Last updated: January 2021
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Understanding Alzheimer’s Disease
Alzheimer’s disease is a neurodegenerative disease that causes the loss of memory, language, and reasoning skills, and it eventually interferes with the ability to carry out simple tasks. There is currently no medically accepted way to prevent, treat, or cure the disease—medical practice focuses on the management of symptoms. However, there are compelling diet, lifestyle, and medical approaches that support quality of life—and offer hope for delaying disease progression. And research scientists are following multiple leads to find ways to prevent and to treat the disease.
Memory loss is normal as you age. It’s normal to forget why you walked into a room and then remember later. It’s also normal to forget names and occasionally have a hard time finding a word. When a person can’t have a conversation because they can’t find the words or they use the wrong word—“tongs” instead of “scissors”—it’s a sign that something else is up.
Early Alzheimer’s disease: The first sign of Alzheimer’s disease is mild cognitive impairment (MCI), in which cognitive abilities—including language, learning, memory, and reasoning—are impaired more than would be expected as a result of aging, but people can still function independently. MCI can also be caused by other kinds of dementia, or it could be due to a medication or some other treatable cause. According to the Alzheimer’s Association, the following are early warning signs and symptoms of Alzheimer’s disease that should be discussed with your doctor (Alzheimer’s Association, 2019a):
•Asking the same question over and over and forgetting recently learned information
•Trouble working with numbers
•Taking longer to do tasks than normal
•Being confused about dates and seasons
•Problems with writing or speaking, struggling to continue a conversation
•Losing things, being unable to retrace steps to find them, accusing others of stealing
•Poor judgment about money
•Not taking care of grooming
•Personality changes—becoming confused, suspicious, anxious, depressed, fearful
Moderate Alzheimer’s disease: Alzheimer’s eventually progresses to a moderate stage that can last for a number of years. Confusion, memory loss, fear, suspicion, and frustration become worse. People may wander off and get lost. They may start sleeping during the day and waking at night. They might not be able to control their bladder and bowels. In this stage, people need help with daily living.
Severe Alzheimer’s disease: In late-stage disease people may need around-the-clock care. They may not be able to carry on a conversation or control their movements. They tend to get infections, especially pneumonia. People live for an average of four to eight years after they are initially diagnosed but can live much longer (Alzheimer’s Association, n.d.).
How Many People Are Affected by Alzheimer’s Disease?
In the US, Alzheimer’s disease is the fifth leading cause of death for women and the eighth for men. The WHO estimates that Alzheimer’s is responsible for 60 to 70 percent of the 50 million cases of dementia worldwide. Over two thirds of the 5 million Americans with this disease are women. Both sex and gender affect the outcomes of many diseases. Are rates of Alzheimer’s disease higher in women only because we tend to live longer? We don’t know the answer to this question yet (Nebel et al., 2018; Snyder et al., 2016).
Potential Causes of Alzheimer’s Disease and Related Health Concerns
Most cases of Alzheimer’s disease are believed to be caused by a combination of genetic, lifestyle, and environmental factors. Less than 1 percent of cases are exclusively genetic and aren’t affected by lifestyle. There appear to be multiple biological processes that can go wrong in the brain in Alzheimer’s disease, meaning that the cause of the disease may vary from person to person.
What defines Alzheimer’s disease and distinguishes it from other causes of dementia are two abnormal structures—plaque containing beta-amyloid and tangles containing a protein called tau. In addition, the brain of a person with advanced Alzheimer’s is atrophied—it has shrunk due to the death of neurons—and it contains dying neurons and debris from dead neurons, as well as signs of inflammation (Alzheimer’s Association, 2017; Strobel, 2019b).
What Causes Dementia?
“Dementia” is a general term for loss of memory, thinking, behavior, and ability to carry out normal daily activities. There are different kinds of dementia and reasons for cognitive impairment other than Alzheimer’s disease: Dementia can result from a buildup of deposits called Lewy bodies or of a protein called TDP-43. Parts of the brain may have a poor blood supply due to a stroke, either from a clogged blood vessel or from a leaky blood vessel. Short-lasting strokes called transient ischemic attacks can also disrupt the blood supply to parts of the brain. These can all cause neurons to die. And more than one of these destructive processes are likely to be going on simultaneously (Power et al., 2018).
BETA-AMYLOID PLAQUE AND TAU TANGLES
In Alzheimer’s disease a protein fragment called beta-amyloid accumulates in plaques outside of neurons. These plaques are thought to contribute to the destruction of nerve-nerve connections (synapses) and to cell death. Beta-amyloid comes from the breakdown of a protein called amyloid precursor protein (APP), and rare mutations in APP always lead to early onset Alzheimer’s disease (Alzheimer’s Association, 2017).
Down Syndrome and Alzheimer’s Disease
People with Down syndrome are more likely than average to develop Alzheimer’s, possibly because of the extra copy of chromosome twenty-one, which includes the gene coding for APP (Alzheimer’s Association, 2017).
In Alzheimer’s disease, the microglial cells and astrocytes that normally clean up amyloid plaque don’t seem to be doing their job. Some of this may be due to a defect in a gene called TREM2, which should be directing microglia to take action (National Institute on Aging, 2017).
Also characteristic of Alzheimer’s is the accumulation inside neurons of tau tangles—made from an abnormal form of a protein called tau. The tangles are thought to keep neurons from transporting nutrients and other molecules necessary for survival (National Institute on Aging, 2017).
COMPROMISED BLOOD SUPPLY
In addition to the characteristic tangles and plaque in and around neurons, in Alzheimer’s disease there are frequently pathologies that reduce the blood supply to the brain, including plaque in blood vessels and ministrokes. Further, the major fuel for the brain, glucose, does not seem to be able to get into the brain normally, and glucose metabolism is reduced (National Institute on Aging, 2017).
Researchers analyzed the results of hundreds of studies to identify factors associated with the risk of developing Alzheimer’s disease. They took into account information coming from controlled trials and from observational studies. Observational, or epidemiological, studies look at large populations of people to try to identify factors that correlate with developing Alzheimer’s disease.
From the observational studies, factors that strongly correlated with lower rates of Alzheimer’s disease were more years of education early in life, greater cognitive activity later in life, and increased body mass index in late life. A higher risk of Alzheimer’s was strongly correlated with depression, diabetes, stress, high blood pressure, head trauma, midlife obesity, coronary artery bypass surgery, and orthostatic hypotension, that is, a drop in blood pressure when standing up after lying down. The authors concluded that a multipronged approach to address all of these factors is appropriate (Yu, et al., 2020).
How Alzheimer’s Disease Is Diagnosed
The way to diagnose Alzheimer’s disease with absolute certainty is through a brain autopsy and the finding of amyloid and tau buildup. This is impractical. Here are some alternatives: Unless a clinical exam is clear, cognitive tests will be used to assess memory and brain function. The Alzheimer’s disease assessment scale-cognitive subscale (ADAS-Cog) is the standard measurement used to measure changes in Alzheimer’s disease clinical trials. The Mini-Mental State Exam (MMSE), Addenbrooke’s cognitive examination, and the Montreal Cognitive Assessment are also validated tests; online tests may not be as accurate. Brain imaging tests, such as a PET scan, can help confirm a diagnosis but are not always clinically available and may not be covered by insurance.
