Did you know there is a relationship between Alzheimer’s & depression?
In the US, Alzheimer’s Disease (AD) is the sixth leading cause of death with greater than 5 million people currently living with the disease. Since the year 2000, deaths from cardiovascular disease have decreased by 14% while there have been an 89% increase in deaths caused by Alzheimer’s. Of people aged over 65 years, one out of every ten is afflicted.
Alzheimer’s disease is a progressive, irreversible brain disorder that was first described in 1906 by Dr. Alois Alzheimer. He observed that characteristic plaques and tangles in the brain tissue of a woman who died of an unusual mental illness.
AD affects memory and cognitive skills, eventually leading to difficulty performing even simple tasks. In the pre-symptomatic stage, beta-amyloid plaques and neurofibrillary tangles (accumulations of tau) build up in certain brain areas causing healthy neurons to work less efficiently. Neurons lose the ability to communicate and function, leading to neuronal death. It appears to start in the hippocampus and entorhinal cortex, areas of the brain that are responsible for forming new memories. Mild cognitive impairment starts in early stages when brain regions shrink as more and more neurons die. Symptoms progress as more damage is done and the brain shrinks further.
Early onset AD accounts for less than 5% of patients with AD and affects people aged 30-60 years old. A number of different single-gene mutations has been observed on chromosomes 21, 14 and 1. Abnormal protein has been found as a result of each of these mutations. Mutations on chromosome 21 cause the formation of abnormal amyloid precursor protein (APP). Mutations on chromosome 14 lead to production of abnormal presenilin 1 while those on chromosome 1 cause production of abnormal presenilin 2. All three genetic mutations lead to a breakdown of APP, generating harmful amyloid plaques.
Late-onset AD (LOAD) is multi-factorial with several genes possibly involved. Non-genetic risk factors such as female gender, limited early childhood education, head trauma, cerebrovascular disease, elevated cholesterol, and smoking have been implicated, but evidence is still lacking. Age is the only risk factor that has been well established. It is suspected that susceptibility for LOAD occurs at multiple genetic locations. The APOE gene on chromosome 19q13 has been observed to be an important risk factor. The APOE*3 allele and the APOE*4 allele seem to increase LOAD risk while APOE*2 decreases risk. LOAD risk has also been observed to increase with a rare missense mutation at codon 28. Genome-wide studies have been conducted in multiple countries. These studies demonstrate that multiple genes are implicated in LOAD and there is a high degree of consistency between linkage and association studies concerning the location of AD genes.
Link between Alzheimer’s and Depression
Neuropsychiatric complications effect 80% of patients with dementia. These sequalae can lead to problems with activities of daily living, rapid cognitive decline, impaired quality of life, earlier nursing home placement and caregiver burnout. Challenges of neuropsychiatric conditions include wandering, anxiety, depression, aggression, resistance to hygienic care, hoarding, social withdrawal, sleep abnormalities, sundowning, abnormal sexual behavior, repetitive questioning, disruptive vocalizations, voiding in inappropriate places, and refusing to take medications/eat/drink.
In an interesting study published in JAMA, researchers concluded that patients with mild cognitive deficiency and depression were more than twice as likely to develop AD as those without depression. Especially at risk are those patients who displayed a resistance to antidepressant medication. Depression is frequently seen in patients with AD and, in fact, it is estimated that between 22.5% and 54.5% of AD patients also are diagnosed with major depression. In one population-based study, 320 patients with mild cognitive insufficiency were investigated and 43% were found to exhibit some neuropsychiatric symptoms with depression being observed in 20% of those.
Late-life depression has been shown to increase the risk of dementia, particularly AD and vascular dementia. A meta-analysis was performed and verified this association, with the incidence of vascular dementia being slighter higher than AD. Adults with late-life depression demonstrate varying degrees of cognitive impairment which may or may not improve with antidepressant medication. The authors of this study report that the results indicate the need for further studies to be done to determine whether prevention of depression would have any impact on onset of dementia.
A study published in the International Journal of Geriatric Psychiatry showed a strong association between depressive symptoms and cognitive decline. These researchers found that the depressive symptoms develop long before any signs of dementia. Based on the results of this study, the researchers felt that a test could be developed that could be used to determine which patients would go on to develop dementia. Additionally, therapies could be developed to treat the depression and slow the progression of cognitive decline.
Often, it is not easy to diagnose depression in a patient with AD. It is suspected that they may share some common pathway in development. Signs and symptoms may be indistinguishable. The common pathophysiology between AD and depression is not completely understood. In both diseases, damage to the neurotransmitter systems is observed. In AD, the cholinergic pathway is most often involved whereas, in depression, the pathways involving serotonin and noradrenaline are more often affected. Another important shared pathophysiology involves invisible microvascular damage in strategic tracts of white matter. In both disease, hippocampal atrophy is a feature. It has been suggested that chronic stress-related hypercortisolism plays a role in hippocampal neuronal death.
Treating depression in patients with Alzheimer’s
There are several treatment options available for depression in patients with AD. However, there are few controlled studies and little empirical data to support any of these treatments. One of the problems with studies is lack of agreement on defining cognitive impairment. Additionally, researchers focus on different depressive symptoms leading to lack of unity in study results. The cited paper examines eight placebo controlled trials of antidepressants from different classes. Results were contradictory with 4 of the 8 studies showing efficacy in the treatment of depression in the setting of AD. The other four studies showed no efficacy. However, there was a reduction in depressive symptoms of 50-75% and a 30-60% mean reduction in standardized scale scores with the use of antidepressants. Many of these studies revealed a significant placebo response, most likely due to the relapsing-remitting nature of AD. Electroconvulsant therapy (ECT) for the treatment of depression in AD is widely considered safe, although there is not much data supporting this. However, high rates of delirium have been reported after treatments of ECT. Some studies have additionally demonstrated that it may improve cognitive decline.
While AD remains one of the worlds’ most common disorders and one of its biggest killers, we can only expect that problem to worsen in the US as baby boomers age. While we gained a library of knowledge into this disorder, it still remains a vague, complicated maze that we need to work our way out of. Treatments for AD have not changed much over the past decade and as it currently stands, there is no treatment. AD patients can only expect to experience cognitive decline. It is clear from multitudes of research that we need to develop and find a cure to treat AD and all its sequalae. It is causing a heavy toll not just on the victims but the caretakers as well.
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About the Author
Linda Girgis MD, FAAFP is a family physician practicing in South River, New Jersey. She was voted one of the top 5 healthcare bloggers in 2016. Follow her on twitter @DrLindaMD.