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Analyses of the National Institute on Aging Late-Onset Alzheimer's Disease Family Study: implication of additional loci.

ABSTRACT: OBJECTIVE:To identify putative genetic loci related to the risk of late-onset Alzheimer disease (LOAD). DESIGN:Linkage analysis and family-based and case-control association analyses from a genomewide scan using approximately 6000 single-nucleotide polymorphic markers at an average intermarker distance of 0.65 cM. SETTING:The National Institute on Aging Genetics Initiative for Late-Onset Alzheimer's Disease (NIA-LOAD) was created to expand the resources for studies to identify additional genes contributing to the risk for LOAD. PARTICIPANTS:We investigated 1902 individuals from 328 families with LOAD and 236 unrelated control subjects. MAIN OUTCOME MEASURES:Clinical diagnosis of LOAD. RESULTS:The strongest overall finding was at chromosome 19q13.32, confirming the effect of the apolipoprotein E gene on LOAD risk in the family-based and case-control analyses. However, single-nucleotide polymorphisms at the following loci were also statistically significant in 1 or more of the analyses performed: 7p22.2, 7p21.3, and 16q21 in the linkage analyses; 17q21.31 and 22q11.21 in the family-based association analysis; and 7q31.1 and 22q12.3 in the case-control analysis. Positive associations at 7q31.1 and 20q13.33 were also significant in the meta-analysis results in a publicly available database. CONCLUSIONS:Several additional loci may harbor genetic variants associated with LOAD. This data set provides a wealth of phenotypic and genotypic information for use as a resource in discovery and confirmatory research.

SUBMITTER: Lee JH

PROVIDER: S-EPMC2694670 | biostudies-literature | 2008 Nov

REPOSITORIES: biostudies-literature

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Analyses of the National Institute on Aging Late-Onset Alzheimer's Disease Family Study: implication of additional loci.

Lee Joseph H JH Cheng Rong R Graff-Radford Neill N Foroud Tatiana T Mayeux Richard R

Archives of neurology 20081101 11

<h4>Objective</h4>To identify putative genetic loci related to the risk of late-onset Alzheimer disease (LOAD).<h4>Design</h4>Linkage analysis and family-based and case-control association analyses from a genomewide scan using approximately 6000 single-nucleotide polymorphic markers at an average intermarker distance of 0.65 cM.<h4>Setting</h4>The National Institute on Aging Genetics Initiative for Late-Onset Alzheimer's Disease (NIA-LOAD) was created to expand the resources for studies to ident ...[more]

PMID: 19001172

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Project description:<p>Alzheimer disease is the most common neurodegenerative disorder of the elderly affecting an estimated five million Americans. Genetic factors contribute to the risk for disease with heritability estimates ranging from 57% to 79%. More than a decade ago, the ε4 variant of APOE was identified and remains the most consistently replicated genetic variant influencing the risk of late onset Alzheimer disease. A segregation analysis suggests there may be four additional genes influencing the age-at-onset of Alzheimer disease. In 2007 there were 968 association studies in 398 candidate genes reported, but none replicated consistently. There are many reasons for the lack of consistency, but one important reason for the lack of progress is the paucity of a sufficient number of well characterized families and patients available to the entire scientific community. The extensive effort and expense required to ascertain such a population has been addressed by the NIA-LOAD Family Study. Its goal is to identify and recruit families with two or more siblings with the late-onset form of Alzheimer's disease and a cohort of unrelated, non-demented controls similar in age and ethnic background, and to make the samples, the clinical and genotyping data and preliminary analyses available to qualified investigators world-wide. Genotyping by the Center for Inherited Disease Research (CIDR) was performed using the Illumina Infinium II assay protocol with hybridization to Illumina Human 610Quadv1_B Beadchips. This genotyping represents the largest collection of families ever assembled with Alzheimer's disease combining the NIA-LOAD Genetics Initiative Multiplex Family Study, the National Cell Repository for Alzheimer's Disease (NCRAD) with additional controls from the University of Kentucky. These genotyping results will serve as a focal point for future research that will identify all of the remaining genetic variants in Alzheimer's disease.</p>

