Depression in Alzheimer’s disease (AD) has a substantial impact on disability, disease progression, and caregiver burden. Furthermore, depressive symptoms in normal aging, as well as in mild cognitive impairment (MCI), are associated with cognitive and functional decline. The association of behavioral symptoms with cognitive decline in normal aging has led to the construct of mild behavioral impairment (MBI) that is defined as a persistent behavioral change with mild psychiatric symptoms but without significant cognitive or functional impairment [1,2]. MBI is associated with increased risk of frontotemporal dementia, as well as AD. The approved medications developed to treat depression in younger individuals are of limited efficacy in older individuals, especially when the symptoms are co-morbid with cognitive impairment. An understanding of the phenomenology and neurobiology of depressive symptoms across the spectrum from normal aging to MCI to AD is urgently needed to develop more effective treatments and prevention strategies in the prodromal stages of AD.
The Handbook of Alzheimer’s Disease (Volume 4) is dedicated to the topic of depression in AD. The papers are a combination of original research articles and reviews of the literature. The papers in this Volume reflect the state of the field in the areas of diagnostic criteria and outcome measures for depression and depressive symptoms, neuropathological, genetic, and imaging studies to elucidate the neurobiological mechanisms and clinical trials of pharmacologic and non-pharmacologic interventions.
With respect to the phenomenology of depression, there are fundamental questions about whether the construct of depression is the same over the spectrum of normal aging to MCI to AD. Can the same diagnostic criteria and symptom assessments be used across this spectrum? Is the depressive syndrome observed the same as major depression defined by the Diagnostic and Statistical Manual? Is it a milder form of depression or is it a broader affective syndrome, including such symptoms as apathy, anxiety, and irritability? In this context, it is important to consider that depression, in combination with these other neuropsychiatric symptoms, is associated with cognitive decline. With respect to measuring changes in depressive symptoms in treatment trials, there is discussion about which are the most appropriate symptoms assessments to use, the assessment instruments developed for major depression or the instruments developed for use in AD. Are the same assessment tools that are appropriate for AD also sensitive to detecting an improvement in depressive symptoms in normal aging and MCI? Studies of epidemiology and neuropsychology consistently observe the substantial impact of depressive symptoms alone or in combination with other neuropsychiatric symptoms on cognitive decline across the spectrum of normal aging, MCI, and AD. There is remarkable consistency across studies even though the studies employ different diagnostic criteria and depression assessment measures.
Studies of neurobiology and neuropathology, neuroimaging, and genetics have implications for addressing many fundamental questions regarding whether depressive symptoms in AD are associated with similar or different genetic polymorphisms, neural circuits, and molecular mechanisms as observed in AD or major depression or both. While there is some overlap in neural networks affected in depression in AD, structural and functional neuroimaging studies suggest greater changes in brain structure, including white matter hyperintensities and function in frontal cortical regions in AD patients with compared to those without depression.  Postmortem studies demonstrate that greater AD pathology and monoamine degeneration is not associated with depression in AD and suggests that other neurobiological mechanisms should be investigated.  The impact of depression in normal aging and MCI may be different than in AD, as suggested by several genetic and neuroimaging studies [5,6]. The overlap between the neurobiological mechanisms implicated in depression and depression in AD was demonstrated in a genome-wide gene- and pathway-based analyses study in older adults  that showed an association between several genetic pathways associated with depression and depression in AD.
Thus, a critical question that may be best addressed with in vivo methods systematically applied across groups is whether the same neurobiological mechanisms underlie depressive symptoms in normal aging, MCI, and AD. An understanding of alterations in affective neural circuitry, neurotransmitter modulation, and synaptic plasticity and relationship to AD pathology is critical to inform the development of more effective treatments. As discussed further below, there is converging evidence for several molecular mechanisms associated with both mood symptoms and AD such as glutamatergic dysfunction, inflammation, cerebrovascular disease, or altered synaptic plasticity [4,7-9]. Even if depression in AD and major depression have a common origin, the co-occurring neurochemical and molecular pathology in AD may explain why treatments effective in major depression may be less effective in treating depression in AD. These observations underscore the importance of: 1) earlier intervention targeting depressive symptoms in normal aging and MCI that may prevent further neurodegeneration and progression to AD; and 2) identifications of new antidepressant targets as informed by neurobiological data, including genetics and neuroimaging approaches.
The further behavioral evaluation of transgenic animal models of AD pathology and the evaluation of the impact of inducing depressive and stress responses may elucidate the relationships between AD pathology, other neurobiological mechanisms, and depressive symptoms and would inform the development of human mechanistic and intervention studies . For example, there are several examples in the literature suggesting a potential role of monoamine pathology associated with AD pathology in depressive symptoms in transgenic mouse models [11,12] that may suggest that monoaminergic deficits may be associated with AD pathology and perhaps, neuropsychiatric symptoms.
With respect to treatment, studies of antidepressants (mainly selective serotonin re-uptake inhibitors) yielded mixed results, there is a suggestion that other treatment targets should be investigated further, such as inflammatory or the glycogen synthase kinase-3 pathways . There are recent advances in the development of novel treatments for depression that are promising and may have implications for the treatment of depression in AD as well as in aging and MCI. It is important to reiterate that the neurobiology of depression in normal aging, MCI, and AD may be different and thus, the same intervention may not be effective across conditions. For example, the “multi-modality” antidepressants that have both pre and post-synaptic monoaminergic effects, including direct receptor effects, may enhance neurotransmitter modulation, and there is some evidence that such agents may treat cognitive deficits, as well . The development of agents targeting mechanisms including glutamatergic dysfunction, inflammation, and enhancing synaptic plasticity may also be effective at treating depression and preventing further decline . Behavioral interventions and/or combined pharmacologic and behavioral interventions targeting mood symptoms or cognitive deficits represent another important opportunity for intervention development . Brain stimulation approaches targeting brain circuits are a major focus of treatment development in the mood disorders field and may be effective in treating depression in AD, as well especially given the evidence that brain stimulation may improve cognition . Both pharmacologic and behavioral intervention studies in MCI are critically needed. Perhaps the most important question and the most challenging to investigate, as mentioned above, is whether the early and intensive treatment of depressive symptoms in MBI and MCI prevent the development of further pathology and delay the dementia transition.
The next decade promises significant advances in animal models, genetics, and neuroimaging in mood disorders and AD, as well as an increasing focus on the study of normal aging and individuals “at risk” for AD. This research will have a great impact on the development of more effective approaches for the clinical management of depression in the context of normal aging, MCI, and AD, as well as understanding of the potential importance of the role of depression treatment in the prevention of dementia. We sincerely hope that the material in the Volume will inspire basic and clinical researchers to undertake research on the impact of depressive symptoms across the spectrum of normal aging to MCI to AD, as well as investigate the role of depressive symptoms as a prodrome or co-morbidity in other neurodegenerative diseases including Parkinson’s and Huntington’s diseases.
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 Ismail Z, Smith EE, Geda Y, Sultzer D, Brodaty H, Smith G, Agüera-Ortiz L, Sweet R, Miller D, Lyketsos CG; ISTAART Neuropsychiatric Symptoms Professional Interest Area (2015) Neuropsychiatric symptoms as early manifestations of emergent dementia: Provisional diagnostic criteria for mild behavioral impairment. Alzheimers Dement, doi: 10.1016/j.jalz.2015.05.017.
 Brommelhoff JA, Sultzer DL (2015) Brain structure and function related to depression in Alzheimer's disease: contributions from neuroimaging research. J Alzheimers Dis 45, 689-703.
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