Older people with HIV (PWH) are at-risk for Alzheimer’s disease (AD) and its precursor, amnestic mild cognitive impairment (aMCI). Identifying aMCI among PWH is challenging because memory impairment is also common in HIV-associated neurocognitive disorders (HAND). The neuropathological hallmarks of aMCI/AD are amyloid-ß42 (Aß42) plaque and phosphorylated tau (p-tau) accumulation. Neurofilament light chain protein (NfL) is a marker of neuronal injury in AD and other neurodegenerative diseases. In this study, we assessed the prognostic value of the CSF AD pathology markers of lower Aß42, and higher p-tau, p-tau/Aß42 ratio, and NfL levels to identify an aMCI-like profile among older PWH and differentiating it from HAND. We assessed the relationship between aMCI and HAND diagnosis and AD biomarker levels

Participants included 74 PWH (Mean age=48 [SD=8.5]; 87.4% male, 56.5% White) from the National NeuroAIDS Tissue Consortium (NNTC). CSF Aß42, Aß40, p-tau and NfL were measured by commercial immunoassay. Participants completed a neurocognitive evaluation assessing the domains of learning, recall, executive function, speed of information processing, working memory, verbal fluency, and motor. Memory domains were assessed with the Hopkins Verbal Learning Test-Revised and the Brief Visuospatial Memory Test-Revised, and aMCI was defined as impairment (<1.0 SD below normative mean) on two or more memory outcomes among HVLT-R and BVMT-R learning, delayed recall and recognition with at-least one recognition impairment required. HAND was defined as impairment (<1.0 SD below normative mean) in 2 or more cognitive domains. A series of separate linear regression models were used to examine how the levels of CSF p-tau, Aß42, p-tau/Aß42 ratio, and NfL relate to aMCI and HAND status while controlling for demographic variables (age, gender, race and education). Covariates were excluded from the model if they did not reach statistical significance.

58% percent of participants were diagnosed with HAND, 50.5% were diagnosed with aMCI. PWH with aMCI had higher levels of CSF p-tau/Aß42 ratio compared to PWH without aMCI (ß=.222, SE=.001, p=.043) while controlling for age (ß=.363, p=.001). No other AD biomarker significantly differed by aMCI or HAND status.

Our results indicate that the CSF p-tau/Aß42 ratio relates specifically to an aMCI-like profile among PWH with high rates of cognitive impairment across multiple domains in this advanced HIV disease cohort. Thus, the p-tau/Aß42 ratio may have utility in disentangling aMCI from HAND and informing the need for further diagnostic procedures and intervention. Further research is needed to fully identify, among a broader group of PWH, who is at greatest risk for aMCI/AD and whether there is increased risk for aMCI/AD among PWH as compared to those without HIV.

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.

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 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).

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.

Many people with HIV (PWH) are at risk for age-related neurodegenerative disorders such as Alzheimer’s disease (AD). Studies on the association between cognition, neuroimaging outcomes, and the Apolipoprotein E4 (APOE4) genotype, which is associated with greater risk of AD, have yielded mixed results in PWH; however, many of these studies have examined a wide age range of PWH and have not examined APOE by race interactions that are observed in HIV-negative older adults. Thus, we examined how APOE status relates to cognition and medial temporal lobe (MTL) structures (implicated in AD pathogenesis) in mid- to older-aged PWH. In exploratory analyses, we also examined race (African American (AA)/Black and non-Hispanic (NH) White) by APOE status interactions on cognition and MTL structures.

The analysis included 88 PWH between the ages of 45 and 68 (mean age=51±5.9 years; 86% male; 51% AA/Black, 38% NH-White, 9% Hispanic/Latinx, 2% other) from the CNS HIV Antiretroviral Therapy Effects Research multi-site study. Participants underwent APOE genotyping, neuropsychological testing, and structural MRI; APOE groups were defined as APOE4+ (at least one APOE4 allele) and APOE4- (no APOE4 alleles). Eighty-nine percent of participants were on antiretroviral therapy, 74% had undetectable plasma HIV RNA (<50 copies/ml), and 25% were APOE4+ (32% AA/Black/15% NH-White). Neuropsychological testing assessed seven domains, and demographically-corrected T-scores were calculated. FreeSurfer 7.1.1 was used to measure MTL structures (hippocampal volume, entorhinal cortex thickness, and parahippocampal thickness) and the effect of scanner was regressed out prior to analyses. Multivariable linear regressions tested the association between APOE status and cognitive and imaging outcomes. Models examining cognition covaried for comorbid conditions and HIV disease characteristics related to global cognition (i.e., AIDS status, lifetime methamphetamine use disorder). Models examining the MTL covaried for age, sex, and

relevant imaging covariates (i.e., intracranial volume or mean cortical thickness).

APOE4+ carriers had worse learning (ß=-0.27, p=.01) and delayed recall (ß=-0.25, p=.02) compared to the APOE4- group, but APOE status was not significantly associated with any other domain (ps>0.24). APOE4+ status was also associated with thinner entorhinal cortex (ß=-0.24, p=.02). APOE status was not significantly associated with hippocampal volume (ß=-0.08, p=0.32) or parahippocampal thickness (ß=-0.18, p=.08). Lastly, race interacted with APOE status such that the negative association between APOE4+ status and cognition was stronger in NH-White PWH as compared to AA/Black PWH in learning, delayed recall, and verbal fluency (ps<0.05). There were no APOE by race interactions for any MTL structures (ps>0.10).

Findings suggest that APOE4 carrier status is associated with worse episodic memory and thinner entorhinal cortex in mid- to older-aged PWH. While APOE4+ groups were small, we found that APOE4 carrier status had a larger association with cognition in NH-White PWH as compared to AA/Black PWH, consistent with studies demonstrating an attenuated effect of APOE4 in older AA/Black HIV-negative older adults. These findings further highlight the importance of recruiting diverse samples and suggest exploring other genetic markers (e.g., ABCA7) that may be more predictive of AD in some races to better understand AD risk in diverse groups of PWH.