It should not be too long before a reliable blood test for beta-amyloid is available commercially; this will make diagnosis much simpler. Blood levels of tau have also been shown to be diagnostic of Alzheimer’s, but this test is not yet available in clinics (Kueper et al., 2018; Livingston et al., 2017; Nakamura et al., 2018; Thijssen et al., 2020)
In 2011, the National Institute on Aging and the Alzheimer’s Association released new diagnostic guidelines for Alzheimer’s:
•Alzheimer’s disease is defined by a gradually developing inability to function at work and home that isn’t otherwise explained.
•An Alzheimer’s disease diagnosis requires at least two of the following: inability to remember new information; inability to handle tasks or make decisions; impaired visuospatial abilities, such as recognizing faces or finding things; impairments with language—speaking, writing, reading—such as an inability to find common words; and changes in personality, such as agitation or withdrawal.
•If cognitive impairment is present but someone is able to function at work and home, they may be judged to have MCI, which may or may not progress to Alzheimer’s disease.
•Other possibilities must be ruled out, such as stroke, other cerebrovascular disease, medications, depression, head trauma, and Lewy body disease.
•Biomarkers can be used to increase the certainty of an Alzheimer’s disease diagnosis, but these tests are not required for diagnosis, are not available in all clinics, and are not yet standardized.
•Low beta-amyloid peptide in the cerebrospinal fluid (CSF)
•PET imaging of brain amyloid
•Elevated tau or phosphorylated tau in the CSF
•Low brain uptake of glucose by PET imaging
•Brain atrophy in certain regions as measured by MRI
(McKhann et al., 2011).
It’s debated in medical circles just how useful the currently imperfect genetic testing is, but rapid advances are being made that seem worth keeping up with. Rare mutations in a protein called presenilin 1 always seems to result in early onset Alzheimer’s disease. Mutations in presenilin 2 results in early onset Alzheimer’s disease about 95 percent of the time. So if you have Alzheimer’s disease symptoms in middle age and have a family history of the disease, your neurologist may order gene tests. The presenilins are enzymes that generate beta-amyloid peptide from APP.
Information about risk level can also come from the gene—APOE4—coding for a protein called apo E4. Apo E4 appears to cause a breakdown of the blood-brain barrier. The majority of people in the US have zero copies of the APOE4 gene. Having one copy increases the risk of developing Alzheimer’s around threefold, and two copies of the APOE4 gene increases risk by around tenfold. There are several problems with tests for the APOE4 gene, and it is not necessarily accepted as a useful test to predict disease risk, so your doctor may or may not want to order it. Changes in Food and Drug Administration (FDA) regulations now allow 23andMe to tell you whether or not you have the APOE4 gene if you buy the Health and Ancestry Service. The increased risk associated with APOE4 may be attenuated in people who also have one copy of a gene called KLOTHO (Belloy et al., 2020; Montagne et al., 2020).
DashGenomics has its own proprietary analysis of the genetic data you get from 23andMe or Ancestry.com, and it will provide you with a risk score, but again, this is not a validated clinical test. Researchers are actively trying to nail down more about the contribution of specific genes to Alzheimer’s disease, and the more volunteers they have to provide clinical data, the better. Which tests are commercially available and which are available only as a part of a research project is continually changing in this fast-moving field. People with cognitive impairment can discuss with their neurologist which genetic tests they think will be useful (Alzheimer’s Association, 2017; Desikan et al., 2017; Mayo Clinic Laboratories, 2019; Murphy & LeVine, 2010; Strobel, 2019a).
Dietary Changes for Alzheimer’s Disease
In the early stages of dementia, it’s difficult to know whether the diagnosis is Alzheimer’s disease or some other type of dementia, and we do not have specific treatments or diets tailored to specific types of dementia. An exception to this may be when the brain isn’t getting enough blood because of diseased blood vessels, as we know quite a bit about diet and cardiovascular health. It’s important not only to provide neurons with optimal nutritional support but to be proactive about cardiovascular health.
A NUTRIENT-RICH DIET FOR NEURONAL HEALTH
The most basic way to support the health of your neurons is to ensure optimal nourishment. A nutrient-rich diet consists of whole foods, not processed foods. When whole plant foods are turned into flour and sugar, magnesium, potassium, and B vitamins are lost, and an opportunity to provide these neuron-supporting nutrients to the brain is also lost.
Nutrients that are especially important for brain function include magnesium, the B vitamins (thiamine, riboflavin, niacin, folate, B6, and B12), lutein, and zeaxanthin—and the best sources of these are vegetable and meats. There is one B vitamin that is not found in plant foods and is extremely important for neuronal health—B12. It can take years to deplete the body of this unusual vitamin, so vegans may feel they are fine without meat or supplements until irreversible damage occurs. Dairy and eggs have some B12, but you need to eat a fair amount, so vegetarians will also benefit from supplements (National Institutes of Health, Office of Dietary Supplements, 2019).
KETOGENIC DIETS AND MCT
Evidence is accumulating that ketogenic diets can improve cognition in people with Alzheimer’s disease by providing the brain with ketone bodies, a fuel alternative to glucose (see the research section of this article). Glucose is the usual fuel for brain cells, but for poorly understood reasons, in Alzheimer’s disease less glucose gets into the brain and less is burned as fuel. Ketone bodies, on the other hand, readily enter the brain, and neurons are able to use them as fuel. Ketone bodies are made in the liver from fats, and most of the body can burn them for energy. They’ve gotten a bad rap at times because too high a level (ketoacidosis) is not healthy—but moderate levels are beneficial.
An extreme version of a ketogenic diet would consist of mostly fat with very little carbohydrate and protein. There are safer and more moderate versions that recommend one to two grams of fat for every gram of protein and carbohydrate combined. Fat consumption is increased because it is what ketone bodies are made from. However, the liver won’t convert fat to ketones if there is much glucose around, so glucose intake must be limited. This is done by limiting dietary carbohydrates including sugar, starch, fruits, bread, and pasta, which are all broken down during digestion to yield glucose. Protein can be made into glucose, so it may be limited also.
A relatively recent version of a ketogenic diet uses a unique type of fat, medium-chain triglyceride (MCT). MCT promotes ketone body production, so less total fat is required in the diet. The fatty acids in MCTs are shorter than those in most fats. To make MCT products, the short fats are extracted from coconut and palm kernel oils. MCT is a vague term—check the label to make sure that a product contains the desirable short fats—caproic, caprylic, capric, and lauric acids (Pinto et al., 2018).
Note: Ketogenic diets and supplements are not without side effects, which can include diarrhea, constipation, and nausea. MCT should be added very gradually to the diet and any discomfort monitored (McDonald & Cervenka, 2018).
COFFEE AND TEA
Coffee and caffeine improve performance on tests of memory and learning, so it makes sense that caffeine could be helpful for cognitive impairment. Looking at large populations and correlating the amount of coffee or tea people drink with whether or not they develop Alzheimer’s disease, most studies have found that moderate caffeine intake appears to go hand in hand with a lower incidence of the disease. Conclusion: Drink coffee if you like, but not so much that you are anxious or don’t sleep well (Hussain et al., 2018; Wierzejska, 2017).
