Alzheimer's Disease Part IV: Preventing and Slowing Down AD

The Princeton train conductor coming down the aisle punching the tickets of every passenger noticed the brilliant physicist, Dr. Albert Einstein frantically looking for his ticket. The conductor said, “Dr Einstein, I know who you are. I’m sure you purchased a ticket. Don’t worry about it.”

Einstein relied, “Young man, I too, know who I am. What I don’t know is where I’m going.”

As normal citizens we don’t know where our life is going, but there are ways to stop or slow down the Alzheimer’s train:

Stay physically fit

• In a study involving 4,600 men and women age 65 years or older those who exercised regularly reduced the chance of developing AD by 30%.
• Studies indicate that regular exercise builds brain cell synapses and improves brain blood flow. 

Reduce stress

• Stress reduction prevents cell death in the hippocampus, the memory switch of the brain. 
• Contemplative prayer, meditation, and yoga are stress reducers that can be incorporated into a daily schedule. 
• Cultivating friendships also reduces stress.

Reduce brain shrinkage with a “good fat” diet

• The risk of developing AD goes up with the number of calories in the diet. 
• Those individuals who consume the most calories double the risk of AD when compared with those who consumed a low calorie, good fat diet.

Drink 3 ½- 5 ounces of red wine each night (Baptists can eat red grapes.) 

• Resveratrol, abundant in grape seed and in red wine, is a powerful antioxidant. 
• Alcohol also dilates arteries by enhancing nitric oxide, just like Viagra.
• Viagra is dandy, but liquor is quicker
• A little wine increases desires, too much gives ceasefires

Take aspirin 

• Anti-inflammatory drugs (NSAID) such as aspirin, ibuprofen and naproxen prevent brain inflammation that plays an important role in the development of AD. 
• Several studies have shown that long-term NSAID use may reduce the risk of Alzheimer's disease by as much as 50%.

Consider estradiol for post-menopausal women

• Estrogen docking sites—places where estrogen attaches itself to brain tissue, including the hippocampus—have been identified indicating estrogen plays a role in memory and cognitive functioning in the brain. 
• Declining levels of estrogen have a negative impact on language skills, mood, concentration and attention. 
• Parenthetically, estrogen has a major role in preventing the development of osteoporosis in women. 
• Because estrogen replacement therapy may increase the risk for heart disease and certain cancers, each woman’s personal and family history must be evaluated before estrogen is prescribed. 
• Most experts recommend the use of natural, soy-based estrogens—estradiol—for replacement therapy because estradiol is the main type of estrogen made by the ovaries.

Hydrate 

• A Big Thicket East Texas doctor once said, “Most people don’t drink enough water and their brains shrivel-up.”

Taking these vitamins will help us remember how to put on our clothes when we are 103 years old:

• B Vitamins
• An MRI study showed that a group that failed to take B vitamins had significantly greater loss of brain tissue when compared to the group which did take B vitamins. 
• Vitamin B12 helps maintain the Myelin sheath, the covering and insulating layer of nerve cells. 
• Vitamin B6 helps the body produce neurotransmitters 
• Vitamin B3 helps brain neurons repair themselves.
•  Vitamin D
• Multiple studies have shown a "clear link" between a vitamin D deficiency and a risk for Alzheimer's.
• Vitamin D stimulates nerve growth within the brain,.
• Vitamin D is one of the nutrients which our body has difficulty producing as we age
• Almost 95% of those over the age of 65 are deficient in vitamin D

•  Vitamin E

• In a United States trial, 613 individuals with mild to moderate Alzheimer's disease were assigned to take either a vitamin E supplement or a placebo. At the end of the 24 month study, researchers found that individuals taking vitamin E showed that were able to complete everyday tasks that individuals in the placebo group failed to complete.

A growing number of herbal remedies and dietary supplements are promoted as memory enhancers 

• Claims about the safety and effectiveness of these products are based largely on testimonials, rather than scientific research.
• Although some may be valid candidates controversy abounds:
• Effectiveness and safety are unknown. 
• Purity is unknown. 
• There exists no guarantee that the products contain the ingredients or amounts listed on the label. 
• Dietary supplements can have serious interactions with prescribed medications. 

