Impact of cerebral small vessel disease on cognitive outcomes in early age at onset MCI and dementia: Findings from the DIASPORA study

Abstract BACKGROUND This study assessed the impact of cerebral small vessel disease (CSVD) on cognition in individuals with early‐onset (EO; <65 years) and late‐onset (LO; ≥65 years) cognitive complaints. METHODS Participants underwent prospective evaluations including cognitive testing, hyperphosphorylated tau‐217 (p‐tau217) and neurofilament‐light‐chain (NfL), and magnetic resonance imaging (MRI). Each CSVD marker was modeled for interaction with group age on results on cognitive outcomes: Montreal Cognitive Assessment (MoCA), Mini‐Mental State Examination (MMSE), Neuropsychiatric Inventory Questionnaire (NPI‐Q), and Clinical Dementia Rating (CDR) scale plus National Alzheimer's Coordinating Center–Frontotemporal Lobar Degeneration module (NACC‐FTLD). RESULTS Altogether, 168 patients (91 EO) were included. white matter hyperintensity (WMH) volume was associated with worse CDR+NACC‐FTLD in EO ( β = 17.8, p = 0.013), remaining significant after adjusting for p‐tau217 and NfL, but not gray matter atrophy. Lacunes were associated with worse CDR plus NACC‐FTLD in EO ( β = 4.3, p = 0.011), with age‐dependent associations with MoCA, MMSE, CDR + NACC‐FTLD, and NPI‐Q ( p < 0.01). DISCUSSION CSVD markers, although less prevalent in EO, had greater clinical impact. These findings highlight an increased vulnerability to vascular pathology in EO patients and the importance of early detection. Highlights Cerebral small vessel disease (CSVD) markers were more impactful in early‐onset than late‐onset dementia. White matter hyperintensity (WMH) volume predicted functional decline in early onset, independent of neurodegeneration. Lacunes showed age‐dependent effects on multiple cognitive outcomes. Findings support early detection of CSVD in younger individuals with dementia.