👤 Jean-Francois Trani

Blood-based biomarkers are increasingly used to characterize Alzheimer's disease (AD)-related pathology, yet substantial heterogeneity exists in how biomarker burden relates to cognitive performance. Grip strength, a marker of frailty and functional reserve, may modify this relationship. We conducted a cross-sectional analysis of 348 participants from the Aging Adult Brain Connectome (AABC) study. Global cognition was assessed using the Preclinical Alzheimer Cognitive Composite (PACC). Plasma biomarkers included phosphorylated tau-217 (pTau Show less

Driving integrates multiple cognitive, sensory, and motor systems and may serve as a real-world indicator of functional decline in aging. Older adults with mild cognitive impairment (MCI) often experience subtle driving changes before formal dementia diagnosis, but longitudinal, real-world evidence is limited. This study examined whether naturalistic driving data can differentiate older adults with MCI from those with normal cognition (NC) over time and evaluated the discriminative ability of driving features compared with conventional risk factors. We conducted a prospective, observational cohort study of community-dwelling older drivers enrolled in the Driving Real-World In-Vehicle Evaluation System Project at Washington University. Participants underwent annual Clinical Dementia Rating assessment, neuropsychological testing, and apolipoprotein ε4 (APOE ε4) genotyping. Driving behaviors were captured daily for up to 40 months using global positioning system-enabled in-vehicle dataloggers, recording trip frequency, duration, distance, time of day, speeding, hard braking, and spatial mobility (entropy, maximum distance, radius of gyration). Longitudinal changes were analyzed using linear mixed-effect models, adjusting for age, sex, race, education, and APOE ε4. Logistic regression with reciever operator curve analysis evaluated discrimination between older adults with MCI and those with NC, compared with conventional sociodemographic and genetic markers. Among 298 participants (MCI, n = 56; NC, n = 242; mean age 75.1 years; 45.6% female), the groups were similar in age, sex, race, and APOE ε4 status at baseline, as well as in most driving behaviors. Over time, drivers with MCI showed greater reductions in monthly trip count (MCI: -0.501, standard error [SE]: 0.21, 95% CI [-0.923 to -0.083] vs NC: -0.523, SE: 0.09, 95% CI [-0.709 to -0.337]; MCI was associated with progressive declines in driving frequency, complexity, and spatial range, supporting naturalistic driving data as a potential unobtrusive digital biomarker for early cognitive decline. Limitations of the study include a predominantly White, highly educated sample and a lack of external validation, warranting cautious interpretation. Continuous monitoring could augment clinical assessments, inform driving safety decisions, and guide interventions to preserve mobility in aging. Show less

Apolipoprotein A-I mimetic peptides are amphipathic alpha-helix peptides that display similar functions to apolipoprotein A-I. Preclinical and clinical studies have demonstrated the safety and efficacy of apolipoprotein A-I mimetic peptides in multiple indications associated with inflammatory processes. In this study, we evaluated the effect of the long-term expression of L37pA in the liver by an adeno-associated virus (AAV-L37pA) on the expression of an adeno-associated virus encoding interferon-alpha (AAV-IFNα). Long-term IFNα expression in the liver leads to lethal hematological toxicity one month after AAV administration. Concomitant administration of AAV-L37pA prevented the lethal toxicity since the IFNα expression was reduced one month after AAV administration. To identify the mechanism of action of L37pA, a genomic and proteomic analysis was performed 15 days after AAV administration when a similar level of IFNα and interferon-stimulated genes were observed in mice treated with AAV-IFNα alone and in mice treated with AAV-IFNα and AAV-L37pA. The coexpression of the apolipoprotein A-I mimetic peptide L37pA with IFNα modulated the gene expression program of IFNα, inducing a significant reduction in inflammatory pathways affecting pathogen-associated molecular patterns receptor, dendritic cells, NK cells and Th1 immune response. The proteomic analysis confirmed the impact of the L37pA activity on several inflammatory pathways and indicated an activation of LXR/RXR and PPPARα/γ nuclear receptors. Thus, long-term expression of L37pA induces an anti-inflammatory effect in the liver that allows silencing of IFNα expression mediated by an adeno-associated virus. Show less