Abstract
Down syndrome (DS), caused by trisomy 21, is the most frequent genetic cause of intellectual disability worldwide. Advances in medical care have markedly increased life expectancy, revealing a new clinical challenge: premature aging and a very high prevalence of Alzheimer’s disease (AD) in adulthood. Nearly all adults with DS develop cerebral amyloid pathology by midlife, largely due to overexpression of the amyloid precursor protein gene located on chromosome 21. However, the onset and severity of dementia vary considerably, suggesting the involvement of additional genetic, cellular, and environmental modifiers.
This narrative review examines the molecular and cellular mechanisms underlying early brain aging in DS, with particular emphasis on Alzheimer-type neurodegeneration. We discuss gene dosage effects and candidate genes implicated in synaptic dysfunction, endo-lysosomal abnormalities as early cellular biomarkers, clinical and neuropsychological challenges in diagnosing dementia in individuals with DS, and recent advances linking gonadotropin-releasing hormone (GnRH) dysfunction to cognitive impairment. Experimental and preliminary clinical evidence suggests that restoration of physiological GnRH signaling may improve cognition and functional brain connectivity in adults with DS.
Understanding DS as a genetically determined form of Alzheimer’s disease offers a unique opportunity to identify early biomarkers and develop preventive or disease-modifying therapies relevant not only to DS but also to sporadic neurodegenerative disorders.
Keywords
Down syndrome, Trisomy 21, Alzheimer’s disease, Premature aging, Amyloid pathology, Endo-lysosomal dysfunction, GnRH, Cognitive decline