{
    "created_at": "2024-04-02T13:14:53.880936Z",
    "data": {
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        "answer": "The genotypes related to Alzheimer's and dementia that have commonalities with those for aging include a locus on chromosome 17 associated with the age at onset, and a specific variant in CCL11. Other genes associated with Alzheimer's include APP, PSEN1, PSEN2, and APOE. These genes are also associated with early-onset Alzheimer's disease. The APOE gene is the strongest genetic risk factor for later onset Alzheimer's. The heritability of late-onset Alzheimer's disease (LOAD) is estimated to be ~60-80%, suggesting a large proportion of individual differences in LOAD risk is driven by genetics.",
        "context": {
            "03a4f57c-3a11-4d3d-a1e9-6d0d8bdb7cb7": [
                {
                    "document_id": "03a4f57c-3a11-4d3d-a1e9-6d0d8bdb7cb7",
                    "text": "\n\nWe briefly comment on rare mutations that shorten life span through the early onset of diseases that are increasingly common during aging in the general population, e.g., familial forms of Alzheimer, breast cancer, coronary artery disease, type II diabetes, etc.The later onset forms of these diseases are associated with causes of death at later ages.A major question is what role the more common allelic variants of these same genes have in \"normal aging\".Although examination of this huge emerging topic goes beyond the present discussion, we may consider the example of Werner's syndrome, a rare autosomal recessive that causes adult onset progeria with a high incidence of cancer and atherosclerosis (70).The absence of Alzheimer-type dementia in Werner's syndrome illustrates the \"segmental\" nature of this and other progerias (70).Thus, heritable shortening of life span should not be considered as a simple acceleration of general aging processes.The Werner's lesion maps to a defective gene encoding a helicase and exonuclease, which also has several polymorphisms.In Japan, 1367Arg was associated with a lower risk of myocardial infarction (70), although it was not associated with longevity in Finland (14).In general, we know little of the genetic factors involved in frailty and morbidity at later ages, which are important to the geneenvironment interactions implied in the major longevity increase seen during the twentieth century."
                }
            ],
            "0af83a97-18ef-47f4-9f0c-872633ca3414": [
                {
                    "document_id": "0af83a97-18ef-47f4-9f0c-872633ca3414",
                    "text": "\n\nIndicative diseases associated with the candidate aging genes"
                }
            ],
            "213afab9-b2fb-40ed-abb7-d80853a0fbf3": [
                {
                    "document_id": "213afab9-b2fb-40ed-abb7-d80853a0fbf3",
                    "text": "D\n\nementia has an age-and sex-standardized prevalence of ~7.1% in Europeans 1 , with Alzheimer's disease (AD) being the most common form of dementia (50-70% of cases) 2 .AD is pathologically characterized by the presence of amyloid-beta plaques and tau neurofibrillary tangles in the brain 3 .Most patients are diagnosed with AD after the age of 65, termed late-onset AD (LOAD), while only 1% of AD cases have an early onset (before the age of 65) 3 .On the basis of twin studies, the heritability of LOAD is estimated to be ~60-80% (refs. 4,5 ), suggesting that a large proportion of individual differences in LOAD risk is driven by genetics.The heritability of LOAD is spread across many genetic variants; however, Zhang et al. 6 suggested that LOAD is more of an oligogenic than a polygenic disorder due to the large effects of APOE variants.Zhang et al. 6 and Holland et al. 7 predicted there to be ~100-10,000 causal variants contributing to LOAD; however, only a fraction have been identified.Increasing the sample size of genome-wide association studies (GWAS) will improve the statistical power to identify the missing causal variants and may highlight additional disease mechanisms.In combination with increasing the number of samples, it is beneficial to use different approaches to identify rare and private variation to help identify additional causal variants and increase understanding of disease mechanisms; however, we deem this to be out of the scope of the current analysis."
