As people with HIV survive to older ages, they become more at risk for Alzheimer’s disease (AD) and its precursor, amnestic mild cognitive impairment (aMCI). Memory impairment is also common in other neurocognitive disorders (NDs), including HIV-associated neurocognitive disorders (HAND), which makes it a challenge to diagnose aMCI among PWH. Therefore, we assessed the utility of cerebrospinal fluid (CSF) AD pathology markers in distinguishing aMCI from HAND in PWH by investigating how these markers differentially relate to aMCI. Participants included 74 PWH (Mean age = 48 [SD = 8.5]; 87.4

Objectives:With the success of antiretroviral therapy (ART), people with HIV (PWH) are living longer. As they age, they increasingly face age-related comorbidities, including neurodegenerative conditions. The astrocyte-neuron lactate shuttle (ANLS) is a key mechanism that couples astrocytic glycolysis to neuronal oxidative metabolism, ensuring an adequate energy supply for synaptic activity. Disruption of this system has been implicated in both Alzheimer's disease (AD) and HIV-associated neurocognitive impairment (HIV-NCI), conditions characterized by some overlapping cognitive deficits yet distinct pathological drivers. Methods:We investigated the expression of major ANLS transporters, including glucose transporters (GLUT1, GLUT3) and monocarboxylate transporters (MCT1, MCT2, MCT4), in postmortem frontal cortex from individuals with AD and PWH. There were two HIV cohorts based on viral suppression (suppressed/non-suppressed), and both were stratified by neurocognitive status (neurocognitively normal/neurocognitively impaired), while AD participants were compared to cognitively healthy participants. Quantitative immunoblotting and immunofluorescence imaging characterized disease-specific alterations. Results:In AD, both endothelial (GLUT155 kDa) and astrocytic (GLUT145 kDa) isoforms were significantly reduced, along with MCT1, indicating widespread impairment of glucose and lactate transport. GLUT3, the neuronal glucose transporter, also showed a marked reduction. In contrast, in virally non-suppressed (VNS) PWH, GLUT145 kDa and MCT4 were downregulated, while virally suppressed (VS) PWH maintained preserved expression. Correlation analyses revealed strong GLUT3-MCT1 coupling in AD, suggestive of coordinated neuronal-astrocytic adaptation, but disrupted GLUT1-MCT4 relationships in VNS PWH, reflecting ANLS uncoupling under viremia. Conclusions:These findings identify shared and distinct patterns of metabolic disruption: degeneration-driven ANLS failure in AD versus inflammation-driven uncoupling in HIV-NCI.

Online relationship seeking is common among adolescent sexual minority men (ASMM), yet research has primarily compared sexual health between ASMM who seek partners online with those who do not, overlooking heterogeneity in dating motivations. We examined associations between motivations for online relationship seeking (dates only vs. both dates/sex) and HIV-related behaviors and assessed racial/ethnic differences in these associations. Data from three timepoints were drawn from a 12-month HIV prevention intervention with ASMM in the U.S. Logistic regressions examined associations between motivations for online relationship seeking and HIV/STI testing, condomless sex without using pre-exposure prophylaxis (PrEP), and PrEP interest. The sample included 266 ASMM aged 13-18 years (Md = 17; 59% ASMM of color). Overall, 38% reported seeking dates only online, whereas 62% sought both dates/sex; the former group was significantly younger, p = .04. ASMM who sought both dates/sex online were more likely to test for HIV (p = .04) and STI (p = .01) than those seeking dates only. Hispanic ASMM were more likely than non-Hispanic peers to engage in condomless sex when not using PrEP (p = .001) and were less likely to test for HIV (p = .02). These findings highlight the need for tailored relationship and sexual health programs, particularly for Hispanic and younger ASMM who more often seek dates only.

