewy bodies and frontotemporal dementia, and increases the likelihood of longevity

The IPDGC (The International Parkinson Disease Genomics Consortium) and EADB (Alzheimer Disease European DNA biobank) are listed correctly as an author to the article, however, they were incorrectly listed more than once

Correction to: A nonsynonymous mutation in PLCG2 reduces the risk of Alzheimer’s disease, dementia with Lewy bodies and frontotemporal dementia, and increases the likelihood of longevity

The IPDGC (The International Parkinson Disease Genomics Consortium) and EADB (Alzheimer Disease European DNA biobank) are listed correctly as an author to the article, however, they were incorrectly listed more than once

The A431E mutation in PSEN1 causing Familial Alzheimer's Disease originating in Jalisco State, Mexico: An additional fifteen families

Nine families with autosomal dominant Alzheimer's disease (AD), all of whom had the Ala431Glu substitution in the PSEN1 gene and came from Jalisco State in Mexico, have been previously reported. As they shared highly polymorphic flanking dinucleotide marker alleles, this strongly suggests that this mutation arose from a common founder. In the current letter, we expand this observation by describing an additional 15 independent families with the Ala431Glu substitution in the PSEN1 gene and conclude that this mutation is not an uncommon cause of early-onset autosomal dominant AD in persons of Mexican origin. � Springer-Verlag 2006

Deflazacort induced stronger immunosuppression than expected

Background: Prospective and case-control studies have demonstrated that memory loss and executive dysfunction occur early in Alzheimer disease (AD). Objective: To investigate these observations by the study of persons at risk for autosomal dominant forms of AD. Methods: Neuropsychological and genetic tests were performed on 51 nondemented at-risk members of 10 Mexican families with two distinct presenilin-1 (PS1) mutations. Test scores were compared between PS1 mutation carriers (MCs; n = 30) and noncarriers (NCs; n = 21) by analyses of variance, co-varying for family and specific mutation. Regression analyses were performed, taking into account age relative to the median age at dementia diagnosis in the family (adjusted age), gender, Beck Depression Inventory (BDI) scores, education, and number of APOE ?4 alleles. Subjects were divided into age tertiles and scores compared within these groups. Composite scores for Verbal Memory, Executive Function/Working Memory, Language, and Visuospatial Function were created, and these scores compared between MCs and NCs. Results: MCs performed worse than NCs on the Mini-Mental State Examination, Trails Making Tests A and B, Delayed Recall of a 10-Word List, and Wechsler Adult Intelligence Scale WAIS Block Design. In multiple linear regression analyses, BDI score, gender, and number of APOE ?4 alleles did not consistently affect test scores. The differences seen between MCs and NCs were due to differences in the oldest tertile. MCs had lower Visuospatial and Executive Function/Working Memory but not Verbal Memory or Language composite scores. Conclusions: This study is consistent with findings in sporadic Alzheimer disease of early problems with memory, Visuospatial function, and particularly with executive function in PSl mutation carriers. Depression, gender, and presence of an APOE ?4 allele did not demonstrate large influences on neuropsychological performance. Copyright " 2005 by AAN Enterprises, Inc.",,,,,,"10.1212/01.wnl.0000172919.50001.d6",,,"http://hdl.handle.net/20.500.12104/43100","http://www.scopus.com/inward/record.url?eid=2-s2.0-23844553466&partnerID=40&md5=8298e983532db3b69c12a64236878d69",,,,,,"4",,"Neurology",,"55

Neuropsychological function in nondemented carriers of presenilin-1 mutations.

BackgroundProspective and case-control studies have demonstrated that memory loss and executive dysfunction occur early in Alzheimer disease (AD).ObjectiveTo investigate these observations by the study of persons at risk for autosomal dominant forms of AD.MethodsNeuropsychological and genetic tests were performed on 51 nondemented at-risk members of 10 Mexican families with two distinct presenilin-1 (PS1) mutations. Test scores were compared between PS1 mutation carriers (MCs; n = 30) and noncarriers (NCs; n = 21) by analyses of variance, co-varying for family and specific mutation. Regression analyses were performed, taking into account age relative to the median age at dementia diagnosis in the family (adjusted age), gender, Beck Depression Inventory (BDI) scores, education, and number of APOE epsilon4 alleles. Subjects were divided into age tertiles and scores compared within these groups. Composite scores for Verbal Memory, Executive Function/Working Memory, Language, and Visuospatial Function were created, and these scores compared between MCs and NCs.ResultsMCs performed worse than NCs on the Mini-Mental State Examination, Trails Making Tests A and B, Delayed Recall of a 10-Word List, and Wechsler Adult Intelligence Scale WAIS Block Design. In multiple linear regression analyses, BDI score, gender, and number of APOE epsilon4 alleles did not consistently affect test scores. The differences seen between MCs and NCs were due to differences in the oldest tertile. MCs had lower Visuospatial and Executive Function/Working Memory but not Verbal Memory or Language composite scores.ConclusionsThis study is consistent with findings in sporadic Alzheimer disease of early problems with memory, visuospatial function, and particularly with executive function in PS1 mutation carriers. Depression, gender, and presence of an APOE epsilon4 allele did not demonstrate large influences on neuropsychological performance