                },
                {
                    "document_id": "213afab9-b2fb-40ed-abb7-d80853a0fbf3",
                    "text": "\nDementia has an age-and sex-standardized prevalence of ~7.1% in Europeans 1 , with Alzheimer's disease (AD) being the most common form of dementia (50-70% of cases) 2 .AD is pathologically characterized by the presence of amyloid-beta plaques and tau neurofibrillary tangles in the brain 3 .Most patients are diagnosed with AD after the age of 65, termed late-onset AD (LOAD), while only 1% of AD cases have an early onset (before the age of 65) 3 .On the basis of twin studies, the heritability of LOAD is estimated to be ~60-80% (refs. 4,5 ), suggesting that a large proportion of individual differences in LOAD risk is driven by genetics.The heritability of LOAD is spread across many genetic variants; however, Zhang et al. 6 suggested that LOAD is more of an oligogenic than a polygenic disorder due to the large effects of APOE variants.Zhang et al. 6 and Holland et al. 7 predicted there to be ~100-10,000 causal variants contributing to LOAD; however, only a fraction have been identified.Increasing the sample size of genome-wide association studies (GWAS) will improve the statistical power to identify the missing causal variants and may highlight additional disease mechanisms.In combination with increasing the number of samples, it is beneficial to use different approaches to identify rare and private variation to help identify additional causal variants and increase understanding of disease mechanisms; however, we deem this to be out of the scope of the current analysis.The largest previous GWAS of LOAD, identified 29 risk loci from 71,880 (46,613 proxy) cases and 383,378 (318,246 proxy) controls 8 .Our current study expands this to include 90,338 (46,613 proxy) cases and 1,036,225 (318,246 proxy) controls.The recruitment of LOAD cases can be difficult due to the late age of onset, so proxy cases can allow for the inclusion of younger individuals by estimating their risk of LOAD using parental status.Proxy cases and controls were defined on the basis of known parental LOAD status weighted by parental age (Supplementary Information).In the current study, we identified 38 loci, including seven loci that have not been reported previously.Functional follow-up analyses implicated tissues, cell types and genes of interest through tissue and cell type enrichment, colocalization and statistical fine-mapping.This study highlights microglia, immune cells and protein catabolism as relevant to LOAD, while identifying previously unidentified genes of potential interest. ResultsGenome-wide inferences.We performed meta-analysis on data from 13 cohorts, totaling 1,126,563 individuals (Supplementary"
                }
            ],
            "38f806a9-f265-4854-b86b-38cf56b57dd8": [
                {
                    "document_id": "38f806a9-f265-4854-b86b-38cf56b57dd8",
                    "text": "Introduction\n\nAlzheimer's disease (AD) is a complex disorder and is the most common form of dementia [1].After age, family history is the single greatest risk factor for AD.AD can be classified into early and late onset forms.Mutations in three genes: PSEN1/2 and APP are known to cause early onset AD in an autosomal dominant manner [2,3].The majority of AD cases, however, are late onset (LOAD) and the APOE e4 allele is the strongest known genetic risk factor.Many additional genetic polymorphisms have been identified, though with substantially lower risk estimates [1,4,5,6,7,8,9,10].LOAD appears to be inherited and/or sporadic and there is evidence of a maternal inheritance pattern [11].Current estimates suggest that more than 20% of inherited LOAD cases are maternally inherited [12]."
                }
            ],
            "3f41e709-4cf1-472b-b12b-804c6ebb07c9": [
                {
                    "document_id": "3f41e709-4cf1-472b-b12b-804c6ebb07c9",
                    "text": "INTRODUCTION\n\nMany common noninfectious diseases exhibit a more severe clinical presentation in older individuals.These diseases often exhibit complex etiology and can affect different tissues and cell types, with a wide spectrum of clinical outcomes.Prominent aging-associated neurodegenerative diseases are Alzheimer's disease (AD), Parkinson's disease (PD), and age-related macular degeneration (AMD), all of which can severely compromise the quality of life and have serious repercussions on both the individual and society at large.These late-onset diseases generally result from the interplay between multiple genetic susceptibility factors and environmental components.Sequencing of the human genome, cataloging of millions of single nucleotide polymorphisms (SNPs) together with the development of a map of common haplotypes, and technological innovations in genotyping are among the major milestones that are facilitating exploration of the genetic basis of common diseases (1,7,50).In the field of AMD genetics, these advances have led to the identification of several genetic susceptibility factors and enabled us to start dissecting the relationship between environmental risk factors and the genetic constitution of each individual (66,118,148).As a result, new opportunities are emerging for improved understanding of disease pathogenesis that may lead to better management and treatment of AMD.Clinical aspects of AMD are discussed only briefly (for a more in-depth discussion, see Reference 79)."