Nutrients and Supplements for Alzheimer’s Disease
Although there is no magic bullet for the prevention or treatment of Alzheimer’s disease, supplements of B vitamins can help support healthy neurons. Herbal supplements for cognitive support are discussed in the alternate therapies section of this article.
Low levels of vitamin B12 and folate have been associated with Alzheimer’s disease, but not consistently. In addition, preliminary research has suggested that supplements of B vitamins may be beneficial in Alzheimer’s disease. Because B vitamins are necessary for good cardiovascular health and neuronal health, in general, it’s a good idea for everyone to get an adequate supply of B12 and folate, as well as thiamine, riboflavin, niacin, and pyridoxine (B6).
If you’re over fifty, there is a good chance you aren’t absorbing B12 from food as well as you used to—and definitely not if you use antacids. Even the US Food and Nutrition Board, which is quite conservative, has recommended that everyone over fifty take a B12 supplement.
Despite claims to the contrary, there really isn’t evidence that one type of B12 supplement is better than another (Boston et al., 2019; Braidy et al., 2018; National Institutes of Health, Office of Dietary Supplements, 2019; Wang et al., 2018; R. Zhao et al., 2018).
A recent review of thirty-eight trials concluded that more evidence was needed to determine whether any of the following supplements by themselves could reduce cognitive decline: omega-3 fatty acids, soy, folic acid, beta-carotene, vitamin C, vitamin D plus calcium, multivitamins, or multi-ingredient supplements.
There has been a lot of talk about ginkgo biloba and cognitive improvement, but research has not shown that it does much on its own. In the Ginkgo Evaluation of Memory Study, 3,000 participants seventy-five and older took daily ginkgo. Results showed that the supplement did not reduce the risk of dementia, including Alzheimer’s disease, and did not slow cognitive decline.
Because these supplements can’t individually cure dementia does not mean that getting optimal levels of nutrients isn’t important for supporting your brain or that herbs are not useful as part of a holistic approach (Butler et al., 2018; DeKosky et al., 2008).
Lifestyle Support for Alzheimer’s Disease
Lifestyle support options are available for caregivers, people with dementia, and those interested in preventing cognitive decline. The basic diet and exercise recommendations may seem like old hat. But perhaps the realization that they can help keep the brain functioning will provide motivation to take them seriously. A 2017 Lancet report concluded that 35 percent of dementia may be preventable by modifying key risk factors: obesity and hypertension, physical inactivity, diabetes, smoking, hearing loss, social isolation, depression, and low levels of education (Livingston et al., 2017).
CAREGIVER SUPPORT GROUPS AND SERVICES
Caring for someone with dementia is challenging and can be overwhelming. Caregivers need support for their own emotional and physical health. Resources are available for those living with Alzheimer’s disease, their families, and caregivers.
•The Alzheimer’s Association offers support groups for caregivers and for people living with Alzheimer’s disease.
•The US Department of Health and Human Services Administration for Community Living provides a variety of resources to promote independent living and inclusion throughout life. It also provides Eldercare Locator, which can connect you to services for older adults and their families.
•The Family Caregiver Alliance hosts an online email support group. You can ask for help or share ideas with other caregivers.
One approach to help soothe the uncertainty, fear, and anger of those suffering with dementia is to simulate the presence of a familiar place. People with dementia may remember late childhood and early adulthood better than more recent events. In “The Comforting Fictions of Dementia Care,” Larissa MacFarquhar describes a memory-care unit in Chagrin Valley, Ohio, that looks like a town from the residents’ childhood, complete with a town square and rocking chairs. To take it one level further, when a resident says: “I want to go home,” they might be led to a bus stop where they can wait until they have forgotten why they are there. Fantasies like this can be very kind, although it isn’t necessarily the best approach for everyone (MacFarquhar, 2018).
SIMULATED PRESENCE THERAPY
Talking with someone familiar is usually comforting for someone with dementia, and the conversation is frequently repetitive and predictable. A loved one can record the usual questions, reassurances, and descriptions of shared experiences and have this recording available for their family member with dementia to listen to or to watch. If the person is in distress or agitated, it’s thought that such tapes could be useful, although there isn’t clear evidence that simulated presence therapy is therapeutic. Companies that help produce these sorts of media may call it trusted voice therapy (Abraha et al., 2017).
In Creative Care, Anne Basting, PhD, makes a case for being open to the reality of people with dementia and for encouraging their creativity and imagination instead of trying to make them remember names and facts and figures. When someone says, “Where is my mother?” the instinct might be to tell them for the hundredth time that she passed away many years ago. Instead, Basting suggests asking, “Are you thinking of her? Can you tell me a story about her?” This response may be contrary to what many staff of nursing homes have been taught—to gently correct people with dementia. But you can see how always being corrected might take a toll on you. Basting describes “beautiful questions” as those with no right or wrong answers. In Creative Care, she also describes the improbable benefits some people with dementia and their caregivers have experienced from rehearsing and performing together in a chorus or a play. If you’re interested, go to the Giving Voice Chorus website for help starting a chorus, and check out TimeSlips, a nonprofit founded by Basting that implements her approach to memory care.
LIFESTYLE INTERVENTION FOR COGNITION
FINGER (Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability) was the first large long-term controlled trial to show that lifestyle intervention can improve cognition. People at risk of developing dementia underwent a program addressing nutrition, physical activity, and cognitive training. They also improved cardiovascular health through management of high blood pressure, cholesterol, and blood sugar. After two years, the intervention group scored significantly better than the control group on a battery of tests.
The nutrition intervention was not difficult—just standard recommendations, such as eating more vegetables and fruits. Physiotherapists led sessions focusing on muscle strength and aerobic activities. Group discussions and computer training modules focused on memory and mental speed. This trial did not include people with Alzheimer’s disease, but participants were chosen because they were judged to have a higher than average risk of dementia. Other lifestyle intervention trials have not demonstrated benefits for cognition, perhaps because the participants were too healthy to benefit.
Overall, the FINGER trial has provided evidence that the usual lifestyle suspects are important for maintaining brain function as we age (Becker et al., 2004; Ngandu et al., 2015; Rosenberg et al., 2018).
People who are physically active are less likely to get Alzheimer’s disease, which makes sense because physical activity can improve blood flow to the brain. Exercise alone is not a magic bullet—although a meta-analysis of controlled studies concluded that there are significant benefits of aerobic exercise. Research from Ozioma Okonkwo, PhD, drives home how important physical activity can be for the brain: “When I looked at the data, the findings were unbelievable. I mean, I could not make this up if I wanted,” said Okonkwo of his 2014 study findings. Middle-aged people at risk of developing Alzheimer’s were tested for a number of biomarkers of the disease, including amyloid plaque, glucose metabolism, memory, and size of the hippocampus. The hippocampus is a region of the brain that plays a major role in memory and learning, and shrinkage (atrophy) of this structure is characteristic of Alzheimer’s disease. Those who were physically active had less hippocampal shrinkage, better glucose metabolism, and less age-related memory loss than people with an inactive lifestyle. We don’t know that being active directly results in healthier brains, but the correlation is worth additional research (Alzheimer’s Disease Research Center, 2017; Chieffi et al., 2017; Groot et al., 2016; National Academies of Sciences, Engineering, and Medicine et al., 2017; Okonkwo et al., 2014).
