Background: Neurodegenerative diseases are a major health problem. To identify factors that can be translated into personalised medicine approaches, ELAPSE-ND picked two diseases as models: Alzheimer’s disease (AD), the most common neurodegenerative disorder, and Spinocerebellar ataxia type 3 (SCA3), the most common autosomal-dominantly inherited ataxia worldwide. AD is attributed to genetic, lifestyle and environmental factors. SCA3 is caused by a CAG expanded repeat (CAGexp) within the ATXN3 gene that leads to polyglutamine aggregation and neuronal toxicity, but that explains only 55% of the variability of the age at onset (AO). Genetic factors therefore modify AD and SCA3. Although so different from each other, it is plausible that an interacting route is shared, leading to opportunities of treatment. The apolipoprotein E (ApoE) has a determining role in the progression of ß amyloid (Aß) deposition and the formation of Aß plaques, a hallmark of AD. The APOE haplotype APOEe4 is the major risk factor for AD, while we have data pointing that APOEe4 is also a risk factor for SCA3. Data also suggest that CAG repeats in the ATXN2 gene, intragenic polymorphisms in ATXN3 and in DNA repair genes modify SCA3. It is plausible to think that these modifiers might also interact with AD pathogenesis, making it relevant to analyse their protective or damaging effects in both AD and SCA3. Aims: ELAPSE-ND aims to identify and characterise genetic modifiers in neurodegeneration, starting with an associative study between genetic variations within candidate genes and AO in multiethnic AD and SCA3 groups. Methods: First, known additional modifiers of AD and SCA3 will be tested reciprocally. Second, common modifiers will be characterised mechanistically in regard to the pathophysiology. Expected outcome: We expect to identify relevant genetic modifiers for neurodegenerative disorders as one step forward towards personalised medicine for neurodegenerative disorders and healthy aging.
