Understanding genetic modulation of episodic memory will yield insight into the biological mechan... more Understanding genetic modulation of episodic memory will yield insight into the biological mechanisms underlying normal cognitive aging and dementia. Genetic studies based on longitudinal measures of episodic memory are scarce, predominantly focused on candidate genes, and have interrogated common genetic variation. We aimed to identify common and rare genetic variation that may be responsible for uncharacterized genetic risk underlying individual differences in longitudinal performance on memory.
Identifying genes underlying memory function will help characterize cognitively resilient and hig... more Identifying genes underlying memory function will help characterize cognitively resilient and high-risk declining subpopulations contributing to precision medicine strategies. We estimated episodic memory trajectories in 35,245 ethnically diverse older adults representing eight independent cohorts. We conducted apolipoprotein E (APOE)-stratified genome-wide association study (GWAS) analyses and combined individual cohorts' results via meta-analysis. Three independent transcriptomics datasets were used to further interpret GWAS signals. We identified DCDC2 gene significantly associated with episodic memory (Pmeta = 3.3 x 10-8 ) among non-carriers of APOE ε4 (N = 24,941). Brain transcriptomics revealed an association between episodic memory maintenance and (1) increased dorsolateral prefrontal cortex DCDC2 expression (P = 3.8 x 10-4 ) and (2) lower burden of pathological Alzheimer's disease (AD) hallmarks (paired helical fragment tau P = .003, and amyloid beta load P = .008). Additional transcriptomics results comparing AD and cognitively healthy brain samples showed a downregulation of DCDC2 levels in superior temporal gyrus (P = .007) and inferior frontal gyrus (P = .013). Our work identified DCDC2 gene as a novel predictor of memory maintenance.
Genetics play an important role in late-onset Alzheimer’s Disease (AD) etiology and dozens of gen... more Genetics play an important role in late-onset Alzheimer’s Disease (AD) etiology and dozens of genetic variants have been implicated in AD risk through large-scale GWAS meta-analyses. However, the precise mechanistic effects of most of these variants have yet to be determined. Deeply phenotyped cohort data can reveal physiological changes associated with genetic risk for AD across an age spectrum that may provide clues to the biology of the disease. We utilized over 2000 high-quality quantitative measurements obtained from blood of 2831 cognitively normal adult clients of a consumer-based scientific wellness company, each with CLIA-certified whole-genome sequencing data. Measurements included: clinical laboratory blood tests, targeted chip-based proteomics, and metabolomics. We performed a phenome-wide association study utilizing this diverse blood marker data and 25 known AD genetic variants and an AD-specific polygenic risk score (PGRS), adjusting for sex, age, vendor (for clinical...
We identified rare coding variants associated with Alzheimer's disease in a three-stage case-... more We identified rare coding variants associated with Alzheimer's disease in a three-stage case-control study of 85,133 subjects. In stage 1, we genotyped 34,174 samples using a whole-exome microarray. In stage 2, we tested associated variants (P…
Exceptional longevity is associated with substantial heritability. The ε4 allele in apolipoprotei... more 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. Offspring from long-lived families and spouse controls were recruited at 3 sites in the United States and Denmark. We used generalized estimating equations to compare the likelihood of carrying risk alleles in offspring (n ¼ 2307) and spouse controls (n ¼ 764), adjusting for age, sex, level of education, and family membership. The likelihood of carrying an APOE ε4 allele or a G allele in rs2075650 was lower (odds ratio [OR], 0.75; p ¼ 0.005 and OR, 0.70; p ¼ 0.002) and the likelihood of carrying an APOE ε2 allele was higher (OR, 1.5; p ¼ 0.007) among family members in the offspring generation than among their spouse controls. 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.
