The main goal of our lab is to elucidate the complex genetics of Alzheimer's disease (AD) by discovery and characterization of genetic factors that influence its risk and modulate biological quantitative phenotypes (endophenotypes), such as gene expression levels and cognition. AD is the most common form of dementia affecting greater than 35 million individuals worldwide and is characterized primarily by memory decline as well as impairment in other cognitive areas, including language, executive function and visuospatial abilities.
Pathologically, it is characterized by senile plaques composed predominantly of extracellular accumulation of the amyloid β (Aβ) peptide, which is processed from amyloid precursor protein and neurofibrillary tangles, which is formed by intracellular accumulation of the abnormally hyperphosphorylated microtubule associated protein, tau.
Without effective therapies, the number of AD patients is expected to exceed 115 million by the year 2050. It is clear that development of effective therapies for a disease requires a thorough understanding of its pathophysiology, risk and protective factors.
Recognizing the underlying genetic component of a disease and identification of genetic risk and protective factors constitute an important approach to elucidate the disease mechanism. This knowledge could aid in the development of novel therapeutic approaches by identifying druggable targets. Furthermore, genetic risk and protective factors could potentially be used as biomarkers to determine at-risk populations in which to commence drug therapy in the pre-symptomatic stage. The identification of deterministic, Mendelian mutations in the amyloid precursor protein (APP), presenilin 1 (PSEN1), and PSEN2 genes responsible for early-onset autosomal dominant familial forms of AD led to a better understanding of the pathophysiology of this disease. These mutations explain less than 1 percent of all AD. The common late-onset form of AD (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. There are a number of approaches in our lab that aim to uncover this as yet unexplained, underlying genetics of LOAD. The details of these approaches and the associated projects are described under Current Projects.
- Genetics of gene expression in Alzheimer's disease (AD)
- Mapping and functional characterization of novel Alzheimer's disease (AD) risk genes and alleles
- Assessment of quantitative biological phenotypes as potential endophenotypes for Alzheimer's disease (AD)