ASSOCIATION BETWEEN ALZHEIMER’S DISEASE
AND DEPRESSION
Haley Cates
Senior Thesis
University of Wyoming
Laramie, WY
Spring 2019
1. Alzheimer’s Disease Epidemiology
Alzheimer’s disease is the most common type of dementia and it accounts for approximately 60 to 70 percent of dementia cases. It is a neurodegenerative disorder that includes cognitive and functional deficits that gradually worsen (Apostolova, 2016), and is, in fact, the most common neurodegenerative disease in the United States. Additionally, it is the sixth most common cause of death and the fifth leading cause of death among people 65 years of age and older. During the last 30 years, mortality from AD has steadily increased (See Fig. 1), and it is now estimated that 5.4 million people in the US have the condition. The elderly are most at risk with AD - 65 is the age when clinical symptoms usually begin to occur (CDC, 2013). Almost two-thirds of AD diagnosed individuals are women (See Fig. 2) (Mielke et al., 2014). Although the greatest risk factor for AD is age, AD is not a natural progression of aging. While the precise cause is unknown, there are several risk factors: lack of cognitive reserve (education and occupational attainment are protective factors), cardiovascular risk factors (smoking,
hypertension, diabetes, and obesity), and lifestyle and psychosocial factors (depression, physical activity, and alcohol consumption) (Sosa-Ortiz et al., 2012).
Diagnosis of Alzheimer’s Disease
Recognizing the signs and symptoms of AD is critical for early diagnosis and treatment. The leading symptom of AD is memory decline. Early on, the memories that are most affected are recent episodic memories. Progression of the disease leads to all episodic memories being destroyed, and further along in the disease progression, this loss includes working and semantic memory. Language disturbance, decline in visuospatial skills, and executive dysfunction are all
cognitive disturbance symptoms that commonly occur in the earlier stages of AD and get worse as the disease progresses. The neuropsychiatric symptoms of AD are often the reason for institutionalization because of the burden they put on the caregiver; these symptoms include anxiety, irritability, depression, and apathy. In the later stages of the disease symptoms such as disinhibition, hallucinations, delusions, and appetite and sleep disturbances occur (Lanctôt et al., 2017).
The rate of Alzheimer’s disease progression varies from patient to patient, but in general, this progression can be categorized into stages. Some models group AD progression into three stages (See Fig. 3), while other models display up to seven stages (Thalhauser et al., 2012). In stage one there is no impairment; memory problems have not begun to occur and there is no evidence of dementia symptoms. In stage two decline begins to occur very mildly. Some memory lapses may begin to occur, but symptoms of dementia are still not present at this stage. Stage three is when cognitive decline becomes worse but is still mild. Friends and family may begin to notice some issues; doctors may be able to detect memory or concentration problems and diagnose the patient with early-stage AD. Some common stage three difficulties include misplacing valuable objects, problems with planning or organizing, problems recalling the right name or word, and forgetting material that was just read. Stage four is the last category of early-stage AD; the cognitive decline is considered moderate and a doctor should be able to clearly detect symptoms. Some of these symptoms include forgetting recent events, becoming moody or withdrawn, and forgetting personal history. Moderately severe cognitive decline is present in stage five. This stage is the first stage of mid-stage AD; noticeable gaps in memory begin to occur and individuals begin to need help with daily activities. Individuals at stage five may forget what day it is and need help choosing proper clothing. Stage six represents severe
cognitive decline. An individual’s memory begins to worsen dramatically, extensive help with daily activities is needed, and changes in personality occur. At this stage, individuals start to forget the name of their caregiver or spouse, wander or get lost, have trouble controlling their bladder or bowels, experience changes in sleep patterns, and begin to forget their personal history. The final stage of AD is stage seven, or the very severe cognitive decline stage. Movement control, response to the environment, and carrying on a conversation are all things that become very difficult. Muscles grow rigid, reflexes and swallowing become impaired, and individuals need full support eating and using the toilet (CBAS, 2018).
