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Peer-reviewedCC BYFrontiers in Aging Neuroscience

White matter hyperintensities and amyloid pathology in cognitively unimpaired aging: topographical, microstructural, and network-level evidence

  • Sana Mohammadi1
  • Sana Mohammadi2
  • Minoo Sharbafshaaer3
  • Minoo Sharbafshaaer4
  • Maria Agnese Pirozzi3
  • Maria Agnese Pirozzi4
  • Francesca Trojsi3
  • Francesca Trojsi4
  • Sadegh Ghaderi5
  • Sadegh Ghaderi6
  • Sadegh Ghaderi7
  • Yasser Iturria-Medina5
5 more authors
  • Yasser Iturria-Medina6
  • Yasser Iturria-Medina7
  • Seyed-Mohammad Fereshtehnejad8
  • Seyed-Mohammad Fereshtehnejad9
  • Seyed-Mohammad Fereshtehnejad10
10 affiliations
  1. 1Department of Medical Sciences, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
  2. 2School of Medicine, Hamadan University of Medical Sciences, Hamadan, Iran
  3. 3Department of Advanced Medical and Surgical Sciences, MRI Research Center (DAMSS), University of Campania “Luigi Vanvitelli”, Naples, Italy
  4. 4Neurology Unit, First Division of Neurology and Neurophysiopathology, AOU University of Campania “Luigi Vanvitelli”, Naples, Italy
  5. 5Department of Neurology and Neurosurgery, Montreal Neurological Institute, McGill University, Montreal, QC, Canada
  6. 6Montreal Neurological Institute, McConnell Brain Imaging Centre, McGill University, Montreal, QC, Canada
  7. 7Ludmer Centre for Neuroinformatics and Mental Health, Montreal, QC, Canada
  8. 8Pacific Parkinson’s Research Centre (PPRC), Djavad Mowafaghian Centre for Brain Health, University of British Columbia, Vancouver, BC, Canada
  9. 9Division of Neurology, Faculty of Medicine, University of British Columbia, Vancouver, BC, Canada
  10. 100Division of Clinical Geriatrics, Department of Neurobiology, Care Sciences and Society (NVS), Karolinska Institute, Stockholm, Sweden
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Abstract

The frequent coexistence of white matter hyperintensities (WMHs) and β-amyloid (Aβ) pathology in cognitively unimpaired older adults complicates interpretation of vascular and neurodegenerative imaging findings. This narrative review synthesizes topographical, microstructural, and network-level evidence in cognitively unimpaired aging, distinguishing biomarker-characterized samples from supportive mixed or symptomatic cohorts. WMHs have heterogeneous etiologies. Posterior and some periventricular patterns are associated with cerebral Aβ in several cohorts, but lobar location and distance from the ventricles are overlapping classifications, and vascular associations are not confined to frontal or deep lesions. Independent and additive cognitive associations are more consistently reported than interactions. Longitudinal executive-function interactions reported in a dissertation and related abstract remain preliminary and non-independent. Some longitudinal studies associate baseline Aβ with subsequent WMH accrual, but findings are not uniform and do not establish causation. APOE-related findings vary with age, population, and amyloid burden. Diffusion MRI detects tissue abnormalities beyond visible lesions, although microstructural and disconnectome measures require prospective validation before they can improve individual prognosis. Anti-amyloid trial evidence identifies MRI safety considerations; effects on chronic WMH progression remain uncertain.

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Cite

BibTeXRIS
BibTeX
@article{mohammadi2026white,
  title = {{White matter hyperintensities and amyloid pathology in cognitively unimpaired aging: topographical, microstructural, and network-level evidence}},
  author = {Sana Mohammadi and Sana Mohammadi and Minoo Sharbafshaaer and Minoo Sharbafshaaer and Maria Agnese Pirozzi and Maria Agnese Pirozzi and Francesca Trojsi and Francesca Trojsi and Sadegh Ghaderi and Sadegh Ghaderi and Sadegh Ghaderi and Yasser Iturria-Medina and Yasser Iturria-Medina and Yasser Iturria-Medina and Seyed-Mohammad Fereshtehnejad and Seyed-Mohammad Fereshtehnejad and Seyed-Mohammad Fereshtehnejad},
  journal = {Frontiers in Aging Neuroscience},
  year = {2026},
  month = oct,
  doi = {10.3389/fnagi.2026.2005174},
  url = {https://doi.org/10.3389/fnagi.2026.2005174},
  note = {CC BY},
}
RIS
TY  - JOUR
TI  - White matter hyperintensities and amyloid pathology in cognitively unimpaired aging: topographical, microstructural, and network-level evidence
AU  - Sana Mohammadi
AU  - Sana Mohammadi
AU  - Minoo Sharbafshaaer
AU  - Minoo Sharbafshaaer
AU  - Maria Agnese Pirozzi
AU  - Maria Agnese Pirozzi
AU  - Francesca Trojsi
AU  - Francesca Trojsi
AU  - Sadegh Ghaderi
AU  - Sadegh Ghaderi
AU  - Sadegh Ghaderi
AU  - Yasser Iturria-Medina
AU  - Yasser Iturria-Medina
AU  - Yasser Iturria-Medina
AU  - Seyed-Mohammad Fereshtehnejad
AU  - Seyed-Mohammad Fereshtehnejad
AU  - Seyed-Mohammad Fereshtehnejad
PY  - 2026
DA  - 2026/10/26
JO  - Frontiers in Aging Neuroscience
DO  - 10.3389/fnagi.2026.2005174
UR  - https://doi.org/10.3389/fnagi.2026.2005174
AB  - The frequent coexistence of white matter hyperintensities (WMHs) and β-amyloid (Aβ) pathology in cognitively unimpaired older adults complicates interpretation of vascular and neurodegenerative imaging findings. This narrative review synthesizes topographical, microstructural, and network-level evidence in cognitively unimpaired aging, distinguishing biomarker-characterized samples from supportive mixed or symptomatic cohorts. WMHs have heterogeneous etiologies. Posterior and some periventricular patterns are associated with cerebral Aβ in several cohorts, but lobar location and distance from the ventricles are overlapping classifications, and vascular associations are not confined to frontal or deep lesions. Independent and additive cognitive associations are more consistently reported than interactions. Longitudinal executive-function interactions reported in a dissertation and related abstract remain preliminary and non-independent. Some longitudinal studies associate baseline Aβ with subsequent WMH accrual, but findings are not uniform and do not establish causation. APOE-related findings vary with age, population, and amyloid burden. Diffusion MRI detects tissue abnormalities beyond visible lesions, although microstructural and disconnectome measures require prospective validation before they can improve individual prognosis. Anti-amyloid trial evidence identifies MRI safety considerations; effects on chronic WMH progression remain uncertain.
SN  - 1663-4365
ER  -