by build-ups of aggregates of the peptide beta-amyloid. apolipoprotein e enhances proteolytic break-down of this peptide, both within and between cells. the isoform apoe-ε4 is not as effective as the others at promoting these reactions, resulting in increased vulnerability to ad in individuals with that gene variation. recently, the amyloid hypothesis of alzheimer's disease has been questioned, and an article in science claimed that "just as removing smoke does not extinguish a fire, reducing amyloid plaques may not affect the course of alzheimer's disease." the role that the e4 variant carries can still be fully explained even in the absence of a valid amyloid hypothesis given the fact that reelin signaling emerges to be one of the key processes involved in alzheimer's disease and the e4 variant is shown to interact with apoer2, one of the neuronal reelin receptors, thereby obstructing reelin signaling. although 40–65% of ad patients have at least one copy of the ε4 allele, apoe4 is not a determinant of the disease. at least one-third of patients with ad are apoe4 negative and some apoe4 homozygotes never develop the disease. yet those with two ε4 alleles have up to 20 times the risk of developing ad. there is also evidence that the apoe2 allele may serve a protective role in ad. thus, the genotype most at risk for alzheimer's disease and at an earlier age is apoe4,4. using genotype apoe3,3 as a benchmark (with the persons who have this genotype regarded as having a risk level of 1.0) and for white populations only, individuals with genotype apoe4,4 have an odds ratio of 14.9 of developing alzheimer's disease. individuals with the apoe3,4 genotype face an odds ratio of 3.2, and people with a copy of the 2 allele and the 4 allele (apoe2,4), have an odds ratio of 2.6. persons with one copy each of the 2 allele and the 3 allele (apoe2,3) have an odds ratio of 0.6. persons with two copies of the 2 allele (apoe2,2) also have an odds ratio of 0.6. estimated worldwide human allele frequencies of apoe in caucasian population allele ε2 ε3 ε4 general frequency 8.4% 77.9% 13.7% ad frequency 3.9% 59.4% 36.7% while apoe4 has been found to greatly increase the odds that an individual will develop alzheimer's, a 2002 study concluded, that in persons with any combination of apoe alleles, high serum total cholesterol and high blood pressure in mid-life are independent risk factors which together can nearly triple the risk that the individual will later develop ad. projecting from their data, some researchers have suggested that lowering serum cholesterol levels may reduce a person's risk for alzheimer's disease, even if they have two apoe4 alleles, thus reducing the risk from nine or ten times the odds of getting ad down to just two times the odds. women are more likely to develop ad than men across most ages and apoe genotypes. premorbid women with the ε4 allele have significantly more neurological dysfunction than men. atherosclerosis knockout mice that lack the apolipoprotein-e gene (apoe−/−) develop extreme hypercholesterolemia when fed a high-fat diet. malaria apoe−/− knockout mice show marked attenuation of cerebral malaria and increased survival, as well as decreased sequestration of parasites and t cells within the brain, likely due to protection of the blood–brain barrier. human studies have shown that the apoe2 polymorphism correlates with earlier infection, and apoe3/4 polymorphisms increase likelihood of severe malaria. interactions interactive pathway map click on genes, proteins and metabolites below to link to respective articles. [[file: |alt=statin pathway edit]] statin pathway edit the interactive pathway map can be edited at wikipathways: "statin_pathway_wp430".