CONICET | Buscador de Institutos y Recursos Humanos

Alzheimers disease (AD) is a neurodegenerative disorder clinically characterized by memory impairment and pathologically characterized by the formation of amyloid plaques and neurofibrillary tangles in the brain. Less than 5% of AD patients can be categorized as early-onset disease (diagnosis before age 65). The cause for this subset of disease has been linked to gene mutations in amyloid precursor protein (APP), presenilin 1 (PSEN1), presenilin 2 (PSEN2) and duplications of APP. The major form of AD, late-onset AD (LOAD), also has a strong genetic component. LOAD is a multifactorial complex disorder with both genetic and environmental components. APOE is the primary genetic risk factor in LOAD. However, the APOE E4 variant does not account for all cases of LOAD. It is present in less than 50% in European AD cases and occurs even less frequently in African, Asian and Hispanic AD populations. Identification of additional genetic variants apart from APOE has been challenging due in part to the smaller effect sizes of these variants to the quantitative traits associated with the disease, such as memory performance, amyloid/tau pathology, or hippocampal atrophy. Genome-wide association studies provide an unbiased approach to test the common variants-common disease hypothesis. Validation of the genetic variants in the context of genetic ancestry may help to define carriers of known genomic variants that contribute to susceptibility. In this sense, a high risk population can be defined as well as individuals with potential for a better response to a drug. Definition of a genetic risk pattern for LOAD may help to predict drug response and define potential targets for screening, and prevention. In this context, we will review and discuss the power and the usefulness of top-10 genetic variation described in LOAD and its relevance in the understanding of the pathology