Depression in Alzheimer’s Disease: The Roles of Cholinergic and Serotonergic Systems

Depression is the leading cause of disease-related disability among women in the world today. Depression is much more common among women than men, with female/male risk ratios roughly 2:1. Recent epidemiological research is reviewed. Implications are suggested for needed future research. The higher prevalence of depression among women than men is due to higher risk of first onset, not to differential persistence or recurrence. Although the gender difference first emerges in puberty, other experiences related to changes in sex hormones (pregnancy, menopause, use of oral contraceptives, and use of hormone replacement therapy) do not significantly influence major depression. These observations suggest that the key to understanding the higher rates of depression among women than men lies in an investigation of the joint effects of biological vulnerabilities and environmental provoking experiences. Advancing understanding of female depression will require future epidemiologic research to focus on first onsets and to follow incident cohorts of young people through the pubertal transition into young adulthood with fine-grained measures of both sex hormones and gender-related environmental experiences. Experimental interventions aimed at primary prevention by jointly manipulating putative biological and environmental risk factors will likely be needed to adjudicate between contending causal hypotheses regarding the separate and joint effects of interrelated risk factors.

Neuronal nicotinic acetylcholine receptors comprise a heterogeneous class of cationic channels that is present throughout the nervous system. These channels are involved both in physiological functions (including cognition, reward, motor activity and analgesia) and in pathological conditions such as Alzheimer's disease, Parkinson's disease, some forms of epilepsy, depression, autism and schizophrenia. They are also the targets of tobacco-smoking effects and addiction. Neuronal nicotinic acetylcholine receptors are pentamers of homomeric or heteromeric combinations of alpha (alpha2-alpha10) and beta (beta2-beta4) subunits, which have different pharmacological and biophysical properties and locations in the brain. The lack of subtype-specific ligands and the fact that many neuronal cells express multiple subtypes initially hampered the identification of the different native nicotinic acetylcholine receptor subtypes, but the increasing knowledge of subtype composition and roles will be of considerable interest for the development of new and clinically useful nicotinic acetylcholine receptor ligands.