Johns Hopkins Medicine

Glioblastoma (GBM) is the most aggressive and malignant type of primary brain tumor, with a median survival time of less than two years and a uniformly poor prognosis, despite multimodal therapeutic approaches, which highlights an urgent need for novel therapeutic targets. In this study, by integrative multi-omics analysis from CPTAC database, DepMap database and seven independent GBM cohorts, four hub genes (CD44, SURF4, IGSF3 and RALGAPA1) were identified as essential genes regulated by cancer driver genes with robust prognostic value. GBM multi-omics data from public and in-house cohorts validated that CD44 and SURF4 might be synthetic lethal partners of loss-of-function tumor suppressor genes. Analysis for immune-related pathway activity revealed complex regulation relationships of the four hub genes in tumor microenvironment (TME). Further investigation on SURF4 in pathway activity, immune therapy response and drug sensitivity proposed that SURF4 emerged as a promising therapeutic target for GBM, even for pan-cancer. Pan-cancer multi-omics exploration suggested that RALGAPA1 may be a tumor suppressor gene. By screening the first-generation and second-generation DepMap database, four genes (CCDC106, GAL3ST1, GDI2 and HSF1) might be considered as synthetic targets after mutation of RALGAPA1 as a tumor suppressor gene.

Rhesus and pigtail macaques are closely related and have similar social structures, yet differences in their behavior, socio‐ecology, and personality have been observed, although not systematically documented. Given these differences, it is important to assess pigtail macaque cognition independently, rather than relying on rhesus macaque findings as a proxy. To gain a better understanding of pigtail macaque cognition, we used a battery of three cognitive tasks. Rhesus macaques were tested on the same tasks to validate our methods and to allow for comparison. Across just three tasks, we found significant differences between the two closely related species. In the three cups task, which tests short‐term memory, both pigtail and rhesus macaques performed significantly better when they had to recall the location of a hidden food reward after a 0 s delay compared to a 15 s delay. However, in the 15 s delay condition, only rhesus macaques performed above chance levels, whereas pigtail macaques did not. In the reversal learning task, which tested rule learning and cognitive flexibility, we found species differences in learning performance. For the quantity discrimination task, which tests numerosity, we found that both rhesus and pigtail macaques were more accurate at discriminating "easy" ratios of foods (e.g., 1 vs. 5 or 2 vs. 6) than the "hard" ratios (e.g., 2 vs. 3 or 4 vs. 5). However, pigtail macaques were more accurate than rhesus macaques in the hard ratio trials. These contribute to a novel understanding of cognition in pigtail macaques while also increasing research rigor in translational research.

Enhancing mental health-related quality of life (MHRQOL) is an important clinical objective for people with HIV (PWH), due to their elevated risk of psychological distress and mental health challenges. Depression, pain, stigma, and discrimination are among the main contributors to poor MHRQOL in this population and can negatively impact PWH’s interaction with their healthcare providers, and vice versa. We used structural equation modeling to examine whether the quality of patient-provider engagement in HIV primary care mediated the effects of depression and prior experiences of discrimination in healthcare settings on later MHRQOL, assessed using the SF- 12 Mental Component Summary (MCS- 12), among a sample of predominately African Americans with HIV and a history of drug use. A total of 331 participants, recruited from HIV clinics and community venues in Baltimore, Maryland, USA, completed three semi-annual surveys between 2014 and 2018. At baseline, the sample showed a high percentage of probable depression (35.6%) and a low MCS- 12 mean score (38.72, SD = 6.88) compared with the US general population norm of 50 (SD = 10). There were significant indirect paths from baseline depression (β = − 0.04, 95% CI = − 0.10, − 0.01) and healthcare discrimination (β = − 0.05, 95% CI = − 0.12, − 0.01) to lower MHRQOL at 12-months, mediated through reduced patient-centered patient-provider engagement with primary care providers at 6-months, after adjusting for baseline assessment of the mediator and the outcome, demographic covariates, substance use, pain level, and time since HIV diagnosis. Findings suggest a potential for mitigating the impacts of depression and healthcare discrimination on MHRQOL through intervening on the quality of patient-provider engagement.

