Phenotypes of white matter hyperintensities, mechanisms and aetiological differentiation: future targets pre-dementia—a systematic review

Abstract White matter hyperintensities (WMHs), a major neuroimaging biomarker of cerebral small vessel disease (CSVD), are increasingly recognized as predictors of dementia risk. The subregional distribution and diverse imaging phenotypes of WMHs, including spatial distribution patterns, morphological characteristics, signal intensity, and concomitant lesions, are correlated with distinct mechanisms and aetiologies. This systematic review synthesizes evidence from 31 studies identified through comprehensive searches of PubMed, Embase, Web of Science and the Cochrane Library, following PRISMA guidelines. A key finding is that frontal/deep confluent WMHs with lacunes in the deep white matter are associated with mixed dementia characterized by CSVD and amyloid-β (Aβ) deposition. In contrast, posterior periventricular WMHs coexisting with hippocampal and temporal lobe atrophy and co-localized Aβ deposition serve as early biomarkers of Alzheimer’s disease. Cerebral amyloid angiopathy related WMHs are characterized by juxtacortical multispot patterns and lobar microbleeds, resulting from vascular Aβ deposition and glymphatic system dysfunction. These findings highlight the etiological heterogeneity of WMHs, where spatial distribution patterns and associated imaging features provide critical insights into underlying pathological mechanisms. The identification of these phenotype-specific correlations offers a framework for improving early diagnosis and developing targeted interventions for dementia subtypes.