Dataset Information

Genetic Variants in KLOTHO Associate With Cognitive Function in the Oldest Old Group.

ABSTRACT: Decline in cognitive abilities is a major concern in aging individuals. A potential important factor for functioning of the central nervous system in late-life stages is the KLOTHO (KL) gene. KL is expressed in various organs including the brain and is involved in multiple biological processes, for example, growth factor signaling. In the present study, 19 tagging gene variants in KL were studied in relation to 2 measures of cognitive function, a 5-item cognitive composite score and the Mini Mental State Examination, in 1,480 Danes 92-100 years of age. We found that heterozygotes for the previously reported KL-VS had poorer cognitive function than noncarriers. Two other variants positioned in the 5' end of the gene, rs398655 and rs562020, were associated with better cognitive function independently of KL-VS, and the common haplotype AG was associated with poorer cognition, consistently across two cognitive measures in two cohort strata. The haplotype effect was stronger than that of KL-VS. Two variants, rs2283368 and rs9526984, were the only variants significantly associated with cognitive decline over 7 years. We discuss an age-dependent effect of KL and the possibility that multiple gene variants in KL are important for cognitive function among the oldest old participants.

SUBMITTER: Mengel-From J

PROVIDER: S-EPMC4978356 | biostudies-literature | 2016 Sep

REPOSITORIES: biostudies-literature

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Genetic Variants in KLOTHO Associate With Cognitive Function in the Oldest Old Group.

Mengel-From Jonas J Soerensen Mette M Nygaard Marianne M McGue Matt M Christensen Kaare K Christiansen Lene L

The journals of gerontology. Series A, Biological sciences and medical sciences 20150924 9

Decline in cognitive abilities is a major concern in aging individuals. A potential important factor for functioning of the central nervous system in late-life stages is the KLOTHO (KL) gene. KL is expressed in various organs including the brain and is involved in multiple biological processes, for example, growth factor signaling. In the present study, 19 tagging gene variants in KL were studied in relation to 2 measures of cognitive function, a 5-item cognitive composite score and the Mini Men ...[more]

PMID: 26405063

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Project description:The emergence of longevity in the modern world has brought a sense of urgency to understanding age-related neurodegenerative diseases such as Alzheimer's disease. Unfortunately, there is a lack of consensus regarding the correlation between the pathological substrates of neurodegeneration and dementia status, particularly in the oldest-old. To better understand the pathological correlates of dementia in the oldest-old, we characterized the topographical spread and severity of amyloid-?, tau, TDP-43 and ?-synuclein pathologies in the 90+ Study, a prospective longitudinal population-based study of ageing and dementia. Neuropathological analysis with immunohistochemically labelled sections was carried out blind to clinical diagnosis on the first 108 participants of the 90+ Study who came to autopsy including participants with dementia (n = 66) and without dementia (n = 42). We used quantitative and/or semi-quantitative measures to assess the burden of amyloid-?, tau, TDP-43 and ?-synuclein pathologies as well as hippocampal sclerosis. Amyloid-? and tau were the predominant pathologies in the 90+ Study cohort and both amyloid-? area and tau area occupied measures were strongly associated with the presence of dementia, as was Braak staging but semi-quantitative plaque scores were not. Notably, TDP-43 pathology also correlated with dementia, while ?-synuclein distribution did not. In addition, hippocampal sclerosis was specific to participants with dementia and correlated with the presence of limbic TDP-43. In contrast to previous reports, we found that tau and amyloid-? continue to be robust pathological correlates of dementia, even in the oldest-old. While individuals with no dementia had limited hippocampal tau and neocortical amyloid-? pathology, dementia associated with an expansion in pathology, including increased neocortical tau and hippocampal amyloid-? plaques, more abundant neocortical amyloid-? deposition and hippocampal sclerosis with its attendant TDP-43 pathology.

Project description:Objectiveto describe the characteristics and survival of the oldest old in England and Wales.Designretrospective analysis of the oldest old from a population-based cohort study.Settingpopulation-based study in England and Wales: two rural and three urban sites.Methodstwo types of analyses were conducted: (i) a descriptive analysis of those individuals who were aged 90 years or more, and 100 years or more, and (ii) a survival analysis of those who reached their 90th, 95th, or 100th birthday during the study. Median survival time was calculated by the Kaplan-Meier method. Effects of socio-demographic characteristics on survival were evaluated using the Cox proportional-hazards regression model.Resultsin total, 958 individuals aged 90 years or more, and 24 individuals aged 100 years or more, had been interviewed at least once during the study. Twenty-seven per cent were living in residential or nursing homes. Women aged 90 years or more were more likely to be living in residential and nursing homes, be widowed, have any disability or have lower MMSE scores. The centenarians were mostly cognitively and functionally impaired. The median survival times for those reaching their 90th (n = 2,336), 95th (n = 638), or 100th birthday (n = 92) during the study were 3.7 years (95% CI: 3.5-4.0), 2.3 (2.1-2.6) and 2.1 (1.7-2.6) years for women, and 2.9 (95% CI: 2.6- 3.1), 2.0 (1.2-3.1) and 2.2 (0.5-2.3) for men, respectively. Those living in residential and nursing homes had a shorter survival when aged 90 years, with similar non-significant effects for those aged 95 and 100 years. After the age of 100 years, the high mortality rate and small sample size limited the ability to detect any differences between the different groups.Conclusioneven at the very oldest ages, the majority live in non-institutionalised settings. Among the oldest old, women were frailer than men. Being male and living in residential nursing homes shortened survival in those aged 90 years or more.

Dataset Information

Genetic Variants in KLOTHO Associate With Cognitive Function in the Oldest Old Group.

Publications

Genetic Variants in KLOTHO Associate With Cognitive Function in the Oldest Old Group.

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