ACE2 has shown effectiveness in treating pulmonary hypertension in multiple animal models and has some promise in early human trials. The key barrier to translation is that enzymatically active ACE2 is difficult to manufacture and exhibits a short half‐life in humans, making chronic administration challenging. Understanding the mechanism of effect is thus key to finding ways to bypass ACE2 while still reproducing therapeutic effects. In this study, we test the hypotheses that ACE2 produces its therapeutic effect through increased Mas1 signaling and that Ang(1‐7) is sufficient as the Mas1 ligand. We found that the ACE2 effect is blocked in Mas1 knockout mice and that the Mas1 agonist AR234960 reproduces the ACE2 effect, indicating that Mas1 activation is necessary and sufficient for the ACE2 therapeutic effect. However, neither AlbudAb‐stabilized Ang(1‐7) nor Ang(1‐7) stabilized through the use of protease inhibitors were capable of reproducing ACE2 effectiveness, indicating that Ang(1‐7) alone does not activate Mas1 in this context. RNA‐seq suggests that the key mechanisms downstream of Mas1 responsible for the therapeutic effect of ACE2 and AR234960 are the rescue of cytoskeletal and microtubule defects. Together, these findings indicate that direct activation of Mas1 will likely be effective in treating pulmonary arterial hypertension, but raise the question of the identity of the endogenous ligand(s).

Background Social, emotional and behavioural (SEB) problems are among the most common chronic disabilities affecting children growing up in poverty. They also have implications for children’s school success as they affect essential social-emotional learning skills such as the ability to comply with rules, regulate emotions and get along with others. These skills are first learnt before kindergarten, in the context of a supportive, responsive and consistent parenting relationship. To date, school-based interventions to improve young children’s SEB competence and learning have primarily targeted students and teachers. Yet, parents are central partners in promoting these skills. This study seeks to improve children’s SEB competence and kindergarten readiness by strengthening parenting skills and parent engagement in early childhood education during prekindergarten (PreK). This hybrid type 2 effectiveness-implementation trial will rigorously evaluate the effects of an evidence-based parenting programme, the Chicago Parent Program (CPP), in PreK on children’s SEB competence, kindergarten readiness, chronic school absenteeism and grade retention in urban and rural schools serving students from low-income families in Maryland. Methods Using a cluster randomised design (n=30 schools, 840 parents; >90% low-income), we will examine the effects of CPP offered universally to PreK parents on parenting skills and parent engagement in children’s education; children’s SEB competence and kindergarten readiness; and chronic absence and grade retention in kindergarten. Schools will be stratified by rural versus urban district, then randomised to CPP or usual practice conditions. Data will be analysed using mixed effects regression models. Using the reach, effectiveness-adoption, implementation, maintenance (RE-AIM) framework and a mixed methods approach, we will assess CPP reach, efficacy, acceptability, adoption, implementation, cost-effectiveness and sustainability when offered in different formats (virtual vs in-person CPP groups) and contexts (urban vs rural). Schools will participate for 2 years with experimental schools offering CPP twice, once in virtual group format and once in an in-person group format (format randomised and counterbalanced). Data will be collected using multiple informants (parents, teachers, district administrative data) and methods (quantitative and qualitative data). Knowledge gained will inform schools in under-resourced urban and rural communities on sustainable, cost-effective strategies for strengthening parent-school connections and improving young children’s SEB competence and academic success. Ethics and dissemination Ethics approval has been granted by Johns Hopkins University School of Medicine (protocol number 00428221) and the Baltimore City Public Schools (protocol number 2024-013). At the conclusion of the study, results will be summarised and shared with parents, teachers, school principals and district leaders for their perspectives on the outcomes. Final reports will be published in scientific journals and presented at professional meetings. Trial registration number NCT06197997 .

