This multicenter study has 3 main findings: first, we demonstrate the influence of VRFs and cSVD on CSF Aβ1-42 levels; second, we found an indirect association of VRFs with amyloid pathology through the presence of cSVD; and third, we showed that cSVD is indirectly associated with tau accumulation, gray matter atrophy (also over time), and cognitive impairment through amyloid pathology. Here, MAPT is linked to Cognitive impairment.