Brain boosters

• Crossword puzzles
• Jigsaw puzzles
• Word scrambles (e.g. nabir = brain)
• Drawing or painting
• Playing brain games (Simon Says, Charades, Cranium, Trivial Pursuit, Pictionary, Scattergories, Scrabble, Outwages, etc)
• Playing a musical instrument (Einstein played the violin. Look what it did for him.)
• Learning a foreign language (Texans can learn to speak American.)
• Memory work
• Memorizing Bible verses, Shakespeare, poems
• After a movie name four or five of the main characters
• Memorize countries and capitals
• Write a one-paragraph summary of a book or magazine article

If you follow all these suggestions you won't have time to "catch" Alzheimer's.

Alzheimer's Disease Part III: Treatment

Cicero told of Damocles who wished the pleasures of a king. Saracen magic placed him at the king’s table eating sumptuous food, drinking the finest wine and enjoying more pleasures than his imagination had conceived. Glancing upward, his eyes transfixed on a sword dangling by a single horsehair just above his head. Damocles turned pale. His hands trembled. His joy vanished as he realized that much pleasure brings much danger.

Perhaps the myth of Damocles over dramatizes the risk of Alzheimer’s. After all over 50% of 90-year-olds never experience the illness. Nonetheless as we grow older we sometimes contemplate the threat of Alzheimer’s dangling by a single horsehair just above our eyes’ imagination.

Scientists still search for a cure.  They’re looking for a little more horsehair for that sword.

The U.S. Food and Drug Administration (FDA) has approved five medications to treat the symptoms of Alzheimer's Disease (AD):

• Aricept (donepezil)—approved in 1996 for all mild to moderate stages of AD
• Can help AD patients do things longer
• Dose: 5 mg daily for one month then 10 mg daily
• Side effects are mild but occasionally consist of nausea, diarrhea, anorexia 
• Useless for severe AD
• Exelon (rivastigmine)—approved in 2000 for all stages
• Dose: Initial dose 1.5 mg twice daily then, if tolerated, 3 mg twice daily and gradually increase to the maximum dose of 6 mg twice daily until maximum benefit is reached.
• 70% of patients who responded poorly to Aricept responded to Exelon.
• As many as 40% of patients may develop intolerable nausea, vomiting, diarrhea and anorexia.
• Razadyne (galantamine)—approved in 2001 for mild to moderate AD
• Initial dose 4 mg twice daily. May gradually increase to 12 mg daily
• GI side effects predominate
• Namenda (memantine)—approved in 2003 for moderate to severe AD
• Dose: 5 mg daily, gradually increase to 10 mg twice daily
• First medication approved to treat severe AD
• Impressively benign side effects
• Namzaric (a combination of donepezil and memantine)—approved in 2014 for moderate to severe AD
• The first and only once-a day capsule that works on two pathways to fight symptoms of moderate to severe AD.
• Initial dose 7mg of memantine and 10 mg of donepezil gradually increase to maximum dose of 28 mg/10mg daily

How Medications for Alzheimer’s Work:

• Brain nerve cells (neurons) connect at the junction of neurons called synapses where tiny bursts of chemicals called neurotransmitters transfer information from one cell to another. AD impairs the function of several neurotransmitters. 
• The neurotransmitters acetylcholine and glutamate seem particularly important in AD.
• Cholinesterase inhibitors—Aricept (donepezil) and Razadyne (galantamine)—block acetylcholinesterase, an enzyme responsible for the normal decomposition of acetylcholine. This inhibition of acetylcholinesterase allows an increase of acetylcholine so that information is passed through the synapse more effectively.
• Exelon (rivastigmine) inhibits two enzymes, acetylcholinesterase and butyrylcholinesterase, increasing the effectiveness of acetylcholine.
• Namenda (memantine) works by regulating the activity of glutamate thus preventing excess calcium to flow into nerve cells that kill neurons. Restoring normal glutamate levels improves learning and memory.

Unfortunately these FDA approved medications fail to treat the underlying disease process or stop cell damage. Instead they merely slow the development of the disease.

Other medications may be useful in treating or preventing the AD. Evaluating the benefit-risk ration is especially important with these meds:

• Premarin(conjugated equine estrogen) improves verbal memory, vigilance and reasoning, and has been associated with decreased dementia risk.
• Contraindicated with blood clots in the calf or lung, infection of leg vessels, severe liver disease and estrogen-dependent cancer.
• 10-20 years of estrogen replacement gives a modest chance for breast cancer.
• Estrace (estradiol) has the same benefits and warnings as Premarin but the tablet is half as expensive.
• Eldepryl (selegiline) inhibits monoamine oxidase that breaks down neurotransmitters
• Serious side effect of a hypertensive crisis when certain foods are eaten
• Non-Steroid Anti-Inflammatory Drugs (NSAIDs) such as Aspiring, Motrin, Naprosyn 
• Clinical research indicates NSAIDs may help prevent AD. 
• Serious side effect: Gastric ulcers
• Statins—Lipitor, Mevacor, Zocor
• May reduce the production of beta-amyloid proteins that cause nerve cell death
• Serious side effect: Liver abnormalities