Objectives: The World Health Organization estimates that 25% of older adults worldwide have disabling hearing loss. Although hearing aids are the conventional management strategy for this condition, the rate of abandonment of these devices is high. Complete abandonment of the device can expose individuals to the negative consequences of untreated hearing loss. Although previous studies have examined the effect of attitudes on hearing aid abandonment, they have not investigated the time over which abandonment occurs. Consequently, previous evidence has not explored whether attitudes toward hearing loss and hearing aids are associated with the speed (i.e., hazard) at which individuals abandon their hearing aids over time. Our primary objective was to determine the effect of attitudes toward hearing loss and hearing aids on both the risk and timing of hearing aid abandonment. A secondary objective was to assess the potential effect of attitudes toward hearing loss and hearing aids on changes in social participation and withdrawal from social activities. Design: We conducted a retrospective cohort study involving 355 patients who received hearing aids from a Chilean public hospital. Device abandonment over time was assessed by asking the patients about the specific month of hearing aid abandonment. Attitudes toward hearing loss and hearing aids were measured using the Spanish version of the Attitudes towards Loss of Hearing Questionnaire (S-ALHQ), while changes in participation and withdrawal from social activities were assessed using the Glasgow Benefit Inventory questionnaire. Univariate and multivariate flexible parametric models were developed to estimate the hazard ratio of hearing aid abandonment over time, with attitudes toward hearing loss and hearing aids as the primary predictors. Furthermore, multivariate multinomial regression models were constructed to evaluate the relationship between attitudes and changes or withdrawal from social activities. Results: The cumulative incidence of hearing aid abandonment was approximately 21%. The median score on the S-ALHQ was 2.45 points (25th to 75th percentile: 2.05 to 2.77). In the flexible parametric survival models, for each average point increase on the S-ALHQ questionnaire, there was a twofold increase in the risk of hearing aid abandonment over time (Hazard Ratio = 2.09; 95% Confidence Interval = 1.30 to 3.40). In addition, an association was found between attitudes and withdrawal from social activities, with a 5.5-fold increase in the risk ratio for withdrawal from social activities (Relative-Risk Ratio = 5.53; 95% Confidence Interval = 1.49 to 20.56). Conclusions: More negative attitudes toward hearing loss and hearing aids were associated with an increased risk of hearing aid abandonment over time, and an increased risk of withdrawal from social activities. Thus, attitudes toward hearing loss and hearing aid use should be considered when implementing hearing rehabilitation programs that include the dispensing of hearing aids.

Importance Bipolar disorder (BD) and major depressive disorder (MDD) aggregate within families, with risk often first manifesting as early psychopathology, including attention-deficit/hyperactivity disorder (ADHD) and anxiety disorders. Objective To determine whether polygenic scores (PGS) are associated with mood disorder onset independent of familial high risk for BD (FHR-BD) and early psychopathology. Design, Setting, and Participants This cohort study used data from 7 prospective cohorts enriched in FHR-BD from Australia, Canada, the Netherlands, Spain, and the US. Participants with FHR-BD, defined as having at least 1 first-degree relative with BD, were compared with participants without FHR for any mood disorder. Participants were repeatedly assessed with variable follow-up intervals from July 1992 to July 2023. Data were analyzed from August 2023 to August 2024. Exposures PGS indexed genetic liability for MDD, BD, anxiety, neuroticism, subjective well-being, ADHD, self-regulation, and addiction risk factor. Semistructured diagnostic interviews with relatives established FHR-BD. ADHD or anxiety disorder diagnoses before mood disorder onset constituted early psychopathology. Main Outcomes and Measures The outcome of interest, mood disorder onset, was defined as a consensus-confirmed new diagnosis of MDD or BD. Cox regression examined associations of PGS, FHR-BD, ADHD, and anxiety with mood disorder onset. Kaplan-Meier curves and log-rank tests evaluated the probability of onset by PGS quartile and familial risk status. Results A total of 1064 participants (546 [51.3%] female; mean [SD] age at last assessment, 21.7 [5.1] years), including 660 with FHR-BD and 404 without FHR for any mood disorder, were repeatedly assessed for mental disorders. A total of 399 mood disorder onsets occurred over a variable mean (SD) follow-up interval of 6.3 (5.7) years. Multiple PGS were associated with onset after correcting for FHR-BD and early psychopathology, including PGS for ADHD (hazard ratio [HR], 1.19; 95% CI, 1.06-1.34), self-regulation (HR, 1.19; 95% CI, 1.06-1.34), neuroticism (HR, 1.18; 95% CI, 1.06-1.32), MDD (HR, 1.17; 95% CI, 1.04-1.31), addiction risk factor (HR, 1.16; 95% CI, 1.04-1.30), anxiety (HR, 1.15; 95% CI, 1.02-1.28), BD (HR, 1.14; 95% CI, 1.02-1.28), and subjective well-being (HR, 0.89; 95% CI, 0.79-0.99). High PGS for addiction risk factor, anxiety, BD, and MDD were associated with increased probability of onset in the control group. High PGS for ADHD and self-regulation increased rates of onset among participants with FHR-BD. PGS for self-regulation, ADHD, and addiction risk factors showed stronger associations with onsets of BD than MDD. Conclusions and Relevance In this cohort study, multiple PGS were associated with mood disorder onset independent of family history of BD and premorbid diagnoses of ADHD or anxiety. The association between PGS and mood disorder risk varied depending on family history status.

