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Alzheimer's disease: Trying to remember the future - (1/8/2020)

By Dr. Ron Gasbarro

The cruelest moniker

"Old Timer’s Disease." This rather heartless term was intended to be amusing, mainly because no one could remember the name of the condition first identified by German psychiatrist and pathologist Alois Alzheimer in 1906 [Berchtold, 1997]. Even though the name was a challenge for some, the condition, characterized by a decline in memory, was documented by Greek and Roman physicians over 2,500 years ago. Since then, the concept of senile dementia has evolved from the vague idea that mental deterioration occurred inevitably in old age, to a condition defined today by a diverse set of clinical and pathological features.

Are dementia and Alzheimer’s disease the same thing? 
Dementia is defined as a nonreversible decline in mental function [AARP, 2019]. The word is a catchall phrase that includes disorders that cause chronic memory loss, including Alzheimer's disease (AD), vascular dementia, alcohol-related dementia, Parkinson’s dementia, frontotemporal dementia, and organic brain syndrome.

In 2019, approximately 5.8 million Americans were living with AD [Alzheimer’s, 2019]. This number includes an estimated 5.6 million people age 65 and older and about 200,000 individuals under age 65 who have younger-onset AD. One in 10 people age 65 and older (10%) has Alzheimer's dementia. Almost two-thirds of Americans with Alzheimer's are women. Older African-Americans are about twice as likely to have Alzheimer's or other dementias as older Caucasians. Hispanics are about one and one-half times as likely to have Alzheimer's or other dementias as older Caucasians. By 2050, the number of people with Alzheimer’s dementia may grow to a projected 13.8 million, barring the development of medical breakthroughs to prevent, slow, or cure Alzheimer’s disease.

Alzheimer’s disease and the brain
We now know that there are specific pathological hallmarks of AD. The tau protein is abundant in neurons of the central nervous system [Lei, 2010]. These proteins become abnormal when beta-amyloid (Aβ) deposition and neurofibrillary tangles (NFTs) develop. These fat globs and snarls in the brain are similar to atherosclerosis when the circulatory system’s arteries become clogged with fat, cholesterol, and calcium plaques, impeding the flow of blood. As the arteries harden and become functionless, so do the brain cells when blocked with the gnk that results in AD.  

Through advancements in physiologic visualization, we can now see what is happening inside the brain. Functional and molecular nuclear medicine imaging with single-photon emission computed tomography (SPECT) and positron emission tomography (PET) techniques provides important information about these basic pathological developments, years before the appearance of clinical symptoms [Valotassiou, 2018]. 

Is the diagnosis dementia due to Alzheimer’s or something else? 
No single test exists that can specifically diagnose AD [Alzheimer’s, 2019]. Instead, physicians, often with the help of specialists such as neurologists, neuropsychologists, geriatricians and geriatric psychiatrists, employ a variety of strategies and tools to make a diagnosis. They include the following: 
Obtaining a medical and family history from the individual, including psychiatric history and history of cognitive and behavioral changes
Asking a family member to provide input about changes in thinking skills and behavior
Conducting imaging to rule out other potential causes of dementia symptoms, such as a tumor or certain vitamin deficiencies 
In some conditions, using brain imaging tools to find out if the individual has high levels of beta-amyloid; normal levels would imply that Alzheimer’s is not the cause of dementia. Hence, medications indicated for AD would not be useful in patients with other types of dementia. 

Fighting the disease with what we have
Presently, Alzheimer’s disease is incurable. However, we are learning how to tame it.

AD interrupts the “power lines” in the brain
The nerve cell, or neuron, is the principle player in the activity of the nervous system. It conveys information both electrically and chemically. Progressive damage to the brain’s neuron and subsequent loss of neurotransmitters – the chemicals that brain cells generate – cause AD [Stella, 2015]. Acetylcholine (AC) is one type of neurotransmitter. Normally, when a nerve cell releases AC, it grabs onto neighboring nerve cells to pass signals from cell to cell. Without enough AC, brain signals never reach their target and more memory and attention loss is experienced. Hence, the earliest anti-AD medications, called cholinesterase inhibitors (AChIs) or memory enhancers, aim to increase the amount of AC by blocking the enzyme (called cholinesterase) that destroys it. The AChIs entered the market in 1996 with donepezil (Aricept®). Donepezil was followed by rivastigmine (Exelon®), galantamine (Razadyne®, Reminyl®, et al.), and tacrine (Cognex®). 

