Obesity is a leading cause of morbidity and mortality in the United States (U.S.) and globally (1, 2). Risk factors for obesity among aging adults include a slowing basal metabolic rate, positive energy balance (increased energy intake and/or decreased physical activity), low or worsening dietary quality, and genetics (3). Among women, body weight gain is also due to an increase in adipose versus other body tissues, and can be secondary to diminishing ovarian function and corresponding estrogen levels, and hypothalamic-pituitary-adrenal and fat-brain axis dysregulation (4). Body adiposity is usually clinically measured using anthropometric measures such as body mass index (BMI, kg/m²), and central or abdominal adiposity via waist circumference (WC). When measured during midlife, some studies suggest that higher levels of either BMI and WC increase risk for subsequent later life cognitive decline, and late-onset Alzheimer’s disease (AD) and Vascular Cognitive Impairments and Dementias (VCID) (5–11).

Adipose tissue is the human body’s largest endocrine organ (12) and secretes more than 700 hormones and proinflammatory cytokines, interleukins, and other bioactive compounds, cumulatively termed adipokines (13, 14). With increasing body adiposity, adipokines contribute to proinflammatory and altered metabolic and vascular risk states, and may cross the blood-brain barrier influencing risk for cognitive impairments, AD and VCID (15). Moreover, the neurovascular unit, where a neuron meets a capillary in the central nervous system (16), is critical for optimal brain function, and may be compromised in obese adults, leading to impaired cognitive function (17).

Central obesity is particularly detrimental for cardiovascular (18) and cerebrovascular disease (19) since it is associated with enhanced deposition of visceral fat, which is more metabolically active than subcutaneous fat (20). In addition, enlargement of the abdominal adipose tissue depot in particular, may exacerbate adipose tissue’s hyper-inflammatory response (21), increase cytokine production and promote other endocrine sequelae (15), influencing brain structure and function – the latter often measured as neuropsychological performance (NP) (15, 22). With the increasing older adult population (23), including among underrepresented and diverse populations, an enhanced understanding of whether higher BMI and central adiposity may lead to impairments and/or changes in neuropsychological performance (NP) in vulnerable populations, such as women living with HIV infection (WLWH) who are surviving to older ages, is needed. Although the number of new HIV cases continues to decrease, women comprise approximate 25% of prevalent (24) and 18% of incident HIV cases in the United States (US) (25) In addition, incident HIV is increasing among women and men older than 50 years of age in the US, and the average age of people with HIV is >50 years in the US when their risk for aging-related NP impairments and decline increase (26).

In an analysis among men living with HIV (MLWH) and without HIV (MWOH) participating in the Multicenter AIDS Cohort Study (MACS), cross-sectionally a higher BMI was inversely associated with motor function and attention/working memory in MWOH only; WC was inversely associated with motor function in MLWH and MWOH (27). Subsequent 10-year NP trajectories analyses showed that an obese BMI was associated with decline in motor performance in MLWH; whereas in MWOH men, obesity was associated with a greater decline in motor function, learning, and memory performance. Our goal was to consider whether similar associations might be observed in WLWH and women without HIV (WWOH) who participated in the Women’s Interagency HIV Study (WIHS) (27). In these analyses, we examined multivariable-adjusted associations of BMI and WC with NP cross-sectionally and prospectively over ~10 years follow-up in virologically-suppressed WLWH and WWOH who were ≥40 years old. Our primary hypothesis was that higher adult BMI and WC would be associated with poorer NP, and this association would be more pronounced among WLWH using both cross-sectional and longitudinal approaches.

Among WLWH and WWOH participating in the WIHS, we used a similar study design and analysis strategy that was published among MLWH and MWOH participating in the MACS (27). Overall associations between anthropometric measures of adiposity and NP decline were not as strong and less consistent among the women compared to the men. Among WLWH, we observed cross-sectional associations between total and central obesity with poorer executive and motor function, respectively. Poorer motor function was also observed among MWOH with higher BMI and at-risk WC among MLWH and MWOH. Longitudinally, the associations between baseline higher total adiposity and NP were mixed for memory among WWOH, however increasing WC was associated with decreasing executive, processing speed and motor function, which is somewhat consistent with the MACS analysis among MWOH (27). Contrastingly, an obese, at-risk waist was associated with improving memory performance over time among WWOH.

