Our genetic data in SVID patients, together with expression data in a vascular dementia mouse model show that 1) APOE transcriptional regulation but not ε4 allele may play a role in brain hypoperfusion and small vessel ischemic disease; 2) APP-Aβ degradation plays a prevalent role upon APP-Aβ production; 3) APP, PSEN1 and PSEN2 are not common pathogenic factors in SVID; 4) CD33, CR1, EPHA1 and the MS4A cluster may be involved in SVID and brain subacute hypoperfusion-ischemia and 4) acute and mainly subacute ischemia may trigger Aβ toxic oligomer formation. This evidence concerns the gene PSEN2 and vascular dementia.