Scapuloperoneal (SP) syndrome encompasses heterogeneous neuromuscular disorders characterized by ... more Scapuloperoneal (SP) syndrome encompasses heterogeneous neuromuscular disorders characterized by weakness in the shoulder-girdle and peroneal muscles. In a large Italian-American pedigree with dominant SP myopathy (SPM) previously linked to chromosome 12q, we have mapped the disease to Xq26, and, in all of the affected individuals, we identified a missense change (c.365G/C) in the FHL1 gene encoding four-and-a-half-LIM protein 1 (FHL1). The mutation substitutes a serine for a conserved trypophan at amino acid 122 in the second LIM domain of the protein. Western blot analyses of muscle extracts revealed FHL1 loss that paralleled disease severity. FHL1 and an isoform, FHL1C, are highly expressed in skeletal muscle and may contribute to stability of sarcomeres and sarcolemma, myofibrillary assembly, and transcriptional regulation. This is the first report, to our knowledge, of X-linked dominant SP myopathy and the first human mutation in FHL1.
Abstract: Each additional copy of the apolipoprotein E4 (APOE4) allele is associated with a highe... more Abstract: Each additional copy of the apolipoprotein E4 (APOE4) allele is associated with a higher risk of Alzheimer's dementia, while the APOE2 allele is associated with a lower risk of Alzheimer's dementia, it is not yet known whether APOE2 homozygotes have a particularly low risk. We generated Alzheimer's dementia odds ratios and other findings in more than 5,000 clinically characterized and neuropathologically characterized Alzheimer's dementia cases and controls. APOE2/2 was associated with a low Alzheimer's dementia odds ratios compared to APOE2/3 and 3/3, and an exceptionally low odds ratio compared to APOE4/4, and the impact of APOE2 and APOE4 gene dose was significantly greater in the neuropathologically confirmed group than in more than 24,000 neuropathologically unconfirmed cases and controls. Finding and targeting the factors by which APOE and its variants influence Alzheimer's disease could have a major impact on the understanding, treatment and ...
<b>Copyright information:</b>Taken from "Precision and type I error rate in the ... more <b>Copyright information:</b>Taken from "Precision and type I error rate in the presence of genotype errors and missing parental data: a comparison between the original transmission disequilibrium test (TDT) and TDTae statistics"BMC Genetics 2005;6(Suppl 1):S150-S150.Published online 30 Dec 2005PMCID:PMC1866784.
Despite several genetic variants identified by large genetic studies, late‐onset Alzheimer’s dise... more Despite several genetic variants identified by large genetic studies, late‐onset Alzheimer’s disease and related dementias (ADRD)’s missing heritability remains extensive. Aging has accelerated globally and over 70% of the elderly population reside in developing countries; by 2050 people with dementia in Latin America is projected to increase 4‐fold. Hispanics are the largest ethnic minority in the US, and have a unique genetic background characterized by admixture of various proportions of European, African, and Native‐American ancestry. Although studies have reported higher incidence and prevalence of ADRD in Hispanics, there are limited investigations on the effect of ancestry on ADRD, in particular Native‐American ancestry.
Cilem prace bylo studovat, s ohledem na předpokladanou oligo-/multigenni dědicnost DN, interaktiv... more Cilem prace bylo studovat, s ohledem na předpokladanou oligo-/multigenni dědicnost DN, interaktivni asociaci vybrane skupiny jednonukleotidových polymorfizmů (SNPs) v kandidatnich genech pro DN u diabetiků 2. typu (T2DM) v Ceske populaci. Pomoci metody s velmi dobrou statistickou silou detekovat kauzalni geneticke rizikove varianty při soucasne kontrole hladiny významnosti s ohledem na mnohocetna srovnani jsme nalezli u osob s T2DM významnou asociaci několika genetických markerů na chromozomech 6 a 7 s diabetickou nefropatii.
Despite several genetic variants identified by large genetic studies, late‐onset Alzheimer’s dise... more Despite several genetic variants identified by large genetic studies, late‐onset Alzheimer’s disease and related dementias (ADRD)’s missing heritability remains extensive. Aging has accelerated globally and over 70% of the elderly population reside in developing countries; by 2050 people with dementia in Latin America is projected to increase 4‐fold. Hispanics are the largest ethnic minority in the US, and have a unique genetic background characterized by admixture of various proportions of European, African, and Native‐American ancestry. Although studies have reported higher incidence and prevalence of ADRD in Hispanics, there are limited investigations on the effect of ancestry on ADRD, in particular Native‐American ancestry.