Medications for symptoms of AD:

• Rexulti is useful for paranoia and agitation. (See my blog entry for info on Rexulti.)
• Seroquel is useful for sedation and sleep in acutely agitated AD patients
• SSRIs, especially Zoloft or Celexa, are useful for AD depression 
• Trintellix, a non-SSRI, is my favorite AD antidepressant because it increases serotonin-7 that has been found to increase cognition.
• Trintellix has yet to catch on as "popular" antidepressant
• Academics would be displeased with Trintellix use in AD depression
• Nausea is a limiting factor
• See my blog entry on Trintellix for more information.
• Trazodone for sleep
• May have some efficacy in treating agitation and aggression associated with AD

Warning: Avoid benzodiazepines such as Valium, Xanax, Ativan and others 

• These medications can act as disinhibitors in the elderly resulting in increased agitation.
• Benzodiazepines often cause confusion in the elderly.
• One longitudinal study involving over 400 AD patients has shown long term use of benzodiazepines to be an associated with AD, not a cause for AD.
• Another longitudinal study of over 400 AD patients refuted these findings.
• Longitudinal studies become extremely complicated because complex statistical analysis is necessary for factoring out multiple variables.

 

Fortunately, 19 AD drugs are in Phase 3 clinical trails (people are taking the drug, not animals) that are on pace to launch in the next five years if proved to be safe and effective and if the FDA does not delay the process. 

Irony: The FDA has delayed many effective drugs that treat life-ending disease because of safety reasons. I guess the members failed college Logic 101. 

The FDA sword cuts off speedy development of AD medications.

Alzheimer's Disease Part II: Risks and Contributing Factors

Here's some good news and bad news for a 73-year-old United States citizen. The good news: According to actuary tables you will live to age 85 or older. The bad news: One out of three 85-year-olds have Alzheimer's Disease and the older we get the more likely we will develop Alzheimer's. Age is the greatest risk factor for Alzheimer's:

• An estimated 5.2 million Americans have Alzheimer's Disease.
• 200,000 individuals under age 60 have early onset Alzheimers.
• One in 9 people age 65 and older (11% of the population) have Alzheimer's.
• Of those with Alzheimer's, the vast majority (82%) are age 75 or older.
• The risk for Alzheimer's doubles every five years after age 65.
• Because women live longer, two-thirds of Americans with Alzheimer's are women.

Contributing factors in Alzheimer's Disease:

• Genetic mutation of chromosomes 1, 14, and 21 are associated with early onset Alzheimer's. An individual with a parent with these genetic mutations has a 50% chance of developing early onset Alzheimer's (under age 60). 
• Everyone inherits one form of the APOE gene from each parent. Less that 1% of Alzheimer's cases are due to these APOE genetic factors. 
• The ε3 form, the most common, occurs in 60% of the population and neither increases or decreases the risk for Alzheimer's.  
• Having the rare ε2 form may decrease one’s risk for Alzheimer's. 
• 30% of the population have the ε4 form. This form increases the risk of developing Alzheimer’s disease.  
• The accumulation of beta-amyloid plaques and tau tangles result in a cascade of invents in the brain that eventually kill neurons. Most researchers believe that the accumulation of plaques and tangles are an end-stage of the disease and not the cause of the disease. Nonetheless, the accumulation of this brain "trash" leads to additional brain cell destruction. 
• Immune cells called microglia try to destroy the invasion of plaques. These microglia release prostaglandins, C-reactive proteins and COX-2 enzymes stimulating inflammation that contributes to brain cell death.
• Accumulation of beta-amyloid plaque can damage mitochondria, structures that produce energy for the cells.When mitochondria malfunction they produce an overabundance of molecules called free radicals causing cell destruction.
• Beta-amyloid plaque may cause excessive amounts of calcium to enter neurons killing brain cells.