BLOOD SUPPLY TO THE BRAIN
An interrupted blood supply to the brain is a major cause of cognitive impairment. This can result from either a blocked blood vessel or from a leaky blood vessel—both of which can cause either a stroke or a ministroke (transient ischemic attack). Death of brain cells results when a lack of blood deprives cells of oxygen, glucose, vitamins, and ketone bodies. If you are at risk of vascular disease from high blood cholesterol, high blood sugar, or high blood pressure, consult your health care team. Diet and lifestyle changes can improve the health of blood vessels as described in our articles on heart disease and diabetes.
Too much cortisol is not good for your brain, especially for the memory-containing hippocampus. In stressed primates, increased levels of cortisol are accompanied by a smaller volume of the hippocampus—as seen in Alzheimer’s disease. Robert Sapolsky, PhD, is known for studying what goes on when humans, zebras, and baboons experience stress—one of his best-known books is Why Zebras Don’t Get Ulcers. His research team at Stanford University has shown that too much cortisol is especially damaging to the hippocampus and to memory. When hippocampal neurons experience low oxygen from clogged blood vessels or from sleep apnea or are subjected to low blood sugar, cortisol can push them over the edge and kill them. The damaging effects of this stress hormone appear to be due to increased inflammation and oxidation (Dumas et al., 2010; Sapolsky, 2001; Schuff et al., 2009; Sorrells et al., 2014).
Mindfulness-based techniques for stress reduction will not prevent or cure dementia, but they may help prevent some of the harmful consequences of stress. A meta-analysis of forty-one studies concluded that meditation, yoga, Tai Chi, or Qigong could improve cognition in adults over sixty. In addition, a recent review concluded that meditation could help delay dementia.
Further, mindfulness training has been shown to be helpful for people with dementia and for their caregivers. Mindfulness training refers to weekly group training sessions on meditative exercises and focusing attention on breathing, bodily sensations, and the feelings and thoughts that arise (Chan et al., 2019; Klimecki et al., 2019; van Boxtel et al., 2019).
SLEEP AND HEALING
There is good evidence that chronically disrupted sleep, whether from sleep apnea or other causes, increases the risk of developing Alzheimer’s disease. People with Alzheimer’s disease tend to wake frequently at night and spend more time in bed during the daytime. But the significance of poor sleep regulation goes way beyond these behaviors. Increased beta-amyloid levels can result from the disruption of sleep. Since beta-amyloid levels go down overnight it appears that cleansing processes are revved up during sleep. Similar to the lymphatic system in the body, a cleansing process for the brain has been dubbed the glymphatic. In the glymphatic system, glial cells and cerebrospinal fluid remove substances like amyloid. This cleansing flow increases and is more efficient at night, at least in preclinical research. If you have sleep problems, it’s worth addressing them (Cedernaes et al., 2017; Vanderheyden et al., 2018).
One cause of disrupted sleep that is clearly associated with cognitive impairment is sleep apnea—when breathing repeatedly stops and starts. During these moments, the brain is being deprived of oxygen. In the most common type of sleep apnea, an obstruction in the upper airway causes breathing to stop for a few seconds to a few minutes, and this can happen multiple times every hour. When breathing resumes, you may hear snoring and gasping and snorting. Remedies include drinking less alcohol, because alcohol relaxes the throat muscles that keep the airway open, and not smoking, because smoking causes airway inflammation and swelling. Diagnosis may include a sleep study and commonly leads to being prescribed a CPAP (positive airway pressure) machine that blows air to keep your airways open (Andrade et al., 2018; National Heart, Lung, and Blood Institute, 2019).
Sleep Aids: Progesterone, Estrogen, and Melatonin
Difficulties sleeping increase as we age, and this is a particular concern for women during menopause, when levels of both progesterone and estrogen decline. Progesterone supplements may be helpful for sleep, and bioidentical progesterone is available by prescription and as an over-the-counter cream.
Estrogen therapy can reduce hot flashes and night sweats that make it difficult to sleep. However, from the discussion in the conventional treatments section of this article, you can see that it’s possible that estrogen hormone replacement therapy (HRT) is not good for brain function—the benefits and risks need to be weighed for each individual (Schüssler et al., 2018).
Melatonin supplements are effective sleep aids, and as a bonus, melatonin has antioxidant and neuroprotective effects that are being studied for their potential benefits in Alzheimer’s disease. In animal models, melatonin can help clear beta-amyloid, and there is evidence that it can decrease amyloid plaque formation. Start with a low dose of melatonin, around one milligram, and if necessary, increase the dose. It’s been shown to be quite safe at much higher levels, but for some people too much causes unpleasant dreams (Balmik & Chinnathambi, 2018; Pappolla et al., 1998; Shi et al., 2018).
Conventional Treatment Options for Alzheimer’s Disease
There are currently no FDA-approved drugs that delay or prevent the death of neurons in Alzheimer’s disease. There are drugs that can help with memory loss and confusion and that can provide significant benefits for a year or more. PET scans may be used to evaluate treatment strategies, but it is not known whether this really helps in the long run (Khosravi et al., 2019; Rabinovici et al., 2019).
Several FDA approved drugs can help temporarily with memory loss and confusion. Cholinesterase inhibitor drugs—Aricept (donepezil), Exelon (rivastigmine), Razadyne (galantamine)—can help maintain the neurotransmitter acetylcholine in the brain and delay or slow the worsening of symptoms. Memantine—Namenda, or Namzaric when combined with donepezil—affects a different neurotransmitter, glutamate, and can improve both the ability to perform daily activities and mental function.
These drugs do not treat the underlying disease or slow its progression, but they can improve symptoms by supporting the brain cells that are still alive. The result is that the remaining supercharged neurons can help the brain function more normally. If you look online, you’ll find people posting positive and negative reviews of these drugs. Anecdotes and clinical studies have shown that in some cases these drugs can provide a meaningful amount of higher-quality time. As with most drugs, these have side effects. The side effects of cholinesterase drugs may include nausea, vomiting, loss of appetite, and increased frequency of bowel movements; the side effects of memantine can be headache, constipation, confusion, and dizziness (Alzheimer’s Association, 2019c).
HORMONE REPLACEMENT THERAPY
Researchers keep trying to find evidence that hormone replacement therapy (HRT) with estrogen has benefits for cognition during menopause. As of yet they have not. Studies to date have shown the opposite: that HRT is not good for the brain. The most damning results have come from the Women’s Health Initiative, which used equine estrogen with or without medroxyprogesterone in women over sixty-five. It’s hypothesized that earlier in menopause HRT is less harmful, but this has not been clearly demonstrated. Bioidentical 17-beta estradiol may be less harmful than equine estrogen—in one study transdermal 17-beta estradiol was associated with less brain shrinkage than equine estrogen. In the absence of a demonstrated benefit and with the possibility of detrimental effects on the brain, it would not seem advisable for women concerned about cognition to use HRT for extended periods of time. Use bioidentical estrogen only if the benefits outweigh the risks for you (V. W. Henderson, 2014; Kantarci et al., 2016; Shumaker et al., 2004).
BEHAVIORAL AND PSYCHOLOGICAL SUPPORT
An international panel of doctors and researchers experienced in managing behavioral and psychological symptoms of dementia published a consensus on treatment guidelines. Before using drugs to treat agitation and other behavioral symptoms, they recommend making modifications to the environment, carrying out tailored activities, such as music therapy, and training caregivers. Ask your doctor about implementing the DICE program for developing tailored solutions. According to this panel, if necessary, the antidepressant citalopram is preferable to an antipsychotic for Alzheimer’s (Kales et al., 2015, 2019).
