The E4 isoform of apolipoprotein E (ApoE) is involved in cardiovascular and cerebrovascular disorders and is the most prevalent risk factor for late onset or sporadic AD. We have also determined the long-term effect of combined treatment (medications and non-pharmacological interventions) in the clinically depressed/demented and AD patients with cardiovascular risk. This study applies the vascular dementia paradigm to ApoE4 Tg+ mice in order to analyze the effects of selective mitochondrial antioxidants Acetyl-L-Carnitine and R-α-Lipoic acid (ALCAR+LA) on the cerebral blood flow (CBF), neuropathology, brain and vessel ultrastructural abnormalities and behavior. We have also compared these results with our ongoing clinical study of clinically depressed and/or demented seniors with cardiovascular disease symptoms. Patients receive ALCAR+LA, Omega-3-6-9 from Fish, Flax and Borage Oils, Coenzyme Q-10, and Melanin analogues QIAPI-1 (developed by Dr. Solis), along with a combination of multivitamins and trace elements (selenium) and dietary changes as part of our recently developed brain activation program. The effects of treatment were analyzed by using MMSE and a continuous visual learning task. ApoE4 associated factors gradually reduced CBF and created brain hypoperfusion when compared to wild-type (WT). The differences in CBF were the greatest in animals aged 6-weeks to 12-months. Transmission electron microscopy (TEM) with colloidal gold immunocytochemistry and in situ hybridization using human and mouse DNA probes showed structural damage and mitochondrial DNA overproliferation and/or deletion in young and aged microvessels endothelium of ApoE4 animals, extending to the cytoplasm of perivascular cells, perivascular nerve terminals, hippocampal neurons, and glial cells. Spatial and temporal memory tests showed a trend towards improving cognitive function in ApoE4 Tg+ mice that were fed selective mitochondrial antioxidants ALCAR+LA. Our clinical results showed that patients who received integrative treatment with mitochondrial antioxidants, selenium and QIAPI-1 exhibited the most significant cognitive improvement at the end of 36 months of treatment. Further expanding this study to large group of patients able to provide much more accurate and conclusive background regarding new and more effective treatment strategies which based on the brain hypometabolism and neuronal energy crisis theory to fight against for these devastative diseases.