The role of PFAS in lipid-mediated vascular contributions to cognitive impairment and dementia: PFAS VascCog Longitudinal Study - Project Summary Per- and polyfluoroalkyl substances (PFAS) represent a class of persistent organic pollutants found in furniture, cookware, home décor, clothing, firefighting foam, food packaging, and contaminants in food and water. PFAS are recognized as an environmental health priority by NIH due to their ubiquitous exposure, resistance to environmental degradation, and bioaccumulation. Growing evidence of their effects on vascular risk factors (e.g. hyperlipidemia, obesity, diabetes, hypertension) and neurotoxicity suggest that PFAS exposure increases Alzheimer’s Disease and Alzheimer’s Disease Related Dementias (AD/ADRD) risk, but empirical data are limited, weak, and inconsistent. Prospective cohort studies linking PFAS and AD/ADRD, with adjudicated clinical outcomes and control for confounding by diet and kidney function, are lacking. We propose to quantify the concentrations of 13 ubiquitous PFAS in archived serum samples from two time points, and the total PFAS exposure burden, in the Northern Manhattan Study (NOMAS, N=1290), an established (25+ year-long) multi- ethnic longitudinal cohort. We hypothesize that PFAS exposure increases the risk of cognitive impairment and AD/ADRD through a mechanistic pathway involving hyperlipidemia and atherosclerosis. PFAS are shown to alter lipid metabolism. NOMAS data have demonstrated a strong relationship between lipids and atherosclerosis. NOMAS participants had blood collected at baseline (1993-2001) and during follow-up (2003-2008), and annual follow-up, with comprehensive data on sociodemographics, vascular events, medical history, medications, health behaviors, diet, lipids, neural imaging, and a range of vascular risk factors. Participants had multiple comprehensive neuropsychological assessments, with extensive adjudication to identify those who developed AD/ADRD and mild cognitive impairment (MCI). NOMAS is ideal due to the diverse population (60% Hispanic, 20% Black, 20% White) at high risk for AD/ADRD and prospectively followed for vascular and cognitive outcomes. We will determine the associations between serum PFAS concentrations with comprehensive lipid profiles, carotid atherosclerosis phenotypes (plaque, intima-media thickness, stiffness), and risk of incident AD/ADRD and MCI, with the goal of identifying the impacts of PFAS on AD/ADRD, mediated through lipid metabolism and atherosclerosis. We will identify key confounders (diet), mediators (vascular risk factors), and effect modifiers (APOE4 genotype). The innovative strengths are the ability to fill important gaps related to the effects of PFAS on adjudicated AD/ADRD, ability to examine race/ethnic disparities in the effects of PFAS, and effect modification by APOE4, inclusion of a broad range of PFAS, and the interdisciplinary team with experience in PFAS exposure analysis and neuroepidemiology, which will lay the foundation for targeted community-wide preventive interventions. The data will provide crucial information on biological mechanisms through which PFAS impact cognitive impairment and AD/ADRD, which will inform public health recommendations on the avoidance of PFAS-containing products, and support regulatory efforts to reduce community PFAS exposure.
