30 - Genetics of Alzheimer's disease

Summary

Introduction

Alzheimer's disease, the most common form of age-related dementia, is characterized by progressive and insidious neurodegeneration of the central nervous system eventually leading to a gradual decline of cognitive function and dementia. The key neuropathological features of AD are abundant amounts of neurofibrillary tangles and β-amyloid (Aβ) deposited in the form of senile plaques. Although the knowledge of disease pathophysiology still remains fragmentary, it is now widely accepted that, similar to other common diseases like diabetes, coronary artery disease, or breast cancer, genes play an essential role in predisposing to onset and/or in modifying the progress of the disease.

Genetically, AD is a complex and heterogeneous disorder: it is complex because there is no single mode of inheritance that accounts for its heritability. Moreover, disease inheritance shows an age-related dichotomy in which rare but highly penetrant mutations transmitted in an autosomal dominant manner are almost exclusively responsible for the early-onset familial forms of AD (EOFAD), while common polymorphisms with low penetrance appear to have their greatest effect on the more frequent late-onset form of the disease (LOAD; Tanzi, 1999). It is heterogeneous because genetic variants in multiple genes on several chromosomes throughout the genome are involved together with non-genetic factors. All of the known factors contribute to the increased accumulation of Aβ (more specifically: Aβ₄₂) owing to an imbalance in production vs degradation/clearance in the cell (Fig. 30.1, 30.2).