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The Contribution of Genetic Factors to Cognitive Impairment and Dementia: Apolipoprotein E Gene, Gene Interactions, and Polygenic Risk.

ABSTRACT: Alzheimer's disease (AD) is a progressive neurodegenerative disease. Although it has been studied for years, the pathogenesis of AD is still controversial. Genetic factors may play an important role in pathogenesis, with the apolipoprotein E (APOE) gene among the greatest risk factors for AD. In this review, we focus on the influence of genetic factors, including the APOE gene, the interaction between APOE and other genes, and the polygenic risk factors for cognitive function and dementia. The presence of the APOE ?4 allele is associated with increased AD risk and reduced age of AD onset. Accelerated cognitive decline and abnormal internal environment, structure, and function of the brain were also found in ?4 carriers. The effect of the APOE promoter on cognition and the brain was confirmed by some studies, but further investigation is still needed. We also describe the effects of the associations between APOE and other genetic risk factors on cognition and the brain that exhibit a complex gene?gene interaction, and we consider the importance of using a polygenic risk score to investigate the association between genetic variance and phenotype.

SUBMITTER: Fan J

PROVIDER: S-EPMC6429136 | biostudies-literature | 2019 Mar

REPOSITORIES: biostudies-literature

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The Contribution of Genetic Factors to Cognitive Impairment and Dementia: Apolipoprotein E Gene, Gene Interactions, and Polygenic Risk.

Fan Jialing J Tao Wuhai W Li Xin X Li He H Zhang Junying J Wei Dongfeng D Chen Yaojing Y Zhang Zhanjun Z

International journal of molecular sciences 20190307 5

Alzheimer's disease (AD) is a progressive neurodegenerative disease. Although it has been studied for years, the pathogenesis of AD is still controversial. Genetic factors may play an important role in pathogenesis, with the apolipoprotein E (APOE) gene among the greatest risk factors for AD. In this review, we focus on the influence of genetic factors, including the APOE gene, the interaction between APOE and other genes, and the polygenic risk factors for cognitive functio ...[more]

PMID: 30866553

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Project description:BackgroundMild cognitive impairment and cognitive impairment, no dementia, are emerging terms that encompass the clinical state between normal cognition and dementia in elderly people. Controversy surrounds their characterization, definition and application in clinical practice. In this article, we provide physicians with practical guidance on the definition, diagnosis and treatment of mild cognitive impairment and cognitive impairment, no dementia, based on recommendations from the Third Canadian Consensus Conference on the Diagnosis and Treatment of Dementia, held in March 2006.MethodsWe developed evidence-based guidelines using systematic literature searches, with specific criteria for study selection and quality assessment, and a clear and transparent decision-making process. We selected studies published from January 1996 to December 2005 that had mild cognitive impairment or cognitive impairment, no dementia, as the outcome. Subsequent to the conference, we searched for additional articles published between January 2006 and January 2008. We graded the strength of evidence using the criteria of the Canadian Task Force on Preventive Health Care.ResultsWe identified 2483 articles, of which 314 were considered to be relevant and of good or fair quality. From a synthesis of the evidence in these studies, we made 16 recommendations. In brief, family physicians should be aware that most types of dementia are preceded by a recognizable phase of mild cognitive decline. They should be familiar with the concepts of mild cognitive impairment and of cognitive impairment, no dementia. Patients with these conditions should be closely monitored because of their increased risk for dementia. Leisure activities, cognitive stimulation and physical activity could be promoted as part of a healthy lifestyle in elderly people and those with mild cognitive impairment. Vascular risk factors should be treated optimally. No other specific therapies can yet be recommended.InterpretationPhysicians will increasingly see elderly patients with mild memory loss, and learning an approach to diagnosing states such as mild cognitive impairment is now warranted. Close monitoring for progression to dementia, promotion of a healthy lifestyle and treatment of vascular risk factors are recommended for the management of patients with mild cognitive impairment.

Project description:BackgroundSocioeconomic disadvantage is a risk factor for dementia, but longitudinal studies suggest that it does not affect the rate of cognitive decline. Our objective is to understand the manner in which socioeconomic disadvantage shapes dementia risk by examining its associations with midlife cognitive performance and cognitive decline from midlife to old age, including cognitive decline trajectories in those with dementia.Methods and findingsData are drawn from the Whitehall II study (N = 10,308 at study recruitment in 1985), with cognitive function assessed at 4 waves (1997, 2002, 2007, and 2012). Sociodemographic, behavioural, and cardiometabolic risk factors from 1985 and chronic conditions until the end of follow-up in 2015 (N dementia/total = 320/9,938) allowed the use of inverse probability weighting to take into account data missing because of loss to follow-up between the study recruitment in 1985 and the introduction of cognitive tests to the study in 1997. Generalized estimating equations and Cox regression were used to assess associations of socioeconomic markers (height, education, and midlife occupation categorized as low, intermediate, and high to represent hierarchy in the socioeconomic marker) with cognitive performance, cognitive decline, and dementia (N dementia/total = 195/7,499). In those with dementia, we examined whether retrospective trajectories of cognitive decline (backward timescale) over 18 years prior to diagnosis differed as a function of socioeconomic markers. Socioeconomic disadvantage was associated with poorer cognitive performance (all p < 0.001). Using point estimates for the effect of age, the differences between the high and low socioeconomic groups corresponded to an age effect of 4, 15, and 26 years, for height, education, and midlife occupation, respectively. There was no evidence of faster cognitive decline in socioeconomically disadvantaged groups. Low occupation, but not height or education, was associated with risk of dementia (hazard ratio [HR] = 2.03 [95% confidence interval (CI) 1.23-3.36]) in an analysis adjusted for sociodemographic factors; the excess risk was unchanged after adjustment for cognitive decline but was completely attenuated after adjustment for cognitive performance. In further analyses restricted to those with dementia, retrospective cognitive trajectories over 18 years prior to dementia diagnosis showed faster cognitive decline in the high education (p = 0.006) and occupation (p = 0.001) groups such that large differences in cognitive performance in midlife were attenuated at dementia diagnosis. A major limitation of our study is the use of electronic health records rather than comprehensive dementia ascertainment.ConclusionsOur results support the passive or threshold cognitive reserve hypothesis, in that high cognitive reserve is associated with lower risk for dementia because of its association with cognitive performance, which provides a buffer against clinical expression of dementia.

Dataset Information

The Contribution of Genetic Factors to Cognitive Impairment and Dementia: Apolipoprotein E Gene, Gene Interactions, and Polygenic Risk.

Publications

The Contribution of Genetic Factors to Cognitive Impairment and Dementia: Apolipoprotein E Gene, Gene Interactions, and Polygenic Risk.

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