INTRODUCTION—Few high penetrance variants that explain risk in Late-onset Alzheimer's disease... more INTRODUCTION—Few high penetrance variants that explain risk in Late-onset Alzheimer's disease (LOAD) families have been found. METHODS—We performed genomewide linkage and identity-by-descent (IBD) analyses on 41 non-Hispanic Caucasian families exhibiting likely dominant inheritance of LOAD, and having no mutations at known familial AD loci and a low burden of APOE ε4 alleles. RESULTS—Two-point parametric linkage analysis identified 14 significantly linked regions, including three novel linkage regions for LOAD (5q32, 11q12.2-11q14.1 and 14q13.3), one of Kunkle et al. Page 2 Alzheimers Dement. Author manuscript; available in PMC 2017 January 01. A uhor M anscript
Late‐onset Alzheimer’s disease (AD) is a complex disorder with multiple genetic risk factors. Lin... more Late‐onset Alzheimer’s disease (AD) is a complex disorder with multiple genetic risk factors. Linkage and association analysis have mapped dozens of loci in pooled analysis of many pedigrees or large numbers of unrelated cases and controls. Identification of the underlying DNA risk variants in the regions of interest (ROIs) has been complicated by both the genetic heterogeneity and the cost, until recently, of comprehensive DNA sequencing in ROIs. The known loci also leave much heritability unexplained.
Importance Compared with non-Hispanic White individuals, African American individuals from the sa... more Importance Compared with non-Hispanic White individuals, African American individuals from the same community are approximately twice as likely to develop Alzheimer disease. Despite this disparity, the largest Alzheimer disease genome-wide association studies to date have been conducted in non-Hispanic White individuals. In the largest association analyses of Alzheimer disease in African American individuals, ABCA7, TREM2, and an intergenic locus at 5q35 were previously implicated. Objective To identify additional risk loci in African American individuals by increasing the sample size and using the African Genome Resource panel. Design, Setting, and Participants This genome-wide association meta-analysis used case-control and family-based data sets from the Alzheimer Disease Genetics Consortium. There were multiple recruitment sites throughout the United States that included individuals with Alzheimer disease and controls of African American ancestry. Analysis began October 2018 and ended September 2019. Main Outcomes and Measures Diagnosis of Alzheimer disease. Results A total of 2784 individuals with Alzheimer disease (1944 female [69.8%]) and 5222 controls (3743 female [71.7%]) were analyzed (mean [SD] age at last evaluation, 74.2 [13.6] years). Associations with 4 novel common loci centered near the intracellular glycoprotein trafficking gene EDEM1 (3p26; P = 8.9 × 10-7), near the immune response gene ALCAM (3q13; P = 9.3 × 10-7), within GPC6 (13q31; P = 4.1 × 10-7), a gene critical for recruitment of glutamatergic receptors to the neuronal membrane, and within VRK3 (19q13.33; P = 3.5 × 10-7), a gene involved in glutamate neurotoxicity, were identified. In addition, several loci associated with rare variants, including a genome-wide significant intergenic locus near IGF1R at 15q26 (P = 1.7 × 10-9) and 6 additional loci with suggestive significance (P ≤ 5 × 10-7) such as API5 at 11p12 (P = 8.8 × 10-8) and RBFOX1 at 16p13 (P = 5.4 × 10-7) were identified. Gene expression data from brain tissue demonstrate association of ALCAM, ARAP1, GPC6, and RBFOX1 with brain β-amyloid load. Of 25 known loci associated with Alzheimer disease in non-Hispanic White individuals, only APOE, ABCA7, TREM2, BIN1, CD2AP, FERMT2, and WWOX were implicated at a nominal significance level or stronger in African American individuals. Pathway analyses strongly support the notion that immunity, lipid processing, and intracellular trafficking pathways underlying Alzheimer disease in African American individuals overlap with those observed in non-Hispanic White individuals. A new pathway emerging from these analyses is the kidney system, suggesting a novel mechanism for Alzheimer disease that needs further exploration. Conclusions and Relevance While the major pathways involved in Alzheimer disease etiology in African American individuals are similar to those in non-Hispanic White individuals, the disease-associated loci within these pathways differ.
