White matter lesions may be an early marker for age-related cognitive decline

Neuroimage Clin. 2022;35:103096. doi: 10.1016/j.nicl.2022.103096. Epub 2022 Jun 22.


Background: Research suggests that cerebral small vessel disease (CSVD), amyloid, and pTau contribute to age-related cognitive decline. It remains unknown how these factors relate to one another and how they jointly contribute to cognitive decline in normal aging. This project examines the association between these factors and their relationship to cognitive decline in cognitively unimpaired older adults without subjective cognitive decline.

Methods: A total of 230 subjects with cerebrospinal fluid (CSF) Aß42, CSF pTau181, white matter lesions (WMLs) used as a proxy of CSVD, and cognitive scores from the Alzheimer's Disease Neuroimaging Initiative were included. Associations between each factor and cognitive score were investigated using regression models. Furthermore, relationships between the three pathologies were also examined using regression models.

Results: At baseline, there was an inverse association between WML load and Aß42 (t = -4.20, p <.001). There was no association between WML load and pTau (t = 0.32, p = 0.75), nor with Aß42 and pTau (t = 0.51, p =.61). Correcting for age, sex and education, baseline WML load was associated with baseline ADAS-13 scores (t = 2.59, p =.01) and lower follow-up executive functioning (t = -2.84, p =.005). Baseline Aß42 was associated with executive function at baseline (t = 3.58, p<.004) but not at follow-up (t = 1.05, p = 0.30), nor with ADAS-13 at baseline (t = -0.24, p = 0.81) or follow-up (t = 0.09, p = 0.93). Finally, baseline pTau was not associated with any cognitive measure at baseline or follow-up.

Conclusion: Both baseline Aß42 and WML load are associated with some baseline cognition scores, but only baseline WML load is associated with follow-up executive functioning. This finding suggests that WMLs may be one of the earliest clinical manifestations that contributes to future cognitive decline in cognitively healthy older adults. Given that healthy older adults with WMLs exhibit declines in cognitive functioning, they may be less resilient to future pathology increasing their risk for cognitive impairment due to dementia than those without WMLs.

Keywords: Cognitive decline; Cognitively normal older adults; Magnetic resonance imaging; White matter lesions.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Alzheimer Disease* / pathology
  • Biomarkers / cerebrospinal fluid
  • Cognition
  • Cognitive Dysfunction* / pathology
  • Humans
  • Magnetic Resonance Imaging
  • Nervous System Diseases* / complications
  • White Matter* / diagnostic imaging
  • White Matter* / pathology


  • Biomarkers