White matter aging across the lifespan in Down syndrome: developmental origins, Alzheimer's disease progression, and therapeutic implications

People with Down syndrome (DS) develop Alzheimer’s disease (AD) neuropathology by the age of 40 years, with cognitive decline common after age 50. While amyloid precursor protein overexpression due to trisomy 21 is a major driver of AD pathology, increasing evidence indicates that DS-related white matter aging involves broader mechanisms beyond amyloid. This review synthesizes neuropathological, neuroimaging, molecular, and fluid biomarker studies linking white matter pathology to cognition in DS.