Pesticide toxicity and its association with Parkinson's disease [Toxicidad de plaguicidas y su asociación con la enfermedad de Parkinson]

Background: Spanish-language screening tests that are sensitive to the early cognitive changes of Alzheimer's disease (AD) are needed. Persons known to be at 50% risk for young-onset AD due to presenilin-1 (PSEN1) mutations provide the opportunity to assess which measures on the Mini-mental State Examination (MMSE) are most sensitive to these early changes. Methods: We performed genetic and Spanish-language cognitive testing on 50 Mexican persons without dementia at risk for inheriting PSEN1 mutations. We then compared the performance on sub-items of the MMSE between PSEN1 mutation carriers (MCs) and non-carriers (NCs) using t-tests and Fisher's exact tests. Exploratory multiple logistic regression analyses were also performed. Results: Twenty-nine persons were MCs and 21 NCs. NCs tended to achieve higher levels of education (p = 0.039) than did MCs. MCs tended to perform more poorly when spelling "MUNDO" backwards and on Orientation, particularly regarding the date. In multiple regression analyses the ability of backwards spelling to predict PSEN1 mutation status was reduced when education was included as an independent variable. Conclusion: Subjects in the earliest stage of PSEN1-related AD showed deficits on orientation to date and in divided attention when spelling backwards. It is unclear if educational level should be considered an associated feature or a con-founding variable in this population although it should be taken into account when considering performance on the MMSE task of divided attention. The relative lack of deficits on delayed recall of three words probably represents the insensitivity of this measure in early AD. This study supports the utility of autosomal dominant AD as a model of the more common sporadic form of the disorder. " 2006 International Psychogeriatric Association.",,,,,,"10.1017/S1041610206003772",,,"http://hdl.handle.net/20.500.12104/43540","http://www.scopus.com/inward/record.url?eid=2-s2.0-33847770795&partnerID=40&md5=4de67b9f2c18c2772ad3c72f6d24ce2b",,,,,,"2",,"International Psychogeriatrics",,"32

Performance on MMSE sub-items and education level in presenilin-1 mutation carriers without dementia

Background: Spanish-language screening tests that are sensitive to the early cognitive changes of Alzheimer's disease (AD) are needed. Persons known to be at 50% risk for young-onset AD due to presenilin-1 (PSEN1) mutations provide the opportunity to assess which measures on the Mini-mental State Examination (MMSE) are most sensitive to these early changes. Methods: We performed genetic and Spanish-language cognitive testing on 50 Mexican persons without dementia at risk for inheriting PSEN1 mutations. We then compared the performance on sub-items of the MMSE between PSEN1 mutation carriers (MCs) and non-carriers (NCs) using t-tests and Fisher's exact tests. Exploratory multiple logistic regression analyses were also performed. Results: Twenty-nine persons were MCs and 21 NCs. NCs tended to achieve higher levels of education (p = 0.039) than did MCs. MCs tended to perform more poorly when spelling "MUNDO" backwards and on Orientation, particularly regarding the date. In multiple regression analyses the ability of backwards spelling to predict PSEN1 mutation status was reduced when education was included as an independent variable. Conclusion: Subjects in the earliest stage of PSEN1-related AD showed deficits on orientation to date and in divided attention when spelling backwards. It is unclear if educational level should be considered an associated feature or a con-founding variable in this population although it should be taken into account when considering performance on the MMSE task of divided attention. The relative lack of deficits on delayed recall of three words probably represents the insensitivity of this measure in early AD. This study supports the utility of autosomal dominant AD as a model of the more common sporadic form of the disorder. © 2006 International Psychogeriatric Association