Biomarkers of microvascular endothelial dysfunction predict incident dementia: a population-based prospective study

J Intern Med. 2017 Jul;282(1):94-101. doi: 10.1111/joim.12621. Epub 2017 May 4.


Background: Cerebral endothelial dysfunction occurs in a spectrum of neurodegenerative diseases. Whether biomarkers of microvascular endothelial dysfunction can predict dementia is largely unknown. We explored the longitudinal association of midregional pro-atrial natriuretic peptide (MR-proANP), C-terminal endothelin-1 (CT-proET-1) and midregional proadrenomedullin (MR-proADM) with dementia and subtypes amongst community-dwelling older adults.

Methods: A population-based cohort of 5347 individuals (men, 70%; age, 69 ± 6 years) without prevalent dementia provided plasma for determination of MR-proANP, CT-proET-1 and MR-proADM. Three-hundred-and-seventy-three patients (7%) were diagnosed with dementia (120 Alzheimer's disease, 83 vascular, 102 mixed, and 68 other aetiology) over a period of 4.6 ± 1.3 years. Relations between baseline biomarker plasma concentrations and incident dementia were assessed using multivariable Cox regression analysis.

Results: Higher levels of MR-proANP were significantly associated with increased risk of all-cause and vascular dementia (hazard ratio [HR] per 1 SD: 1.20, 95% confidence interval [CI], 1.07-1.36; P = 0.002, and 1.52; 1.21-1.89; P < 0.001, respectively). Risk of all-cause dementia increased across the quartiles of MR-proANP (p for linear trend = 0.004; Q4, 145-1681 pmol L-1 vs. Q1, 22-77 pmol L-1 : HR: 1.83; 95%CI: 1.23-2.71) and was most pronounced for vascular type (p for linear trend = 0.005: HR: 2.71; 95%CI: 1.14-6.46). Moreover, the two highest quartiles of CT-proET-1 predicted vascular dementia with a cut-off value at 68 pmol L-1 (Q3-Q4, 68-432 pmol L-1 vs. Q1-Q2,4-68 pmol L-1 ; HR: 1.94; 95%CI: 1.12-3.36). Elevated levels of MR-proADM indicated no increased risk of developing dementia after adjustment for traditional risk factors.

Conclusions: Elevated plasma concentration of MR-proANP is an independent predictor of all-cause and vascular dementia. Pronounced increase in CT-proET-1 indicates higher risk of vascular dementia.

Keywords: adrenomedullin; atrial natriuretic peptide; biomarkers; dementia; endothelial dysfunction; endothelin.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adrenomedullin / blood*
  • Aged
  • Atrial Natriuretic Factor / blood*
  • Biomarkers / blood
  • Brain / physiopathology*
  • Dementia / blood
  • Dementia / diagnosis*
  • Dementia / physiopathology*
  • Endothelin-1 / blood*
  • Endothelium, Vascular / physiopathology*
  • Female
  • Follow-Up Studies
  • Humans
  • Male
  • Peptide Fragments / blood*
  • Prospective Studies
  • Protein Precursors / blood*
  • Risk Factors


  • Biomarkers
  • C-terminal proendothelin-1
  • Endothelin-1
  • Peptide Fragments
  • Protein Precursors
  • mid-regional pro-adrenomedullin, human
  • midregional pro-atrial natriuretic peptide, human
  • Adrenomedullin
  • Atrial Natriuretic Factor