                },
                {
                    "document_id": "3f41e709-4cf1-472b-b12b-804c6ebb07c9",
                    "text": "\nAging-associated neurodegenerative diseases significantly influence the quality of life of affected individuals.Genetic approaches, combined with genomic technology, have provided powerful insights into common late-onset diseases, such as age-related macular degeneration (AMD).Here, we discuss current findings on the genetics of AMD to highlight areas of rapid progress and new challenges.We also attempt to integrate available genetic and biochemical data with cellular pathways involved in aging to formulate an integrated model of AMD pathogenesis."
                },
                {
                    "document_id": "3f41e709-4cf1-472b-b12b-804c6ebb07c9",
                    "text": "\n\nAging-associated neurodegenerative diseases significantly influence the quality of life of affected individuals.Genetic approaches, combined with genomic technology, have provided powerful insights into common late-onset diseases, such as age-related macular degeneration (AMD).Here, we discuss current findings on the genetics of AMD to highlight areas of rapid progress and new challenges.We also attempt to integrate available genetic and biochemical data with cellular pathways involved in aging to formulate an integrated model of AMD pathogenesis."
                }
            ],
            "4c2f8dcb-02a1-4968-a117-bdf505cad02f": [
                {
                    "document_id": "4c2f8dcb-02a1-4968-a117-bdf505cad02f",
                    "text": "Genetics of Alzheimer Disease: Early-Onset AD\n\nIn the early to mid-1990s, genetic studies of AD focused on extended families with high burden of disease (two or more cases among first-degree relatives), and used linkage analysis of highly polymorphic genetic markers called short tandem repeats (STRs, or microsattelites) in order to identify genomic regions co-transmitting with disease in affected family members.This strategy, followed by \"fine mapping\"-the positional cloning of candidate genes-was used to identify genes and genetic variants contributing to AD risk.The first three genes known to cause AD were identified among families with multiple early-onset cases (age-at-onset <60 years): APP, encoding amyloid precursor protein [Goate et al., 1991], and PS1 and PS2, encoding presenilins I and II respectively [Levy-Lahad et al., 1995;Rogaev et al., 1995;Sherrington et al., 1995], each transmitting disease-causing variants in the predicted autosomal-dominant fashion."
                },
                {
                    "document_id": "4c2f8dcb-02a1-4968-a117-bdf505cad02f",
                    "text": "\nAlzheimer's disease (AD) (MIM: 104300) is a highly heritable disease with great complexity in its genetic contributors, and represents the most common form of dementia.With the gradual aging of the world's population, leading to increased prevalence of AD, and the substantial cost of care for those afflicted, identifying the genetic causes of disease represents a critical effort in identifying therapeutic targets.Here we provide a comprehensive review of genomic studies of AD, from the earliest linkage studies identifying monogenic contributors to early-onset forms of AD to the genome-wide and rare variant association studies of recent years that are being used to characterize the mosaic of genetic contributors to late-onset AD (LOAD), and which have identified approximately $20 genes with common variants contributing to LOAD risk.In addition, we explore studies employing alternative approaches to identify genetic contributors to AD, including studies of AD-related phenotypes and multi-variant association studies such as pathway analyses.Finally, we introduce studies of next-generation sequencing, which have recently helped identify multiple lowfrequency and rare variant contributors to AD, and discuss ongoing efforts with next-generation sequencing studies to develop statistically well-powered and comprehensive genomic studies of AD.Through this review, we help uncover the many insights the genetics of AD have provided into the pathways and pathophysiology of AD."