Pathophysiology
The precise cause of Alzheimer’s disease remains unknown, but there are several biological markers that can be noted. For example, patients with AD have beta-amyloid plaque build-up in the brain (See Fig. 4) (Murphy & Levine, 2010). Amyloid precursor protein (APP) is produced in neurons and metabolized very quickly. This metabolism leads to beta-amyloid peptide production (O’Brien & Wong, 2011). The production and secretion of beta-amyloid is facilitated by synaptic stimulation, so its production and secretion is normal in the brain. Beta-amyloid, by itself, is not toxic and may even have a physiological function, but when the beta-amyloid begins to aggregate into plaques it starts to affect the brain negatively (Gouras et al., 2015). The plaques accumulate in the extracellular space of the brain, disrupting neuronal function, and leading to neuronal death (Carter & Lippa, 2001). However, not all patients with beta amyloid plaques show symptoms of AD (Dickinson et al., 1992). Another pathological feature of AD is the deposition of tau protein in the form of intraneuronal fibrillary tangles (See Fig. 4). Tau protein belongs to a group of proteins called Microtubule-Associated Proteins
(MAPs); it keeps the cytoskeleton of the cell organized by promoting microtubule assembly. In Alzheimer’s disease, the tau protein is hyper-phosphorylated and aggregates into fibrillary tangles inside the neuron (Kolarova et al., 2012). Both of these AD pathological features lead to neuronal death and synaptic loss, causing cerebral atrophy (See Fig. 4) (Pini et al., 2016).
Apolipoprotein E4 (APOE4) is a commonly known genetic risk factor for Alzheimer’s disease. Approximately 65 to 80 percent of all patients with AD carry the APOE4 gene (Huang, 2011). The human apolipoprotein E (APOE) gene has three polymorphic alleles – E2, E3, and E4. The E2 allele has protective effects against AD, whereas the E4 allele has non-protective effects against AD. Apolipoprotein E has an important role in beta-amyloid metabolism, affecting the deposition of the protein. Beta-amyloid deposition is increased in carriers of the APOE4 gene, leading to an increase in cerebral beta-amyloid plaques. Apolipoprotein E also mediates lipid transport from one cell or tissue type to another, maintaining lipid homeostasis. Apolipoprotein E4 is associated with hypercholesterolemia and hyperlipidemia, leading to atherosclerosis, coronary heart disease, and stroke. These conditions all contribute to an increased risk of AD. Furthermore, APOE4 can trigger inflammatory cascades that result in damage to the brain’s vasculature, playing a role in AD pathogenesis (Liu et al., 2013).
Prevention of Alzheimer’s Disease
Nonpharmacological treatments alone, or in conjunction with other treatments play a role in the prevention of AD. Implementing certain lifestyle strategies such as physical activity, mental challenges, energy restriction, and socialization can be beneficial in the prevention of the disease (Mendiola-Precoma et al., 2016). It has been reported that physical exercise attenuates or limits the progression of neurodegenerative diseases. The increase of cardiac output leads to
increased cerebral blood flow, triggering neurobiological mechanisms in the brain. Repeating this process with regular exercise contributes to increased cerebral angiogenesis, neurogenesis, synaptogenesis, and neurotransmitter synthesis and improves cognition and mobility (Paillard et al., 2015).
Cognitively stimulating the brain through activities has been shown to increase neuronal density leading to increased cognitive function through brain plasticity. The increased number of neurons in the brain of an individual that participates in these cognitively stimulating tasks may provide them with enough reserve to perform cognitive tasks without impairment, even with the presence of numerous beta-amyloid plaques and tau tangles (Jedrziewski et al., 2015).
Brain pathophysiology and caloric restriction have been shown to be related in different AD mouse models. In these mice, a decrease of phosphorylated tau and amyloid-beta deposition was observed in the brain (Mendiola-Precoma et al., 2016). A study by Emily Dhurandhar and others found that treatment with a hunger-inducing ghrelin agonist reduces AD-related cognitive deficits and pathology; this is similar to the effect of caloric restriction on the development of AD pathology (2013).
Socialization has a large effect on our physical and mental well-being, as loneliness has been shown to be associated with depression, alcohol abuse, obesity, diabetes, hypertension, AD, and cancer. These effects of loneliness are risk factors for dementia itself (Mendiola-Precoma et al., 2016). In fact, loneliness is associated with more than a twofold risk of developing dementia because it is associated with cognition loss in older age. Rapid decline in global cognition, semantic memory, perceptual speed, and visuospatial ability occurs when an individual is lonely (Mushtaq et al., 2014).
