**Abstract**

Alzheimer dementia (AD) is a complex, aging-associated disease whose effects on the brain (an organ made up by nonreplaceable cells) are devastating. Disease is not curable, but progress in pathobiology shows that intervention on aging can make primary prevention of AD feasible. According to the amyloid-cascade hypothesis, mechanisms of AD include: an age-related alteration of free radical metabolism in membranes, leading to a higher yield in the toxic Aβ1-42 peptide and an overwhelming impact on the weaker repair mechanisms of the aging cells. The proposed intervention on aging with anti-AD effects includes a daily assumption of antioxidants (red wine polyphenols enriched with resveratrol), a reinforcement of membrane antioxidant defenses by the assumption of polyunsaturated fatty acids at the first meal after fasting, and an enhancement of cell repair function (at the proteasome and autophagy level by an intermittent feeding regimen and physical exercise plus the assumption of antilipolytic agents during time of fasting). The beneficial effects of diet and physical activity on the endogenous production of protective nerve growth factors are magnified by an enriched environment. Treatment has already been started on healthy individuals at a higher risk of AD in the city of Volterra**.**

**Keywords:** Alzheimer's disease, proteasome, autophagy, antioxidants, PUFAs, APP, cholesterol, antilipolytic drugs, calorie restriction, physical exercise, brain plasticity, nerve growth factors

### **1. Introduction**

Like many other degenerative diseases, AD is an irreversible and progressive cerebropathy, the cause of one of the most common types of dementia affecting the elderly. It is a brain disorder characterized by the accumulation of two main protein aggregates, senile plaques and neurofibrillary tangles, leading to a progressive neuronal degeneration. It causes death after years of disability, progressive loss of memory, inability to perform normal daily activities, and, finally, dementia. The senile plaques are generated by the deposition in human brain of fibrils of the β-amyloid peptide (Aβ), a fragment derived from the proteolytic processing of the amyloid precursor protein (APP). There is evidence that oxidative stress might be the main factor that turns APP into a proteolytically processable substrate. The neurofibrillary tangles (NFTs) are seen as a compact filamentous network formed by paired helical filaments (PHFs), whose major component is a hyperphosphorylated Tau protein. Two main protein kinases appear to be involved in the anomalous tau phosphorylation: the cyclin-dependent kinase Cdk5 and glycogen synthase kinase GSK3. Dysfunction of the ubiquitin-proteasome system may be the cause [1] possibly together with a secondary failure of the engulfed lysosomal degradation resulting in apoptosis. Pathology is a consequence of the extensive neuronal death, and when it manifests clinically, it is already incurable. Human, social, and health costs of this incurable disease are immense. It is highly desirable indeed an effective primary prevention to postpone the appearance of the debilitating manifestations, hopefully to the time of death.
