Rosenberg's Molecular and Genetic Basis of Neurological and Psychiatric Disease, Volume 1 (Seventh Edition): Chapter 7 - Pharmacogenomic approaches to the treatment of sporadic Alzheimer’s disease

A common genetic variant in the apolipoprotein E (APOE) gene called E4 was shown to be strongly linked to both sporadic and familial late-onset Alzheimer’s disease (AD). Neurochemical evidence obtained in autopsy-confirmed sporadic AD and control cases over the years clearly indicates that the presence of APOE4 allele in humans directly compromises several neurotransmitters systems in the aging adult brain, indirectly affecting drug responsiveness in genetically distinct populations of subjects. These include the cholinergic, noradrenergic, dopaminergic systems, and the vasopressinergic pathways. In addition to APOE4, novel genetic markers modulating drugs’ responsiveness and adverse side effect profiles have been identified in clinical drug trials and their pharmacogenomic properties were shown to clearly extend beyond the cholinergic system. This chapter carefully examines the specific role of genetic variants found to affect cholinergic and noncholinergic neurotransmission, as well as the pathophysiological regulators of AD neurobiology.