Characterization of neurodegenerative pathologies in adult and pediatric subjects with Down syndrome

BackgroundDown syndrome (DS) is frequently associated with Alzheimer's disease neuropathologic change (ADNC). However, studies assessing the full spectrum of neurodegenerative pathologies using modern consensus and staging criteria remain limited.ObjectiveWe aimed to elucidate the progression of neurodegenerative pathologies in DS and to explore the prevalence of comorbid pathologies across a broad age range (0-76 years), using comprehensive neuropathological assessments.MethodsWe conducted a two-phase analysis. First, we investigated an institutional dataset, followed by a pooled analysis incorporating data from the National Alzheimer's Coordinating Center and four published studies. Pathologies assessed included amyloid-β (Aβ), tau, α-synuclein, TDP-43, cerebral amyloid angiopathy (CAA), other cerebrovascular diseases (CVD), hippocampal sclerosis (HS), and basal ganglia mineralizations (BGM).ResultsDiffuse Aβ plaques appeared by age 11, with neuritic plaques emerging in the mid-thirties. Mild tau pathology, including pre-tangles and neuropil threads, first emerged in the second decade, with neurofibrillary tangles fully present in the fourth decade, always concurrent with Aβ plaques. All individuals over 30 exhibited ADNC. α-Synuclein pathology was observed in 27% of cases, while aging-related tau astrogliopathy (ARTAG), HS, and limbic-predominant age-related TDP-43 encephalopathy neuropathologic change (LATE-NC) were rare. CVD was present in approximately 60%, CAA was nearly universal (98%) after age 50, and 18% had BGM. Brain weight was consistently below the 25th percentile, even in younger individuals without ADNC.ConclusionsDS shows a distinct neurodegenerative trajectory with early Aβ deposition. CAA, arteriolosclerosis, BGM, and α-synuclein pathology were highly prevalent, while ARTAG and LATE-NC were infrequently observed.