Confirmed risk factors

At the present time, only four risk factors for Alzheimer's disease can be regarded as confirmed beyond reasonable doubt: (1314) old age, a family history of dementia, Down syndrome, and apolipoprotein E (ApoE) genotype.

Old age

We have already seen that the incidence of Alzheimer's disease rises steeply with age. (12) Old age is by far the most important risk factor. Family history

Risk is around 3.5 times higher in individuals who have a first-degree relative (parent or sibling) with Alzheimer's disease. (15) However, the risk varies depending on the age at which the relative developed the disease: family history is a stronger risk factor in middle-aged cases than in the elderly. The highest risk is in those rare families with an autosomal dominant pattern of inheritance, where 50 per cent of first-degree relatives develop the disease. In late-onset cases, a person at risk may die before developing the disease. Therefore, we must take lifespan into account when estimating the risk to a relative. One estimate is that a first-degree relative has a 5 per cent risk if they live to 70 years of age, a 16 per cent risk to age 80, and a 33 per cent risk to age 90. (!6)

Down syndrome

People with Down syndrome always develop Alzheimer's disease pathology before the age of 40 years. Their increased risk is due to their having an extra copy of the b-amyloid precursor gene, which is on chromosome 21 (see above). However, declines in everyday functioning are often not seen until a much older age. The reason for the lag between pathology and clinical changes is not understood.

ApoE genotype

The ApoE gene on chromosome 19 affects the risk for Alzheimer's disease. Unlike the mutations mentioned above, alleles of this gene do not, in themselves, cause the disease; they only increase or decrease risk. The gene has three common alleles (e2, e3, and e4), giving possible genotypes of e2/e2, e2/e3, e2/e4, e3/e3, e3/e4, and e4/e4. The e3/e3 genotype is the most common in the population. The e4/e4 genotype is associated with a much higher risk of Alzheimer's disease compared with the e3/e3 genotype (around 15 times in Caucasians), while the e2/e4 and e3/e4 genotypes are associated with a somewhat higher risk (around three times the risk in Caucasians)/,!7) The e2/e2 and e2/e3 genotypes are slightly protected relative to e3/e3 (around a 40 per cent lower risk). The e4 allele is less common in

Orientals than in Caucasians, which might account for the lower incidence of Alzheimer's disease reported in some Oriental studies.

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