Abstract and Introduction
Abstract
Background: There are contradicting reports on the associations between Apolipoprotein E4 (ApoE ε4) and brain outcomes in HIV with some evidence that relationships may be greatest in older age groups.
Methods: We assessed cognition in 76 clinically stable HIV-infected participants over age 60 and genotyped ApoE. Sixty-one of these subjects underwent structural brain magnetic resonance imaging and diffusion tensor imaging.
Results: The median age of the participants was 64 years (range: 60–84) and the median estimated duration of HIV infection was 22 years. Apo ε4 carriers (n = 19) were similar to noncarriers (n = 57) in sex (95% vs. 96% male), and education (16.0 vs. 16.2 years) ApoE ε4 carriers demonstrated greater deficits in cognitive performance in the executive domain (P = 0.045) and had reduced fractional anisotropy and increased mean diffusivity throughout large white matter tracts within the brain compared with noncarriers. Tensor-based morphometry analyses revealed ventricular expansion and atrophy in the posterior corpus callosum, thalamus, and brainstem among HIV-infected ApoE ε4 carriers compared with ε4 noncarriers.
Conclusions: In this sample of older HIV-infected individuals, having at least 1 ApoE ε4 allele was associated with decreased cognitive performance in the executive functioning domain, reduced brain white matter integrity, and brain atrophy. Brain atrophy was most prominent in the posterior corpus callosum, thalamus, and brainstem. This pattern of cognitive deficit, atrophy, and damage to white matter integrity was similar to that described in HIV, suggesting an exacerbation of HIV-related pathology; although emergence of other age-associated neurodegenerative disorders cannot be excluded.
Introduction
The demographic shifts associated with aging among the HIV-infected population in the U.S. are well established.[1] Around 50% of HIV cases reported to the U.S. Centers for Disease Control and Prevention are over the age of 50.[2] In 2008, there were more than 50,000 HIV-infected adults in the U.S. over age 60.[3] Analyses of past cohort studies demonstrate extension of life expectancy with combination antiretroviral therapy (cART).[4]
Risk for HIV-associated neurocognitive disorders (HAND) increases with age and, despite access to cART, HAND occurs in up to one-half of adults living with HIV.[5] Older HIV-infected patients who are already at risk for HAND also face elevated risk of age-related neurodegenerative disorders with the chances of developing dementia increasing with age, doubling every 5 years after age 65.[6,7] It remains unknown if HIV impacts the frequency or severity of age-associated neurodegenerative disorders.
ApoE ε4 is a substantial genetic risk factor for Alzheimer's disease (AD), particularly late-onset AD (ie, after age 65).[8] ApoE ε4 has been linked with poorer cognitive performance in both healthy nondemented individuals and among individuals with mild cognitive impairment.[9,10] The presence of ApoE ε4 is associated with poorer outcomes in other neurological conditions as well, including head injuries and seizures.[11,12] Imaging studies reveal an association between ApoE ε4 and both medial temporal lobe and hippocampal atrophy in HIV-uninfected populations, as well as evidence for disrupted brain network activity.[8,13]
Studies of ApoE ε4 in HIV-infected populations suggest this genotype plays a role in HIV neuropathology; a more complete review of these studies was recently published by Panos et al.[14] Before cART use became widespread, HIV-infected individuals with at least 1 ApoE ε4 allele were twice as likely to have dementia compared with those without.[15] In a more recent cohort study, HIV-infected individuals who are homozygous for ApoE ε4 have accelerated disease progression compared with those with the E3/e3 or E3/E4 genotype, although rates of dementia are reported to be similar by ApoE ε4 carrier status.[16] In a small study of young HIV-infected South African adults, researchers report poorer performance on memory tasks and decreased fractional anisotropy (FA) of the corpus callosum in ApoE ε4 carriers compared with noncarriers.[17]
In older age, one cross-sectional study notes risk for HIV-associated dementia in relation to ApoE ε4 carrier status (age >50 years); and, this is not seen in coenrolled younger participants (age <40 years).[18] Similarly, several recent reports among younger samples fail to identify risk. One such report from the CHARTER group (mean age = 40 years, 25% over age 50 years) finds no difference in HAND prevalence between ApoE ε4 carriers and noncarriers nor did they identify neuroimaging differences by carrier status.[19,20] Similarly, investigations from the Multicenter AIDS Cohort Study (MACS, with mean ages at enrollment across groups between 30 to 40 years) do not identify an impact of ApoE ε4 on development of cognitive impairment among participants who tested normal at baseline.[21] One group carefully tested the hypothesis that age may influence the association between ApoE ε4 carrier status and cognitive outcomes using data from the National NeuroAIDS Tissue Consortium noting detrimental effects on HAND diagnosis, executive functioning, and information processing in older age (>50 years) but not in those of younger age.[14]
In this study, we investigate the risk of ApoE ε4 carrier status in a group of older HIV-infected participants where concern for neurodegenerative disorders is higher because of age. Our cross-sectional analyses examine neuropsychological testing performance, cognitive diagnoses, brain morphometry, and diffusion tensor imaging (DTI) data in relation to ApoE ε4 carrier status.
J Acquir Immune Defic Syndr. 2016;73(4):426-432. © 2016 Lippincott Williams & Wilkins
