Searching for pro-inflammatory gene clusters to assess the Alzheimer’s disease (AD) risk profile for the prevention and early therapy of the disease

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Background: Epidemiological studies showed that anti-inflammatory drugs decreased the incidence and prevalence of AD. Inflammatory responses are associated with neuropathology hallmarks of AD brain and mechanisms regulating inflammation and immune responses have been suggested to be involved in the pathogenesis of age-associated cognitive decline and AD. Investigations focused on SNPs in immunoregulatory genes showed that selected immune genes were associated with an increased risk of the disease and/or a differential rate of cognitive decline. Objective(s): The combination of different SNPs of diverse immune genes may have an addictive effect on cognitive decline in the elderly and AD risk. In particular, pooling several SNPs of these genes gives rise to apro-inflammatory genetic cluster associated with abnormal or poorly regulated inflammatory responses. The identification of these pro-inflammatory gene clusters can be applied to healthy subjects to determine their intrinsic risk of pro-inflammatory predisposition with relevance for brain degeneration. Methods: Several hundreds of patients with clinical diagnosis of AD and non demented controls have been genotyped for SNPs in IL-1β, IL-6, IL-10, ACT, APOE and Hydroxy-Methyl-Glutaryl- Coenzime A reductase (HMG-CoA red.). The association of each SNP with AD risk has been determined. A score for each allele or genotype has been assigned and an algoritm to assess individual intrinsic risk has been developed. A longitudinal study (a four year follow-up) of a 1000 elderly living in the Northern Italy has been concluded. Each participants has been genotyped for the above SNPs and the predictive power for age associated cognitive impairment and senile dementia of gene clusters for pro-inflammatory predisposition (PIP) has been tested. Conclusions: Using the gene clusters associated with (PIP) and associated with AD is possible to predict the individual intrinsic risk of developing age associated cognitive impairment in healthy subjects. These groups of subjects will be offered to enter a follow up with annual clinical examination, cognitive testing and functional neuro-imaging. An anti-inflammatory therapy will be suggested, when cognitive testing and/or functional neuro-imaging would detect abnormalities. If this approach is correct, by using this technology a substantial decrement of prevalence and incidence of dementia in near future might be achieved