                },
                {
                    "document_id": "4c2f8dcb-02a1-4968-a117-bdf505cad02f",
                    "text": "\n\nAlzheimer's disease (AD) (MIM: 104300) is a highly heritable disease with great complexity in its genetic contributors, and represents the most common form of dementia.With the gradual aging of the world's population, leading to increased prevalence of AD, and the substantial cost of care for those afflicted, identifying the genetic causes of disease represents a critical effort in identifying therapeutic targets.Here we provide a comprehensive review of genomic studies of AD, from the earliest linkage studies identifying monogenic contributors to early-onset forms of AD to the genome-wide and rare variant association studies of recent years that are being used to characterize the mosaic of genetic contributors to late-onset AD (LOAD), and which have identified approximately $20 genes with common variants contributing to LOAD risk.In addition, we explore studies employing alternative approaches to identify genetic contributors to AD, including studies of AD-related phenotypes and multi-variant association studies such as pathway analyses.Finally, we introduce studies of next-generation sequencing, which have recently helped identify multiple lowfrequency and rare variant contributors to AD, and discuss ongoing efforts with next-generation sequencing studies to develop statistically well-powered and comprehensive genomic studies of AD.Through this review, we help uncover the many insights the genetics of AD have provided into the pathways and pathophysiology of AD."
                }
            ],
            "6d98da1a-9964-4be7-bb67-47f829dcd2cf": [
                {
                    "document_id": "6d98da1a-9964-4be7-bb67-47f829dcd2cf",
                    "text": "Indeed, as\nage increases, there is an exponential increase in the incidence of\nAD, with a corresponding effect on healthcare costs and quality of\nlife. AD is a complex disease involving several genetic and environmental components (Hardy, 1997; Munoz & Feldman, 2000), and\n15% of patients have a genetic predisposition. Almost 100 candidate\ngenes are currently known to be involved in the development of AD,\nand only 4 (APP, PSEN1, PSEN2, APOE) in humans have been\nproven to play a direct role in AD pathogenesis (Thomas & Fenech,\n2007)."
                }
            ],
            "70b52a1e-834b-43c0-9e6a-3010bc3a06ae": [
                {
                    "document_id": "70b52a1e-834b-43c0-9e6a-3010bc3a06ae",
                    "text": "T\n\nhe genetics of Alzheimer disease (AD) to date support an age-dependent dichotomous model whereby earlier age of disease onset (Ͻ60 years) is explained by 3 fully penetrant genes (APP [NCBI Entrez gene 351], PSEN1 [NCBI Entrez gene 5663], and PSEN2 [NCBI Entrez gene 5664]), whereas later age of disease onset (Ն65 years) representing most cases of AD has yet to be explained by a purely genetic model.The APOE gene (NCBI Entrez gene 348) is the strongest genetic risk factor for later onset, although it is neither sufficient nor necessary to explain all occurrences of disease.Numerous putative genetic risk alleles and genetic variants have been reported.Although all have relevance to biological mechanisms that may be associated with AD pathogenesis, they await replication in large representative populations.Genome-wide association studies have emerged as an increasingly effective tool for identifying genetic contributions to complex diseases and represent the next frontier for furthering our understanding of the underlying etiologic, biological, and pathologic mechanisms associated with chronic complex disorders.There have already been success stories for diseases such as macular degeneration and diabetes mellitus.Whether this will hold true for a genetically complex and heterogeneous disease such as AD is not known, although early reports are encouraging.This review considers recent publications from studies that have successfully applied genome-wide association methods to investigations of AD by taking advantage of the currently available high-throughput arrays, bioinformatics, and software advances.The inherent strengths, limitations, and challenges associated with study design issues in the context of AD are presented herein."
