Apolipoprotein E4 Noncarriers Research Articles

41 Examining the independent and additive effects of family history of dementia and apolipoprotein e4 on neurocognitive performance among people with HIV

Objective:Among people with HIV (PWH), the apolipoprotein e4 (APOE-e4) allele, a genetic marker associated with Alzheimer’s disease (AD), and self-reported family history of dementia (FHD), considered a proxy for higher AD genetic risk, are independently associated with worse neurocognition. However, research has not addressed the potential additive effect of FHD and APOE-e4 on global and domain-specific neurocognition among PWH. Thus, the aim of the current investigation is to examine the associations between FHD, APOE-e4, and neurocognition among PWH.Participants and Methods:283 PWH (Mage=50.9; SDage=5.6) from the CNS HIV Anti-Retroviral Therapy Effects Research (CHARTER) study completed comprehensive neuropsychological and neuromedical evaluations and underwent APOE genotyping. APOE status was dichotomized into APOE-e4+ and APOE-e4-. APOE-e4+ status included heterozygous and homozygous carriers. Participants completed a free-response question capturing FHD of a first- or second-degree relative (i.e., biologic parent, sibling, children, grandparent, grandchild, uncle, aunt, nephew, niece, half-sibling). A dichotomized (yes/no), FHD variable was used in analyses. Neurocognition was measured using global and domain-specific demographically corrected (i.e., age, education, sex, race/ethnicity) T-scores. t-tests were used to compare global and domain-specific demographically-corrected T-scores by FHD status and APOE-e4 status. A 2x2 factorial analysis of variance (ANOVA) was used to model the interactive effects of FHD and APOE-e4 status. Tukey’s HSD test was used to follow-up on significant ANOVAs.Results:Results revealed significant differences by FHD status in executive functioning (t(281)=-2.3, p=0.03) and motor skills (t(278)=-2.0, p=0.03) such that FHD+ performed worse compared to FHD-. Differences in global neurocognition by FHD status approached significance (t(281)=-1.8, p=.069). Global and domain-specific neurocognitive performance were comparable among APOE-e4 carriers and noncarriers (ps>0.05). Results evaluating the interactive effects of FHD and APOE-e4 showed significant differences in motor skills (F(3)=2.7, p=0.04) between the FHD-/APOE-e4+ and FHD+/APOE-e4- groups such that the FHD+/APOE-e4- performed worse than the FHD-/APOE-e4+ group (p=0.02).Conclusions:PWH with FHD exhibited worse neurocognitive performance within the domains of executive functioning and motor skills, however, there were no significant differences in neurocognition between APOE-e4 carriers and noncarriers. Furthermore, global neurocognitive performance was comparable across FHD/APOE-e4 groups. Differences between the FHD-/APOE-e4+ and FHD+/APOE-e4- groups in motor skills were likely driven by FHD status, considering there were no independent effects of APOE-e4 status. This suggests that FHD may be a predispositional risk factor for poor neurocognitive performance among PWH. Considering FHD is easily captured through self-report, compared to blood based APOE-e4 status, PWH with FHD should be more closely monitored. Future research is warranted to address the potential additive effect of FHD and APOE-e4 on rates of global and domain-specific neurocognitive decline and impairment over time among in an older cohort of PWH, where APOE-e4 status may have stronger effects.

White matter hyperintensity volume (WMHV) association with APOE e4 carriers and non-carriers (P11-5.005)

