Alzheimer's disease: genetic variables and risk.

T he risk of Alzheimer's disease may come down to the expression of various forms of the human apolipoprotein E gene (apoE). Jean-Cosme Dodart and colleagues 1 have recently shown that injecting a variant of apoE into the brains of mice has an effect on the formation of the amyloid plaques characteristic of Alzheimer's disease. Their research contributes more evidence that apoE is a major risk factor for Alzheimer's disease and points to gene delivery as a potential treatment for the most common form of dementia among elderly people worldwide. Genetic risk factors Two hallmarks characterize Alzheimer's disease: plaques and tangles. The plaques are chains of amino acids that are pieces of the amyloid precursor protein, whereas the tangles are aggregates of the protein tau. It appears that the amyloid plaques are precursors to the formation of tangles; 2 whether or not this is the case, it is clear that these 2 abnormalities ultimately lead to loss of cognitive function. Significant effort has gone into attempting to understand the genetic factors that play a role in the formation of plaques and tangles. Although 3 genes have been identified and linked to early-onset Alzheimer's disease , only apoE has been shown to be consistently linked to the more common late-onset form of the disease. The human apoE gene has 3 versions (apoE-ε2,-ε3,-ε4), each of which encodes a protein involved in the transport of tri-glycerides and cholesterol. Interestingly , apoE-ε4 was shown to be associated with an increased risk of Alzheimer's disease in Caucasians homozygous for apoE-ε4 (odds ratio [OR] 14.9, 95% confidence interval [CI] 10.8–20.6). Conversely, in the same study, apoE-ε2 appeared to decrease this risk (OR 0.6, 95% CI 0.2–2.0 for ε2/ε2 and OR 0.6, 95% CI 0.5–0.8 ε2/ε3). 3 In 2000, Holtzman and colleagues found that apoE-ε4 promotes the laying down of amyloid plaques in mice, which further highlights the importance of this genetic factor. 4 However, how the ApoE protein contributes to the pathology of Alzheimer's disease was still not clear, and direct in-vivo demonstration that versions of ApoE affect plaque formation was lacking. Delivering apoE to the brain Dodart and colleagues took an elegant approach to investigating these questions by injecting viruses capable of expressing one of the subtypes of apoE into the brains of a mouse model of Alzheimer's that formed amy-loid plaques but lacked apoE. Five weeks later, the researchers were able to detect the …