The goal of the Genetics of Alzheimer's Disease and Endophenotypes Laboratory of Nilufer Ertekin-Taner, M.D., Ph.D., at Mayo Clinic is to elucidate the complex genetics of Alzheimer's disease by discovery and characterization of genetic factors that influence its risk and modulate biological quantitative phenotypes (endophenotypes), such as gene expression levels and cognition.

Alzheimer's disease (AD) is the most common form of dementia, affecting greater than 35 million individuals worldwide. It is characterized primarily by memory decline as well as impairment in other cognitive areas, including language, executive function and visuospatial abilities. Without effective therapies, the number of people with AD is expected to exceed 115 million by the year 2050. It is clear that development of effective therapies for the disease requires a thorough understanding of its pathophysiology, risk and protective factors.

The lab focuses on recognizing the underlying genetic component and identification of genetic risk and protective factors in the disease mechanism. This knowledge could aid in the development of novel therapeutic approaches by identifying druggable targets. Further, genetic risk and protective factors could potentially be used as biomarkers to determine at-risk populations to commence drug therapy in the presymptomatic stage.

Pathologically, AD is characterized by senile plaques composed predominantly of extracellular accumulation of the amyloid-beta peptide, which is processed from amyloid precursor protein and neurofibrillary tangles. These are formed by intracellular accumulation of the abnormally hyperphosphorylated microtubule associated protein, tau.

The identification of deterministic Mendelian mutations in the amyloid precursor protein (APP), presenilin 1 (PSEN1) and presenilin 2 (PSEN2) genes responsible for early-onset autosomal dominant familial forms of AD have led to a better understanding of the pathophysiology of this disease; however, these mutations explain less than 1 percent of all cases.

The common late-onset Alzheimer's disease (LOAD) also has a substantial genetic component that is only partially explained by apolipoprotein ε4, the only widely accepted genetic risk factor for late-onset AD. The lab has a number of approaches that aim to uncover the underlying genetics of LOAD. The details of these approaches and the associated projects are described under Projects.