Each additional copy of the apolipoprotein E4 (APOE4) allele is associated with a higher risk of ... more Each additional copy of the apolipoprotein E4 (APOE4) allele is associated with a higher risk of Alzheimer’s dementia, while the APOE2 allele is associated with a lower risk of Alzheimer’s dementia, it is not yet known whether APOE2 homozygotes have a particularly low risk. We generated Alzheimer’s dementia odds ratios and other findings in more than 5,000 clinically characterized and neuropathologically characterized Alzheimer’s dementia cases and controls. APOE2/2 was associated with a low Alzheimer’s dementia odds ratios compared to APOE2/3 and 3/3, and an exceptionally low odds ratio compared to APOE4/4, and the impact of APOE2 and APOE4 gene dose was significantly greater in the neuropathologically confirmed group than in more than 24,000 neuropathologically unconfirmed cases and controls. Finding and targeting the factors by which APOE and its variants influence Alzheimer’s disease could have a major impact on the understanding, treatment and prevention of the disease.
INTRODUCTION: We estimated the prevalence and risk factors for mild cognitive impairment (MCI) an... more INTRODUCTION: We estimated the prevalence and risk factors for mild cognitive impairment (MCI) and its subtypes in Mexican population using the cognitive aging ancillary study of the Mexican Health and Aging Study. METHODS: Using a robust norms approach and comprehensive neuropsychological criteria, we determined MCI in a sample of adult Mexicans (N=1,807;55-97years). Additionally, we determined prevalence rates using traditional criteria. RESULTS: Prevalence of amnestic MCI was 5.9%. Other MCI subtypes ranged 4.3% to 7.7%. MCI with and without memory impairment was associated with older age and rurality. Depression, diabetes and low educational attainment were associated with MCI without memory impairment. Using traditional criteria, prevalence of MCI was lower (2.2% amnestic MCI, other subtypes ranged 1.3%-2.4%). DISCUSSION: Older age, depression, low education, diabetes, and rurality were associated with increased risk of MCI among older adults in Mexico. Our findings suggest tha...
Understanding genetic modulation of episodic memory will yield insight into the biological mechan... more Understanding genetic modulation of episodic memory will yield insight into the biological mechanisms underlying normal cognitive aging and dementia. Genetic studies based on longitudinal measures of episodic memory are scarce, predominantly focused on candidate genes, and have interrogated common genetic variation. We aimed to identify common and rare genetic variation that may be responsible for uncharacterized genetic risk underlying individual differences in longitudinal performance on memory.
Identifying genes underlying memory function will help characterize cognitively resilient and hig... more Identifying genes underlying memory function will help characterize cognitively resilient and high-risk declining subpopulations contributing to precision medicine strategies. We estimated episodic memory trajectories in 35,245 ethnically diverse older adults representing eight independent cohorts. We conducted apolipoprotein E (APOE)-stratified genome-wide association study (GWAS) analyses and combined individual cohorts' results via meta-analysis. Three independent transcriptomics datasets were used to further interpret GWAS signals. We identified DCDC2 gene significantly associated with episodic memory (Pmeta = 3.3 x 10-8 ) among non-carriers of APOE ε4 (N = 24,941). Brain transcriptomics revealed an association between episodic memory maintenance and (1) increased dorsolateral prefrontal cortex DCDC2 expression (P = 3.8 x 10-4 ) and (2) lower burden of pathological Alzheimer's disease (AD) hallmarks (paired helical fragment tau P = .003, and amyloid beta load P = .008). Additional transcriptomics results comparing AD and cognitively healthy brain samples showed a downregulation of DCDC2 levels in superior temporal gyrus (P = .007) and inferior frontal gyrus (P = .013). Our work identified DCDC2 gene as a novel predictor of memory maintenance.
