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.