Inflammation, metabolic dysregulation and environmental neurotoxins and risk of cognitive decline and impairment in midlife

Carla R. Schubert, Mary E. Fischer, A. Alex Pinto, Adam J. Paulsen, Yanjun Chen, Guan Hua Huang, Barbara E.K. Klein, Michael Y. Tsai, Natascha Merten, Karen J. Cruickshanks

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Background: Age-related declines in cognitive function may begin in midlife. Purpose: To determine whether blood-based biomarkers of inflammation, metabolic dysregulation and neurotoxins are associated with risk of cognitive decline and impairment. Methods: Baseline blood samples from the longitudinal Beaver Dam Offspring Study (2005–2008) were assayed for markers of inflammation, metabolic dysregulation, and environmental neurotoxins. Cognitive function was measured at baseline, 5-year (2010–2013) and 10-year (2015–2017) examinations. Participants without cognitive impairment at baseline and with cognitive data from at least one follow-up were included. Cox proportional hazards models were used to evaluate associations between baseline blood biomarkers and the 10-year cumulative incidence of cognitive impairment. Poisson models were used to estimate the relative risk (RR) of 5-year decline in cognitive function by baseline blood biomarkers. Models were adjusted for age, sex, education, and cardiovascular related risk factors. Results: Participants (N = 2421) were a mean age of 49 years and 55% were women. Soluble vascular cell adhesion molecule-1 (sVCAM-1Tertile(T)3 vs T1-2 hazard ratio (HR) = 1.72, 95% confidence interval (CI) = 1.05,2.82) and hemoglobin A1C (HR = 1.75, 95% CI = 1.18,2.59, per 1% in women) were associated with the 10-year cumulative incidence of cognitive impairment. sVCAM-1 (RRT3 vs T1-2 = 1.45, 95% CI = 1.06,1.99) and white blood cell count (RR = 1.10, 95% CI = 1.02,1.19, per 103/μL) were associated with 5-year cognitive decline. Conclusions: Biomarkers related to inflammation and metabolic dysregulation were associated with an increased risk of developing cognitive decline and impairment. These results extend previous research in cognitive aging to early markers of cognitive decline in midlife, a time when intervention methods may be more efficacious.

Original languageEnglish (US)
Pages (from-to)149-157
Number of pages9
JournalNeurological Sciences
Issue number1
StatePublished - Jan 2023

Bibliographical note

Funding Information:
This work was supported by R01AG021917(Karen J. Cruickshanks) from the National Institute on Aging and an unrestricted grant from Research to Prevent Blindness, Inc., to the Department of Ophthalmology and Visual Sciences. The content is solely the responsibility of the authors and does not necessarily reflect the official views of the National Institute on Aging or the National Institutes of Health.

Publisher Copyright:
© 2022, Fondazione Società Italiana di Neurologia.


  • Epidemiology
  • Hemoglobin A1C
  • Longitudinal
  • Vascular cell adhesion molecule
  • White blood cell count

PubMed: MeSH publication types

  • Journal Article


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