HIV persistence within anatomical reservoirs remains the primary barrier to achieving an HIV cure. While antiretroviral therapy effectively suppresses plasma viremia, it does not eliminate integrated proviral genomes that persist in long-lived cellular compartments. The central nervous system (CNS) is a clinically important HIV reservoir, characterized by immune privilege and the persistence of tissue-resident infection despite effective antiretroviral therapy (ART). Evidence from postmortem studies reveals that HIV DNA, RNA, and even intact replication-competent proviruses remain detectable in brain tissue from virally suppressed people with HIV. Evidence derived primarily from in situ approaches and viable-cell studies supports myeloid-lineage reservoirs, particularly microglia and CNS-associated macrophages, as key cellular sources of persistence, while the extent and biological relevance of astrocyte infection remains debated. These reservoirs exhibit transcriptional activity and are associated with chronic neuroinflammation, which may contribute to HIV-associated neurocognitive disorders, despite systemic viral suppression. Here, we synthesize recent findings from autopsy brain studies, including work enabled by major biorepositories, such as the National NeuroHIV Tissue Consortium and rapid-autopsy programs, including the Last Gift, both of which are essential for studying HIV reservoirs in the CNS. We summarize methodologies for detecting and characterizing HIV in brain tissue, highlight heterogeneous patterns of regional distribution and compartmentalization, and review emerging links between CNS persistence and neuroinflammation. We conclude with priorities for harmonized tissue processing, multi-modal single-cell and spatial profiling, and coordinated cross-cohort analyses to clarify the contribution of CNS reservoirs to neuroHIV pathogenesis and systemic rebound.

With over half of people with HIV (PWH) in the U.S. entering older adulthood, identifying markers to distinguish Alzheimer’s disease (AD) and its precursor, amnestic mild cognitive impairment (aMCI), from other forms of neurocognitive impairment among PWH is urgent. We examined how HIV and aMCI status relate to AD CSF biomarkers in adult PWH and people without HIV (PWoH) characterized for aMCI. We included 80 PWH from the National NeuroHIV Tissue Consortium and 80 PWoH from the Wisconsin Registry for Alzheimer’s Prevention. Binary logistic regressions of AD-related CSF biomarker positivity (Aβ42, Aβ42/Aβ40, t-tau, p-tau181, Aβ42/t-tau) were conducted with HIV serostatus, aMCI status, HIV x aMCI interaction, and demographic covariates. Among PWH, we examined how HIV-disease characteristics relate to AD biomarker positivity. No HIV x aMCI interactions were detected. Regardless of aMCI status, having HIV was associated with higher odds of CSF Aβ42 (OR = 7.97) and Aβ42/Aβ40 (OR = 6.06) positivity, suggesting increased cerebral Aβ plaque burden. Regardless of HIV serostatus, having aMCI was associated with higher odds of CSF p-tau181 positivity (OR = 3.64). Neither HIV nor aMCI status related to Aβ42/t-tau positivity. No HIV-disease characteristics related to AD biomarker positivity. Higher CSF Aβ positivity in PWH versus PWoH, regardless of aMCI status, suggests that HIV disease promotes amyloidosis; however, whether positive CSF biomarkers in PWH raises risk for future cognitive impairment and AD remains to be explored longitudinally. Like PWoH, elevated CSF p-tau181 among PWH may indicate increased risk for AD-related memory impairment.

Methamphetamine use is prevalent among people with HIV (PWH) and complicates HIV care. Integrated substance use and HIV care services are recommended, yet rarely available. Contingency management (CM) is an evidence-based treatment for methamphetamine use, but its implementation within HIV primary care is limited. This study identified determinants and strategies to support CM implementation in HIV care. Key informants from an HIV clinic at an academic medical center (n = 15 patients; n = 15 providers) completed semi-structured interviews and a survey. A rapid qualitative analysis guided by the Exploration, Preparation, Implementation, Sustainment (EPIS) framework identified implementation determinants, and potential strategies were classified using the Expert Recommendations for Implementing Change (ERIC) compilation. Both patient and provider participants rated CM as acceptable (M = 3.72 and 4.55/5) and appropriate (M = 3.85 and 4.54/5). Providers also rated CM as feasible (M = 4.08/5) and reported strong support for integrating CM into HIV care, citing the high priority of addressing methamphetamine use. Facilitators included the clinic’s person-centered culture and providers’ familiarity with substance use treatment. Barriers included perceptions that reinforcer values in standard CM protocols were low, limited staffing, and competing provider demands. Suggested implementation strategies included adapting CM (e.g., increasing reinforcer value), patient-directed outreach/advertisements, and provider education and support (e.g., reminders about CM availability and referral processes). Findings indicate strong support for integrating CM into HIV primary care, while noting challenges to implementation. Addressing these determinants through targeted multi-level implementation strategies may enhance CM adoption and sustainment in HIV care settings.

