Elsevier

Neurobiology of Aging

Volume 28, Issue 11, November 2007, Pages 1637-1643
Neurobiology of Aging

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

https://doi.org/10.1016/j.neurobiolaging.2006.07.007Get rights and content

Abstract

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-1α, IL-1β, TNF-α, IFN-γ, 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 APOEɛ4. 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 APOEɛ4. 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 APOEɛ4 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-1β 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.

Introduction

Inflammation is accepted to be a feature of Alzheimer's disease (AD) pathology [10], [13], [15], [16], [17], [18], [19], [21], [22], [23], [28], [30], [33], [35], [39]. Inflammatory processes can be observed in the AD brain; circulating acute phase reactant levels in middle age predict AD risk in old age; certain functional promoter polymorphisms in cognate genes that modulate inflammation are often found at elevated frequency among AD cases. However, alleles that up-regulate inflammation are not, taken individually, found to be elevated in every sample of cases, nor is any one polymorphism sufficient to predict risk for individuals, nor has the relative importance of APOE[3] polymorphism and immunologic mediators been established. No attempt has been made to integrate this information to better describe risk for AD or to gauge whether these factors taken together define sufficient risk sets for AD.

We integrated information on functional gene variants found for apolipoprotein E (APOE), interleukin 10 (IL-10; 3 loci), alpha-(1)-antichymotrypsin (ACT; 2 loci), 3-hydroxy-3-methylglutaryl-Coenzyme A reductase (HMGCR) [12], [15], interleukin 1-alpha (IL-1α), interleukin 1-beta (IL-1β), tumor necrosis factor alpha (TNF-α). interferon gamma (IFN-γ), and interleukin 6 (IL-6). The sample consisted of 260 AD patients and 190 unaffected control subjects from Northern Italy. These subjects and loci were initially investigated as part of a project to detect gene variants in innate immunity that predict AD status [20], [25], [27], [11]. Given that AD neuropathology accumulates with age at differing rates for individuals, subjects were considered according to age and AD status. Information on the rate of cognitive decline was included in the analysis to determine whether gene variants in innate immunity influence the rate of cognitive decline among AD cases as well as risk for AD. Potentially, this might point towards therapeutic interventions.

The approach taken to integrate all this information is termed grade-of-membership analysis (GoM) [37]. Using GoM, the user specifies a number of latent groups, here, extreme pure type risk sets or profiles, to be identified. Each risk set is defined by probabilities for each outcome, here, AD status, rate of cognitive decline and the various genotypes found for the loci. At the same time, individuals are related to the groups via membership scores ranging from zero denoting no resemblance to the risk set to one, i.e. the individual matches the risk set exactly. The scores for high-risk sets were then input into logistic models to estimate the odds of AD and produce 95% CI. This approach has identified sufficient genetic risk sets for Alzheimer's disease [6], vulnerable and robust sets of gene variants in mitochondrial complex I in Parkinson's disease [7], and multilocus genotypes specific to breast cancer and fibroadenoma [8].

Four risk sets were identified: one set had low intrinsic risk and a low probability of carrying pro-inflammatory gene variants or APOEɛ4 (set I). Three sufficient risk sets were identified: early onset was associated with a high density of pro-inflammatory alleles (set II). Late onset AD was associated with a lower density (ages 65–74; set III) or homozygous subset (ages 75 and older; set IV) of these alleles plus a high probability of carrying APOE ɛ4. A total of 97% of subjects who were cases were substantially like the sufficient risk sets, i.e. had >50% membership in these sets. Hence, the investigated genes and loci were highly relevant to AD. Of equal importance, 25% of the presently unaffected control subjects <age 65 were genetically like the cases, implying high risk for AD in the future.

Section snippets

Study subjects

The subjects lived in Northern Italy and represent AD cases managed by the Neurology Department, Bologna University Hospital [24]. Each of the 260 cases met diagnostic criteria for probable AD [29] and, as part of standard clinical management, received acetylcholine esterase inhibitors from the time of diagnosis. Age at onset spanned more than 50 years (<55, 3%; 55–64, 14%; 65–74, 37%; 75–84, 40%; 85+, 6%). Annual decline in MMSE score [9] from the time of diagnosis was averaged over 2 years

The risk profile groups

Risk sets I to IV are described in Fig. 1. Set I represents low intrinsic risk: there is a low density of pro-inflammatory gene variants at the investigated loci. Sets II, III, and IV represent sufficient risk sets for AD: there are high densities of pro-inflammatory gene variants. The sufficient risk sets were age-specific: early onset AD/rapid cognitive decline (II), late-onset AD occurring at ages 65–74/moderate decline (III), and late-onset AD occurring at ages 75+/slow rate of cognitive

Discussion

This study is the first to integrate genetic information on APOE genotype and functional promoter polymorphisms in genes that modulate innate immunity to define age-specific sufficient risk sets of alleles, demonstrate that most (97%) AD cases strongly resemble these high intrinsic risk sets, and identify presently unaffected middle-aged control subjects who may be at elevated risk based on genetic resemblance to present, usually older, cases (25%). Specific risk sets of pro-inflammatory

Acknowledgements

We thank the study participants and their families. Research supported by Italian COFIN and Italian CURA to FL.

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