Vascular burden and cognition: Mediating roles of neurodegeneration and amyloid PET

for the Medical Imaging Trial Network of Canada (MITNEC) and Alzheimer's Disease Neuroimaging Initiative (ADNI)

Research output: Contribution to journalArticlepeer-review

9 Scopus citations


It remains unclear to what extent cerebrovascular burden relates to amyloid beta (Aβ) deposition, neurodegeneration, and cognitive dysfunction in mixed disease populations with small vessel disease and Alzheimer's disease (AD) pathology. In 120 subjects, we investigated the association of vascular burden (white matter hyperintensity [WMH] volumes) with cognition. Using mediation analyses, we tested the indirect effects of WMH on cognition via Aβ deposition (18F-AV45 positron emission tomography [PET]) and neurodegeneration (cortical thickness or 18F fluorodeoxyglucose PET) in AD signature regions. We observed that increased total WMH volume was associated with poorer performance in all tested cognitive domains, with the strongest effects observed for semantic fluency. These relationships were mediated mainly via cortical thinning, particularly of the temporal lobe, and to a lesser extent serially mediated via Aβ and cortical thinning of AD signature regions. WMH volumes differentially impacted cognition depending on lobar location and Aβ status. In summary, our study suggests mainly an amyloid-independent pathway in which vascular burden affects cognitive function via localized neurodegeneration. Highlights: Alzheimer's disease often co-exists with vascular pathology. We studied a unique cohort enriched for high white matter hyperintensities (WMH). High WMH related to cognitive impairment of semantic fluency and executive function. This relationship was mediated via temporo-parietal atrophy rather than metabolism. This relationship was, to lesser extent, serially mediated via amyloid beta and atrophy.

Original languageEnglish (US)
Pages (from-to)1503-1517
Number of pages15
JournalAlzheimer's and Dementia
Issue number4
StatePublished - Apr 2023


  • Alzheimer's disease
  • amyloid
  • biomarker
  • cognition
  • cortical atrophy
  • glucose metabolism
  • neurodegeneration
  • small vessel disease
  • vascular
  • white matter disease
  • white matter hyperintensities

ASJC Scopus subject areas

  • Epidemiology
  • Health Policy
  • Developmental Neuroscience
  • Clinical Neurology
  • Geriatrics and Gerontology
  • Cellular and Molecular Neuroscience
  • Psychiatry and Mental health


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