<h3>Objective:</h3> Determine whether white matter hyper-intensity volume (WMHV) differs with APOE4 carriage. <h3>Background:</h3> Apolipoprotein E4 (APOE4) allele is associated with an increased risk for both Alzheimer’s Disease (AD) and cardiovascular disease (CVD). APOE4 association with WMHV (a measure of small vessel vasculopathy) is ambiguous. While APOE4 carriage is associated with greater AD pathology, it remains unclear whether cerebrovascular damage is also associated with APOE4 carriage. The aim of this meta-analysis is to determine whether WMHV is associated with APOE carrier status. <h3>Design/Methods:</h3> 12 studies from Pubmed and EMBASE were found where data for sample size, age, WMHV, study setting, and WMHV quantification method were extracted from each article. Random effect models were used to estimate raw and standardized mean differences for WMHV in APOE4 carriers and non-carriers in addition to subgroup analyses (clinic and community). Analyses were carried out using the ‘metacont’ function in the ‘meta’ package in R 4.0.3. <h3>Results:</h3> The 12 studies yielded a total sample size of 16,738 (e4 carrier n=4,721; e4 non-carrier n=12,017) with an average age of 69.72 years. The primary analysis found no significant difference in WMHV between e4 carriers and non-carriers (95% CI (−0.01, 0.15), p = 0.09) with a moderate level between-study heterogeneity (I2 = 64%, 95% CI (33%, 81%). Subgroup analyses showed a small effect size indicating that APOE4 carriers had a greater WMHV (n = 8, 95% CI (0.02, 0.16), p = 0.008) with moderate heterogeneity (I2 = 55%, 95% CI (1%, 80%). No significant difference in WMHV by APOE4 status was noted among clinic-based studies (n = 3, 95% CI (−0.60, 0.41), p = 0.70). <h3>Conclusions:</h3> Our findings show an insignificant difference in WMHV between APOE4 carriers and non-carriers. However, utilized community-based samples showed that WMHV was greater in e4 carriers. This suggests that non-APOE factors have a greater influence on WMHV. <b>Disclosure:</b> Mr. Stipho has nothing to disclose. Mr. Stipho has nothing to disclose. Michael Ahmadi has nothing to disclose.

Platelet-derived growth factor-BB and white matter hyperintensity burden in APOE4 carriers.

Background:The apolipoprotein-e4 (APOE4) gene increases risk for developing late-onset Alzheimer’s disease (AD) and has been linked to increased microvascular dysfunction, including pericyte degeneration and blood-brain barrier breakdown. Platelet-derived growth factor-BB (PDGF-BB) is a glycoprotein involved in blood-brain barrier and pericyte maintenance. Increased PDGF-BB levels have been reported in white matter in AD brain tissue. However, the association between circulating levels of PDGF-BB and cerebral white matter damage in older adults remains unknown.Methods:Participants included community-dwelling older adults (age range 55–90 years, M = 73.1 years; SD =7.5; 61.0% male) from the Alzheimer’s Disease Neuroimaging Initiative who underwent venipuncture and blood plasma immunoassay for PDGF-BB, brain MRI scanning with T2-FLAIR for volumetric quantification of white matter hyperintensities (WMH) and APOE4 genotyping (N = 64). Linear regression analyses examined the relationship between plasma PDGF-BB levels and WMH volume, adjusting for age, sex, intracranial volume (ICV) and stratifying by APOE4 status.Results:Greater levels of circulating PDGF-BB were related to greater WMH volume, even after accounting for age, sex, ICV and APOE4 carrier status (p = 0.040). Nineteen (29.2%) were APOE4 carriers. When stratified by APOE4 status, the relationship between PDGF-BB and WMH volume was only significant for APOE4 carriers (p = 0.007), but not non-carriers (p = 0.448), after adjusting for age, sex and ICV.Discussion:These findings reveal a differential relationship between PDGF-BB and WMH volume for APOE4 carriers versus non-carriers. The APOE4 variant leads to accelerated cerebrovascular injury and cognitive decline. Elevated levels of PDGF-BB in carriers may suggest a role for pericytes and blood-brain barrier dysfunction in white matter damage, vascular cognitive impairment and AD. Additional studies will elucidate the role of PDGF ligands and receptors in these conditions.

An Exploratory Analysis of Changes in Mental Wellbeing Following Curcumin and Fish Oil Supplementation in Middle-Aged and Older Adults.

Curcumin has previously been shown to enhance mood in non-depressed older adults. However, observed benefits were limited to short-term supplementation (4 weeks). In a 16 week randomized, double-blind, placebo-controlled, 2 × 2 factorial design trial, we supplemented overweight or obese non-depressed adults (50–80 years) with curcumin (160 mg/day), fish oil (2000 mg docosahexaenoic acid +400 mg eicosapentaenoic acid/day), or a combination of both. Secondary outcomes included mental wellbeing measures (mood states and subjective memory complaints (SMCs)) and quality of life (QoL). Furthermore, plasma apolipoprotein E4 (APOE4) was measured to determine whether APOE4 status influences responses to fish oil. Curcumin improved vigour (p = 0.044) compared to placebo and reduced SMCs compared to no curcumin treatment (p = 0.038). Fish oil did not affect any mood states, SMCs or QoL; however, responses to fish oil were affected by APOE4 status. In APOE4 non-carriers, fish oil increased vigour (p = 0.030) and reduced total mood disturbances (p = 0.048) compared to placebo. Improvements in mental wellbeing were correlated with increased QoL. Combining curcumin with fish oil did not result in additive effects. This exploratory analysis indicates that regular supplementation with either curcumin or fish oil (limited to APOE4 non-carriers) has the potential to improve some aspects of mental wellbeing in association with better QoL.

