Association of midlife vascular risk and AD biomarkers with subsequent cognitive decline

Neurology. 2020 Dec 8;95(23):e3093-e3103. doi: 10.1212/WNL.0000000000010946. Epub 2020 Sep 28.


Objective: To determine whether vascular risk and Alzheimer disease (AD) biomarkers have independent or synergistic effects on cognitive decline and whether vascular risk is associated with the accumulation of AD pathology as measured by change in biomarkers over time.

Methods: At baseline, participants (n = 168) were cognitively normal and primarily middle-aged (mean 56.4 years, SD 10.9 years) and had both vascular risk factor status and proximal CSF biomarkers available. Baseline vascular risk was quantified with a composite vascular risk score reflecting the presence or absence of hypertension, hypercholesterolemia, diabetes, current smoking, and obesity. CSF biomarkers of β-amyloid (Aβ)1-42, total tau (t-tau), and phosphorylated tau (p-tau) were used to create dichotomous high and low AD biomarker groups (based on Aβ1-42 and tau). Linear mixed-effects models were used to examine change in a cognitive composite score (mean follow-up 13.9 years) and change in CSF biomarkers (mean follow-up 4.2 years).

Results: There was no evidence of a synergistic relationship between the vascular risk score and CSF AD biomarkers and cognitive decline. Instead, the vascular risk score (estimate -0.022, 95% confidence interval [CI] -0.043 to -0.002, p = 0.03) and AD biomarkers (estimate -0.060, 95% CI -0.096 to -0.024, p = 0.001) were independently and additively associated with cognitive decline. In addition, the vascular risk score was unrelated to levels of or rate of change in CSF Aβ1-42, t-tau, or p-tau.

Conclusions: The results of this observational cohort study suggest that vascular risk and biomarkers of AD pathology, when measured in midlife, act along independent pathways and underscore the importance of accounting for multiple risk factors for identifying cognitively normal individuals at the greatest risk of cognitive decline.

Publication types

  • Observational Study
  • Research Support, N.I.H., Extramural

MeSH terms

  • Aged
  • Aged, 80 and over
  • Alzheimer Disease* / cerebrospinal fluid
  • Alzheimer Disease* / epidemiology
  • Alzheimer Disease* / physiopathology
  • Amyloid beta-Peptides / cerebrospinal fluid*
  • Biomarkers / cerebrospinal fluid
  • Cardiovascular Diseases* / cerebrospinal fluid
  • Cardiovascular Diseases* / epidemiology
  • Cardiovascular Diseases* / physiopathology
  • Cognitive Dysfunction* / cerebrospinal fluid
  • Cognitive Dysfunction* / epidemiology
  • Cognitive Dysfunction* / physiopathology
  • Diabetes Mellitus / epidemiology
  • Female
  • Follow-Up Studies
  • Humans
  • Hypercholesterolemia / epidemiology
  • Hypertension / epidemiology
  • Male
  • Middle Aged
  • Obesity / epidemiology
  • Peptide Fragments / cerebrospinal fluid*
  • Risk Factors
  • Smoking / epidemiology
  • tau Proteins / cerebrospinal fluid*


  • Amyloid beta-Peptides
  • Biomarkers
  • MAPT protein, human
  • Peptide Fragments
  • amyloid beta-protein (1-42)
  • tau Proteins