Alzheimer’s disease comes in two basic variants: a common form known as late-onset AD that strikes people over age 65, and a rare early-onset form, which can strike people as young as their 30s or 40s. Inherited variations in three genes – called the PS1, PS2, and APP genes – are known to cause the early-onset form, and about half the cases of early-onset AD may be due to presence of one or more of these genes. But early-onset AD accounts for only about 5-10% of all AD cases. Finding the genetic bases of the common, late-onset form has proven more elusive. In fact, late-onset Alzheimer’s is sometimes called “sporadic” Alzheimer’s, reflecting the idea that we can’t predict whom it will strike or when.
Until recently, the only gene known to be associated with late-onset AD was APOE, a gene associated with clearing cholesterol from the bloodstream. APOE comes in three common variants, known as E2, E3, and E4. People carrying E4 are about three times more likely to develop late-onset AD than those carrying E3; people carrying E2 are at a slightly reduced risk for the disease. But the link between APOE and AD is not terribly strong; many people carrying E2 still develop AD, while some carrying E4 never do. Apparently, other genetic or environmental factors must play a role too.
Now, two large-scale studies have identified three additional genes that appear to play a role in determining an individual’s risk for late-onset AD. One study conducted by researchers in France considered over 15,000 elderly people with and without AD, and found that the people with AD were much more likely to have specific variants on genes known as CLU and CR1. These genes may help regulate how the body clears beta amyloid, the protein that accumulates in the brains of people with AD; variants of these genes that are less effective at this task may contribute to an individual’s susceptibility to the disease. A second study out of the UK examined over 16,000 people with and without AD, and replicated the findings with CLU as well as identifying a third genetic variant, on the PICALM gene, that also occurred more often in individuals with AD.
CLU, CR1, and PICALM join APOE as significant risk factors for the common, late-stage form of AD. Together, the four genes may account for as much as 40-50% of AD cases. Knowing the genetic variants associated with a disease is a long way from being able to prevent or cure that disease, but it’s an important step: now, researchers at least have some idea of where to begin targeting their efforts.
Further reading:
D Harold and others (2009). Genome-wide association study identifies variants at CLU and CR1 associated with Alzheimer’s disease. In, Nature Genetics, vol. 41, pp. 1088-1093.
JC Lambert and others (2009). Genome-wide association study identifies variants at CLU and CR1 associated with Alzheimer’s disease. In, Nature Genetics, vol. 41, pp. 1094-1099.