Sex difference in the association of APOE4 with cerebral glucose metabolism in older adults reporting significant memory concern

There is accumulating evidence that the association of apolipoprotein E4 (APOE4) with the risk of developing Alzheimer’s disease (AD) is modified by sex. However, the associations of APOE4 status and sex with AD-related markers in older adults with significant memory concern (SMC) remain elusive. Among individuals with SMC (n = 106), we investigated the associations of APOE4 status and sex with multiple AD-related markers, including verbal memory, hippocampal volumes, cerebral glucose metabolism and cortical amyloid burden. In individuals with SMC, we found a significant APOE4*sex interaction for cerebral glucose metabolism, but not verbal memory, hippocampal volumes or cortical amyloid burden. Specifically, female APOE4 carriers showed significantly higher cerebral glucose metabolism compared to female APOE4 non-carriers whereas male APOE4 carriers had lower cerebral glucose metabolism than male APOE4-noncarriers. In conclusion, the effect of APOE4 on cerebral glucose metabolism is altered by sex in individuals with SMC.

Brain Oxygen Extraction by Using MRI in Older Individuals: Relationship to Apolipoprotein E Genotype and Amyloid Burden.

Background Apolipoprotein E4 (APOE4) is a major genetic risk factor for late-onset Alzheimer disease. However, the mechanisms by which APOE4 affects the brain, underpinning this risk, have not been fully elucidated. Purpose To investigate the influence of APOE4 on global cerebral oxygen extraction fraction (OEF) and possible mediation through amyloid burden by using MRI-based brain oxygen extraction technique. Materials and Methods Participants were enrolled from a longitudinal prospective study, the Biomarkers for Older Controls at Risk for Dementia study (data collected from January 2015 to December 2017), of whom 35% (50 of 143 participants) were APOE4 carriers. OEF was measured by using a T2-relaxation-under-spin-tagging MRI technique with a 3.0-T MRI system. PET acquired with carbon 11-labeled Pittsburgh compound B tracer was available in 119 participants to measure amyloid burden. Cognitive performance was assessed by using domain-specific composite scores including executive function, episodic memory, visual-spatial processing, and language. Linear regression analysis was performed to investigate the relationship between APOE4, OEF, and amyloid burden. The association between OEF and cognitive function was studied for the entire study cohort and separately for the APOE4 carriers and noncarriers. Results A total of 143 cognitively healthy individuals (mean age 6 standard deviation, 69.1 years 6 8.2; 57 men and 86 women) were studied. APOE4 genetic status was associated with lower OEF (noncarriers, 41.1% 6 5.8; one E4 allele, 40.1% 6 4.9; two E4 alleles, 36.7% 6 4.5; P = .03). Furthermore, among APOE4 carriers, lower OEF correlated with lower executive function scores (b = 0.079 z score for each percent change in OEF; P = .03). Amyloid burden and OEF were independently associated with APOE4 but were not associated with one another, suggesting that the effect of APOE4 on OEF is not mediated by amyloid. Conclusion MRI-based brain oxygen extraction shows that cognitively healthy carriers of the apolipoprotein E4 gene manifest diminished brain oxygen extraction capacity independent of amyloid burden. ©RSNA, 2019 Online supplemental material is available for this article.

The Impact of APOE ɛ4 in Alzheimer's Disease Differs According to Age.

We evaluated how the impact of apolipoprotein E4 (APOE4) differs according to age in Alzheimer's disease (AD) patients. We recruited 846 AD patients and 815 cognitively normal controls and categorized into three groups with respect to their age (<65, 65-74, and ≥75 years). We evaluated the risk of AD in APOE4 carriers and compared cortical thickness and cognitive function according to APOE4 status in each age group. At the point of this study, in young (<65 years) AD, APOE4 noncarriers had the most severe frontal and perisylvian atrophy, while in old (≥75 years) AD, APOE4 carriers had the most severe medial temporal atrophy. In AD under 75 years, APOE4 noncarriers and heterozygotes showed worse performance in language, visuospatial, and frontal function compared to homozygotes, while, in old (≥75 years) AD, APOE4 homozygotes showed worse performance in memory compared to noncarriers. As the detrimental effects of APOE4 seen in older AD patients were not found in younger AD patients, we suggest that some unrevealed factors are associated with cortical atrophy and non-amnestic cognitive dysfunction in young AD with APOE4 noncarriers.

