The apolipoprotein E genotype predicts longitudinal transitions to mild cognitive impairment but not to Alzheimer's dementia: Findings from a nationally representative study.

Abstract

Objective The ε4 allele of the apolipoprotein E (APOE) genotype is the most widely accepted genetic risk factor for Alzheimer’s dementia (AD), but findings on whether it is a risk factor for the AD prodrome, mild cognitive impairment (MCI), have been inconsistent. In a prospective longitudinal design, we investigated (a) whether transitions to MCI and other forms of neurocognitive impairment without dementia (CIND) are more frequent among normal ε4 carriers than among noncarriers and (b) whether subsequent transitions to AD from MCI and from other forms of CIND are more frequent among ε4 carriers than among noncarriers. Method The frequency of the ε4 allele was studied in older adults (mean age > 70), who had participated in two or more waves of neuropsychological testing and diagnosis in the Aging, Demographics, and Memory Study (ADAMS) of the United States Department of Health and Human Services, National Institutes of Health, National Institute on Aging’s Health and Retirement Study, conducted by the University of Mchigan. The association between ε4 and longitudinal transitions to specific types of CIND and dementia can be determined with this data set. Results Epsilon 4 increased the rate of progression from normal functioning to MCI (58% of new diagnoses were carriers) but not to other forms of CIND. The rate of progression to AD from MCI or from other forms of CIND was not increased by ε 4. Conclusions The results support the hypothesis that ε4 is a risk factor for transitions from normal functioning to MCI but not for subsequent transitions to AD. In the ADAMS sample, the reason ε 4 is elevated in AD individuals is because it is already elevated in MCI individuals, who are the primary source of new AD diagnoses.

Apolipoprotein E e4 and Cognitive Function: A Modifiable Association? Results from Two Independent Cohort Studies

“…In our study, excluding patients with incident dementia, which limits possible confounding due to incident dementia, did not have a major impact on the results. This indicates that the effects of APOE e4 are not necessarily prodromal to dementia disease and that they might also affect cognitive performance in non-demented people, an interpretation in line with the findings of Brainerd et al [4], who found that APOE e4 increases the rate of transition from normal functioning to cognitive impairment without dementia, but not from cognitive impairment to AD.…”

“…Also, our sensitivity analyses with amnestic memory and executive function show that associations of APOE e4 in the general population with and without CVD are strongly driven by the memory component of the COGTEL total scores, which supports previous results suggesting that in the general population APOE e4 is only a risk factor for amnestic memory but not for other forms of cognitive impairment [4]. …”

“…Our results imply a potential usefulness of APOE genotyping among people with high TC levels and CVD in order to identify individuals at high risk for cognitive impairment, which is also supported by longitudinal data indicating that APOE e4 status predicts future diagnoses of cognitive impairment without dementia in the general population [4]. …”

“…Very few studies investigated associations of APOE genotype with cognitive performance in population-based cohort studies and results were mostly inconsistent, supposedly because of small samples and the possible inclusion of participants with latent dementia, who might experience stronger cognitive decline already in early subclinical stages of the disease [4,20]. In our study, excluding patients with incident dementia, which limits possible confounding due to incident dementia, did not have a major impact on the results.…”

“…The APOE e4 genetic polymorphism has been consistently associated with increased risk for Alzheimer's disease (AD), cardiovascular disease (CVD) and hypercholesterolemia [3]. Less consistent associations have been found between the APOE e4 allele and reduced cognitive performance in the general population [4,5,6]. …”