The majority of research works to date suggest that Major Depressive Disorder (MDD) is a
risk factor for dementia and may predispose to cognitive decline in both early and late onset variants.
The presence of depression may not, however, reflect the cause, rather, an effect: it may be a response to
cognitive impairment or alters the threshold at which cognitive impairment might manifest or be detected.
An alternative hypothesis is that depression may be part of a prodrome to Alzheimer’s Disease
(AD), suggesting a neurobiological association rather than one of psychological response alone. Genetic
polymorphisms may explain some of the variances in shared phenomenology between the diagnoses, the
instance, when the conditions arise comorbidly, the order in which they are detected that may depend on
individual cognitive and physical reserves, as well as the medical history and individual vulnerability.
This hypothesis is biologically sound but has not been systematically investigated to date. The current
review highlights how genetic variations are involved in the development of both AD and MDD, and the
risk conferred by these variations on the expression of these two disorders comorbidly is an important
consideration for future studies of pathoaetiological mechanisms and in the stratification of study samples
for randomised controlled trials.