Apolipoprotein E genotype status affects habitual human blood mononuclear cell gene expression and its response to fish oil intervention.

People who carry the apolipoprotein E4 (APOE4) single nucleotide polymorphism have an increased risk of cardiovascular disease (CVD). Fish-oil supplementation may help in the prevention of CVD, though interindividual differences in the response to n-3 PUFAs have been observed. We aimed to assess the impact of APOE genotype on peripheral blood mononuclear cell whole genome gene expression at baseline and following a fish-oil intervention. Participants received 6 months of fish-oil supplementation containing 1800 mg of eicosapentaenoic acid and docosahexaenoic acid per day. APOE genotype and peripheral blood mononuclear cell whole genome gene expression before and after supplementation were measured. We characterized the differences in gene expression profiles in carriers of APOE4 (N = 8) compared to noncarriers (N = 15). At baseline, 1320 genes were differentially expressed and the fish-oil supplementation differentially regulated 866 genes between APOE4 carriers and noncarriers. Gene set enrichment analysis showed that carriers had a higher gene expression of cholesterol biosynthesis and IFN signaling pathways. Fish-oil supplementation reduced expression of IFN-related genes in carriers only. The increased expression of IFN signaling and cholesterol biosynthesis pathways might explain part of the association between APOE4 and CVD. Fish-oil supplementation may particularly benefit APOE4 carriers by decreasing expression of IFN-related genes.

Vitamin C Supplementation, APOE4 Genotype and Cognitive Functioning in a Rural-Dwelling Cohort.

Apolipoprotein E4 (APOE4) genotype has been implicated as a moderating factor in cognitive function studies. Although prior studies have suggested that vitamin C is associated with better cognitive function in elders, link between the two has been mixed. Limited data exist as to whether the APOE4 genotype influences these associations. Therefore, this study sought to determine whether the association between vitamin C and cognition in a rural community dwelling cohort differs by the APOE4 genotype. Data were analyzed on 582 participants (n=183 men; n=399 women) from a rural community-based cohort. Cognition was assessed using the Repeatable Battery for the Assessment of Neuropsychological Status and The Executive Interview. APOE genotyping was ascertained by standard methods. The relation between vitamin C supplementation and cognition were analyzed first with ANOVA and then ANCOVA with age, gender, education as covariates. Analyses were initially run in the full sample and then split by APOE4 presence (yes/no). Overall, Vitamin C supplementation was associated with significantly better immediate memory (p=0.04), visuospatial skills (p=0.002), language (p=0.01), and global cognitive functioning (p=0.006). Among APOE4 non-carriers, vitamin C supplementation was positively associated with immediate memory (F[1,392] =6.7, p=0.01), visuospatial skills (F[1,391]=10.6, p=0.001), language (F[1,392]=13.0, p<0.001), attention (F[1,386]=7.9, p=0.005, and global cognition (F[1,382]=11.0, p=0.001. However, there was no significant link between vitamin C supplementation and cognition among APOE4 carriers. Vitamin C supplementation was found to be positively associated with cognition among this rural-dwelling community-based sample; however, the associations appeared to differ by APOE4 status. These data may suggest that targeted genotype-specific cognitive enhancement studies are needed to clarify the potential benefits of vitamin C supplementation.

Large intracranial volume accelerates conversion to dementia in males and APOE4 non-carriers with mild cognitive impairment.

It is unclear how brain reserve interacts with gender and apolipoprotein E4 (APOE4) genotype, and how this influences the progression of Alzheimer's disease (AD). The association between intracranial volume (ICV) and progression to AD in subjects with mild cognitive impairment (MCI), and differences according to gender and APOE4 genotype, was investigated. Data from subjects initially diagnosed with MCI and at least two visits were downloaded from the ADNI database. Those who progressed to AD were defined as converters. The longitudinal influence of ICV was determined by survival analysis. The time of conversion from MCI to AD was set as a fiducial point, as all converters would be at a similar disease stage then, and longitudinal trajectories of brain atrophy and cognitive decline around that point were compared using linear mixed models. Large ICV increased the risk of conversion to AD in males (HR: 4.24, 95% confidence interval (CI): 1.17-15.40) and APOE4 non-carriers (HR: 10.00, 95% CI: 1.34-74.53), but not in females or APOE4 carriers. Cognitive decline and brain atrophy progressed at a faster rate in males with large ICV than in those with small ICV during the two years before and after the time of conversion. Large ICV increased the risk of conversion to AD in males and APOE4 non-carriers with MCI. This may be due to its influence on disease trajectory, which shortens the duration of the MCI stage. A longitudinal model of progression trajectory is proposed.