Despite similar longitudinal cohort studies of women and men with and without HIV infection, lack of similar results between the WIHS and the MACS cohorts could be due to sample heterogeneity including differences in biological sex; median baseline age (despite the age inclusion criterion of ≥40 years for analyses in both women and men, men were on average, older (50 years) than women (45 years)); baseline BMI (men had a lower prevalence (29%) of overweight and obesity versus 39% in women); race (men were predominantly White (69.5%) versus 10% of women); and men had higher socioeconomic status and educational attainment.

Other analyses among WIHS participants at different stages of the adult life course have suggested mixed associations between anthropometric measures of overweight and obesity (i.e., BMI, WC) and NP. Cross-sectionally, based on NP data collected from 2005-2008, among WLWH who were average age 38 years, an underweight BMI (<18.5 kg/m²) was associated with poorer NP as evidenced by poorer executive function (longer Trails A and Trails B completion) and poorer processing speed (longer test completion times). In contrast, women with an obese BMI (≥30 kg/m²) was related to better executive function (via Trails B) and also worse executive performance (via the Stroop interference test). Among obese WWOH, worse performance on the Stroop color naming test, a measure of processing speed, was observed.

We also analyzed 10-year change in BMI (from 2009-2019) in association with subsequent NP among a subset of WIHS participants who transitioned from average age 40 to 50 years in Brooklyn, New York and Chicago, Illinois, USA. Increasing BMI over a 10-year follow-up predicted slower processing speed (P=0.043) among all women; and among WLWH, poorer EF (P=0.01) and global (P=0.04) performance. Therefore, among WLWH, over subsequent 10 years follow-up with receipt of increasingly effective ART, expected trajectories of increasing aging-associated anthropometric and metabolic measures of adipose tissue influenced associations among BMI, WC, and NP. These associations differed in WWOH.

Important issues related to analyses across HIV aging studies of vascular risk factors and NP require additional exploration. First, the BMI and WC cut-offs that are traditionally used to classify people as overweight and obese were defined for adult non-Latinx White and WWOH populations (42–45). While data suggest the validity of these cut-offs among non-White populations for predicting cardiovascular disease, diabetes, and mortality, other cut-offs may be more relevant to NP and brain aging, especially for underrepresented Black WLWH (46, 47). In 2004, the World Health Organization Expert Panel (48) put forward pragmatic rather than evidence-based BMI cut-offs specific for Asian people (healthy BMI, 18.5–23.9 kg/m²; overweight, 24.0–27.9 kg/m²; obese ≥28.0 kg/m²) (49). However, no guidance has been published for Non-Latinx Black people, people of African descent, or other ethnic and racial people groups. This was the rationale for using both continuous and traditional categorical anthropometric exposure variables in our analysis. Second, overweight and obesity cut-offs for older adults are debated (50–52). Studies suggest that a higher cut-off for overweight and obesity among older adults are more appropriate (50). Third, chronological age and temporality in adiposity-NP associations over the life course must continue to be explored (53). Here we evaluated adiposity and NP among women who were age ≥40 years at baseline (median age, 45 years) over approximately 8 years. Median age 45 years is approximately 20 years before a potential late-onset AD diagnosis, and perhaps too early in the aging brain process to observe more apparent and/or consistent cross-sectional and longitudinal associations of vascular risk factors including adiposity with NP. Fourth, related to historical and ongoing observational studies of older adults, birth cohort differences are important. Being born in the mid-20^th century compared to earlier years will be accompanied by global secular trends such as higher population levels of BMI and educational attainment. Fifth, adverse social determinants of health such as early-life stressors, trauma, and barriers to healthcare services (31, 54, 55), common among WIHS participants and other WLWH, are associated with overweight and obesity, poorer NP, and late-life AD and VCID outcomes in uninfected populations (56, 57). Sixth, mid-life fluctuations in NP are more likely to occur with co-morbidities (58), and misuse of alcohol and other substances (59). However, we adjusted for these factors at baseline. Seventh, we hypothesized that ART may have a neuroprotective role since associations of higher adiposity with declining NP were accentuated in WWOH. This potential protective effect of ART is supported by ongoing clinical trials exploring the use of efavirenz, nucleoside reverse transcriptase inhibitors, and nucleoside analogs in the treatment of AD without HIV [49]. Finally, more research generally, is needed on the role of endocrine adipose tissue and the fat-brain axis.