A 4-h preservation time threshold for cardiac allografts is the current standard in heart transplantation, but novel technologies are proposed to decrease the morbidity associated with prolonged allograft storage. This study examined adult heart transplant recipients from 2000–2015 and 2020–2023 in the United States, stratified into an early (2000–2015) and modern era (2020–2023), then into standard (≤ 4 h) and prolonged (≥ 5 h) preservation time groups within each era. This study reinforced the 4-h threshold in the early era, where prolonged preservation significantly increased one-year mortality (HR 1.60, 95% CI 1.36–1.90). However, this association was no longer significant in the modern era (HR 1.14, 95% CI 0.85–1.50). A sub-analysis showed that using machine perfusion devices for allograft storage was not associated with one-year mortality (HR 1.15, 95% CI 0.79–1.70). Spline analysis demonstrated possible inflection points between 4 and 5 h and 8–9 h in the modern era, and further analysis found that 5–8 h of preservation did not increase one-year mortality (HR 1.09, 95% CI 0.80–1.47) relative to the ≤ 4 h group. In conclusion, the association between cardiac allograft preservation duration and morbidity has decreased in the modern era. Today, a 4-h preservation duration threshold may be too restrictive.

Reduced functional capacity and poor sleep quality are common in pulmonary arterial hypertension (PAH). Wearable devices are an emerging, user‐friendly tool to capture activity and sleep information. We aimed to determine whether Fitbit‐derived activity and sleep trends provide clinically meaningful information in patients with PAH. Our prospective observational study recruited patients with PAH from across the United States using remote enrollment strategies and in‐person efforts. Participants wore a Fitbit device for 12 weeks at baseline and a subgroup with 1‐year follow‐up. A matched control cohort was generated from the All of Us Research Program and we evaluated changes in patients with PAH compared to matched controls. Among 110 patients with baseline monitoring, average daily steps correlated with 6MWD (r = 0.61, p < 0.001) and percent rapid eye movement (REM) sleep (r = 0.28, p = 0.008). In 44 PAH participants who completed baseline and 1‐year monitoring, there was a group‐time interaction for percent light sleep (p = 0.024) and percent REM sleep (p = 0.034), which demonstrated that sleep quality worsened in patients with PAH over 1 year compared to matched controls. Average daily steps decreased in patients with PAH from 5200 [IQR 3212–7458] at baseline to 4651 [IQR 2912–6827] at 1 year (p = 0.008). In conclusion, our study demonstrated the potential clinical value of wearable devices by showing that activity and sleep quality are reduced in PAH compared to matched controls and these measures decline over time. Future studies should investigate if monitoring these health behaviors detects early functional decline and whether targeted interventions may improve outcomes.

