Associations of blood biomarkers of glial cell dysfunction and neuronal injury with future cognitive decline and incident dementia

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Abstract
INTRODUCTION: Prospective studies of blood‐based biomarkers reflecting pathogenic processes, other than Alzheimer‐specific pathologies, that contribute to dementia in diverse cohorts are lacking. METHODS: We jointly fitted linear mixed‐effect models and proportional hazards models to examine associations of midlife glial fibrillary acidic protein (GFAP), chitinase‐3‐like protein 1 (YKL‐40), soluble cluster of differentiation‐14 (sCD14), neurofilament light chain (NfL), total tau (t‐tau), and ubiquitin C‐terminal hydrolase L1 (UCHL1) levels in serum (collected in 1993 to 1995) with cognitive decline and incident dementia (ascertained over 29 years through 2022) in the community‐based Atherosclerosis Risk in Communities Study. sCD14 and YKL‐40 were measured in 3082 participants and the other four biomarkers in 1766 participants. RESULTS: Higher serum GFAP, YKL‐40, sCD14, and NfL were associated with faster cognitive decline and elevated dementia rate (e.g., 1 standard deviation [SD] higher log‐base2 YKL‐40 was associated with −0.11SD faster 25‐year cognitive decline (95% confidence interval [CI]: −0.15,−0.07) and 45% higher dementia hazard (hazard ratio [HR]: 1.45 [95% CI: 1.25, 1.68]). Higher t‐tau and UCHL1 were also associated with faster cognitive decline. DISCUSSION: Midlife blood biomarkers reflecting glial and neuronal dysfunction and neuroinflammation are associated with early cognitive impairment.
Funding Information
  • National Heart, Lung, and Blood Institute (75N92022D00001)
  • National Heart, Lung, and Blood Institute (75N92022D00002)
  • National Heart, Lung, and Blood Institute (75N92022D00003)
  • National Heart, Lung, and Blood Institute (75N92022D00004)
  • National Heart, Lung, and Blood Institute (75N92022D00005)
  • National Institutes of Health (U01HL096812)
  • National Institutes of Health (U01HL096814)
  • National Institutes of Health (U01HL096899)
  • National Institutes of Health (U01HL096902)
  • National Institutes of Health (U01HL096917)
  • National Institutes of Health (U19NS120384)
  • National Institutes of Health (UH3NS100605)
  • National Institutes of Health (andUF1NS125513)
  • National Institute on Aging (R00AG052830)
  • National Institute of Neurological Disorders and Stroke (Intramural Research Program)

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