Improved power for characterizing longitudinal amyloid-β PET changes and evaluating amyloid-modifying treatments with a cerebral white matter reference region.

In this article, we describe an image analysis strategy with improved power for tracking longitudinal amyloid-β (Aβ) PET changes and evaluating Aβ-modifying treatments. Our aims were to compare the power of template-based cerebellar, pontine, and cerebral white matter reference regions to track 24-mo florbetapir standardized uptake value (SUV) ratio (SUVR) changes; to relate those changes to 24-mo clinical declines; and to evaluate Aβ-modifying treatments in Aβ-positive (Aβ+) and Aβ-negative (Aβ-) patients with probable Alzheimer dementia (pAD), in patients with mild cognitive impairment (MCI), in cognitively normal controls (NCs), and in cognitively normal apolipoprotein E4 (APOE4) carriers and noncarriers. We used baseline and follow-up (∼24 mo) florbetapir PET scans from 332 Aβ+ and Aβ- subjects participating in the multicenter Alzheimer's Disease Neuroimaging Initiative. Each of the proposed analyses included 31 pAD patients, 187 MCI patients, and 114 NCs. Cerebral-to-white matter, cerebellar, and pontine SUVRs were characterized in terms of their longitudinal variability; their power to track longitudinal fibrillar Aβ increases in Aβ+ and Aβ- subgroups and cognitively normal APOE4 carriers and noncarriers; the sample sizes needed to detect attenuated accumulation of or clearance of fibrillar Aβ accumulation in randomized clinical trials; and their ability to relate 24-mo fibrillar Aβ increases to clinical declines. As predicted, cerebral-to-white matter SUVR changes were significantly less variable and had significantly greater power to detect 24-mo fibrillar Aβ increases and evaluate Aβ-modifying treatment effects in Aβ+ pAD, MCI, and NC subjects and cognitively normal APOE4 carriers. They were also distinguished by the ability to detect significant associations between 24-mo Aβ increases and clinical declines. A cerebral white matter reference region may improve the power to track longitudinal fibrillar Aβ increases, to characterize their relationship to longitudinal clinical declines, and to evaluate Aβ-modifying treatments in randomized clinical trials.

Apolipoprotein e4 affects topographical changes in hippocampal and cortical atrophy in Alzheimer's disease dementia: a five-year longitudinal study.

Apolipoprotein E4 (APOE4) is a genetic risk factor for developing Alzheimer's disease (AD). Once AD manifests clinically, however, the effects of APOE4 are less clear. Therefore, we investigated the longitudinal effects of APOE4 on topographical changes in AD patient brain atrophy. We prospectively recruited 35 patients with AD (19 APOE4 carriers and 16 non-carriers), and 14 normal controls, then followed them for five years. We measured hippocampal deformities and cortical thickness. Hippocampal comparison between APOE4 carriers and non-carriers with AD showed carriers had rapid changes in the head and body, while non-carriers had rapid changes in a small portion of the body. Cortical thickness comparison between APOE4 carriers and non-carriers with AD dementia showed carriers had rapid thinning in the lateral frontal, temporal, and parietal regions, while no region showed more rapid cortical thinning in non-carriers than in carriers. These findings underlined the importance of the APOE4 allele for designing and interpreting future treatment trials in patients with AD dementia.

White Matter Hyperintensities are associated with Amyloid Burden in APOE4 Non-Carriers

Previous preclinical studies have suggested a close relationship between cerebrovascular disease (CVD) and Alzheimer's disease. However, a direct correlation between CVD and amyloid burden has not yet been shown in humans. If there is a relationship between CVD and amyloid burden, it is possible that the apolipoprotein E4 (APOE4) genotype may have an effect on this relationship because APOE4 is a risk factor for the development of AD. We therefore evaluated the effects of APOE4 on the relationship between white matter hyperintensities (WMH), a marker of CVD, and amyloid burden, measured by 11C-Pittsburgh compound B (PiB) PET. We recruited 53 patients with subcortical vascular cognitive impairments, who had both WMH on MRI and amyloid deposition assessed by PiB PET. Twenty-two of these patients were APOE4 carriers (41.5%). In the APOE4 non-carriers, a significant positive correlation was shown between the volume of WMH and PiB retention (β = 7.0 × 10-3, p = 0.034) while no significant correlation was found in APOE4 carriers (β = -9.0 × 10-3, p = 0.085). Statistical parametric mapping analyses in APOE4 non-carriers showed that WMH were associated with PiB retention in the bilateral medial occipitotemporal gyrus, cuneus, and superior cerebellum. Our results suggested that WMH are correlated with amyloid burden especially in the posterior brain regions in APOE4 non-carriers. However, this correlation was not observed in APOE4 carriers, perhaps because in these subjects the influence of APOE4 overrides the effect of CVD.