The 15th Annual International Workshop on Aging and HIV (October 24-25, 2024) centered on integrating aging-related science into HIV research and care and aimed to advance interdisciplinary exchange and identify actionable priorities for research and practice. This article summarizes keynote presentations on geroscience-informed aging mechanisms; clinical manifestations of aging with HIV, including frailty, neurocognitive impairment, and perinatally acquired HIV; polypharmacy; scalable geriatric-HIV care models and implementation; and career development. It identifies priorities for advancing the field, including geroscience-informed trials, frailty and cognitive screening, deprescribing, scalable geriatric-HIV care models, and research addressing aging challenges in perinatally acquired HIV.

Objective: Black individuals in the United States are disproportionately affected by HIV and experience disparities in antiretroviral therapy (ART) adherence. This study examined components of the Health Belief Model (HBM) and related psychosocial factors as predictors of ART adherence across multiple adherence measures. Methods: Participants were 91 Black adults with HIV recruited from a federally qualified health center (FQHC) and enrolled in a single-arm text messaging-based adherence support intervention. ART adherence was assessed using three measures: (1) a continuous adherence measure, (2) a visual analog scale (VAS), and (3) daily text message-reported responses. Selected HBM constructs (perceived benefits, perceived severity, perceived barriers, and self-efficacy) and related psychosocial factors (supports and beliefs) were examined as predictors of these three adherence outcomes. Linear mixed-effects models assessed associations between psychosocial predictors and longitudinal adherence outcomes. Results: The sample was primarily comprised of men and older individuals, most of whom had disclosed their HIV status to others. In multivariable models including all predictors, greater self-efficacy was associated with higher adherence on both the continuous adherence measure (β = .18, t = 2.11, p = .04) and VAS (β = .21, t = 2.54, p = .01), but not the daily text message responses. Greater perceived barriers were associated with lower adherence on the continuous adherence measure and VAS (p’s <.001) and showed a trend toward lower text message responses (t = –0.79, p = .06). Greater support for adherence was marginally associated with higher VAS scores (t = 1.95, p = .06). Other psychosocial predictors were not significantly associated with adherence outcomes. Conclusions: In this older cohort of Black adults receiving HIV care, self-efficacy and perceived barriers emerged as the most salient correlates of retrospective self-reported ART adherence. Findings support the potential value of interventions that strengthen self-efficacy and reduce perceived adherence challenges.

IntroductionAdvanced cognitive aging remains a major concern for people living with HIV (PWH), even in the context of viral suppression. This underscores the need for sensitive tools that can detect subtle cognitive change. Mobile cognitive assessments offer a scalable and ecologically valid approach, yet their sensitivity to longitudinal change in clinical populations is not well established.MethodsWe examined longitudinal performance and predictors of change on a 14-day mobile Verbal Learning Test (mVLT) administered remotely at baseline and again 12–46 months (M = 26.7) later in 24 PWH and 13 HIV-negative controls aged 51–74, and compared these trajectories with change on standard in-person neuropsychological testing.ResultsAggregate mean mVLT performance improved over time among controls, but this was not evident among PWH (i.e., a significant group X time interaction). In contrast, longitudinal trajectories did not differ by group on the standard in-person Hopkins Verbal Learning Test-Revised, suggesting greater sensitivity of the mobile measure in this sample. Age moderated mVLT trajectories, such that increasing age was associated with worse longitudinal trajectories in PWH, whereas age was unrelated to change in controls. Among PWH, worse mVLT trajectories were associated with higher cerebrovascular risk, lower social functioning, and poorer baseline global learning performance, but not depressive symptoms, HIV disease markers, or other medical comorbidities.DiscussionThese preliminary findings suggest that the mVLT captures group-level differences in longitudinal learning trajectories and heterogeneity in performance over time among PWH, in line with contemporary models of cognitive aging in HIV. With replication in larger samples, mobile assessments could support scalable monitoring of cognitive function in PWH.