• Because estrogen protects against Alzheimer's, early menopause and hysterectomy contribute to Alzheimer's. Menopause marks the time for women to consider supplemental estrogen to protect against Alzheimer's, osteoporosis, wrinkles, and dry skin. In most cases the benefits of estrogen outweigh the risks. Those taking estrogens need careful monitoring, of course.
• High caloric intake promotes inflammation.
• "Super-size Me" advocates have an increased risk for Alzheimer's because trans-fats, snack food, and fried foods lower levels of good cholesterol and raise the levels of C-reactive protein, a substance that causes inflammation.
• Emotional stress contributes to the death of neurons in the hippocampus. The hippocampus (the tiny sea-horse shaped organ sitting near the middle of the brain) is the main memory switching station of the brain. After age 45, the hippocampus loses about 6% of its cells every ten years. Emotional stress exacerbate these losses.
• People who are physically inactive are more likely to develop Alzheimer's than those who exercise regularly.
• People with fewer years of education appear to be at higher risk for Alzheimer's. Statistics are misleading, however. One of the brightest professors at Texas A&M had severe life-ending Alzheimer's. We all know highly educated and extremely intelligent people with Alzheimer's.

Next: Treating Alzheimer's disease

Alzheimer's Disease Part I: Diagnosis

Because most of my readers reside in the age group that begins to worry about memory loss, I have decided to write a series of essays on Alzheimer's Disease. 

Alzheimer's disease is one of 75 or so medical illnesses that can cause memory impairment and cognitive decline. This all inclusive term for memory impairment is dementia. The causes of dementia can be recalled using the acrostic, COGNITIVE. (Making-up mnemonics enabled me to graduate from medical school.):

• Chronic traumatic encephalopathy--closed head injuries caused by blows to head
• Opiates and other drugs
• Grapes make alcohol that destroy brain cells causing memory impairment
• Neurological illnesses such as Parkinson's, multiple sclerosis, Huntington's
• Insipid infirmity--Alzheimer's is a slowly progressing memory defect leading to an infirm condition
• Tumors of the brain
• Infections of the brain such as meningitis, HIV, Jakob-Creutzfeldt
• Vascular defects such as strokes
• Endocrine abnormalities such as diabetes, thyroid and adrenal illnesses 

Of all the illnesses that cause dementia, Alzheimer's is the most common. Approximately 50% of people with dementia have Alzheimer's as the cause of their memory disturbance. About 10% of people with dementia have excessive alcohol intake as the cause of their cognitive decline. Another 10% of people with dementia have vascular causes--small strokes of the brain (multi-infarct strokes). The other 30% of dementias are caused by dozens of illnesses represented by the COGNITIVE acrostic. 

A study at Boston University School of Medicine showed that 110 of 111 autopsies conducted on professional football players had signs of chronic traumatic encephalopathy. More closed head injury investigations (car accidents, falls, physical abuse, sports) may move traumatic blows to the head as one of the leading causes of dementia. 

An initial sign of Alzheimer's disease may be depressive symptoms--waking in the middle of the night with the inability to return to sleep, appetite disturbance, decreased libido, poor concentration, and apathy. These depressive symptoms may mean brain cells are dying. Early treatment of depression may prevent or slow down the progression of Alzheimer's. Of course, older people can have primary depression unrelated to Alzheimer's. 

Alzheimer's begins insidiously:

• Short term memory begins to fade. 
• The Alzheimer's patient fails to recall events of the past few days---a phone call from the grandchildren, conversations with a friend--while recollections from long ago remain intact. 
• Names and telephone numbers are forgotten. 
• Attempts to cover up intellectual deficits result in social withdrawal, confabulation (making up stories), and exaggeration of personality traits. 
• Endeavors to complete tasks requiring logical reasoning produces anxiety and irritability. 
• Inhibitions vanish. 
• Planning deteriorates. 

Alzheimer's patients who function fairly well in the day may have a difficult time at night--the so called "sundown" syndrome. During the golden hour shadows lengthen. The fading light diminishes environmental cues. With increasing darkness Alzheimer's patients become disoriented. Confusion precipitates anger, agitation, paranoid delusions, illusions, and hallucinations.

As the illness progresses daytime confusion rivals nocturnal agitation. 

• Remote memory begins to fade. 
• Details regarding occupation, family life and childhood events grow fainter. 
• Eventually loved ones go unrecognized.
• Vulgar language, neglect of personal hygiene and disregard for conventional rules of conduct mark the progressive downhill course.
• As mental functions gradually deteriorate, imprecise vocabulary degenerates to incomprehensible speech.
• Eventually the names of body parts are forgotten.
• The insidious deterioration advances to anorexia, malnutrition, infection, loss of respiratory drive and death. 

Next: Causes, Contributors and Co-Conspirators of Alzheimer's Disease