Background Although rapid antiretroviral therapy (ART) and same-day pre-exposure prophylaxis models (henceforth “rapid START”) are feasible, acceptable, and cost-effective in various contexts, significant barriers have hindered their broader implementation and scalability in the United States. Ryan White-funded clinics are cornerstones for HIV services, yet strategies are urgently needed to facilitate equitable rapid START adoption across contexts. This study aimed to identify common factors influencing rapid START to inform strategies applicable throughout jurisdictional settings. Methods The Network for Implementation Science in HIV examined the current implementation of rapid START among diverse Ryan White Part A-D–funded organizations across seven Ending the HIV Epidemic jurisdictions across the United States. Semistructured interviews (n = 13) were administered from March 2023 to August 2024, with HIV leadership across jurisdictions to identify rapid START implementation determinants and strategies to catalyze rapid START delivery. Data were deductively analyzed using the Consolidated Framework for Implementation Research. Results Prominent barriers to rapid ART implementation across settings included provider/patient hesitancy and awareness gaps, siloed care systems, and funding complexities. Prominent implementation facilitators included learning collaboratives, technology integration, and clear contracting language. Key constraints to same-day pre-exposure prophylaxis implementation included funding inequities and suboptimal client/patient awareness, whereas enablers included integrated care models, availability of starter packs, and medication-assistance programs. Conclusions Several consistent key barriers and facilitators spanned multiple Ending the HIV Epidemic jurisdictions despite contextual differences (eg, Medicaid expansion). Collaborative efforts between system leaders and service providers were universally characterized as essential for equitable adoption and penetration of rapid START models.

Background Ending the HIV Epidemic strategies include rapid ART Initiation (R-ART), rapid pre-exposure prophylaxis (R-PrEP), and status neutral approaches (status neutral), but implementation across heterogeneous settings in the United States is not well characterized. Setting Ryan White (RW)–funded HIV treatment clinics located in select Ending the HIV Epidemic priority areas in the United States. Methods Clinics were sent a survey to assess experiences offering R-ART, R-PrEP, and status neutral (collectively called “rapid START”). Primary outcomes were rapid START adoption and characteristics of implementing vs. nonimplementing clinics. Secondary outcomes included perceptions, barriers, and facilitators of R-ART and R-PrEP. Results The response rate was 48% (40 of 83). The 40 respondents represented 57 clinics who reported providing HIV-related services to more than 70,000 individuals annually. R-ART uptake was 85% (range 43%–100%), status neutral 65% (range 57%–75%), and R-PrEP 60% (range 0%–88%). No rural-identifying organizations reported offering R-ART or R-PrEP compared with 96% and 76% of urban-identifying organizations, respectively. Positive perceptions of acceptability, appropriateness, and feasibility for R-ART and R-PrEP were high among all levels of implementation and strongest among those offering R-ART and R-PrEP. The most frequent barriers to R-ART were provider- and clinic-level and for R-PrEP were system-level (lack of insurance coverage) followed by patient-, provider-, and clinic-level issues. Conclusion This survey of diverse RW-funded clinics shows high uptake of R-ART and significant if less consistent uptake of R-PrEP and status neutral. Future research should focus on identifying broadly implementable strategies to expand adoption along with tailored approaches, especially in areas with lower health care access.