2. Depression and Alzheimer’s Disease Co-Incidence
Depression and dementia have been considered mutually exclusive; however, there is a growing agreement that depression and dementia may coexist. Depression is a disorder of affect; Alzheimer’s disease is a disorder of cognition, however there are many symptoms that are shared between the two. Depressed patients can appear demented, with complaints of memory and cognition difficulties. Suffering from a dysphoric mood, losing interest in enjoyable activities, and experiencing difficulties with eating and sleeping can all make patients with dementia appear clinically depressed (Teri & Wagner, 1992). Additionally, approximately 50 percent of patients with AD may suffer from an episode of depression at least once during the course of their dementia (Lara et al., 2016). Because of the similar symptoms of depression and dementia it can be difficult to clinically distinguish between the two (See Fig. 5 and Fig. 6) or to elucidate possible causality. The most common cognitive deficits that are shown in both depression and dementia are memory, attention, processing speed, and executive functions. Apathy is another symptom that is present is both dementia and depression, and presents in 25 to 50 percent of patients with AD. Apathy is known as a syndrome of lack of motivation and is shown by diminished goal-directed motor behavior, diminished goal-directed cognition, and diminished emotional response. An association has been found between apathy and faster cognitive and functional decline (Gutzmann & Qazi, 2015). One study investigated AD patients and the association between their dementia and depression. There were ‘good’ days where the patients showed no signs of depression as well as improved global cognition, function, interest, and initiation. On ’bad’ days the patient’s depression was apparent, they were being verbally repetitive, and showed poor memory and increased agitation. To conclude, it was found that
some AD patients commonly experience temporary mood disturbances and this is what distinguishes AD patients with comorbid depression from those without comorbid depression (Rockwood et al., 2014).
Diagnosis of Depression
Many diagnostic scales have been developed to assess depression in AD including the Cornell scale for depression in dementia (CSDD), the dementia mood assessment scale (DMAS), and the neuropsychiatric inventory (NPI). The NPI scale is most commonly used to assess the psychopathology in dementia, not just depression (Gutzmann & Qazi, 2015). The assessment of ten behavioral disturbances occurring in dementia patients is conducted including the presence of irritability, apathy, agitation, euphoria, etc. Information is obtained through a series of screening questions given to the assessor by a caregiver of the patient (Cummings et al., 1994). Studies have shown that the NPI scale is valid and reliable and is more effective in evaluating a wider range of psychopathology than other existing instruments (de Medeiros et al., 2012).
Treatment of Depression
Antidepressants are the most common form of pharmacological treatment for depression in dementia patients, although efficacy is not confirmed. There is some evidence of symptom improvement from antidepressants, but comorbid conditions and differences in the
administration of the antidepressants have led to inconclusive findings in many studies. The preferred antidepressant treatment used in patients with dementia are selective serotonin reuptake inhibitors (SSRIs) (Gutzmann & Qazi, 2015). While the National Institute for Health and
for AD is started (Leicester, 2007), the American Psychiatric Association (APA) suggests an antidepressant trial as a treatment option (Rabins et al., 2007). Other pharmaceutical agents suggested for treatment include: venlafaxine (selective serotonin and norepinephrine reuptake inhibitor), mirtazapine (tetracyclic), and bupropion (aminoketone). Electroconvulsive therapy (ECT) is another possible treatment for demented patients suffering from moderate to severe depression (Gutzmann & Qazi, 2015). A study by Hausner and others (2011), showed an improvement in depressive symptoms with ECT; the cognitive deficits that arose during the therapy only lasted for a short period of time.
Interpersonal psychotherapy (IPT), cognitive behavioral therapy (CBT), and problem adaption therapy (PATH) are all nonpharmacological options for treatment of depression in individuals with dementia (Gutzmann and Qazi, 2015). Interpersonal psychotherapy is a short-term treatment that focuses on depressive symptom resolution through the evaluation of the patient’s interpersonal relationships. There are three phases of IPT. The first phase establishes the focus and identifies the difficulties in the patient’s interpersonal sphere. The second phase implements coping strategies and reviews the coping strategy successes and failures at the weekly sessions. The last phase concentrates on preparing the patient to carry on the coping strategies on their own after the IPT treatment (Miller, 2008).