Despite effective antiretroviral therapy, HIV persists in the central nervous system (CNS) and may contribute to neuroinflammation and cognitive impairment. How viral persistence, immune responses, and regional CNS T-cell architecture relate to cognitive functioning remains unclear. We performed a cross-sectional, multi-compartmental immune-genomic study in 12 people with HIV on long-term viral suppression enrolled in the Last Gift rapid autopsy program. Quantitative HIV reservoir measures (total-episomal DNA, unspliced-multiply spliced RNA) and paired αβ T-cell receptor repertoire (TCRR) sequencing were performed in peripheral blood mononuclear cells and five CNS regions: hippocampus, frontal motor cortex, basal ganglia, occipital cortex, and spinal cord. Cognitive performance was assessed within one year of death. Tissue-resolved associations between cognition and HIV reservoir, TCRR architecture (richness, diversity, clonality), and pathogen-specific T-cell clonotypes (HIV, CMV, EBV, and riboflavin derivatives) were evaluated using participant-clustered multivariable models. False discovery rate was applied. HIV DNA and RNA were detectable across all tissues but were not associated with cognitive performance or TCRR metrics. Peripheral TCRR architecture was unrelated to cognition, whereas higher TCRR richness and diversity in the hippocampus and spinal cord were associated with worse verbal, motor, and attention/working memory scores. Higher TCRR richness in the spinal cord was also associated with better recall. T-cell receptor clonotype frequency distributions differed across CNS regions, consistent with regional immune compartmentalization. Epitope-inference analyses revealed pathogen-dependent associations: higher number of HIV-specific T-cell clonotypes in the basal ganglia was associated with better global and attention/working memory scores, whereas riboflavin derivative-specific clonotypes in frontal motor cortex were associated with better motor performance. CMV-specific clonotypes showed nominal associations with worse learning and memory. CNS-localized T-cell receptor architecture and antigenic imprinting related more closely to neurocognitive variability than quantitative measures of HIV persistence under viral suppression, highlighting regional specialization of T-cell responses as a potential correlate of brain health.

Opioid use disorder (OUD), which frequently co-occurs with HIV infection, causes long-term neurological disease, yet the epigenetic and transcriptomic effects of OUD and HIV on specific cell types and regions of the brain are poorly understood. To assess the cell-type specific impacts of OUD and HIV across the human brain, we measured single cell transcriptomes and epigenomes of 580,353 cells in the prefrontal cortex, amygdala and cerebellum of 44 donors. We cataloged over 750k candidate cis-regulatory elements (cCREs) and identified gene regulatory networks (GRNs) of transcription factor activity across 35 neuronal and non-neuronal cell types. We identified specific neuronal and glial populations whose cCREs were significantly enriched for genetic risk of addiction-related traits. In OUD donors, we found evidence for reduced metabolic function in neurons in the PFC and cerebellum as well as increased gene expression related to voltage-gated calcium channel activity in the cerebellum. Using a cerebellar organoid model, fentanyl treatment reduced metabolic activity while increasing neuronal activity. Across brain regions, HIV activated immune-related pathways in glial populations, while comorbid OUD and HIV exacerbated metabolic changes in cortical glial cells. Cerebellum-specific Bergmann glia, in addition to forebrain microglia and astrocytes, showed expansion of reactive state identity in HIV. These results highlight shared and specific changes to immune, synaptic, and metabolic processes in OUD and HIV across brain regions and reveal that cerebellar cell types are distinctly affected by opioid abuse.

BACKGROUND:Heterosexual sex accounts for 87% of new HIV diagnoses among cisgender women. We sought to explore the intersection of partner dynamics and oral preexposure prophylaxis (PrEP) adherence among cisgender women in heterosexual serodiscordant relationships. METHODS:From June 2017-August 2018, we conducted semi-structured in-depth interviews using a social ecological model framework. Twenty cisgender women in serodiscordant relationships, who participated in a PrEP demonstration project to evaluate adherence and retention in San Diego and Los Angeles, participated in in-depth interviews. Interviews were audio-recorded and transcribed, and transcripts were analyzed using thematic analysis. RESULTS:Among the 20 participants, the median age was 37.5 years (IQR 32, 48), with n = 6 (30%) identifying as Black and n = 5 (25%) as Hispanic. Sixty-five percent of women had protective drug levels based on real-time tenofovir-diphosphate drug level assays at the study visit prior to their interviews. Some partners played a significant role in PrEP adherence, often showing support by vocalizing encouragement and appreciation, offering reminders to take PrEP, and sometimes administering PrEP. Other partners were unsupportive and discouraged PrEP use, which may have hindered adherence. HIV and PrEP stigma were identified as potential barriers for women to take PrEP and disclose their PrEP use to others. CONCLUSIONS:Within the context of this PrEP demonstration project, partner dynamics impacted PrEP adherence for HIV-negative cisgender women in serodiscordant relationships. We urge further investigation of relationship dynamics and PrEP adherence and persistence specifically among US-based cisgender women.