This study has several strengths. The WIHS was a large longitudinal cohort study with repeated NP assessments in well-characterized WLWH and WWOH who are underrepresented in the brain health literature, based on HIV status, Non-Latinx Black race and health disparities. Easily obtained anthropometric measures of obesity (BMI and WC) and NP were rigorously collected over time using standardized protocols. Trained research study staff measured body weight, body height, and WC, and conducted face-to-face NP assessments. WLWH were well-phenotyped and had to be taking ≥2 antiretroviral therapies and demonstrate an HIV-1 RNA <400 copies/mL at more than 80 percent of their visits. Finally, our statistical approaches were appropriate for the study design and data available. For our descriptive Table 1 , we used the Wilcoxon rank sum test to address a few small cell sizes. In contrast, the NP outcomes are continuous and measured in hundreds of women for which linear regression models and repeated measures analyses with generalized estimating equations work well because of large sample theory, even if the T-score distributions differ somewhat from assessment to assessment.

Limitations of our study should also be considered. Inclusion of women ≥40 years at baseline with the eldest age 56 years, may have minimized robust associations that are more commonly observed among older adults. Our cohort did not include brain or whole-body composition fluid or imaging biomarker data. We did not adjust for multiple comparisons given the small sample size, however we provided β-coefficients and 95%CI for each comparison. Information on other neurological outcomes that are associated with HIV, e.g., peripheral neuropathy, were not adequately collected in the WIHS. The clinical relevance of our findings given the observed point estimates and 95%CIs, may be limited during this chronological stage of a woman’s life course. While a strength, our inclusion criteria for WLWH of HIV-1 RNA <400 copies/mL and ≥2 ART may have reduced variability in adiposity exposures and NP outcomes since some ART may be beneficial for NP and/or cause weight gain. In addition, as research study participants who receive regular information about their overall health, these women differ from WLWH and WWOH who do not participate in research studies and/or do not receive adequate healthcare. However continued monitoring of BMI and WC trajectories into later life will provide important insights regarding associations observed in specific chronological age observation windows. In addition, inclusion of women based on completion of only two (or more) NP assessments did not allow for a true analytic trajectories approach over time among all participants. Finally, our duration of follow-up was slightly less than 10 years, which may have been too short at this adult life stage. Longer follow-up to older ages and additional measures of NP will clarify trajectories and allow understanding of the temporal nuances of this association.

Publicly available datasets were analyzed in this study. This data can be found here: https://airtable.com/shrVDP51W5J2qcNeT. The WIHS provides deidentified data for replication studies andother forms of analytic inquiry on approval by the studyinvestigators (https://statepi.jhsph.edu/mwccs/).

The studies involving human participants were reviewed and approved by Multiple sites IRBs: The study was approved by the Institutional Review Board (IRB) of each participating site in accordance with the Declaration of Helsinki. Each participating institution’s IRB has been formally designated to review and monitor biomedical research involving human subjects, with the primary responsibility being the protection of subjects from undue risk and from deprivation of personal rights and dignity, which are the cornerstones of ethical research (For the southern sites: University of Mississippi Medical Center; University of North Carolina at Chapel Hill; University of Alabama at Birmingham; University of Miami and Emory University. Brooklyn: SUNY Downstate Medical Center and Kings County Medical Center. Bronx: Montefiore Medical Center; Beth Israel Medical Center; Mount Sinai School of Medicine. Chicago: Cook County Health & Hospitals System; Rush University Medical Center; University of Illinois at Chicago. San Francisco: University of California, San Francisco; Alameda Health System; Sutter Health; Santa Clara Valley Medical Center; San Mateo Medical Center. District of Columbia: Georgetown University; Montgomery County Department of Health and Human Services; Inova; Howard University and Whitman-Walker Clinic. The patients/participants provided their written informed consent to participate in this study. The institutional review boards of each WIHS clinical researchsite approved the WIHS research protocol and all participantsprovided written informed consent.

DRG and LHR: Major role in the acquisition of data, study concept or design, analysis or interpretation of data, drafting/revision of the manuscript. MK: contributed to the design of the study, the statistical analysis, interpretation of the study findings and drafting the manuscript. AAApp contributed to interpretation of the study findings and drafting the manuscript. AAAdi: major role in the acquisition of data. SH and HM: major role in the acquisition of the data; study concept or design, contributed to interpretation of the study findings and drafting the manuscript. MF, ED, WM, CM, MP, AS, PT and KW: major role in the acquisition of data; contributed to interpretation of the study findings and drafting the manuscript. All authors contributed to the article and approved the submitted version.