Background Community-engaged research (CEnR) is fundamental to effective HIV prevention and treatment implementation, although limited in practice. We describe CEnR lessons learned by researchers in HIV-related implementation science to improve future CEnR. Setting Academic-community research partnerships funded by the 2019–2021 National Institutes of Health Ending the HIV Epidemic (EHE) supplement awards. Methods Seven individual awardees representing 8 EHE awards documented partnership characteristics and key CEnR experiences in an online form. Three semi-structured reflection sessions subsequently discussed experiences, identifying opportunities and barriers using qualitative thematic analysis, iterative dialogue, and illustrative case studies. Results Awardees identified both partnerships newly established for the grant (60%) and preexisting collaborations (40%). Key perceived CEnR benefits included: new and better project ideas; improved project implementation; and priorities to guide future research. Prominent barriers included: administrative burdens resulting in delayed funding access that constrained partner engagement; limited grant timelines and funding for essential preimplementation partnership building; and limited recognition of key CEnR activities in academic success metrics. Adaptive responses to barriers included focusing short award periods on exploratory aims and building on extant community activities. Conclusions Systems-level redesign at the funder and university levels could improve CEnR equity, including accepting financial risk between grant award and funding receipt to facilitate completion of essential prework such as Institutional Review Board approvals and prevent the exclusion of the more financially constrained community partners or forcing unfunded effort provision and establishing appropriate support and promotion criteria for CEnR-engaged faculty. Thus, enabling CEnR good practices can improve future HIV-related implementation research and EHE goal achievement.

Background Xenotransplantation (XTx) is a promising strategy to address the organ shortage. Clinical application will likely require off-site procurement from designated pathogen-free (DPF) facilities, introducing unavoidable cold ischemic time (CIT). The impact of CIT and organ preservation method on graft function in XTx remains unclear. Methods We evaluated eight cases of pig-to-baboon kidney xenotransplantation performed after five hours of CIT, comparing static cold storage (SCS) to hypothermic machine perfusion (HMP) preservation. Outcomes were assessed relative to six additional pig-to-baboon transplants performed with minimal CIT. Results All grafts preserved with SCS experience hyperacute rejection within 90 min of reperfusion, even in recipients with low levels of preformed anti-pig antibodies. In contrast, all HMP-preserved grafts reperfuse without clinical evidence of injury and maintain function for more than 14 days. Grafts transplanted with minimal CIT show similarly favorable outcomes. Conclusions Porcine kidneys are highly sensitive to ischemia-reperfusion injury after cold preservation across xenogeneic barriers. Routine SCS leads to early graft failure, while HMP mitigates ischemic injury and may enable successful clinical XTx despite prolonged CIT.

The thalamic ventral posterior (VP) nuclear complex includes several subnuclei, including the VPM, VPL, VPI, and VMb, each with distinct inputs, axonal trajectories, and staining properties. Understanding the three-dimensional organization of neuronal fiber structures of the VP complex is crucial for understanding intra-thalamic and thalamocortical connections related to somatosensory processing. In this study, an ex vivo block of the human brain was scanned using mesoscopic Diffusion Tensor Imaging (DTI), and the four VP subnuclei were identified using existing histological atlases as references. The VP subnuclei were characterized using a mean diffusivity (MeanD) map, orientation-coded fractional anisotropy (FA) map, and tractography obtained from DTI. The results demonstrated differential patterns in MeanD and orientation-coded FA maps among the four subnuclei, underscoring the potential of mesoscale imaging to identify and differentiate these subnuclei. The tractography identified patterns of afferent and efferent fibers unique to each nucleus, offering insights into their functional roles in sensory processing. The findings highlighted the advantages of DTI in visualizing the direction of fibrous structures and conducting three-dimensional tractography, offering a foundation for further investigations into in vivo imaging applications and the neural mechanisms of somatosensory disorders, including central pain syndrome.

