Pathologic Mechanisms of Depression in Alzheimer Disease

Investigators sought to determine whether there exists a mechanistic association between Alzheimer disease (AD) and depression, including whether progression of depressive symptoms is related to cognitive decline during beginning stages of AD or whether depression could predict risk of developing AD.

Approximately 40% of individuals with Alzheimer disease (AD) have depression.1 In such cases, the complex interplay between the underlying neurologic pathologies and the special needs of individuals with AD gives rise to a unique set of challenges with respect to the diagnosis, treatment, and prognosis of both depression and AD.

Is there an association between depression and AD?

As Robert Wilson, PhD, a professor in the department of neurological sciences, Rush University Medical College, and neuropsychologist in the division of behavioral sciences, Rush Alzheimer’s Disease Center, Chicago, Illinois, pointed out, “Depression and AD are both very common, so we should expect some co-occurrence.”

Still, he believes there is little evidence indicating a mechanistic association between the 2 conditions.

Dr Wilson noted, “Our approach has been to test 2 hypotheses regarding AD as a cause of depression. First, depressive symptoms should increase as people are developing AD. We have found no evidence of such an increase; in fact, there may be some decrease in depressive symptoms as dementia develops. Second, depressive symptoms should be related to the pathologies underlying AD and other late-life dementias, but this does not appear to be the case. Complicating matters further is that depression depends in part on a continuity and awareness of experience that is progressively eroded in dementia, making depressed behavior difficult to maintain as the disease develops and progresses.”

In contrast, a study by Jennifer Gatchel, MD, a researcher in the department of psychiatry, Massachusetts General Hospital, Boston, Massachusetts, and her team suggested that progression of depressive symptoms is associated with cognitive decline during the initial stages of AD.2 Indeed, there is a possibility that depression could be a risk factor for the development of AD. Another possibility is that depression could be an initial symptom of AD; however, further studies are needed to explore these possibilities.1

Regardless of whether there is a pathologic association, the number of hospitalizations and mortality rates is higher for individuals with both depression and AD than for individuals with either condition alone. Furthermore, the co-occurrence of these conditions drastically reduces the quality of life for both patients and their caregivers.1 Therefore, it is imperative to develop effective diagnostic and treatment strategies specifically for depression comorbid with AD.

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Although the association between depression and AD is highly complicated, several studies are ongoing to unearth pathological processes common to both conditions that could potentially indicate an association between the two. Such common pathways could serve as prospective biomarkers for early diagnosis or potential targets for treatment.

Possible mechanisms underlying the co-occurrence of depression and AD

Several mechanisms underlying the co-occurrence of depression and AD have been explored.1

Structural factors

Corticolimbic networks, which are known to be important for emotional and cognitive processes, have been observed to be disrupted in both depression and AD. In addition, reduction in grey matter in the cortex and atrophy in the anterior cingulate cortex and hippocampus are associated with both conditions; however, no causal link has been established between these processes and these conditions.

Neurotransmitter imbalance

The role of neurotransmitters in the co-occurrence of depression and AD remains controversial. Specifically, dopamine, glutamate, and γ-aminobutyric acid are being explored as potential factors that could link both conditions, whereas serotonin and noradrenaline dysregulation do not appear to influence the development of depression in AD.

Dysregulation of other molecular processes

Both depression and AD are associated with chronic stress, hypothalamic-pituitary-adrenal axis dysfunction, neuroinflammatory processes such as increase in microglial activity and proinflammatory cytokines, reduction in levels of brain-derived neurotrophic factor, and decreased levels of zinc transporters in the prefrontal cortex.

Genetic factors

Although multiple studies have explored the influence of genetic factors on the comorbidity of depression and AD, the 2 conditions do not appear to have a common genetic link.

Current diagnostic strategies for depression in AD

Depression in individuals with AD is most effectively diagnosed using assessment tools and criteria that have been developed specifically for the geriatric population, as depressive symptoms in this population are different from those in younger individuals. Examples of such scales include the Geriatric Depression Scale, Cornell Scale for Depression in Dementia, and National Institute of Mental Health diagnostic criteria for depression in AD. These scales may be used for the diagnosis of depression, as well as determining disease severity and prognosis. When cognitive decline impedes the individual’s ability to recall depressive symptoms, the Cornell Scale for Depression in Dementia may be more reliable, as it considers input from the caregiver.

Challenges in the diagnosis of depression in AD

“A complicating issue in the diagnosis of depression in AD is that there is some overlap between the symptoms of depression and AD (eg, difficulty concentrating) and the fact that we have treatments for depression but not for AD,” says Dr Wilson. “So, if both conditions are possibly present, many clinicians will opt to try treating depression.”

In addition, depression manifests differently in the elderly compared with younger populations. Therefore, general diagnostic criteria used for depression in general populations might not be applicable to depression in the elderly or in individuals with cognitive impairment. For example, elderly individuals with depression may not fit the criteria described by the Diagnostic and Statistical Manual of Mental Disorders: they may report general symptoms associated with depression, such as fatigue, insomnia, or anorexia, instead of a depressive mood, which makes it more challenging to narrow the condition down to depression. Underreporting of depressive symptoms is also common in AD because of cognitive decline or because the individual might consider these symptoms as a normal response to the aging process.3

In contrast, overestimation of depression may occur when symptoms associated with physical conditions of the individual are misinterpreted as depressive symptoms. Therefore, any existing physical condition needs to be considered during diagnosis.3

Future possibilities in the diagnosis of depression comorbid with AD

Neuroimaging techniques have frequently been used to explore anatomic features and pathologic processes that link depression and AD. Identification of such mechanistic links between the 2 conditions may lead to biomarker-based diagnosis, stratification of disease, and prognosis, specifically for depression comorbid with AD.

The co-occurrence of depression and AD takes a huge toll on the quality of life of both patients and their caregivers. Therefore, it is critical to develop more reliable strategies for depression diagnosis and risk identification in AD so that appropriate and timely measures can be taken.


1. Galts CPC, Bettio LEB, Jewett DC, et al. Depression in neurodegenerative diseases: common mechanisms and current treatment options. Neurosci Biobehav Rev. 2019;102:56-84.

2. Gatchel JR, Rabin JS, Buckley RF, et al. Longitudinal association of depression symptoms with cognition and cortical amyloid among community-dwelling older adults. JAMA Netw Open. 2019;2(8):e198964.

3. Burke AD, Goldfarb D, Bollam P, Khokher S. Diagnosing and treating depression in patients with Alzheimer’s disease. Neurol Ther. 2019;8(2):325-350.