Alternate Treatment Options for Alzheimer’s Disease
To learn about lifestyle interventions that might be helpful before or after an Alzheimer’s diagnosis, read The End of Alzheimer’s by Dale Bredesen, MD (which we cover a bit below).
If you are interested in trying botanicals, consider starting with curcumin (from turmeric) and bacopa (also covered below).
As always, consult your doctor before changing your regimen.
THE BREDESEN PROTOCOL
Dale Bredesen, MD, developed the Bredesen protocol—information and algorithms designed to prevent and reverse cognitive decline. With the use this protocol, also called ReCODE or MEND, improvements have been reported for the first time in people with Alzheimer’s disease. The protocol is described in Bredesen’s book, The End of Alzheimer’s: The First Program to Prevent and Reverse Cognitive Decline. Bredesen was the president and CEO of the Buck Institute for Research on Aging, and he directed research on Alzheimer’s disease at UCLA, UCSF, and the Burnham Institute in La Jolla, California.
Using the Bredesen protocol, people with Alzheimer’s or other cognitive impairment showed improvements in test scores or subjective ratings, and some were able to return to work. The approach is holistic, intensive, and demanding, and it uses a three-pronged approach to help keep neurons alive: reduce inflammation, provide nutrition to brain cells, and reduce toxic insults to brain cells. Some of the more interesting components are fasting at least twelve hours nightly; carefully controlling levels of insulin, cortisol, and other hormones; and avoiding gluten. Bredesen prescribes an array of supplements unusual for a medical doctor: ashwagandha, bacopa, turmeric, vitamins D3 and K2, resveratrol, citicoline, and others. Some of the more common stress- and inflammation-reducing components include minimizing simple carbohydrate intake; getting plenty of sleep; doing plenty of exercise, yoga, and meditation; and listening to music.
Note that this research consists of case studies—there weren’t untreated controls for comparison, so these results are considered preliminary. Also, Bredesen is candid about the fact that he only treats highly motivated patients due to the difficulty of following the protocol. He has trained a large number of practitioners to carry out the protocol, and the results from one hundred people with Alzheimer’s disease, other dementia, or MCI, treated at multiple centers, were published in 2018. Improvements in cognition were reported for many people. Qualified practitioners and more information can be found through Apollo Health, where Bredesen is currently chief science officer. In our article “A New Approach to Treating Alzheimer’s,” Bredesen discusses the implementation of his three-pronged program (D. Bredesen, 2017; D. E. Bredesen, 2014; D. E. Bredesen et al., 2016, 2018).
A multipronged holistic approach is not unique to Bredesen. After analysis of hundreds of studies on possible risk factors for Alzheimer’s, Yu et al. (2020) recommend addressing the following factors and more in order to prevent the disease: high blood homocysteine, depression, stress, diabetes, head trauma, high blood pressure, obesity in midlife, physical exercise, smoking, sleep, and cardiovascular diseases. They did not recommend estrogen replacement therapy. And Schechter et al. (2020) recommend treating early disease with a multimodal strategy addressing nutrition, physical activity, hormones, metabolism, and more.
A number of herbs used traditionally in Ayurvedic medicine for mental clarity have been the subject of research on cognition. Of these, only turmeric has shown promise in people with cognitive impairment. Bacopa and gotu kola have been shown to have benefits for healthy people.
•Turmeric’s active constituent, curcumin, has anti-inflammatory and antioxidant effects. In animal research, it has improved survival of neurons and reduced plaque and tangles. Breakthrough clinical research published in 2018 by Gary Small, MD, and others at the Brain Research Institute at UCLA showed that curcumin can improve memory, attention, and mood and that it can also lower the amounts of plaques and tangles in the hypothalamus. People were given a high dose of a uniquely bioavailable form of curcumin, Theracurmin, containing ninety milligrams of curcumin, twice daily for eighteen months. Because 40 percent of the people in this study were classified with MCI, Theracurmin’s benefits may be relevant for Alzheimer’s disease. This finding has not yet been replicated, and definitive studies on people with disease have not yet been carried out (Lim et al., 2001; Small et al., 2018).
•Brahmi (Bacopa monnieri), known colloquially as bacopa, is one of the better studied and more effective herbs for cognitive support, although we do not have evidence that it helps people with MCI or Alzheimer’s disease. A number of—but not all—double-blind, placebo-controlled studies showed that healthy older adults given bacopa for as little as four weeks performed significantly better on tests of memory, attention, and cognitive processing than people receiving a placebo (Calabrese et al., 2008; Morgan & Stevens, 2010; Nathan et al., 2001; Peth-Nui et al., 2012; Raghav et al., 2006; Stough et al., 2008).
•Gotu kola (Centella asiatica) has been used in traditional Chinese medicine as well as in Ayurveda to improve mental clarity, and there is evidence from animal and clinical studies that it can support mood and memory. However, benefits have not been demonstrated clinically for any type of dementia (Farooqui et al., 2018; Orhan, 2012).
•Ashwagandha (Withania somnifera) is an adaptogenic herb from the Ayurvedic tradition that is used to help the body deal with stress and anxiety. As described in the lifestyle section of this article, excessive stress and high cortisol are linked to brain atrophy and cognitive deficits. Research has confirmed benefits of ashwagandha for lowering cortisol levels, stress, and anxiety and for memory and cognition (Chandrasekhar et al., 2012; Chengappa et al., 2013).
•Holy basil (tulsi) is another adaptogenic herb used in Ayurveda. Benefits of holy basil have been demonstrated clinically for forgetfulness and for sleep problems. Because of the relationships between stress, sleep, and cognition, it follows that adaptogenic herbs could have benefits for all three concerns (Jamshidi & Cohen, 2017; Saxena et al., 2012).
LION’S MANE MUSHROOM
Lion’s mane mushroom (Hericium erinaceus) has been used in Asia and Europe medicinally, and has been shown to support memory and brain health in animal research. A small blinded clinical study in Japan reported that taking three grams Hericium erinaceus daily for eight weeks improved cognition in people with mild cognitive impairment (Mori et al., 2009).
Working with an Herbalist or a Holistic Healer
Holistic approaches often require dedication, guidance, and working closely with an experienced practitioner. Functional, holistic-minded practitioners (MDs, DOs, and NDs) may use herbs, nutrition, mindfulness, meditation, and exercise to support the entire body and its ability to heal itself.
Traditional Chinese medicine degrees include LAc (licensed acupuncturist), OMD (doctor of Oriental medicine), or DipCH (NCCA) (diplomate of Chinese herbology from the National Commission for the Certification of Acupuncturists). Traditional Ayurvedic medicine from India is accredited in the United States by the American Association of Ayurvedic Professionals of North America and the National Ayurvedic Medical Association. There are several certifications that designate an herbalist. The American Herbalists Guild provides a listing of registered herbalists, whose certification is designated RH (AHG).
