There is compelling evidence that genetic predisposition underlies the development of Alzheimer's disease. However, the most obviously genetic cases are also the rarest. Most cases identified are "sporadic" with no clear family history. It is probable that environmental factors have to interact with a genetic susceptibility to cause development of disease. Head injury has been consistently shown to be linked to later development of AD in epidemiological studies. In addition, small cranial diameter has been shown to correlate well with early onset of recognizable symptoms. The most commonly accepted explanation for this last feature is that larger brains simply may have more cells that can afford to be lost. Inheritance of the epsilon 4 allele of the ApoE gene is regarded as a risk factor for development of disease, but large-scale genetic association studies raise the possibility that even this does not indicate susceptibility so much as how early one is likely to develop Alzheimer's. There is speculation among genetic experts that there are other risk and protective factor genes that may influence the development of late onset Alzheimer's disease (LOAD). Intriguing work is currently going on investigating the possibility that the regulatory regions of various Alzheimer's associated genes could be important in sporadic Alzheimer's, especially inflammatory activation of these genes. These hypotheses include the inflammatory 5-lipoxygenase gene [1].

Studies have not shown strong link with toxins, vitamins, metals or diet, although rabbits fed a high-cholesterol diet in the presence of copper ions in their water did develop amyloid brain lesions and cognitive deficiencies [2], [3]. Likewise, linkage has been found between zinc or copper and reactive oxidative stress contributing to Alzheimer's pathology [4], and the amyloid precursor protein has been shown to alter expression in response to metal supplementation and chelation [5], [6], [7]. Therefore, it is hasty and premature to dismiss any and all environmental effects out of hand. There have been studies that link aluminium to the progression of Alzheimer's, but the results from these studies have not been confirmed and are not widely accepted by Alzheimer's experts.

Rare cases are caused by dominant genes that run in families. These cases often have an early age of onset. Mutations in presenilin-1 or presenilin-2 genes have been documented in some families. Mutations of presenilin 1 (PS1) lead to the most aggressive form of familial AD (FAD). Evidence from rodent studies suggests that the FAD mutation of PS1 results in impared hippocampal-dependent learning which is correlated with reduced adult neurogenesis in the dentate gyrus (Wang et al, 2004). Mutations in the APP gene on chromosome 21 can also cause early onset disease.

Genetic linkage
Alzheimer's disease is linked to the 1st, 14th, 9th, 19th, and/or 21st chromosomes. While some genes predisposing to AD have been identified, most cases are sporadic. However, sporadic AD most often involves some form of genetic susceptibility.

Epidemiology
Alzheimer's disease is the most frequent type of dementia in the elderly and affects almost half of all patients with dementia.

2-3% of persons aged 65 show signs of the disease, while 25 - 50% of persons aged 85 have symptoms of Alzheimer's and an even greater number have some of the pathological hallmarks of the disease without the characteristic symptoms. The proportion of persons with Alzheimer's begins to decrease after age 85 because of the increased mortality due to the disease, and relatively few people over the age of 100 have the disease.

Prevention
Efforts to find effective treatments for Alzheimer's after-the-fact have so far been disappointing. Age is the primary risk factor for Alzheimer's. The baby boom is approaching its golden years. Indeed, much of the concern about the solvency of governmental social safety nets is founded on estimates of the costs of caring for baby boomers, assuming that they develop Alzheimer's in the same proportions as earlier generations.

One study ("Leisure Activities and the Risk of Dementia in the Elderly," New England Journal of Medicine [8]) found that people who played chess on a regular basis went on to get Alzheimer's at a substantially lower rate than the general population. The chess relationship was stronger than any other factor, including dancing and solving crossword puzzles, both of which were also shown to be inversely proportional to getting Alzheimer's disease.

In a number of retrospective studies, regular physical exercise has appeared to be inversely related to the development of Alzheimer’s. The Alzheimer's risk of those exercising regularly was half that of the least active. This research is consistent with the observation that virtually all measures designed to promote cardiac fitness and reduce stroke risk also seem to reduce Alzheimer's risk. However in one study, dance appeared to be the only exercise effective in reducing risk. One explanation is that dancing requires the use of complex mental skills such as performing correct steps while at the same time keeping track of the music. The presence of cardiovascular risk factors -- diabetes, hypertension, high cholesterol and smoking -- in middle age (ages 40 to 44) was found very strongly associated with late-life dementia (Neurology 2005;64:277-281. PMID 15668425).