BACKGROUND Alzheimer's disease (AD) is characterized by the abnormal accumulation of amyloid‐beta (Aβ) and tau that can be quantified in vivo through cerebrospinal fluid (CSF) sampling. Physical activity has emerged as a possible modifier of AD risk; however, its impact on CSF biomarkers and cognitive function is not yet fully understood. We examined whether higher levels of physical activity modifies associations between AD CSF biomarkers and cognitive function. METHODS One hundred and seventeen adults free of dementia from the BIOCARD study (mean age 72.2 ± 8.0 years, 70% women) wore a wrist accelerometer for 1 week, underwent lumbar puncture to collect CSF, and completed a comprehensive neuropsychological exam. Multivariable linear regression analyses were used to examine whether physical activity (total activity counts over the 10 most active hours of the day) moderates the association between AD CSF biomarkers [Aβ42/40, phosphorylated tau (p‐tau181), and total tau] and cognitive composite scores (episodic memory, executive function). RESULTS There were significant interactions between physical activity and p‐tau181 (p = 0.016) as well as between physical activity and total tau (p = 0.004) in relation to the executive function composite score. Among participants with higher levels of physical activity, the adverse relationship between CSF‐measured tau and executive function was diminished. In contrast, there were no significant interactions for episodic memory, and physical activity did not interact with Aβ42/40 (all interactions p > 0.05). CONCLUSION A physically active lifestyle may provide protection against AD‐related cognitive decline by reducing the impact of tau pathology. Highlights Older age was associated with lower levels of physical activity, worse CSF biomarker profiles, and poorer cognition. Physical activity moderates the impact of tau pathology on executive function but shows no significant effect on amyloid‐beta pathology. Physical activity may enhance cognitive reserve, thereby attenuating the influence of accumulating AD pathology on cognition.

INTRODUCTION Understanding the interplay between genetic factors and lifestyle choices in cognitive health is crucial for enhancing late‐life quality. This study examines the effects of Apolipoprotein E (APOE) genotypes and healthy lifestyles on life expectancy with and without cognitive impairment (CI) in Chinese older adults. METHODS Data from 6488 participants aged at least 65 in the Chinese Longitudinal Healthy Longevity Survey (CLHLS) were analyzed using continuous‐time three‐state Markov models. Cognitive function was assessed with the Mini‐Mental State Examination (MMSE). RESULTS APOE ε4 allele carriers had a higher risk of transitioning from cognitively healthy (CH) to impaired, while ε2 carriers had a reduced risk of transitioning from healthy to death. Participants with 4 or 5 healthy lifestyle factors experienced significant protective effects, extending the cognitively healthy life expectancy. DISCUSSION These findings underscore the importance of promoting healthy lifestyles to delay cognitive decline, regardless of genetic predispositions, particularly in the Asian context. Highlights Compared with ε3 homozygotes, APOE ε4 carriers in China have a higher risk of transitioning from CH to CI, and APOE ε2 carriers with CH have a lower risk of transitioning to death. Healthy lifestyles can extend life expectancy, primarily extending CH life expectancy. Healthy lifestyles reduce the risk of CI and delay its onset in later life, regardless of APOE genetic risk.

Purpose To measure T1 relaxation times of metabolites at 3 T in a healthy aging population and investigate age dependence. Methods A cohort of 101 healthy adults was recruited with approximately 10 male and 10 female participants in each “decade” band: 18 to 29, 30 to 39, 40 to 49, 50 to 59, and 60+ years old. Inversion‐recovery PRESS data (TE/TR: 30/2000 ms) were acquired at 8 inversion times (TIs) (300, 400, 511, 637, 780, 947, 1148, and 1400 ms) from voxels in white‐matter‐rich centrum semiovale (CSO) and gray‐matter‐rich posterior cingulate cortex (PCC). Modeling of TI‐series spectra was performed in Osprey 2.5.0. Quantified metabolite amplitudes for total N‐acetylaspartate (tNAA2.0), total creatine at 3.0 ppm (tCr3.0), and 3.9 ppm (tCr3.9), total choline (tCho), myo‐inositol (mI), and the sum of glutamine and glutamate (Glx) were modeled to calculate T1 relaxation times of metabolites. Results T1 relaxation times of tNAA2.0 in CSO and tNAA2.0, tCr3.0, mI, and Glx in PCC decreased with age. These correlations remained significant when controlling for cortical atrophy. T1 relaxation times were significantly different between PCC and CSO for all metabolites except tCr3.0. We also propose linear models for predicting metabolite T1s at 3 T to be used in future aging studies. Conclusion Metabolite T1 relaxation times change significantly with age, an effect that will be important to consider for accurate quantitative MRS, particularly in studies of aging.