Project description:<p><b>Multiplex Family Study</b><br/>The purpose of the NIA Genetics Initiative: Multiplex Family Study is to identify families with multiple members diagnosed with late-onset Alzheimer's Disease. Families will be characterized clinically and blood samples will be collected to establish cell lines. If a blood sample is not available, autopsy samples will be collected for DNA extraction and storage. Our goal is to recruit 1,000 families over the course of the study. Clinical and demographic data from these families will be collected at the local site and coded data, without identifiers, will be sent and included in a national database of families with Alzheimer's Disease. This database, along with the biological samples, will be housed at the National Cell Repository for Alzheimer's Disease (NCRAD) at Indiana University. The Center or provider and the Cell Repository must sign a Material Transfer Agreement for shipment of biological samples and phenotypic data to NCRAD. The biological samples and data from these families will be available to qualified researchers, who must sign a Material Transfer Agreement before receiving DNA and data. An oversight committee known as the Cell Bank Advisory Committee (CBAC) will review and monitor the process of family identification and enrollment, data collection, the establishment of cell lines and access to samples.</p> <p><b>LOAD CIDR Project</b><br/>The first 362 families of the Multiplex Family Study (including 2,105 family members) were included in a 6K SNP genome-wide scan at the NIH-supported, Center for Inherited Disease Research (CIDR). An additional 297 unrelated, healthy controls were also genotyped at CIDR. The average age of onset of AD in the genotyped sample is 74 years and 62% of the sample is women. While primarily Caucasian, 3% are African-American, and 3% are of Hispanic ancestry. 72% of the families had at least 2 affected siblings, whereas 21% had 3 or more sampled affected individuals and 7% had 4 or more genotyped, affected family members.</p>

Project description:A National Institute on Aging-Alzheimer's Association (NIA-AA) workgroup recently published a research framework in which Alzheimer disease is defined by neuropathologic or biomarker evidence of β-amyloid plaques and tau tangles and not by clinical symptoms. To estimate the sex- and age-specific prevalence of 3 imaging biomarker-based definitions of the Alzheimer disease spectrum from the NIA-AA research framework and to compare these entities with clinically defined diagnostic entities commonly linked with Alzheimer disease. The Mayo Clinic Study of Aging (MCSA) is a population-based cohort study of cognitive aging in Olmsted County, Minnesota. The MCSA in-person participants (n = 4660) and passively ascertained (ie, through the medical record rather than in-person) individuals with dementia (n = 553) aged 60 to 89 years were included. Subsets underwent amyloid positron emission tomography (PET) (n = 1524) or both amyloid and tau PET (n = 576). Therefore, this study included 3 nested cohorts examined between November 29, 2004, and June 5, 2018. Data were analyzed between February 19, 2018, and March 26, 2019. The sex- and age-specific prevalence of the following 3 biologically defined diagnostic entities was estimated: Alzheimer continuum (abnormal amyloid regardless of tau status), Alzheimer pathologic change (abnormal amyloid but normal tau), and Alzheimer disease (abnormal amyloid and tau). These were compared with the prevalence of 3 clinically defined diagnostic groups (mild cognitive impairment or dementia, dementia, and clinically defined probable Alzheimer disease). The median (interquartile range) age was 77 (72-83) years in the clinical cohort (n = 5213 participants), 77 (70-83) years in the amyloid PET cohort (n = 1524 participants), and 77 (69-83) years in the tau PET cohort (n = 576 participants). There were roughly equal numbers of women and men. The prevalence of all diagnostic entities (biological and clinical) increased rapidly with age, with the exception of Alzheimer pathologic change. The prevalence of biological Alzheimer disease was greater than clinically defined probable Alzheimer disease for women and men. Among women, these values were 10% (95% CI, 6%-14%) vs 1% (95% CI, 1%-1%) at age 70 years and 33% (95% CI, 25%-41%) vs 10% (95% CI, 9%-12%) at age 85 years (P < .001). Among men, these values were 9% (95% CI, 5%-12%) vs 1% (95% CI, 0%-1%) at age 70 years and 31% (95% CI, 24%-38%) vs 9% (95% CI, 8%-11%) at age 85 years (P < .001). The only notable difference by sex was a greater prevalence of the mild cognitive impairment or dementia clinical category among men than women. Results of this study suggest that biologically defined Alzheimer disease is more prevalent than clinically defined probable Alzheimer disease at any age and is 3 times more prevalent at age 85 years among both women and men. This difference is mostly driven by asymptomatic individuals with biological Alzheimer disease. These findings illustrate the magnitude of the consequences on public health that potentially exist by intervening with disease-specific treatments to prevent symptom onset.

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Analyses of the National Institute on Aging Late-Onset Alzheimer's Disease Family Study: implication of additional loci.

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Analyses of the National Institute on Aging Late-Onset Alzheimer's Disease Family Study: implication of additional loci.

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