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

Domenico Lio, Calogero Caruso, Elisa Porcellini, Elizabeth H. Corder, Federico Licastro

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64 Citations (Scopus)

Abstract

BACKGROUND: A number of studies associate Alzheimer's disease with APOEpolymorphism and alleles which favor the increased expression of immunologicalmediators such as cytokines or acute phase proteins. We integrated thisinformation to better define risk and determine the relative importance of APOEand 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 for260 AD patients and 190 controls enrolled in Northern Italy. A fuzzy latentclassification approach, namely grade-of-membership analysis (GoM), was taken to identify extreme pure type risk sets, or profiles. This approach automaticallyrelates individuals to each profile via graded membership scores.FINDINGS: Four extreme pure type risk sets were identified. Set I defined lowintrinsic risk and had a low probability of carrying pro-inflammatory alleles or APOE epsilon4. Three sufficient risk sets were identified: early onset AD (setII) was characterized by a high density of pro-inflammatory alleles, a rapidcognitive decline and independent of APOE epsilon4. Late onset AD had a lowerdensity (ages 65-74, set III), or a subset homozygous (ages 75+, set IV), forthese alleles and a high probability of one or two APOE epsilon4 alleles. A totalof 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 controlsubjects. IL-10, HMGCR, ACT, and IL-1beta gene variants were each moreinformative in identifying the risk sets than was APOE.INTERPRETATION: AD likely has many determinants including APOE polymorphism andgene variants that modulate innate immunity. Identification of these factors,risk prediction for individuals, and successful prevention and treatment trialsrequire integration of relevant information.
Original languageEnglish
Pages (from-to)1637-1643
Number of pages7
JournalNeurobiology of Aging
Volume28
Publication statusPublished - 2007

All Science Journal Classification (ASJC) codes

  • General Neuroscience
  • Ageing
  • Clinical Neurology
  • Developmental Biology
  • Geriatrics and Gerontology

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