Genetics play an important role in late-onset Alzheimer’s Disease (AD) etiology and dozens of gen... more Genetics play an important role in late-onset Alzheimer’s Disease (AD) etiology and dozens of genetic variants have been implicated in AD risk through large-scale GWAS meta-analyses. However, the precise mechanistic effects of most of these variants have yet to be determined. Deeply phenotyped cohort data can reveal physiological changes associated with genetic risk for AD across an age spectrum that may provide clues to the biology of the disease. We utilized over 2000 high-quality quantitative measurements obtained from blood of 2831 cognitively normal adult clients of a consumer-based scientific wellness company, each with CLIA-certified whole-genome sequencing data. Measurements included: clinical laboratory blood tests, targeted chip-based proteomics, and metabolomics. We performed a phenome-wide association study utilizing this diverse blood marker data and 25 known AD genetic variants and an AD-specific polygenic risk score (PGRS), adjusting for sex, age, vendor (for clinical...
We identified rare coding variants associated with Alzheimer's disease in a three-stage case-... more We identified rare coding variants associated with Alzheimer's disease in a three-stage case-control study of 85,133 subjects. In stage 1, we genotyped 34,174 samples using a whole-exome microarray. In stage 2, we tested associated variants (P…
Exceptional longevity is associated with substantial heritability. The ε4 allele in apolipoprotei... more 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. Offspring from long-lived families and spouse controls were recruited at 3 sites in the United States and Denmark. We used generalized estimating equations to compare the likelihood of carrying risk alleles in offspring (n ¼ 2307) and spouse controls (n ¼ 764), adjusting for age, sex, level of education, and family membership. The likelihood of carrying an APOE ε4 allele or a G allele in rs2075650 was lower (odds ratio [OR], 0.75; p ¼ 0.005 and OR, 0.70; p ¼ 0.002) and the likelihood of carrying an APOE ε2 allele was higher (OR, 1.5; p ¼ 0.007) among family members in the offspring generation than among their spouse controls. 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.
Scapuloperoneal (SP) syndrome encompasses heterogeneous neuromuscular disorders characterized by ... more Scapuloperoneal (SP) syndrome encompasses heterogeneous neuromuscular disorders characterized by weakness in the shoulder-girdle and peroneal muscles. In a large Italian-American pedigree with dominant SP myopathy (SPM) previously linked to chromosome 12q, we have mapped the disease to Xq26, and, in all of the affected individuals, we identified a missense change (c.365G/C) in the FHL1 gene encoding four-and-a-half-LIM protein 1 (FHL1). The mutation substitutes a serine for a conserved trypophan at amino acid 122 in the second LIM domain of the protein. Western blot analyses of muscle extracts revealed FHL1 loss that paralleled disease severity. FHL1 and an isoform, FHL1C, are highly expressed in skeletal muscle and may contribute to stability of sarcomeres and sarcolemma, myofibrillary assembly, and transcriptional regulation. This is the first report, to our knowledge, of X-linked dominant SP myopathy and the first human mutation in FHL1.
Abstract: Each additional copy of the apolipoprotein E4 (APOE4) allele is associated with a highe... more Abstract: Each additional copy of the apolipoprotein E4 (APOE4) allele is associated with a higher risk of Alzheimer's dementia, while the APOE2 allele is associated with a lower risk of Alzheimer's dementia, it is not yet known whether APOE2 homozygotes have a particularly low risk. We generated Alzheimer's dementia odds ratios and other findings in more than 5,000 clinically characterized and neuropathologically characterized Alzheimer's dementia cases and controls. APOE2/2 was associated with a low Alzheimer's dementia odds ratios compared to APOE2/3 and 3/3, and an exceptionally low odds ratio compared to APOE4/4, and the impact of APOE2 and APOE4 gene dose was significantly greater in the neuropathologically confirmed group than in more than 24,000 neuropathologically unconfirmed cases and controls. Finding and targeting the factors by which APOE and its variants influence Alzheimer's disease could have a major impact on the understanding, treatment and ...
<b>Copyright information:</b>Taken from "Precision and type I error rate in the ... more <b>Copyright information:</b>Taken from "Precision and type I error rate in the presence of genotype errors and missing parental data: a comparison between the original transmission disequilibrium test (TDT) and TDTae statistics"BMC Genetics 2005;6(Suppl 1):S150-S150.Published online 30 Dec 2005PMCID:PMC1866784.
