Genetic risk profiles for Alzheimer's disease: Integration of APOE genotype and variants that up-regulate inflammation

BACKGROUND: A number of studies associate Alzheimer's disease with APOE polymorphism and alleles which favor the increased expression of immunological mediators such as cytokines or acute phase proteins. We integrated this information to better define risk and determine the relative importance of APOE and immunological mediators. METHODS: We investigated functional gene variants for APOE, IL-10 (3 loci), ACT (2 loci), HMGCR, IL-1alpha, IL-1beta, TNF-alpha, IFN-gamma, and IL-6 found for 260 AD patients and 190 controls enrolled in Northern Italy. A fuzzy latent classification approach, namely grade-of-membership analysis (GoM), was taken to identify extreme pure type risk sets, or profiles. This approach automatically relates individuals to each profile via graded membership scores. FINDINGS: Four extreme pure type risk sets were identified. Set I defined low intrinsic risk and had a low probability of carrying pro-inflammatory alleles or APOE epsilon4. Three sufficient risk sets were identified: early onset AD (set II) was characterized by a high density of pro-inflammatory alleles, a rapid cognitive decline and independent of APOE epsilon4. Late onset AD had a lower density (ages 65-74, set III), or a subset homozygous (ages 75+, set IV), for these alleles and a high probability of one or two APOE epsilon4 alleles. A total of 97% of the subjects who were cases strongly resembled, i.e. had at least 50% membership in, the sufficient risk sets, as did 25% of middle aged control subjects. IL-10, HMGCR, ACT, and IL-1beta gene variants were each more informative in identifying the risk sets than was APOE. INTERPRETATION: AD likely has many determinants including APOE polymorphism and gene variants that modulate innate immunity. Identification of these factors, risk prediction for individuals, and successful prevention and treatment trials require integration of relevant information.