Memantine (Namenda®) is classified as an NMDA (N-methyl-D-asparate) receptor antagonist [Stella, 2015]. NMDA allows for the transfer of electrical signals between brain cells and the spinal column. The drug’s usefulness in AD is based on the hypothesis that some AD symptoms are related to changes in NMDA receptors that allow for abnormal, excessive excitation of the receptors by glutamate, another neurotransmitter. Memantine works by binding to the NMDA receptor and preventing excessive excitation by glutamate. Currently, there are no other Alzheimer's medications that have this mechanism of action. 

Cognitive enhancers, including cholinesterase inhibitors and memantine, are used to treat dementia, but their effectiveness for mild cognitive impairment – as opposed to moderate and severe dementia – is not been fully elucidated. One meta-analysis of patients taking cognitive enhancers for mild cognitive impairment revealed that the medications did not improve cognition or function but were associated with a greater risk of gastrointestinal adverse reactions, including significant nausea, vomiting, diarrhea, anorexia/decreased appetite, and weight loss [Tricco, 2013]. The risk of dehydration increased secondary to prolonged vomiting or diarrhea. 

Attacking beta-amyloid plaques
Researchers have theorized that AD pathogenesis is driven by the production and deposition of the β-amyloid peptide (Aβ) deposits in the brain [Murphy, 2010]. Thus, research has focused on breaking up these deposits that cripple the flow of information from the brain to the rest of the body. One such drug, aducanumab, a monoclonal antibody, has been observed to have modest efficacy in reaching its target. However, sufficient evidence warrants additional studies of anti-amyloid agents [Tolar, 2019].

Eating all your choline? 
Researchers at Arizona State University investigated whether the dietary nutrient choline could alleviate the effects of Alzheimer's by studying AD mice [Arizona, 2019]. While all plant and animal cells require choline to maintain their structural integrity, scientists have long been aware that this nutrient is important for brain function. Studies in AD mice found that choline acts to protect the brain from AD in two ways [Velazquez, 2019]. First, choline blocks the production of beta-amyloid plaques. Second, choline dietary supplementation reduces the activation of microglia, which when overactive, can cause brain cell death. The study investigators noted that while the exact cause of AD is not fully know, a recent report showed that the increase in dementia cases may be linked to a life-long lack of dietary choline [Velazquez, 2019]. The authors noted that because choline is a very safe alternative compared to many medications, it is a strong candidate for AD prevention research. 

According to the United States Department of Agriculture (USDA), foods high in choline include soybeans, sunflower seeds, legumes, grains, brewer’s yeast, fish, iceberg lettuce, beef liver, beef steak, oats, flaxseeds, sesame seeds, and egg yolks. The most common form of choline supplement is lecithin, derived from soy. Lecithin is available in any health food store. 

What does the future have in store for AD?
The predictions are that the incidence of AD will increase exponentially over the next several decades. This is will be a drain on our healthcare budgets, as more people need medical and physical care. Yet, science marches on and once we can predict AD early, the chances of managing it skyrocket. 

Testing the spinal fluid
The inability for a nerve cell to transmit information to other nerve cells is an early pathologic sign of AD. Neurogranin is a postsynaptic neuronal protein that can be measured in the cerebrospinal fluid (CSF). Researchers have observed significantly more neurogranin in the CSF of AD patients, suggesting that the protein may be a powerful marker for diagnosis and prognosis of AD [Tarawneh, 2016]. However, because it is a more invasive procedure, the technique is usually reserved for patients who are in the “mild cognitive impairment” stage, when they still have relatively good memory and functioning.