Aberrant functional connectivity in Papez circuit correlates with memory performance in cognitively intact middle-aged APOE4 carriers

The main objective of this study is to detect the early changes in resting-state Papez circuit functional connectivity using the hippocampus as the seed, and to determine the associations between altered functional connectivity (FC) and the episodic memory performance in cognitively intact middle-aged apolipoprotein E4 (APOE4) carriers who are at risk of Alzheimer's disease (AD). Forty-six cognitively intact, middle-aged participants, including 20 APOE4 carriers and 26 age-, sex-, and education-matched noncarriers were studied. The resting-state FC of the hippocampus (HFC) was compared between APOE4 carriers and noncarriers. APOE4 carriers showed significantly decreased FC in brain areas that involve learning and memory functions, including the frontal, cingulate, thalamus and basal ganglia regions. Multiple linear regression analysis showed significant correlations between HFC and the episodic memory performance. Conjunction analysis between neural correlates of memory and altered HFC showed the overlapping regions, especially the subcortical regions such as thalamus, caudate nucleus, and cingulate cortices involved in the Papez circuit. Thus, changes in connectivity in the Papez circuit may be used as an early risk detection for AD.

P.1.030 Three week bright-light intervention has dose-related effects on threat-related corticolimbic reactivity and functional coupling

The main objective of this study is to detect the early changes in resting-state Papez circuit functional connectivity using the hippocampus as the seed, and to determine the associations between altered functional connectivity (FC) and the episodic memory performance in cognitively intact middle-aged apolipoprotein E4 (APOE4) carriers who are at risk of Alzheimer's disease (AD). Forty-six cognitively intact, middle-aged participants, including 20 APOE4 carriers and 26 age-, sex-, and education-matched noncarriers were studied. The resting-state FC of the hippocampus (HFC) was compared between APOE4 carriers and noncarriers. APOE4 carriers showed significantly decreased FC in brain areas that involve learning and memory functions, including the frontal, cingulate, thalamus and basal ganglia regions. Multiple linear regression analysis showed significant correlations between HFC and the episodic memory performance. Conjunction analysis between neural correlates of memory and altered HFC showed the overlapping regions, especially the subcortical regions such as thalamus, caudate nucleus, and cingulate cortices involved in the Papez circuit. Thus, changes in connectivity in the Papez circuit may be used as an early risk detection for AD.

Apolipoprotein E4 genotype does not increase risk of HIV-associated neurocognitive disorders

This is a cross-sectional, observational study to evaluate the hypothesis that HIV-seropositive (HIV+) apolipoprotein E4 (APOE4) carriers are at increased risk for HIV-associated neurocognitive disorders (HAND) compared to APOE4 noncarriers with HIV in the CNS HIV Antiretroviral Therapy Effects Research (CHARTER) Group sample. APOE genotype was determined in 466 CHARTER participants with varying disease stages and histories of antiretroviral treatment who did not have severe psychiatric or medical comorbid conditions that preclude diagnosis of HAND. HAND diagnoses were based on results of comprehensive neurobehavioral evaluation and use of current neuroAIDS diagnostic criteria. HAND status consists of two levels: neuropsychologically normal status (i.e., no HAND) and any HAND diagnosis (i.e., asymptomatic neurocognitive impairment, minor neurocognitive disorder, HIV-associated dementia). Logistic regression analyses revealed no association between APOE4 carrier status and HAND, and there were no interactions between APOE4 carrier status and ethnicity, age, substance use disorders, duration of infection, or nadir CD4. Results did not differ when analysis was restricted to symptomatic HAND, and no APOE4 gene dose-dependent relationship to HAND emerged. APOE4 status was not associated with concurrent HAND in this large, well-characterized sample. This does not preclude emergence of an association between APOE4 status and HAND as this population ages. Prospective, longitudinal studies are needed to examine APOE4 as a risk factor for neurocognitive decline, incident HAND at older ages, and potential associations with cerebrospinal fluid amyloid.