Environ Res

Background:Although potential neurotoxicity of perfluoroalkyl and polyfluoroalkyl substances (PFAS) is suggested, previous epidemiologic studies have reported a \u2018protective\u2019 association between serum PFAS concentration and cognition function. Poor outcome assessment, residual confounding, non-monotonic dose-responses (NMDRs), and the role of reduced kidney function in PFAS excretion may be alternative explanations of these findings.Objectives:We examined the association of perfluoroalkyls with cognitive functions assessed using the Consortium to Establish a Registry for Alzheimer\u2019s Disease word learning and recall; the Animal Fluency; and the Digit Symbol Substitution tests.Methods:We included 903 adults aged 6560 years from the National Health and Nutrition Examination Survey (NHANES) 2011-2014. We computed a composite z-score as an average of four individual cognitive z-scores and used it as the outcome. Linear and generalized additive models were used to evaluate linear and non-linear associations.Results:With the linearity assumption, perfluorooctanoate (PFOA) and perfluorononanoate (PFNA) were significantly positively associated with composite z-score after adjustment for age, sex, race/ethnicity, education, smoking, poverty-income ratio, health insurance, food security, alcohol, and physical activity. Smoothing plots suggested NMDRs, especially for perfluorooctane sulfonate (PFOS) with a U-shape dose-response. When restricting to participants without chronic kidney disease (CKD) (n=613), the positive associations for PFOA and PFNA observed in the whole population diminished, whereas PFOS was inversely and significantly associated with composite z-score. Also, negative confounding effects of fish/seafood consumption seem to be substantial. Effect estimates of composite z-score were 120.055 (95% CI: 120.097, 120.012, P=0.01) for a doubling increase in PFOS.Discussion:These findings suggest that the previous epidemiologic findings of a \u2018protective\u2019 association between PFAS and cognition may be explained by CKD, NMDRs and confounding by fish consumption. PFOS at the current population exposure level in the U.S. may be a risk factor for cognitive decline in older adults with normal kidney function.P30 ES017885/ES/NIEHS NIH HHS/United StatesR01 ES026578/ES/NIEHS NIH HHS/United StatesR01 ES026964/ES/NIEHS NIH HHS/United StatesT42 OH008455/OH/NIOSH CDC HHS/United States2022-01-01T00:00:00Z33068581PMC77364788792vault:3627