                },
                {
                    "document_id": "70b52a1e-834b-43c0-9e6a-3010bc3a06ae",
                    "text": "\n\nArch Neurol.2008;65(3): 329-334   Alzheimer disease (AD) is the most common cause of dementia and the most prevalent neurodegenerative disorder associated with aging. 1 Alzheimer disease is a heterogeneous disorder with a complex etiology owing to genetic and environmental influences as causal or risk modifiers.The neuropathologic hallmarks of disease are extracellular amyloid plaques and intracellular neurofibrillary tangles of hyperphosphorylated tau protein. 2 Only 10% of AD cases occurring before 60 years of age (early-onset AD) are due to rare, fully penetrant (autosomal dominant) mutations in 3 genes: A␤ precursor protein (APP) on chromosome 21, 3 presenilin 1 (PSEN1) on chromosome 14, 4 and presenilin 2 (PSEN2) on chromosome 1. 5,6In contrast, most cases of AD are later in onset (Ն 65 years of age) (late-onset AD), are nonfamilial, and are likely the result of highly prevalent genetic variants with low penetrance. 7To date, the only genetic risk factor for lateonset AD remains the apolipoprotein E gene (APOE), specifically the ε4 allele, which is moderately penetrant, accounting for up to 50% of cases. 8owever, a robust literature reports numerous putative genetic risk alleles and promising genetic variants.Recent reports from individual studies reveal significant associations with the sortilin-related receptor (SORL1 [NCBI Entrez gene 6653]) 9,10 and glycine-rich protein 2-associated binding protein 2 (GAB2 [NCBI Entrez gene 9846]) 11 on chromosome 11; death-associated protein kinase 1 (DAPK1 [NCBI Entrez gene 1612]), 12 ubiquilin 1 (UBQLN1 [NCBI Entrez gene 299798]), 13 and adenosine triphosphate-binding cassette transporter 1, subfamily A (ABCA1 [NCBI Entrez gene 19]), on chromosome 9 14 ; and low-density lipoprotein receptor-related protein 6 (LRP6 [NCBI Entrez gene 4040]) on chromosome 12. 15 All of these putative variants still lack replication in large representative populations but have relevance to neuropathologic mechanisms and pathways that may be associated with AD pathogenesis (   A large meta-analysis from the AlzGene database 16 17 All are associated with relevant biological mechanisms and pathways but await replication to further elucidate their utility as significant markers for AD."
                }
            ],
            "7fee50dc-7172-4574-a3e7-4961060a655b": [
                {
                    "document_id": "7fee50dc-7172-4574-a3e7-4961060a655b",
                    "text": "Background\n\nAlzheimer's disease (AD) is the most common neurodegenerative disorder and the leading cause of dementia in the elderly [1].Diagnosis of AD is based on the presence of neurofibrillary tangles and amyloid plaques [2], and symptoms typically include memory loss and impaired cognitive ability.Although the pathological hallmarks associated with dementia-related symptoms in AD appear largely similar between both the early-onset and late-onset forms of the disease, their underlying etiologies contrast [3].Whereas early-onset AD is a familial autosomal dominant disorder caused by rare, highly penetrant mutations in one of a small set of genes (APP, PSEN1, and PSEN2), the more common late-onset form of the disease (accounting for 90-95 % of cases) occurs sporadically, and risk is determined by complex underlying mechanisms [3][4][5][6].Estimates based on twin concordance rates suggest heritability of late-onset AD is as high as 70 %, implicating major roles for genetic as well as non-genetic factors [6].Indeed, through candidate gene studies, as well as more recent genome-wide association studies (GWASs) and whole-exome sequencing, both common and rare variants associated with the late-onset form of AD have been identified [7][8][9][10][11].Collectively, however, common GWAS variants account for only a modest proportion (~30 %) of the underlying variance in disease susceptibility [12].Several environmental factors are also thought to play a role [5,6], yet exactly how these contribute to risk, onset, and progression remains poorly defined."
                }
            ],
            "8275b075-735b-44dc-b549-32ee94dec32e": [
                {
                    "document_id": "8275b075-735b-44dc-b549-32ee94dec32e",
                    "text": "\nAlzheimer's disease is the most common type of dementia, and it is characterized by a decline in memory or other thinking skills.The greatest risk factor for Alzheimer's disease is advanced age.A recent genome-wide study identified a locus on chromosome 17 associated with the age at onset, and a specific variant in CCL11 is probably responsible for the association.The association of a protective haplotype with a 10-year delay in the onset of Alzheimer's disease and the identification of a CCL11 variant with possible functional roles in this association might allow the future development of immunomodulators with the potential to halve disease incidence."
                },
                {
                    "document_id": "8275b075-735b-44dc-b549-32ee94dec32e",
                    "text": "\n\nAlzheimer's disease is the most common type of dementia, and it is characterized by a decline in memory or other thinking skills.The greatest risk factor for Alzheimer's disease is advanced age.A recent genome-wide study identified a locus on chromosome 17 associated with the age at onset, and a specific variant in CCL11 is probably responsible for the association.The association of a protective haplotype with a 10-year delay in the onset of Alzheimer's disease and the identification of a CCL11 variant with possible functional roles in this association might allow the future development of immunomodulators with the potential to halve disease incidence."
