by Dr Manjari Murali
I recently had the pleasure of meeting a nice lady of retirement age, who we shall call Patty. I typically enjoy talking to older adults because they have interesting stories to tell, and they have a knack of giving advice without making you feel like a disobedient child. In this case however, I was unable to carry on a conversation, partly because I was humbled by Patty’s situation, and partly because I feared I might find myself in her place later in life. I met Patty at the doctor’s office where she was being diagnosed with probable early-stage Alzheimer’s disease.
At first glance, Patty seemed like a normal older adult, but her test results where indicating otherwise. Except for being on long-term antidepressant therapy, Patty seemed healthy. It is not uncommon for a person of child-rearing age to experience episodes of depression as a consequence of stress. This combined with the current scientific understanding that the neuropathology of Alzheimer’s disease begins at least 10-15 years before the onset of dementia, got me seriously thinking about my risk of developing the disease. So I researched the biomedical literature for a possible link between depression and Alzheimer’s disease, and low and behold I found one!
Alzheimer’s disease is a degenerative brain disorder that affects memory, thinking, language skills, and behavior. It develops progressively over a number of years, such that a person in advanced stages of the disease is heavily dependent on their caregivers for activities of daily living. The molecular abnormalities of the disease begin well before the first clinical signs of dementia appear, which makes early diagnosis difficult. To add insult to injury, we have not yet identified the cause(s) of the disease, and no curative or disease-modifying treatment currently exists. Approximately 35.6 million people live with dementia today, and this number is expected to double every 20 years. The statistics together with the profound impact Alzheimer’s disease has on affected families, the health care system, and society at large have created an urgent need to develop effective treatment.
Scientists now agree that we need to return to the neurological beginnings of Alzheimer’s disease and identify the root cause(s) to develop a cure. To identify the root cause, scientists should examine altered functional and structural features in the Alzheimer’s brain compared to the normal aged brain
Even at the first signs of memory loss, there are heavy plaque and tangle deposits (the hallmark features of Alzheimer’s disease – see animation) in the brain. In 1996, Dr Dennis Selkoe of Brigham and Women’s Hospital in Boston proposed the famous amyloid hypothesis, which states that accumulation of Aβ42 (the main component of plaques) initiates biological events that cause synaptic changes, neurotransmitter loss, tangle formation, cell death, and inflammation. Critics however, argue that amyloid deposits might be the result of cellular dysfunction caused by proceeding and yet undiscovered biological events.
Medical conditions that often co-exist with Alzheimer’s disease can provide valuable clues to the earliest neurological events that trigger Alzheimer’s. Clinical depression is one such condition. People with a history of depression are vulnerable to developing Alzheimer’s, and people in the early stages of clinical Alzheimer’s often suffer from depression. These observations indicate that depression and Alzheimer’s disease might share common biological origins. Dr Susana Azner and Dr Gitte Knudson of the University of Copenhagen propose that stressful life events which increase glucocorticoid hormone levels in the hippocampus, a brain region involved in learning, disrupt synaptic activity in this region. These altered molecular mechanisms combined with genetic vulnerability might predispose an individual to develop depression and Alzheimer’s disease.
This leaves us with the question, “Is there a relationship between stress, synaptic dysfunction, and Aβ?” I believe that Dr Robert Malinow’s group has provided evidence for a possible converging point between Aβ and these earlier biological events. They discovered that synaptic activity (which can be altered by stress) modulates Aβ production in the hippocampus, and increased Aβ levels cause long-term depression, a physiological mechanism of learning. This in turn decreases synaptic activity and weakens learning and memory.
Much research is still required to verify if stress, synaptic activity, and Aβ constitute the original sequence of biological events that trigger Alzheimer’s disease. Nevertheless, I believe this is a plausible beginning.
Dr Manjari Murali lives in the US and is a published author, college instructor, and an independent contractor for the Alzheimer’s Association
Aznar S & Knudson GM. (2011) Depression and Alzheimer’s Disease: Is Stress the Initiating Factor in a Common Neuropathological Cascade? J Alzheimers Dis. 23(2): 177-93. DOI: 10.3233/JAD-2010-100390.
Hsieh H, Boehm J, Sato C, Iwatsubo T, Tomita T, Sisodia S, & Malinow R. (2006) AMPAR removal underlies Abeta-induced synaptic depression and dendritic spine loss. Neuron, 52(5), 831-43. PMID: 17145504
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