👤 Saurabh Asthana

To determine whether long-term residential air pollution [AP; ozone (O₃) and fine particulate matter (PM₂.₅)] is associated with (1) incident mild cognitive impairment (MCI) or Alzheimer’s disease (AD), (2) biomarkers of core and AD-relevant pathology, and (3) whether these relationships are moderated by APOE4+/- (carrier/non-carrier of one or both ε4 alleles) status or mediated by neuroinflammation. Sample included 795 participants (Mage 68.7 ± 7.9; 68% female) from the Wisconsin Alzheimer’s Disease Research Center and Wisconsin Registry for Alzheimer’s Prevention parent studies, both enriched for AD risk at enrollment based on parental AD history. Residential zip code and 2009–2021 EPA-based annual AP reports were used to estimate individual exposure. Cox proportional hazards models assessed MCI/AD risk. Linear regressions examined the relationships between AP exposure and biomarkers of core and AD-relevant pathology, with and without APOE4 + stratification. Causal mediation analysis examined whether markers of inflammation mediated the AP-AD pathology relationships. Neither O₃ nor PM₂.₅ exposure predicted MCI/AD incidence nor core AD pathology (Ps > 0.05). Higher PM₂.₅ was associated with higher CSF GFAP levels ( Show less

Using longitudinal data from multiple cohorts, we evaluated plasma P-tau217 as a predictor of when cognitive impairment occurs in AD. P-tau217 concentrations were analyzed as continuous and binary variables using cohort-specific biomarker positivity thresholds. Association of plasma P-tau217 with prevalent and incident cognitive impairment were assessed using logistic regression and Cox models, stratified by Elevated P-tau217 levels were significantly associated with the onset of cognitive impairment. Among Plasma P-tau217 levels and the presence Show less

Core 1 biomarkers, such as amyloid positron emission tomography, capture the earliest biological changes leading to Alzheimer's disease (AD). While APOE is a major genetic factor, the contribution of other variants to Core 1 biomarkers remains unclear. The goal of this study was to determine whether genetic regulators of Core 1 biomarker levels predicted AD pathology better than genetic regulators of clinical AD. Among 955 non-Hispanic White individuals, polygenic scores (PGSs) were built using genome-wide association studies (GWASs) of amyloid PET, plasma tau phosphorylated at threonine 181 (p-tau181), cerebrospinal fluid (CSF) p-tau181, and clinical AD. Hispanic-specific PGSs were constructed in 515 individuals using plasma p-tau181 and clinical AD GWASs. Baseline and longitudinal associations with plasma biomarkers and cognition were assessed, and replication was conducted in separate cohorts. The Core 1 biomarker PGSs predicted AD pathology and associated cognitive performance better than the AD PGSs in both populations. The Core 1 PGSs show improved predictive value for AD-related plasma biomarkers and early cognitive changes. APOE ε4 explained more variance in plasma p-tau217 than in plasma p-tau181. PGSs based on Core 1 biomarkers outperformed AD PGSs in predicting plasma biomarkers and cognitive decline among asymptomatic individuals in non-Hispanic White and Hispanic individuals. However, the improvement in predictive power was modest and may vary by age. While the variance in p-tau181 and p-tau217 explained by individual Core 1 PGSs remains limited, the distinct genetic signals captured by the best-performing PGSs across different Core 1 biomarkers may provide an opportunity for developing an integrative Core 1 PGS that more effectively predicts plasma p-tau181 and p-tau217 levels than AD-based PGS. Show less

Obesity is a growing public health concern that affects the longevity and lifestyle of all human populations including children and older individuals. Diverse factors drive obesity, making it challenging to understand and treat. While recent studies highlight the importance of GPCR signaling for metabolism and fat accumulation, we lack a molecular description of how obesogenic signals accumulate and propagate in cells, tissues, and organs. In this issue of the JCI, Jiang et al. utilized germline mutagenesis to generate a missense variant of GRP75, encoded by the Thinner allele, which resulted in mice with a lean phenotype. GPR75 accumulated in the cilia of hypothalamic neurons. However, mice with the Thinner allele showed defective ciliary localization with resistance to fat accumulation. Additionally, GPR75 regulation of fat accumulation appeared independent of leptin and ADCY3 signaling. These findings shed light on the role of GPR75 in fat accumulation and highlight the need to identify relevant ligands. Show less

One strategy for combating cancer-drug resistance is to deploy rational polytherapy up front that suppresses the survival and emergence of resistant tumor cells. Here we demonstrate in models of lung adenocarcinoma harboring the oncogenic fusion of ALK and EML4 that the GTPase RAS-mitogen-activated protein kinase (MAPK) pathway, but not other known ALK effectors, is required for tumor-cell survival. EML4-ALK activated RAS-MAPK signaling by engaging all three major RAS isoforms through the HELP domain of EML4. Reactivation of the MAPK pathway via either a gain in the number of copies of the gene encoding wild-type K-RAS (KRAS(WT)) or decreased expression of the MAPK phosphatase DUSP6 promoted resistance to ALK inhibitors in vitro, and each was associated with resistance to ALK inhibitors in individuals with EML4-ALK-positive lung adenocarcinoma. Upfront inhibition of both ALK and the kinase MEK enhanced both the magnitude and duration of the initial response in preclinical models of EML4-ALK lung adenocarcinoma. Our findings identify RAS-MAPK dependence as a hallmark of EML4-ALK lung adenocarcinoma and provide a rationale for the upfront inhibition of both ALK and MEK to forestall resistance and improve patient outcomes. Show less