                }
            ],
            "8881b5b0-fd7a-400d-9dd2-d4c3f9b012b4": [
                {
                    "document_id": "8881b5b0-fd7a-400d-9dd2-d4c3f9b012b4",
                    "text": "INTRODUCTION\n\nAlzheimer's disease (AD) is a common debilitating disorder with a prevalence that rises steeply with age from below 1% at 65 years to as high as 40% after the age of 90 [Bachman et al., 1992].Genes are known to play a role in the development of AD.Twin studies show heritabilities of around 60% [Bergem et al., 1997;Gatz et al., 1997].Indeed, variation in four genes has already been shown to cause rare forms of early-onset AD [the Amyloid Precursor Protein Gene (APP); Goate et al., 1991; Presenilin 1 (PS1); Sherrington et al., 1995; Presenilin 2 (PS2); Levy Lahad et al., 1995, Rogaev et al., 1995] or increase the general risk of disease development [Apolipoprotein E (APOE), Corder et al., 1993].As well as increasing disease susceptibility, APOE e4 alleles are associated with reduced age at onset (AAO) and appear to show their strongest effect below 70 years [Farrer et al., 1997].There is also evidence from both twin [Pedersen et al., 2001] and family studies [Tunstall et al., 2000;Li et al., 2002] that AAO in AD is heritable.Daw et al. [2000] have estimated that in addition to APOE, there are at least four loci with similar effect sizes, which contribute to AAO in AD."
                }
            ],
            "8b03aabf-8965-42c9-a054-44592bd98e86": [
                {
                    "document_id": "8b03aabf-8965-42c9-a054-44592bd98e86",
                    "text": "Introduction\n\nAlzheimer's disease (AD), a devastating neurodegenerative disease, is the most common form of dementia among the elderly.Genetically, AD is a complex and multifactorial disease with the possible involvement of multiple genes.The rare early-onset form of the disease usually follows an autosomal-dominant inheritance pattern and to date three genes have been identified: amyloid precursor protein (APP) and presenilin 1 and 2 (PSEN1 and PSEN2).The common late-onset form of the disease is much more complex than the early-onset form and until recently the apolipoprotein E (APOE) gene was the only major genetic factor accounting for 20-29% of the risk for late-onset AD. 1,2 Recent large genome-wide association studies (GWAS) have identi-fied nine additional genes for late-onset AD, including CR1, BIN1, CLU (a.k.a.4][5][6][7] There is high heritability for AD risk (up to 80%), 8 but the total risk attributable to all confirmed loci is about 50%, indicating the presence of additional risk genes for late-onset AD."
                }
            ],
            "c59757a9-deea-491e-a93c-3dfdb3d217f8": [
                {
                    "document_id": "c59757a9-deea-491e-a93c-3dfdb3d217f8",
                    "text": "\n\nNE OF EVERY 5 PERSONS AGED 65 years is predicted to develop Alzheimer disease (AD) in their lifetime, and genetic variants may play an important part in the development of the disease. 1 The apparent substantial heritability of late-onset AD 2 is inadequately explained by genetic variation within the well-replicated genes (apolipoprotein E [APOE; RefSeq NG_007084], presenilin-1 [PSEN1; RefSeq NG_007386], presenilin-2 [PSEN2; RefSeq NG_007381], and amyloid beta precursor protein [APP;"
                }
            ]
        },
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        "document_id": "6AD8F2432A4CDFAA63C74712C1165B0E",
        "engine": "gpt-4",
        "first_load": false,
        "focus": "api",
        "keywords": [
            "APOE&e4",
            "Alzheimers&disease",
            "genome-wide&association&studies",
            "amyloid-beta",
            "tau&neurofibrillary&tangles",
            "PSEN1",
            "PSEN2",
            "APP",
            "late-onset&AD",
            "early-onset&AD"
        ],
        "metadata": [],
        "question": "Describe the genotypes related to alzheimers and dementia which have commonalities with those for aging?",
        "subquestions": null,
        "task_id": "6AD8F2432A4CDFAA63C74712C1165B0E",
        "usage": {
            "chatgpt": 10216,
            "gpt-4": 5973,
            "gpt-4-turbo-preview": 5048
        },
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    "document_id": "6AD8F2432A4CDFAA63C74712C1165B0E",
    "task_id": "6AD8F2432A4CDFAA63C74712C1165B0E"
}