Testing saliva
Be great if all one had to do is spit into a cup and a diagnosis of AD can be made decades before irreversible symptoms appear. While no such test is immediately forthcoming in that regard, researchers are assessing the value of a saliva test. Early studies on patients with mild dementia have shown that the degrees of salivation as well as the end products of oxidative stress and antioxidant levels correlate with mini mental state examination (MMSE) score [Choromanska, 2017]. The MMSE is a questionnaire used extensively in clinical and research to gauge cognitive impairment. 

Have some mushrooms with your tea!
A 2019 study suggested that people age 60 and older could lower their chance of mild cognitive impairment – a precursor of AD – by 43% if they consumed 5 to 10 ounces of mushrooms per week compared to those who ate less than 5 ounces [Feng, 2019]. The investigators explained that the amount of antioxidants in the fungi protected the brain against substances that destroy brain cells. 

The theory behind these “magic” mushrooms is that as food is metabolized into energy, free radicals are released. Free radicals are oxygen atoms with unpaired electrons that wreak havoc to cells, proteins and DNA as they search to pair up with other oxygen atoms. Replenishing antioxidants in the body, then, may help protect against this oxidative stress. 

Many other foods have antioxidants – dark chocolate, pecans, kale, etc. However, mushrooms, especially those of the wild porcini variety, have two extremely powerful antioxidants, ergothioneine and glutathione. In fact, countries that eat considerable amounts of mushrooms, such as Italy and France, have lower rates of AD, which Americans do [Kalaras, 2017]. These antioxidants will be studied more to assess whether they are directly responsible for curtailing damage to the brain.    

Is memory loss a reason to be afraid?
We now have ways to categorize the different stages of dementia [UNC, 2020]. The basic stages of dementia are as follows:

Very early signs
A biomarker is a measurable substance in the body whose presence is indicative of some phenomenon such as disease, infection, or environmental exposure. The biomarker may be present in the blood, urine, or cerebrospinal fluid. Biomarkers can indicate exposure to a substance, the presence of a disease, or the progression of a disease over time. An example of a biomarker in diagnosing Alzheimer’s disease is the tau protein. Such tools are critical to helping scientists detect and understand the very early signs and symptoms of dementia.

Mild Cognitive Impairment (MCI) 
MCI is when you are aging and developing memory problems greater than what is expected for your age. However, you are not experiencing personality changes or other problems that are characteristic of Alzheimer’s disease. Researchers cannot yet definitively say that people with MCI will or will not go on to develop Alzheimer’s disease, or if its progress to Alzheimer’s disease can be prevented or delayed. Studies have shown that if one is experiencing MCI and having trouble moving one’s legs and feet, one may be twice as likely to develop Alzheimer’s disease as a person without this movement symptom. [Hooghiemstra, 2017].

Mild Dementia
Signs and symptoms include memory loss, confusion about the location of familiar places, taking longer than usual to accomplish normal daily tasks, trouble handling money and paying bills, poor judgment leading to bad decisions, loss of spontaneity and sense of initiative, mood and personality changes, increased anxiety or aggression.

Moderate Dementia
Signs and symptoms include increased memory loss and confusion, shortened attention span, inappropriate angry outbursts, problem recognizing family and close friends, and difficulty with language (reading, writing, numbers). Also, there is an inability to learn new things or cope with unexpected situations, difficulty organizing thoughts and thinking logically, repetitive statements or movements, occasional muscle twitches, restlessness, agitation, anxiety, tearfulness, and wandering (especially in late afternoon or at night). Psychiatric symptoms include hallucinations, delusions, suspiciousness, paranoia, irritability, loss of impulse control, and an inability to carry out activities that involve multiple steps in sequence (getting dressed, making coffee, and setting the table).

Severe Dementia
Signs and symptoms include weight loss, seizures, skin infections, difficulty swallowing, increased sleep, groaning, moaning or grunting, lack of bladder or bowel control.

If you feel that your condition is not related to outside causes, or that you may fall under one of the above categories, you should consider making an appointment with a physician or other medical specialist.

Ron Gasbarro, PharmD, is a registered pharmacist, medical writer, and principal at Rx-Press.com. 



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