INTRODUCTION: Age-related macular degeneration (AMD) is increasingly linked to systemic cardiovascular and metabolic dysfunction as well as cerebral small vessel disease. Subretinal drusenoid deposits (SDD) and basal laminar deposits (BLamD) have emerged as structural biomarkers associated with AMD progression and systemic vascular compromise. This study aimed to investigate associations between hypertension, dyslipidemia, and cerebrovascular disease - transient ischemic attack, stroke, and myocardial infarction - and retinal structural alterations in AMD patients presenting SDD in order to assess the relationship with progression of disease. METHODS: Thirty-eight eyes of 31 patients with AMD and SDD were examined in this retrospective longitudinal study. Retinal imaging, including near-infrared reflectance and spectral-domain optical coherence tomography (SDOCT), was used to characterize retinal alterations. Systemic cardiovascular and small vessel disease profiles were obtained from the clinical history. Morphometric changes in retinal layers were quantified through SDOCT and correlated with systemic metabolic and vascular parameters. RESULTS: During a mean follow-up of 2.1 ± 0.86 years, 44.7% of eyes progressed to advanced AMD: 23.6% to complete RPE and outer retinal atrophy (cRORA)/geographic atrophy, and 21% to macular neovascularization. High-risk vascular diseases were present in 32.3% of patients. BLamD significantly increased progression risk (P = 0.03), whereas conventional drusen did not (P = 0.79). Higher serum triglycerides correlated negatively with outer retinal layer changes (r = -0.66, P = 0.004) and perifoveal thinning (r = -0.75, P < 0.001), while HDL showed positive correlations. Hypertension was frequent (87.1%) but not independently predictive of progression. CONCLUSION: AMD patients with SDD exhibit significant associations between systemic cardio/cerebro-vascular disease and metabolic dysregulation and retinal structural degeneration. BLamD further increase progression risk, underscoring their relevance as imaging biomarkers of vascular and metabolic compromise.