Small Vessel Disease and Associations with Cerebrospinal Fluid Amyloid, Tau, and Neurodegeneration (ATN) Biomarkers and Cognition in Young Onset Dementia

Background: Small vessel disease (SVD) and Alzheimer's disease (AD) frequently coexist; however, it remains unclear how they collectively affect cognition. Objective: We investigated associations between SVD and AD biomarkers, namely amyloid, tau, and neurodegeneration (ATN) in young onset dementia (YOD) and explored how SVD and ATN interact to affect cognition. Methods: 80 YOD individuals were recruited from a memory clinic. SVD burden (SVD+) was operationalized as a score >1 on the Staals scale and ATN was measured using cerebrospinal fluid (CSF). Results: SVD+ was associated with lower CSF A beta(1-42) (B = -0.20, 95%CI: -0.32 to -0.08) and greater neurodegeneration, indexed as hippocampal atrophy (B= -0.24, 95%CI: -0.40 to -0.04). SVD+ was not associated with tau. Cognitive impairment was associated with CSF A beta(1-42) (B = -0.35, 95%CI: -0.55 to -0.18) but not SVD. Rather, SVD was indirectly associated with cognition via reduced CSF A beta(1-42), specifically with global cognition (B = -0.03, 95%CI: -0.09 to -0.01) and memory (B = 0.08, 95%CI:.01 to.21). SVD was indirectly associated with cognition via increased neurodegeneration in grey matter (Global cognition: B= -0.06, 95%CI: -0.17 to -0.03; Memory: B= 0.05, 95%CI: 0.01 to 0.18) and the hippocampus (Global cognition: B= -0.05, 95%CI: -0.11 to -0.01; Memory: B= 0.06, 95%CI: 0.01 to 0.17). Conclusion: In YOD, SVD burden was associated with AD pathology, namely CSF A beta(1-42). SVD indirectly contributed to cognitive impairment via reducing CSF A beta(1-42) and increasing neurodegeneration.