Cognitive behavioral therapy (CBT) focuses on the idea that depression is a result of persistent negative and distorted perceptions about oneself, one’s experiences, and one’s future. This leads to the idea that depression can be treated by teaching the patient how to recognize their distortions and then modify these distortions. The social-learning theory of depression is also focused on the idea that depression is a behavior learned and maintained through positive and negative reinforcement contingencies, so depression can be treated by altering the
contingencies that maintain depressive behaviors and stimulate non-depressive behaviors by the introduction of new contingencies. For patients with severe cognitive impairment the caregiver is also present in the CBT sessions. The patient is encouraged to view their depression as
something that can be changed for the better, which restores hope. The role of the caregiver is immense, as they hold the responsibility of learning how to identify problems, plan behavioral intervention, and modify intervention to accommodate changes in the patient. The caregiver is responsible for involving the patient in pleasurable activities and documenting how this affects the patient’s mood. They are also responsible for decreasing problem behaviors and increasing the occurrence of incompatible behaviors so patients can work on their social skills (Teri & Gallagher-Thompson, 1991).
Problem adaption therapy (PATH) focuses on the patient, caregiver, and home environment and involves problem solving in its therapeutic framework. Individuals with dementia are often not able to meet the demands of their environment, leading to depression. Depression is reduced through problem solving and the patient’s adaption to their environment. Like CBT, caregiver participation is encouraged in PATH because the caregiver plays an important role in helping the patient carry out the therapy. The caregiver helps the patient solve everyday problems using environmental adaption techniques, and also increase the patient’s engagement in pleasurable activities (Kiosses et al., 2010).
3. Depression as a Risk Factor for Alzheimer’s Disease
The relationship between Major Depressive Disorder (MDD) and Alzheimer’s disease has been studied extensively with conflicting findings. Because depression may be a comorbid condition with AD, the timing of depression development within one’s lifetime is important
when discussing the possibility of depression being a risk fact for Alzheimer’s disease. If an individual develops depression 10 to 25 years or more before their AD onset, then the depression could be an independent risk factor for the AD. If depression develops in the year before
diagnosis of AD, the depression is considered a symptom of the AD (Sanmugam, 2015). Many studies have suggested that Major Depressive Disorder can be considered a risk factor for AD. In the Mirage study the greatest association between depression and AD
development was in the subjects that experienced depression within one year of their AD onset, suggesting that the subject’s depression may have been a symptom of the AD. However, there was still an association with the subjects whose depression occurred more than one year before the AD onset, although the association was lower. Depressive symptoms that occurred in
subjects more than twenty-five years before their AD onset still had modest association between their depression and AD development (Green et al., 2003).
A study conducted by Speck, and others (1995), analyzed the relationship between AD and depression using 294 patients with a mean age of 78.5 years old. These patients were chosen by conducting a risk factor interview on those who had a diagnosis of dementia, and a diagnosis of probable Alzheimer’s disease. 300 subjects were selected as controls by conducting a brief cognitive exam to confirm no presence of dementia. Data was collected through in-person interviews and a positive correlation between depression and dementia was found. The results suggested that depression occurring ten or more years before onset increases the risk for AD and there is a critical time in which depression can influence AD risk.
In contrast, however, several studies have concluded that depression is not a risk factor for AD, including a study by Singh-Manoux, and others (2017). This study was a 28-year follow-up study (1985 to 2013) that started with the recruitment of 10,189 people, 35 to 55 years of age.
The subject’s depressive symptoms were assessed on nine occasions during the study using questionnaires. It was found that those reporting depressive symptoms in the early phase of the study (1985) did not have significantly increased risk for dementia; however, those reporting depressive symptoms in the late phase of the study (2003) had an increased risk for dementia. Their finding suggests that depression is a prodromal feature of dementia, not a risk factor.
Also, a community-based cohort study was conducted using 288 participants with a mean age of 77.52 years old. All participants were assessed for abnormalities in cognition and mood in 1998 and deemed cognitively normal, but later some experienced depressive mood disturbances. Over seven years, those who developed dementia (48 participants) were evaluated and it was found that there was no strong evidence to support the hypothesis that depression was linked to the development of dementia (Becker et al., 2009).
