Dataset Information

APOE-related risk of mild cognitive impairment and dementia for prevention trials: An analysis of four cohorts.

ABSTRACT:

Background

With the onset of prevention trials for individuals at high risk for Alzheimer disease, there is increasing need for accurate risk prediction to inform study design and enrollment, but available risk estimates are limited. We developed risk estimates for the incidence of mild cognitive impairment (MCI) or dementia among cognitively unimpaired individuals by APOE-e4 dose for the genetic disclosure process of the Alzheimer's Prevention Initiative Generation Study, a prevention trial in cognitively unimpaired APOE-e4/e4 homozygote individuals.

Methods and findings

We included cognitively unimpaired individuals aged 60-75 y, consistent with Generation Study eligibility criteria, from the National Alzheimer's Coordinating Center (NACC) (n = 5,073, 158 APOE-e4/e4), the Rotterdam Study (n = 6,399, 156 APOE-e4/e4), the Framingham Heart Study (n = 4,078, 67 APOE-e4/e4), and the Sacramento Area Latino Study on Aging (SALSA) (n = 1,294, 11 APOE-e4/e4). We computed stratified cumulative incidence curves by age (60-64, 65-69, 70-75 y) and APOE-e4 dose, adjusting for the competing risk of mortality, and determined risk of MCI and/or dementia by genotype and baseline age. We also used subdistribution hazard regression to model relative hazard based on age, APOE genotype, sex, education, family history of dementia, vascular risk, subjective memory concerns, and baseline cognitive performance. The four cohorts varied considerably in age, education, ethnicity/race, and APOE-e4 allele frequency. Overall, cumulative incidence was uniformly higher in NACC than in the population-based cohorts. Among APOE-e4/e4 individuals, 5-y cumulative incidence was as follows: in the 60-64-y age stratum, it ranged from 0% to 5.88% in the three population-based cohorts versus 23.06% in NACC; in the 65-69-y age stratum, from 9.42% to 10.39% versus 34.62%; and in the 70-75-y age stratum, from 18.64% to 33.33% versus 38.34%. Five-year incidence of dementia was negligible except for APOE-e4/e4 individuals and those over 70 y. Lifetime incidence (to age 80-85 y) of MCI or dementia for the APOE-e4/e4 individuals in the long-term Framingham and Rotterdam cohorts was 34.69%-38.45% at age 60-64 y, 30.76%-40.26% at 65-69 y, and 33.3%-35.17% at 70-75 y. Confidence limits for these estimates are often wide, particularly for APOE-e4/e4 individuals and for the dementia outcome at 5 y. In regression models, APOE-e4 dose and age both consistently increased risk, as did lower education, subjective memory concerns, poorer baseline cognitive performance, and family history of dementia. We discuss several limitations of the study, including the small numbers of APOE-e4/e4 individuals, missing data and differential dropout, limited ethnic and racial diversity, and differences in definitions of exposure and outcome variables.

Conclusions

Estimates of the absolute risk of MCI or dementia, particularly over short time intervals, are sensitive to sampling and a variety of methodological factors. Nonetheless, such estimates were fairly consistent across the population-based cohorts, and lower than those from a convenience cohort and those estimated in prior studies-with implications for informed consent and design for clinical trials targeting high-risk individuals.

SUBMITTER: Qian J

PROVIDER: S-EPMC5360223 | biostudies-literature | 2017 Mar

REPOSITORIES: biostudies-literature

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Publications

APOE-related risk of mild cognitive impairment and dementia for prevention trials: An analysis of four cohorts.

Qian Jing J Wolters Frank J FJ Beiser Alexa A Haan Mary M Ikram M Arfan MA Karlawish Jason J Langbaum Jessica B JB Neuhaus John M JM Reiman Eric M EM Roberts J Scott JS Seshadri Sudha S Tariot Pierre N PN Woods Beth McCarty BM Betensky Rebecca A RA Blacker Deborah D

PLoS medicine 20170321 3

<h4>Background</h4>With the onset of prevention trials for individuals at high risk for Alzheimer disease, there is increasing need for accurate risk prediction to inform study design and enrollment, but available risk estimates are limited. We developed risk estimates for the incidence of mild cognitive impairment (MCI) or dementia among cognitively unimpaired individuals by APOE-e4 dose for the genetic disclosure process of the Alzheimer's Prevention Initiative Generation Study, a prevention t ...[more]

PMID: 28323826

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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:Mild behavioral impairment (MBI) is a high-risk state for incident dementia and comprises five core domains including affective dysregulation, impulse dyscontrol, social inappropriateness, psychotic symptoms, and apathy. Apathy is among the most common neuropsychiatric symptoms (NPS) in dementia but can also develop in persons with normal cognition (NC) or mild cognitive impairment (MCI). The later-life emergence and persistence of apathy as part of the MBI syndrome may be a driving factor for dementia risk. Therefore, we investigated MBI-apathy-associated progression to dementia, and effect modification by sex, race, cognitive diagnosis, and apolipoprotein E (APOE) genotype. Dementia-free National Alzheimer's Coordinating Center participants were stratified by persistent apathy status, based on Neuropsychiatric Inventory (NPI)-Questionnaire scores at two consecutive visits. Hazard ratios (HRs) for incident dementia for MBI-apathy and NPI-apathy relative to no NPS, and MBI-apathy relative to no apathy, were determined using Cox proportional hazards regressions, adjusted for baseline age, sex, years of education, race, cognitive diagnosis, and APOE genotype. Interactions with relevant model covariates were explored. Of the 3932 participants (3247 with NC), 354 had MBI-apathy. Of all analytic groups, MBI-apathy had the greatest dementia incidence (HR = 2.69, 95% confidence interval [CI]: 2.15-3.36, P < 0.001). Interaction effects were observed between cognitive diagnosis and APOE genotype with the NPS group. The contribution of apathy to dementia risk was greater in NC (HR = 5.91, 95% CI: 3.91-8.93) than in MCI (HR = 2.16, 95% CI: 1.69-2.77, interaction P < 0.001) and in all APOE genotypes, was greatest in APOE ɛ3 (HR = 4.25, 95% CI: 3.1-5.82, interaction P < 0.001). Individuals with MBI-apathy have a markedly elevated risk for future dementia, especially when symptoms emerge in those with NC. Both cognitive status and APOE genotype are important moderators in the relationship between MBI-apathy and incident dementia. MBI-apathy may represent a group in whom apathy is a preclinical or prodromal manifestation of dementia and identify a precision medicine target for preventative interventions.

Dataset Information

APOE-related risk of mild cognitive impairment and dementia for prevention trials: An analysis of four cohorts.

Background

Methods and findings

Conclusions

Publications

APOE-related risk of mild cognitive impairment and dementia for prevention trials: An analysis of four cohorts.

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