[This corrects the article DOI: 10.1371/journal.pone.0312912.].

Prevalence and incidence of HIV among people aged 50 years and older continue to rise worldwide, generating increasing awareness among care providers, scientists, and the HIV community about the importance of brain health in older adults with HIV. Many age-related factors that adversely affect brain health can occur earlier and more often among people with HIV, including epigenetic ageing, chronic medical conditions (eg, cardiovascular disease), and age-related syndromes (eg, frailty). Extensive dialogue between HIV community leaders, health-care providers, and scientists has led to the development of a multidimensional response strategy to protect and enhance brain health in people ageing with HIV that spans across public health, clinical spaces, and research spaces. This response strategy was informed by integrated ageing care frameworks and is centred on prevention, early detection, and management of brain health issues associated with HIV (eg, neurocognitive disorders), with specific considerations for low-resource or middle-resource countries. A collaborative, international, and data-informed update of the diagnostic criteria for HIV-associated neurocognitive disorders is a cornerstone of the proposed response strategy. The proposed response strategy includes a dynamic, international, online knowledge hub that will provide a crucial community resource for emerging evidence on the brain health of people ageing with HIV.

As the U.S. population of people with HIV (PWH) ages, PWH exhibit high rates of adverse health outcomes including everyday functioning decline. We aimed to (1) identify trajectories of self-reported everyday functioning and (2) examine baseline predictors (demographics, cognitive domains, psychiatric and medical comorbidities, HIV-disease characteristics) of trajectories among PWH. 742 PWH completed up to five semi-annual visits over two years. Latent growth mixture modeling identified a linear 3-class solution with good statistical fit and interpretability. Most PWH (88%) had good baseline functioning with stability. Two classes had elevated baseline functional declines with worsening (7%) or improvement (5%). Greater depressive symptoms and motor skills impairment predicted higher odds of impaired functioning. Having chronic pulmonary disease increased odds of improvement, which may reflect connection to care, while older age increased odds of worsening. Most aging PWH demonstrate stable everyday functioning; however, interventions for depression and motor skills may improve functioning.

OBJECTIVE:Diagnosing HIV-Associated Neurocognitive Disorders (HAND) requires attributing neurocognitive impairment and functional decline at least partly to HIV-related brain effects. Depressive symptom severity, whether attributable to HIV or not, may influence self-reported functioning. We examined longitudinal relationships among objective global cognition, depressive symptom severity, and self-reported everyday functioning in people with HIV (PWH). METHODS:Longitudinal data from 894 PWH were collected at a university-based research center (2002-2016). Participants completed self-report measures of everyday functioning to assess both dependence in instrumental activities of daily living (IADL) and subjective cognitive difficulties at each visit, along with depressive symptom severity (BDI-II). Multilevel modeling examined within- and between-person predictors of self-reported everyday functioning outcomes. RESULTS:Participants averaged 6 visits over 5 years. Multilevel regression showed a significant interaction between visit-specific global cognitive performance and mean depression symptom severity on likelihood of dependence in IADL (p = 0.04), such that within-person association between worse cognition and greater likelihood of IADL dependence was strongest among individuals with lower mean depressive symptom severity. In contrast, participants with higher mean depressive symptom severity had higher likelihoods of IADL dependence regardless of cognition. Multilevel modelling of subjective cognitive difficulties showed no significant interaction between global cognition and mean depressive symptom severity (p > 0.05). CONCLUSIONS:The findings indicate a link between cognitive abilities and IADL dependence in PWH with low to moderate depressive symptoms. However, those with higher depressive symptoms severity report IADL dependence regardless of cognitive status. This is clinically significant because everyday functioning is measured through self-report rather than performance-based assessments.

