Alzheimer genetic risk factors

Sorbi, S., et al., "Genetic Risk Factors in Familial Alzheimer s Disease," Mech Ageing Dev., 122, 1951-1960 (2001). 

Mace, S., Cousin., E, Rrcard, S., et al. (2005) ABCA2 is a strong genetic risk factors for early-onset Alzheimer s disease. Neurobiol. Dis., 18, 119-125. 

An apolipoprotein E variant is the only unequivocal genetic risk factor for late-onset Alzheimer s disease in a variety of ethnic groups. Caucasians and Japanese with the apo-E-s4 isoform have between 10 and 30 times the risk of developing Alzheimer s by 75 years of age. While the exact mechanism is unknown, evidence suggests an interaction with amyloid. Alzheimer s disease is characterised by plaques consisting of the peptide beta-amyloid. Apolipoprotein E enhances proteolytic breakdown of this peptide. However, the isoform apo-E-e4 is much less effective, which might result in an increased vulnerability to Alzheimer s in individuals with that gene variation. 

There are special genetic risk factors for Alzheimer s disease - such as, for instance, the e4 allele of the apolipoprotein E (APOE) gene, isotonic variation in CYP46, CYP46 C - that significantly increase the risk of Alzheimer s disease development (Bookheimer et al. 2000 Borroni et al. 2004). Accordingly, it seems reasonable to assume that the majority of those who precipitate the disease are carriers of risk factors. 

In conclusion, Alzheimer s disease is linked with age because age is a function of oxidative stress. Factors that exacerbate oxidative stress early in life accelerate the onset of dementia, while factors that alleviate oxidative stress postpone dementia. However, unless we abolish oxidative stress we can never get rid of Alzheimer s disease. The difficulty is that we cannot abolish oxidative stress, because it is necessary to coordinate our resistance to infections and other physical stresses but we can probably modulate it with a little more subtlety. At the beginning of this section on Alzheimer s disease, I posed a question why do people without known risk factors still get dementia I believe we have answered the question. They still get oxidative stress. Another permutation of the same question may throw a more practical light on the prevention of dementia. Why do some people with known genetic risk factors (such as ApoE4) not get Alzheimer s disease What do they have that is protecting them These are questions we will touch on in the final chapter. 

Myllykangas, L., Polikoski, T., Sulkava, R., et al. (2000) Cardiovascular risk factors and Alzheimer s disease a genetic association study in a popular aged 85 or over. Neurosci. Lett., 292, 195-198. 

At present it has been postulated that between 30-50 and 95% of the population risk for development of AD may be attributed to genetic factors (21,24). However, when the autosomal dominant mutation cases of high penetrance are considered, that percentage drops to less than 5% (21). The most comprehensive and current lists of all mutations that may be considered as AD genetic determinants or risk factors are maintained by Online Mendelian Inheritance in Man (OMIM) (25) and Alzheimer Disease Mutation Database (ADMB) (26). 

Before drawing this chapter to a close with some parallels in other age-related diseases, what have we learnt from Alzheimer s disease First, the known genetic mutations affect a small fraction of people with Alzheimer s disease and their effects are delayed until middle age. This delay implies that, as in mice and monkeys, oxidative stress must cross a threshold before neurons die en masse and dementia can be diagnosed clinically. Second, all other known risk factors for Alzheimer s disease, including Down syndrome, ApoE4 and herpes simplex infection, are associated with a rise in oxidative stress. Third, oxidative stress alone is sufficient to cause dementia in old age in people with no known risk factors (about half the people who succumb to dementia in old age). Fourth, factors that lower oxidative stress, such as aspirin and vitamin E, can postpone the onset of dementia by a few years, if not indefinitely. 

Geuetic factors have been linked to both early- and late-onset AD. Alterations to chromosomes 1,14, and 21 have been associated with early-onset AD, whereas the presence of apo E4 alleles increase a person s risk of developing late-onset AD. However, genetic causes of AD have been associated with only a small percentage of Alzheimer s patients, and the exact cause of AD remains unknown. 

---