Despite several genetic variants identified by large genetic studies, late‐onset Alzheimer’s dise... more Despite several genetic variants identified by large genetic studies, late‐onset Alzheimer’s disease and related dementias (ADRD)’s missing heritability remains extensive. Aging has accelerated globally and over 70% of the elderly population reside in developing countries; by 2050 people with dementia in Latin America is projected to increase 4‐fold. Hispanics are the largest ethnic minority in the US, and have a unique genetic background characterized by admixture of various proportions of European, African, and Native‐American ancestry. Although studies have reported higher incidence and prevalence of ADRD in Hispanics, there are limited investigations on the effect of ancestry on ADRD, in particular Native‐American ancestry.
Cilem prace bylo studovat, s ohledem na předpokladanou oligo-/multigenni dědicnost DN, interaktiv... more Cilem prace bylo studovat, s ohledem na předpokladanou oligo-/multigenni dědicnost DN, interaktivni asociaci vybrane skupiny jednonukleotidových polymorfizmů (SNPs) v kandidatnich genech pro DN u diabetiků 2. typu (T2DM) v Ceske populaci. Pomoci metody s velmi dobrou statistickou silou detekovat kauzalni geneticke rizikove varianty při soucasne kontrole hladiny významnosti s ohledem na mnohocetna srovnani jsme nalezli u osob s T2DM významnou asociaci několika genetických markerů na chromozomech 6 a 7 s diabetickou nefropatii.
Despite several genetic variants identified by large genetic studies, late‐onset Alzheimer’s dise... more Despite several genetic variants identified by large genetic studies, late‐onset Alzheimer’s disease and related dementias (ADRD)’s missing heritability remains extensive. Aging has accelerated globally and over 70% of the elderly population reside in developing countries; by 2050 people with dementia in Latin America is projected to increase 4‐fold. Hispanics are the largest ethnic minority in the US, and have a unique genetic background characterized by admixture of various proportions of European, African, and Native‐American ancestry. Although studies have reported higher incidence and prevalence of ADRD in Hispanics, there are limited investigations on the effect of ancestry on ADRD, in particular Native‐American ancestry.
INTRODUCTION—Few high penetrance variants that explain risk in Late-onset Alzheimer's disease... more INTRODUCTION—Few high penetrance variants that explain risk in Late-onset Alzheimer's disease (LOAD) families have been found. METHODS—We performed genomewide linkage and identity-by-descent (IBD) analyses on 41 non-Hispanic Caucasian families exhibiting likely dominant inheritance of LOAD, and having no mutations at known familial AD loci and a low burden of APOE ε4 alleles. RESULTS—Two-point parametric linkage analysis identified 14 significantly linked regions, including three novel linkage regions for LOAD (5q32, 11q12.2-11q14.1 and 14q13.3), one of Kunkle et al. Page 2 Alzheimers Dement. Author manuscript; available in PMC 2017 January 01. A uhor M anscript
Late‐onset Alzheimer’s disease (AD) is a complex disorder with multiple genetic risk factors. Lin... more Late‐onset Alzheimer’s disease (AD) is a complex disorder with multiple genetic risk factors. Linkage and association analysis have mapped dozens of loci in pooled analysis of many pedigrees or large numbers of unrelated cases and controls. Identification of the underlying DNA risk variants in the regions of interest (ROIs) has been complicated by both the genetic heterogeneity and the cost, until recently, of comprehensive DNA sequencing in ROIs. The known loci also leave much heritability unexplained.