New and Promising Research on Alzheimer’s Disease
There is a lot of research underway on the varied aspects of Alzheimer’s disease. Good cases have been made that infections by viruses, bacteria, and fungi contribute to Alzheimer’s. Beta-amyloid has antimicrobial properties, and the brain may be making this peptide to help fight off an infection. That would explain why multiple types of infections have been linked to Alzheimer’s—beta-amyloid may be a general defense mechanism (Soscia et al., 2010). Other researchers are working on potential diagnostic tools, including one that uses the ability to detect odors as a biomarker. Supportive treatments are being evaluated, including ketogenic diets, and scientists are testing antibodies to beta-amyloid for their ability to stop disease progression.
How Do You Evaluate Clinical Studies and Identify Promising Results?
The results of clinical studies are described throughout this article, and you may wonder which treatments are worth discussing with your doctor. When a particular benefit is described in only one or two studies, consider it of possible interest, or perhaps worth discussing, but definitely not conclusive. Repetition is how the scientific community polices itself and verifies that a particular treatment is of value. When benefits can be reproduced by multiple investigators, they are more likely to be real and meaningful. We’ve tried to focus on review articles and meta-analyses that take all the available results into account; these are more likely to give us a comprehensive evaluation of a particular subject. Of course, there can be flaws in research, and if by chance all of the clinical studies on a particular therapy are flawed—for example with insufficient randomization or lacking a control group—then reviews and meta-analyses based on these studies will be flawed. But in general, it’s a compelling sign when research results can be repeated.
Some clear-cut data have shown that there are multiple types of fungi in the brains of people with Alzheimer’s disease. No fungi were detected in the control brains. Candida albicans, Sacharomyces cerevisiae, and other species have been detected by DNA analysis and by other techniques in brain regions affected in Alzheimer’s. Researchers hypothesize that fungal infections could either be a cause of or at least contribute to the disease. Beta-amyloid peptide is particularly potent against the fungus C. albicans. It may be relevant that fungal infection can be misdiagnosed as Alzheimer’s disease and treated successfully with antifungal drugs. In one case, an Alzheimer’s-like dementia cleared up with treatment for Cryptococcal meningitis, a serious infection of the brain caused by a common fungus found in soil and in bird droppings (Ala et al., 2004; Calabrese et al., 2008; Hoffmann et al., 2009).
Could herpes viruses help predispose the brain to Alzheimer’s disease? The herpes variant most strongly linked to Alzheimer’s is HSV-1, the herpes virus commonly associated with cold sores. There is no proof that herpes causes Alzheimer’s, and the viruses are also found in healthy brains, but there is evidence that herpes and Alzheimer’s commonly occur together, particularly in people with the APOE4 gene, which is a risk factor for Alzheimer’s disease. Herpes viruses can lie dormant in cells for years and can be reactivated by stress, immunosuppression, fever, and brain trauma. Reactivated HSV-1, but not lifelong infection, appears to go along with Alzheimer’s.
In 2018, researchers reported that higher amounts of HSV-6a and HSV-7 viruses—the ones that cause roseola rash in kids—were present in the brains of people who had Alzheimer’s disease compared to people without the disease (Readhead et al., 2018). However, a year later, other researchers scrutinized these findings and concluded that there was not a significant link between HSV-6a or HSV-7 and Alzheimer’s disease (Jeong & Liu, 2019).
If herpes is contributing to Alzheimer’s disease, then antiviral drugs could be therapeutic. Davangere Devanand, MD, of Columbia University and the New York State Psychiatric Institute, is conducting a controlled clinical trial to test the viral hypothesis. Participants will be given the anti-HSV drug, valacyclovir, for eighteen months. The accumulation of amyloid and tau in the brain will be measured at the beginning and end of the trial. Enrollment for the study is open as of December 2019 (Hogestyn et al., 2018).
The microbes that have been found in the brains of people who suffered from Alzheimer’s disease include several kinds of spirochete bacteria. Are they causative? Coincidental? Do microbes gain access to damaged brains? When spirochete bacteria from diseased brains are incubated with healthy brain cells in culture, they cause tangles and plaques and Alzheimer’s-like pathology. One of the microbes implicated is the spirochete Borrelia burgdorferi, which is also one of the species that causes Lyme disease. And one of the manifestations of Lyme disease is a dementia called Lyme neuroborreliosis, which can be treated with antibiotics. Walking abnormally, gait disturbances, falls, tremors, and a history of tick bites might point toward this particular kind of dementia. There are case studies of patients with dementia who were eventually determined to have Lyme disease (Kristoferitsch et al., 2018; Miklossy, 2008).
The periodontal pathogen Treponema pallidum and other Treponema species are spirochete bacteria that have also been implicated in Alzheimer’s disease. Because chronic periodontitis has been found along with Alzheimer’s disease, it’s hypothesized that periodontal infections might contribute indirectly by causing inflammation. Inflammation can increase the susceptibility of neurons to other damaging factors, such as amyloid, tau, oxidation, and infection. Practice good dental hygiene, but don’t be too enthusiastic because poking the gums can also let bacteria into the blood (Harding et al., 2017; Miklossy, 2011).
The infectious agent in mad cow disease is proteins that have folded incorrectly and can cause other proteins to misfold. These infectious proteins, which are self-propagating, are called prions. There is some evidence that beta-amyloid may be similarly self-propagating. In mouse models of Alzheimer’s disease, aggregates of beta-amyloid can be self-propagating and infectious. Whether prion-like self-propagating infectious beta-amyloid contributes to human disease is not known (Watts & Prusiner, 2018).
Dennis Selkoe, MD, and colleagues at Harvard Medical School think that the large plaques of beta-amyloid that build up in the brain in Alzheimer’s disease are not the culprits for memory loss. They blame instead the short chains of beta-amyloid that can more easily move around the brain. According to Selkoe, the millions of copies of beta-amyloid that have aggregated and formed plaque aren’t doing a lot of harm. The problem is when short chains of two or three or four beta-amyloid peptides, called oligomers, float into synapses, especially in the hippocampus, the center of memory. His team took oligomers from the brains of deceased people who had been diagnosed with Alzheimer’s disease and injected them into rat brains. Even very tiny amounts caused the animals to become forgetful. Tests to screen patients for the toxic oligomers are being developed (Hwang et al., 2019; Yang et al., 2017; J. Zhao et al., 2018).
SQUEEZING THE BRAIN’S BLOOD SUPPLY
Reduced blood flow to the brain is one of the earliest changes seen as Alzheimer’s disease progresses. It’s not due solely to plaque buildup in arteries, which is a common cause of dementia. Researchers at University College, London, have discovered a reason for restricted blood flow: They’ve shown that beta-amyloid can cause the cells surrounding capillaries—pericytes—to contract and to squeeze the vessels, narrowing them. This may mean that one way in which beta-amyloid causes damage to neurons is by reducing their blood supply, starving them of oxygen and glucose. Targeting pericyte function could be a new therapeutic approach (Nortley et al., 2019).
SENSE OF SMELL
The usual tests to assess our cognitive status evaluate our memory and our ability to carry out tasks. An interesting new biomarker for brain function is odor-detection impairment. An impaired ability to identify odors appears to be a marker of MCI and of Alzheimer’s disease. Impaired odor detection also correlates with brain volume, a measure of brain health. The brain shrinks with age, and shrinkage is greater in Alzheimer’s disease. The hope is that assessing a person’s sense of smell could be a simple, noninvasive way to judge how well therapies are working (Devanand et al., 2019; Hagemeier et al., 2016).
