Objectives: The longitudinal ADELAHYDE-2 study aims to identify the factors associated with cognitive impairment/decline and white matter hyperintensities burden. Methods: Longitudinal single-center study comprising two visits separated by approximately 7 years. A total of 131 patients completed the two visits. The primary outcome was global memory composite scale, while the secondary outcome was white matter hyperintensities (WMH/Fazekas scale) load. Results: Global memory at visit 2 (V2) was largely influenced by age, smoking status, glycated hemoglobin, and history of stroke already present at visit 1 (V1). These variables accounted for ∼51% of the memory alterations at V2. WMH at V2 was likely influenced by age, left ventricular hypertrophy, diabetes mellitus, carotid intima-media thickness, and body mass index at V1. These findings accounted for ∼37% of the WMH changes at V2. Increase in pulse wave velocity from V1 to V2 showed a trend for association with memory deterioration (adjusted estimates = 0.06; P = .067), whereas smoking and increase in systolic blood pressure (trend) were associated with an increment in WMH (adjusted estimates = 0.49; P = .047 and adjusted estimates = 0.01; P = .08, respectively). On the other hand, angiotensin-converting enzyme inhibitor/angiotensin receptor blockers and statins (trend) were likely to be protective (adjusted estimates for angiotensin-converting enzyme inhibitor/angiotensin receptor blockers = -0.49; P = .049, and adjusted estimates for statins = -0.46; P = .055). Conclusions: Several readily identifiable factors are associated with memory deterioration and WMH, many of which are potentially modifiable. Interventions aimed to control these risk factors need to be tested prospectively in order to assess their cognitive protective value.