White matter hyperintensities are higher among early-onset Alzheimer's disease participants than their cognitively normal and early-onset nonAD peers: Longitudinal Early-onset Alzheimer's Disease Study (LEADS)

Alzheimers Dement. 2023 Nov;19 Suppl 9(Suppl 9):S89-S97. doi: 10.1002/alz.13402. Epub 2023 Jul 25.


Introduction: We compared white matter hyperintensities (WMHs) in early-onset Alzheimer's disease (EOAD) with cognitively normal (CN) and early-onset amyloid-negative cognitively impaired (EOnonAD) groups in the Longitudinal Early-Onset Alzheimer's Disease Study.

Methods: We investigated the role of increased WMH in cognition and amyloid and tau burden. We compared WMH burden of 205 EOAD, 68 EOnonAD, and 89 CN participants in lobar regions using t-tests and analyses of covariance. Linear regression analyses were used to investigate the association between WMH and cognitive impairment and that between amyloid and tau burden.

Results: EOAD showed greater WMHs compared with CN and EOnonAD participants across all regions with no significant differences between CN and EOnonAD groups. Greater WMHs were associated with worse cognition. Tau burden was positively associated with WMH burden in the EOAD group.

Discussion: EOAD consistently showed higher WMH volumes. Overall, greater WMHs were associated with worse cognition and higher tau burden in EOAD.

Highlights: This study represents a comprehensive characterization of WMHs in sporadic EOAD. WMH volumes are associated with tau burden from positron emission tomography (PET) in EOAD, suggesting WMHs are correlated with increasing burden of AD. Greater WMH volumes are associated with worse performance on global cognitive tests. EOAD participants have higher WMH volumes compared with CN and early-onset amyloid-negative cognitively impaired (EOnonAD) groups across all brain regions.

Keywords: Alzheimer's disease; EOAD; WMH; amyloid; tau PET; tau positron emission tomography; white matter hyperintensities.

Publication types

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

MeSH terms

  • Alzheimer Disease* / complications
  • Alzheimer Disease* / diagnostic imaging
  • Amyloid
  • Amyloid beta-Peptides / metabolism
  • Amyloidogenic Proteins
  • Cognitive Dysfunction* / complications
  • Cognitive Dysfunction* / diagnostic imaging
  • Humans
  • Magnetic Resonance Imaging
  • White Matter* / diagnostic imaging
  • White Matter* / metabolism
  • tau Proteins / metabolism


  • Amyloid beta-Peptides
  • tau Proteins
  • Amyloidogenic Proteins
  • Amyloid