NOURISHING BRAIN SYNAPSES
Preliminary research has reported benefits from a multivitamin supplement in people with mild Alzheimer’s disease. The goal was to provide optimal support for as long as possible to neurons that had not yet been destroyed by the disease. People with mild Alzheimer’s disease were given Souvenaid (Fortasyn Connect) for twenty-four weeks. At the end of the study, these participants scored better on memory tests than a control group.
More recently, people with MCI who used Souvenaid for one year were compared to people who chose not to take the supplement. Taking the supplement was associated with better results on tests of memory. Souvenaid was also associated with better PET scan results—brain metabolism worsened over a year in controls but not in those taking the supplement. However, people in both groups progressed to full-blown dementia at the same rate.
These were small studies, and the results are not definitive, but regardless it makes sense to provide nutrients known to be vital for brain function. Souvenaid contains the omega-3 fats DHA and EPA, phospholipids, choline, uridine monophosphate, vitamin E, selenium, vitamin B12, vitamin B6, and folic acid (Manzano Palomo et al., 2019; Scheltens et al., 2012).
MCT AND KETONE BODIES
In Alzheimer’s disease, neurons may not be getting enough glucose, and starvation of neurons may be contributing to cognitive decline. As an alternative to glucose, the brain will use ketone bodies as a fuel if they are available. We can get our bodies to produce ketone bodies by consuming a ketogenic diet or by consuming MCT.
Investigators at Johns Hopkins University School of Medicine reported that a ketogenic diet improved memory and vitality in early Alzheimer’s disease. Their results are considered quite preliminary because it was difficult to recruit people and caregivers willing and able to implement the diet. From the original group of twenty-seven people recruited to the study, only five people in the control group and nine people assigned to the ketogenic diet completed the trial. And only a subset of those on the ketogenic diet had any evidence of ketone body production. But in this subset, significantly better memory scores and energy were documented after only six weeks (Brandt et al., 2019).
There have been quite a few studies, mostly quite small, that have reported positive effects of MCT on cognition (Pinto et al., 2018). In a clinical trial at the Université de Sherbrooke in Quebec, people with MCI consumed thirty grams of MCT daily for six months. Ketone bodies greatly increased in the brain, and improvements in memory and processing speed were observed (Fortier et al., 2019). In another study, people with clinical dementia consumed one and a half to three tablespoons daily of NOW Foods MCT oil as part of a high-fat, low-carb diet. After three months, their scores on tests of cognition improved (Taylor et al., 2017). Intriguingly, two small studies reported improved cognition scores shortly after a single meal of MCTs (Krikorian et al., 2012).
Axona is an MCT medical food regulated by the FDA and available by prescription. Axona contains caprylic acid, a ketogenic fat derived from coconut and palm kernel oils. This product was tested in people with mild to moderate Alzheimer’s disease to see whether it would affect cognition and daily function. The group given around fifty grams of Axona daily scored significantly better on some tests of cognition and function than the group receiving a placebo (Alzheimer’s Association, 2019b; Galvin, 2013; S. T. Henderson et al., 2009).
These findings are considered promising, and multiple clinical trials are following up on them. Wake Forest University in North Carolina is recruiting people with cognitive impairment for a four-month clinical trial comparing a low-carbohydrate ketogenic diet to a low-fat diet. The Université de Sherbrooke and the University of British Columbia in Vancouver are recruiting people with Alzheimer’s disease who will receive up to fifty grams of MCT daily and be monitored for adverse effects, blood ketone body levels, and changes in brain chemistry.
L-Serine Supplements in Mice
Scientists have reported that giving supplements of the amino acid L-serine to mice with Alzheimer’s disease improves their memory. Serine promotes memory-forming connections between nerves, and low levels of serine in Alzheimer’s disease appear to contribute to defects in forming memories. Serine is made from glucose, and low serine production in the brain is attributed to the abnormally low glucose metabolism characteristic of Alzheimer’s.
It remains to be seen whether these findings are relevant for human disease. When mice are bred or engineered to create a mouse model for a human disease, they frequently do not mimic the disease very well or predict whether therapeutics will be effective in humans (Le Douce et al., 2020).
The proton pump inhibitor drugs like omeprazole are used to treat acid reflux by decreasing the production of acid by the stomach. Long-term use of these drugs has been associated with an increased risk of developing Alzheimer’s disease. Researchers at the Karolinska Institute have discovered why: Omeprazole and related drugs are potent inhibitors of the enzyme that makes acetylcholine. And acetylcholine is a neurotransmitter that’s crucial for memory. We don’t know how significant this effect is, but it would seem prudent to avoid extended use of these drugs in dementia (Kumar et al., 2020).
Nonsteroidal anti-inflammatory drugs surfaced in the news when preliminary research suggested that they might be helpful for Alzheimer’s disease. Drugs in this class include indomethacin, naproxen, aspirin, celecoxib (you might know these by the brand names Indocin, Aleve, Naprosyn, or Celebrex). Unfortunately, since then, clinical studies on people with Alzheimer’s disease have not shown significant benefits from these drugs.
This is a good example of why it’s important not to get too excited about preliminary results from animal research or from correlations. In this case, a correlation was reported between using nonsteroidal anti-inflammatory drugs and a lower rate of Alzheimer’s disease. People who reported taking anti-inflammatories were developing Alzheimer’s disease less often than expected. The correlation turned out to be a coincidence. Benefits of these drugs were also reported from animal research. We learn a lot from animal research, but much of the time it leads to dead ends (Ardura-Fabregat et al., 2017).
GENTLE SOUND STIMULATION
Our brains consolidate memories while we sleep, specifically during slow-wave sleep. This is the deepest stage of non-REM (rapid eye movement) sleep. In people with cognitive impairment, there is less slow-wave activity in the brain. Acoustic stimulation has been used overnight to increase people’s slow-wave activity, and this treatment has been associated with better scores on tests of memory. Extending this work to people with MCI, when researchers used specific sound stimulation overnight, they were able to increase the amount of slow-wave sleep in some of the people. The increase in slow-wave sleep was associated with better performance on a word-recall memory test in the morning. And this was after only one night. These very preliminary results are based on only a few subjects, and we’ll be eager to see whether this finding can be repeated (Papalambros et al., 2019).
Clinical Trials for Alzheimer’s Disease
Clinical trials are research studies intended to evaluate a medical, surgical, or behavioral intervention. They are done so that researchers can study a particular treatment that may not have a lot of data on its safety or effectiveness yet. If you’re considering signing up for a clinical trial, it’s important to note that if you’re placed in the placebo group, you won’t have access to the treatment being studied. It’s also good to understand the phase of the clinical trial: Phase 1 is the first time most drugs will be used in humans so it’s about finding a safe dose. If the drug makes it through the initial trial, it can be used in a larger phase 2 trial to see whether it works well. Then it may be compared to a known effective treatment in a phase 3 trial. If the drug is approved by the FDA, it will go on to a phase 4 trial. Phase 3 and phase 4 trials are the most likely to involve the most effective and safest up-and-coming treatments.
In general, clinical trials may yield valuable information; they may provide benefits for some people but have undesirable outcomes for others. Speak with your doctor about any clinical trial you are considering.