Importance Compared with non-Hispanic White individuals, African American individuals from the sa... more Importance Compared with non-Hispanic White individuals, African American individuals from the same community are approximately twice as likely to develop Alzheimer disease. Despite this disparity, the largest Alzheimer disease genome-wide association studies to date have been conducted in non-Hispanic White individuals. In the largest association analyses of Alzheimer disease in African American individuals, ABCA7, TREM2, and an intergenic locus at 5q35 were previously implicated. Objective To identify additional risk loci in African American individuals by increasing the sample size and using the African Genome Resource panel. Design, Setting, and Participants This genome-wide association meta-analysis used case-control and family-based data sets from the Alzheimer Disease Genetics Consortium. There were multiple recruitment sites throughout the United States that included individuals with Alzheimer disease and controls of African American ancestry. Analysis began October 2018 and ended September 2019. Main Outcomes and Measures Diagnosis of Alzheimer disease. Results A total of 2784 individuals with Alzheimer disease (1944 female [69.8%]) and 5222 controls (3743 female [71.7%]) were analyzed (mean [SD] age at last evaluation, 74.2 [13.6] years). Associations with 4 novel common loci centered near the intracellular glycoprotein trafficking gene EDEM1 (3p26; P = 8.9 × 10-7), near the immune response gene ALCAM (3q13; P = 9.3 × 10-7), within GPC6 (13q31; P = 4.1 × 10-7), a gene critical for recruitment of glutamatergic receptors to the neuronal membrane, and within VRK3 (19q13.33; P = 3.5 × 10-7), a gene involved in glutamate neurotoxicity, were identified. In addition, several loci associated with rare variants, including a genome-wide significant intergenic locus near IGF1R at 15q26 (P = 1.7 × 10-9) and 6 additional loci with suggestive significance (P ≤ 5 × 10-7) such as API5 at 11p12 (P = 8.8 × 10-8) and RBFOX1 at 16p13 (P = 5.4 × 10-7) were identified. Gene expression data from brain tissue demonstrate association of ALCAM, ARAP1, GPC6, and RBFOX1 with brain β-amyloid load. Of 25 known loci associated with Alzheimer disease in non-Hispanic White individuals, only APOE, ABCA7, TREM2, BIN1, CD2AP, FERMT2, and WWOX were implicated at a nominal significance level or stronger in African American individuals. Pathway analyses strongly support the notion that immunity, lipid processing, and intracellular trafficking pathways underlying Alzheimer disease in African American individuals overlap with those observed in non-Hispanic White individuals. A new pathway emerging from these analyses is the kidney system, suggesting a novel mechanism for Alzheimer disease that needs further exploration. Conclusions and Relevance While the major pathways involved in Alzheimer disease etiology in African American individuals are similar to those in non-Hispanic White individuals, the disease-associated loci within these pathways differ.
Each additional copy of the apolipoprotein E4 (APOE4) allele is associated with a higher risk of ... more Each additional copy of the apolipoprotein E4 (APOE4) allele is associated with a higher risk of Alzheimer’s dementia, while the APOE2 allele is associated with a lower risk of Alzheimer’s dementia, it is not yet known whether APOE2 homozygotes have a particularly low risk. We generated Alzheimer’s dementia odds ratios and other findings in more than 5,000 clinically characterized and neuropathologically characterized Alzheimer’s dementia cases and controls. APOE2/2 was associated with a low Alzheimer’s dementia odds ratios compared to APOE2/3 and 3/3, and an exceptionally low odds ratio compared to APOE4/4, and the impact of APOE2 and APOE4 gene dose was significantly greater in the neuropathologically confirmed group than in more than 24,000 neuropathologically unconfirmed cases and controls. Finding and targeting the factors by which APOE and its variants influence Alzheimer’s disease could have a major impact on the understanding, treatment and prevention of the disease.
INTRODUCTION: We estimated the prevalence and risk factors for mild cognitive impairment (MCI) an... more INTRODUCTION: We estimated the prevalence and risk factors for mild cognitive impairment (MCI) and its subtypes in Mexican population using the cognitive aging ancillary study of the Mexican Health and Aging Study. METHODS: Using a robust norms approach and comprehensive neuropsychological criteria, we determined MCI in a sample of adult Mexicans (N=1,807;55-97years). Additionally, we determined prevalence rates using traditional criteria. RESULTS: Prevalence of amnestic MCI was 5.9%. Other MCI subtypes ranged 4.3% to 7.7%. MCI with and without memory impairment was associated with older age and rurality. Depression, diabetes and low educational attainment were associated with MCI without memory impairment. Using traditional criteria, prevalence of MCI was lower (2.2% amnestic MCI, other subtypes ranged 1.3%-2.4%). DISCUSSION: Older age, depression, low education, diabetes, and rurality were associated with increased risk of MCI among older adults in Mexico. Our findings suggest tha...
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