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    Apolipoprotein E ε4 Genotypes Affect Cognitive Resilience
    ANWEN SHAO | Zhejiang University
    There has been a steadily growing number of studies examining cognitive decline in elderly people. However, the mechanisms are largely unknown. Previous studies reported that carrier of apolipoprotein E (APOE [OMIM 107741]) ε4 are at high risk for cognitive decline and Alzheimer disease. Experimental and clinical studies have suggested that APOE ε4 can accelerate the aggregation of β-amyloid and in turn lead to neuronal degeneration and, eventually, to cognitive decline and Alzheimer disease. The study conducted by Kaup et al investigated the underlying factors associated with cognitive resilience among black and white older adults carrying APOE ε4 respectively. This research demonstrated some factors helping minimize the deleterious effect of ε4 allele on cognition, e.g. the literacy level, educational level and age. According to this, the authors suggested that enhancing cognitive reserve may be the promising targeting towards promoting cognitive resilience in black and white APOE ε4 carriers.[1] However, as an observational cohort study, the established bias should be addressed. Actually, APOE ε4 allele includes homozygous and heterozygous genotypes, which may exert different effects on cognitive decline. It was reported that APOE ε4 homozygotes have as high as 15 times the risk while APOE ε4 heterozygotes up to four times the risk for developing Alzheimer disease when compared with persons homozygous for APOE ε3.[2] Thus, APOE ε4 homozygous and heterozygous affected cognitive decline developing in varying degrees, and in this context, it should be included in univariate analysis to diminish the bias between groups as well as in multivariate analysis to accomplish the regression model. In this article, the authors also concluded that factors which affected cognitive resilience were different in white and black older adults. However, it should be noticed that the distribution of homozygous and heterozygous in white and black people varies greatly[3,4], which may result in different pathogenic conditions and cognitive resilience levels. Thus, taking this fundamental factor into consideration may elicit more accurate conclusions.In addition, as long as 11 years’ follow-up, the article did not mention how to deal with the censored data, e.g. the subjects died or failed to follow-up, which was also an important part in STROBE statement.Reference1. Kaup AR, Nettiksimmons J, Harris TB, et al. Cognitive Resilience to Apolipoprotein E epsilon4: Contributing Factors in Black and White Older Adults. JAMA Neurol. 2015.2. Wolf AB, Valla J, Bu GJ, et al. Apolipoprotein E as a beta-amyloid-independent factor in Alzheimer's disease. Alzheimers Res Ther. 2013;5(5).3. Blair CK, Folsom AR, Knopman DS, Bray MS, Mosley TH, Boerwinkle E. APOE genotype and cognitive decline in a middle-aged cohort. Neurology. 2005;64(2):268-276.4. Farrer LA1, Cupples LA, Haines JL et al. Effects of age, sex, and ethnicity on the association between apolipoprotein E genotype and Alzheimer disease. A meta-analysis. APOE and Alzheimer Disease Meta Analysis Consortium. JAMA. 1997 Oct 22-29;278(16):1349-56.
    CONFLICT OF INTEREST: None Reported
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    Original Investigation
    March 2015

    Cognitive Resilience to Apolipoprotein E ε4: Contributing Factors in Black and White Older Adults

    Author Affiliations
    • 1Sierra Pacific Mental Illness Research, Education, and Clinical Center, San Francisco Veterans Affairs Medical Center, San Francisco, California
    • 2Department of Psychiatry, University of California, San Francisco
    • 3Laboratory of Epidemiology and Populations Science, Intramural Research Program, National Institute on Aging, Bethesda, Maryland
    • 4Section on Gerontology and Geriatric Medicine, Department of Medicine, Wake Forest School of Medicine, Winston-Salem, North Carolina
    • 5Department of Preventive Medicine, University of Tennessee Health Science Center, Memphis
    • 6Department of Epidemiology, University of Pittsburgh, Pittsburgh, Pennsylvania
    • 7Department of Epidemiology and Biostatistics, University of California, San Francisco
    • 8Department of Neurology, University of California, San Francisco
    JAMA Neurol. 2015;72(3):340-348. doi:10.1001/jamaneurol.2014.3978
    Abstract

    Importance  Apolipoprotein E (APOE) ε4 is an established risk factor for cognitive decline and the development of dementia, but other factors may help to minimize its effects.

    Objective  Using APOE ε4 as an indicator of high risk, we investigated factors associated with cognitive resilience among black and white older adults who are APOE ε4 carriers.

    Design, Setting, and Participants  Participants included 2487 community-dwelling older (aged 69-80 years at baseline) black and white adults examined at 2 community clinics in the prospective cohort Health, Aging, and Body Composition (Health ABC) study. The baseline visits occurred from May 1997 through June 1998. Our primary analytic cohort consisted of 670 APOE ε4 carriers (329 black and 341 white participants) who were free of cognitive impairment at baseline and underwent repeated cognitive testing during an 11-year follow-up (through 2008) using the Modified Mini-Mental State Examination.

    Main Outcomes and Measures  We stratified all analyses by race. Using the Modified Mini-Mental State Examination scores, we assessed normative cognitive change in the entire cohort (n = 2487) and classified the APOE ε4 carriers as being cognitively resilient vs nonresilient by comparing their cognitive trajectories with those of the entire cohort. We then conducted bivariate analyses and multivariable random forest and logistic regression analyses to explore factors predictive of cognitive resilience in APOE ε4 carriers.

    Results  Among white APOE ε4 carriers, the strongest predictors of cognitive resilience were, in relative order of importance, no recent negative life events, a higher literacy level, advanced age, a higher educational level, and more time spent reading. Among black APOE ε4 carriers, the strongest predictors of cognitive resilience were, in relative order of importance, a higher literacy level, a higher educational level, female sex, and the absence of diabetes mellitus. In follow-up logistic regression models, higher literacy level (adjusted odds ratio [OR], 9.50 [95% CI, 2.67-60.89]), a higher educational level (adjusted OR for college graduate vs less than high school, 3.81 [95% CI, 1.13-17.56]), and age (adjusted OR for 73-76 vs 69-72 years, 2.01 [95% CI, 1.13-3.63]) had significant independent effects in predicting cognitive resilience among white APOE ε4 carriers. Among black APOE ε4 carriers, a higher literacy level (adjusted OR, 2.27 [95% CI, 1.29-4.06]) and a higher educational level (adjusted OR for high school graduate/some college vs less than high school, 2.86 [95% CI, 1.54-5.49]; adjusted OR for college graduate vs less than high school, 2.52 [95% CI, 1.14-5.62]) had significant independent effects in predicting cognitive resilience.

    Conclusions and Relevance  Although APOE ε4 carriers are at high risk for cognitive decline, our findings suggest possible intervention targets, including the enhancement of cognitive reserve and improvement of other psychosocial and health factors, to promote cognitive resilience among black and white APOE ε4 carriers.

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