To find studies that are currently recruiting for Alzheimer’s disease, go to clinicaltrials.gov and to the Alzforum Clinical Trial Registries. Alzforum has an excellent database of information on drugs that have been tested and are currently being tested in clinical studies. The Alzheimer’s Association TrialMatch will help you find trials you may be eligible for. UCSF’s Brain Health Registry is compiling a pool of people who are willing to complete short cognitive tests regularly so they can track brain health—they will not tell you about your risk of dementia, but they will notify you if you are eligible for specific clinical trials. And we’ve also outlined some below.
A combination of lifestyle modifications including healthy diet, physical activity, and social and intellectual challenges reduced development of Alzheimer’s disease in a Finnish study (FINGER)—and was more effective than any drug tried so far. Can this be repeated in an American setting? Laura Baker, PhD, and Mark Espeland, PhD, at Wake Forest University Health Sciences, together with Rachel Whitmer, PhD, from the University of California, Davis, and Miia Kivipelto, MD, PhD, from the Karolinska Institute in Sweden are going to find out. Their study is trying to determine whether an intensive, structured lifestyle intervention will protect cognitive function. Participants must be between sixty and seventy-nine years old and have a close relative with memory impairment.
One approach to treating Alzheimer’s disease has been to target amyloid plaque with antibodies that should signal its destruction. A number of clinical trials using several antibodies to beta-amyloid have yielded disappointing results. An antibody called crenezumab that can bind to and help clear amyloid oligomers and aggregates has been tested clinically in multiple studies without success. The companies Biogen and Eisai announced that they were discontinuing phase 3 studies of aducanumab, an antibody that targets aggregated forms of beta-amyloid. However, after a reanalysis of clinical trial data, Biogen announced that the highest dose of aducanamab had slowed cognitive decline in some people, and that it will proceed with development of this antibody as a drug (Alzforum, 2019).
It’s theorized that antibodies that have not previously been effective in clinical trials could be more effective if treatment were started earlier in disease progression. Biogen and Eisai are recruiting people with early Alzheimer’s disease at 154 study locations to see whether the antibody BAN2401 can improve clinical ratings of dementia and the amount of amyloid detected by PET scans. Hoffmann-La Roche is recruiting people with early disease at 221 locations—the antibody gantenerumab will be given by subcutaneous injection (Gold, 2017; Honig et al., 2018; Morris, 2019).
INHIBITING TAU AGGREGATION
TauRx Therapeutics is studying a drug (LMTX, hydromethylthionine) that inhibits the aggregation of tau proteins and has shown promise in mouse models. In previous clinical trials of people with Alzheimer’s disease, this drug was judged to be ineffective because a large dose of 250 milligrams was no better than 8 milligrams. However, looking more carefully at the data made it clear that both doses improved people’s scores on tests measuring cognition. The 8-milligram dose now needs to be shown to be superior to a placebo (Schelter et al., 2019).
A SEIZURE DRUG TO QUIET THE BRAIN
Richard Mohs, PhD, at AgeneBio is heading up a multicenter study in the US and Canada of an oral drug, levetiracetam (AGB101), to see whether it will slow disease progression in people with MCI due to Alzheimer’s disease. This drug is used clinically to prevent seizures, and preliminary research suggests that it can reduce the hyperactivity of neural networks that occurs in Alzheimer’s.
A DRUG TO IMPROVE NEURAL FUNCTION
The Tetra PICASSO Alzheimer’s Disease Trial wants to harness the brain’s natural mechanisms for supporting memory, to improve functioning in the presence of amyloid buildup. Under the direction of Scott Reines, MD, Tetra Discovery Partners will evaluate the drug BPN14770 at multiple locations in the US. The hope is that the drug will be able to increase levels of the messenger molecule cAMP in the brain, which will then support neuronal function and memory.
GAMMA BRAIN WAVES, LIGHT, AND SOUND
Alzheimer’s may be associated with impairments of gamma brain waves. So Li-Huei Tsai, PhD, the director of MIT’s Picower Institute for Learning and Memory, looked at effects of inducing gamma waves. It turned out that in mice, exposure to flickering light (forty hertz) not only induced gamma waves but decreased amyloid plaque (Martorell et al., 2019). Sound at forty hertz could also be used to induce gamma waves, reduce amyloid plaque, and improve cognition.
Andrey Vyshedskiy, PhD, is working with a company called Alzheimer’s Light to conduct an observational study of people with Alzheimer’s disease and cognitive impairment. Forty-hertz light will be used together with cognitive therapy, which consists of a program called AlzLife—it uses games such as sudoku and tic-tac-toe to exercise your brain.
Another trial is using transcranial alternating current stimulation (tACS) tuned at a frequency of forty hertz to induce gamma waves in the brains of people with Alzheimer’s disease. Alvaro Pascual-Leone, MD, PhD, the chief of the Division of Cognitive Neurology, is directing this study at the Beth Israel Deaconess Medical Center in Boston. The study is trying to determine whether twenty-two sessions of tACS can reduce the amount of amyloid detected by PET scans.
Nicotine stimulates some of the same receptors in the brain that acetylcholine, the memory neurotransmitter, binds to. Promising results have been reported with nicotine patches and injections in people with Alzheimer’s disease. A pilot study by Paul Newhouse, MD, at Vanderbilt University showed that transdermal nicotine patches improved cognitive performance in people with mild cognitive impairment (Newhouse et al., 2012). Newhouse and Paul Aisen, MD, of the USC Alzheimer’s Therapeutic Research Institute (ATRI), are currently conducting a larger multicenter clinical study of people with MCI. This is not a recommendation to start smoking.
Preliminary research has linked low vitamin D with an increased risk of dementia and Alzheimer’s disease (Miller et al., 2015). At the UC Davis Alzheimer’s Disease Center in Walnut Creek, California, John Olichney, MD, is asking whether vitamin D supplements can slow cognitive decline and the rate of brain atrophy in people with either normal cognition or MCI (ages sixty-five to ninety). A high dose of 4,000 international units (IU) vitamin D will be compared to 600 IU in the phase 2 trial.
Resources for Alzheimer’s Disease
•The Alzheimer’s Association is a volunteer organization providing help to people with Alzheimer’s disease and their caregivers. The site provides information on everything from care options to caregiver health. It can also point you to a local chapter.
•Alzforum provides summaries of the latest Alzheimer’s-related research articles and a database of gene variants associated with Alzheimer’s. It also has a database of therapeutic drugs and curates a virtual exhibit hall where companies describe the products they are developing.
•The National Institute on Aging provides information on Alzheimer’s and other forms of dementia. It covers everything from caregiving to the latest research.
Relevant Reading on goop
•In “A New Approach to Treating Alzheimer’s,” Dale Bredesen, MD, describes the success he has had with his multifactorial program.
•In “Could Alzheimer’s Begin in the Gut?” Stephen Gundry, MD, outlines the diet plan he uses to support brain health.
•Richard Isaacson, MD, discusses why Alzheimer’s affects more women than men and gives his diet and lifestyle recommendations for preventing and treating dementia.
•Lisa Mosconi, PhD, INHC, provides detailed recommendations for diet and supplements in “A Scientist’s Guide to Eating for Brain Health.”
•Rudy Tanzi, PhD, discusses his research on the brain microbiome and the brain-directed supplements he uses.
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