Modifiable Risk Factors
Findings suggest that up to 50 percent of AD cases are possibly attributed to modifiable risk factors; most likely, these findings are similar for all-cause dementia. The modifiable risk factor that contributed to the largest proportion of AD cases worldwide was low education. Mental stimulation is important in helping to build a cognitive reserve, which then enables individuals to continue normally functioning despite experiencing neurodegenerative changes (Stern, 2002). Potentially, millions of symptomatic AD cases worldwide could be prevented if educational opportunities throughout life could be enhanced (Barnes & Yaffe, 2011). Smoking contributed to the second largest number of AD cases worldwide due to the increased prevalence of vascular disease. Tobacco smoke also contains hundreds of neurotoxins that may contribute to AD due to oxidative stress, inflammatory processes, and other mechanisms (Swan
&Lessov-Schlaggar, 2007). The third largest proportion of AD cases worldwide and first in the USA was due to physical inactivity. Several cardiovascular risk factors such as diabetes, hypertension, and obesity – all of which can be associated with low physical activity – are also risk factors for dementia (Profenno et al., 2010). Physical activity is also beneficial for improving brain structure and function (Cotman et al., 2007). Animal studies have shown structural changes in the brain at the cellular level (neurogenesis, gliogenesis, synaptogenesis, and angiogenesis) and the
molecular level (neurotransmission system alteration and the increase of some neurotrophic factors). Functional differences have been shown with improvements in spatial abilities and executive functions as a result of physical activity (Mandolesi et al., 2018). Depression
contributed to the second largest proportion of AD cases in the US and fourth largest worldwide. Vascular disease and depression have a reciprocal relationship; vascular disease has been
hypothesized as a potential mechanism by which depression increases dementia and cognitive impairment risk (Vermeer et al., 2003). Alteration in cognitive function may be due to an increase is stress-related hormones, lower levels of neuronal growth factors, and a reduction in hippocampal volume, all of which are also associated with depression (Alexopoulos, 2003).
If depression is a risk factor for developing dementia, then one must wonder whether treating the depression will decrease the risk. As mentioned, there is evidence that depression can lead to loss of hippocampal volume, especially when depressive symptoms are persistent. It has also been found that depression may contribute to cellular ageing acceleration. These cognitive changes can result in reduced cognitive function, ultimately leading to dementia. Older adults with depression that receive successful treatment show improved cognitive performance (Almeida et al., 2017). Since an estimated 5 to 11 percent of Alzheimer’s disease cases may be attributed to depression (Norton et al., 2014), it is hypothesized that if the depression in these
cases could be prevented or properly treated, the prevalence of dementia in the population would be reduced by the same amount. Indeed, the results of a 14-year longitudinal study of older men not only confirmed depression as a risk factor for dementia but also found that the severity of the depressive symptoms was correlated with the risk of dementia – i.e. men with more severe symptoms of depression had a greater risk for dementia. Unfortunately, the conclusion was made that the use of antidepressants did not decrease the risk of developing dementia (2017).
4. Conclusion
Further research is needed to understand the individual etiologies of Alzheimer’s disease and depression in order to understand their connection. In particular, prospective studies that control for all other diseases are difficult to conduct, but needed to fully understand the connection between AD and depression. Furthermore, removing the societal stigma of
depression may allow for increased diagnosis and participation in studies on the mental illness. Ideas for future studies include: looking into the treatment of depression and whether it delays the onset of AD, and researching the effect of certain activities, such as music and dance, on the symptoms of AD.
The participation of individuals in the community is important in improving the moods of the elderly. Taking advantage of volunteer opportunities and providing these opportunities through clubs and organizations could help improve social interaction between dementia patients and others. Providing social support will not only help these patients, but also help raise
awareness.
Appendix
Figure 1 shows percentage changes in causes of death between 2000 and 2013. (https://www.sciencedirect.com/science/article/pii/S1552526016000856)
Figure 2 shows Alzheimer’s disease risk by age and sex.
Figure 3 shows the three stages of Alzheimer’s disease.
(http://www.pharmacytimes.com/publications/issue/2014/january2014/alzheimers-disease-a-disease-of-deterioration)
Figure 4 shows the pathophysiology of a normal brain versus a brain with Alzheimer’s disease. (http://alzheimer-organizacional.wikia.com/wiki/Alzheimer_organizacional_Wiki)
Figure 5 shows brain activity (using PET scans) as a patient’s Alzheimer’s disease progresses. (https://radiologyregional.com/radiologyregional/index.php?option=com_content&view=article
&id=159&Itemid=100091)
Figure 6 shows brain activity (using PET scans) of a patient not in a depressive episode and a patient in a depressive episode.
(https://www.quora.com/Does-depression-cause-permanent-brain-damage-Ive-been-depressed-for-5-years-now)
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