Purpose:Minority stress theory posits health disparities among sexual minority men (SMM; i.e., non-heterosexual) result from experiences of sexual minority stigma (SMS). This systematic review synthesizes quantitative findings on the association between minority stress and stimulant use among US adult SMM. Methods:PubMed, PsycInfo, CINAHL, and Scopus searches between November 2022 and October 2023 identified 991 studies, with 13 meeting selection criteria: English, peer-reviewed publication reporting an estimated minority stressor-stimulant use association among US adult SMM. Minority stressors included enacted, internalized, or anticipated SMS or identity concealment. Stimulants included methamphetamine, cocaine/crack cocaine, and diverted prescriptions. Proportions of studies and estimates indicating statistically significant associations were examined in total and for each minority stressor-stimulant pair. Results:Many studies included primarily Black/Latino (69.2 %), urban (76.9 %), young adult samples (38.5 %). Significant associations were reported in 42.9 % (6/13) of studies but represented only 38.2 % (13/34) of unique estimates. Most estimates involving composite stimulant outcomes were nonsignificant (86.7 %, 13/15). Most estimates of enacted SMS-methamphetamine (66.7 %, 2/3), internalized SMS-methamphetamine (66.7 %, 4/6), and internalized SMS-cocaine/crack cocaine (83.3 %, 5/6) associations were significant. Findings suggest sexual orientation (i.e., gay vs bisexual) may moderate internalized SMS effects. Few studies examined prescription stimulants and none examined anticipated SMS or identity concealment. Conclusions:Further research is needed examining the use of various stimulants independently, not in composite, and testing for moderation by sexual orientation. Findings suggest multi-level approaches targeting enacted SMS and individual-level approaches targeting internalized SMS may benefit SMM who use methamphetamine or cocaine/crack cocaine, respectively.

Background:Black people with HIV (PWH) show poorer rates of antiretroviral therapy (ART) adherence compared to other racial/ethnic groups in the United States. Social determinants of health (SDOH) may influence ART adherence, and disparities in SDOH are known to disproportionately impact Black communities. The iC-CHANGE study evaluated the efficacy of a personalized, culturally adapted, text messaging intervention to improve ART adherence among Black PWH and incorporated self-report measures of ART adherence at study visits. This analysis sought to examine the relationship between SDOH and longitudinal ART adherence measures. Methods:Participants (90 Black PWH) were sent text messages through a two-way, fully automated text-messaging intervention, and attended in person study visits (12-week intervals). Measures of ART adherence included a visual analog scale, 3-item quantitative questionnaire, and text message responses. The relationship between SDOH and ART adherence measures were evaluated using linear and logistic mixed effects regression models. Results:Majority of the participants (n=90) were male (82.0%) and mean (SD) age was 46.5 (11.7) years at baseline. Housing stability was significantly associated with ART adherence, such that individuals without stable housing had lower scores on the 3-item self-report adherence scale (β = -4.04, p = .001), the visual analog adherence scale (β = -4.15, p= .02), and text message responses (β = -.03, p =.02) compared to individuals with stable housing. Older age was also associated with higher adherence on the visual analog scale (β = 0.003, p = .008), but lower adherence in daily text message responses (β = -0.06, p = .03). Health literacy also showed a positive association with ART adherence as measures by text message responses (β = 0.03, p < .02). Conclusion:These findings highlight the need for targeted interventions addressing housing stability and health literacy to improve ART adherence among Black individuals with HIV. Integrating these factors with clinical care may significantly enhance treatment outcomes and contribute to health equity.

OBJECTIVE:Examine the associations of gait speed with global and domain-specific neurocognition in older people with HIV (PWH) versus people without HIV (PWoH). METHODS:Participants included 285 PWH and 214 PWoH 50 years and older (Mage = 60.1, SD age = 7.1) who completed a gait examination and a comprehensive neurocognitive assessment. RESULTS:Gait speed was significantly slower in PWH ( M = 3.3 s, SD = 1.1) than PWoH ( M  = 3.0 s, SD  = 0.9; P  = 0.006). Slower gait speed was significantly associated with poorer global neurocognition ( β = -0.17, P  = 0.009) and deficits in multiple neurocognitive domains, including verbal fluency, executive functioning, processing speed, and motor skills, after adjusting for sociodemographic, HIV-related, and medical characteristics in PWH. A significant interaction between gait speed and HIV status emerged for verbal fluency, suggesting differential cognitive impacts ( β = -0.45, P  = 0.008). CONCLUSIONS:Our findings highlight nuanced relationships between gait speed and neurocognition, emphasizing the need for longitudinal research to establish causal mechanisms and potential clinical screening approaches.