Development of Prevention and Intervention Recommendations for Alzheimer’s Disease

Dementia is a generic term which refers to a condition characterized by progressive deterioration of cognitive function, especially the encoding of new information into memory, with frequent impairment of executive function, which interferes with activities of daily living. Dementia usually affects older adults and is most commonly caused by Alzheimer's disease (AD). But many other organic diseases affecting the brain may cause dementia, including cerebrovascular disease, frontotemporal dementia, Lewy body disease, Parkinson's disease, and traumatic brain injury. Further, the likelihood of such conditions increases with advancing age, so more than one brain disorder is often responsible for dementia, frequently including AD.

The most important consideration is prevention of dementia and the related brain damage. There are established approaches to prevention of some dementing conditions but approaches to prevention and treatment of AD are less clear. There are a variety of approaches that have been considered and evaluated for AD prevention and intervention. The Handbook of Prevention and Alzheimer's Disease, Volume 10 of the Advances in Alzheimer’s Disease series, provides an in-depth analysis of most of the approaches which have been considered to benefit AD patients or studied as possible AD prevention strategies. This is followed by the Handbook of Intervention and Alzheimer’s Disease, Volume 11 of the Advances in Alzheimer’s Disease series, which discusses factors that modulate brain health and the importance of optimized brain health for the outcomes of therapeutic strategies.

This post provides a view of AD prevention from a 2002 article from the Long Island Alzheimer’s Foundation Newsletter, with some updating comments, to provide a historical view of many of the strategies outlined in these Handbooks. This article was written after meeting Janet Walsh (now Resnick). Ms. Walsh’s father had been diagnosed with AD, after which she founded the Long Island Alzheimer’s Foundation, in 1988. She later participated in a study at the New York Hospital-Cornell Medical Center, where she was informed that she carried the apolipoprotein E ε4/ε4 genotype (The New York Times, May 3, 1998), which is associated with a substantial increase of AD risk. Later, I met Ms. Walsh at a meeting of the American Association for Geriatric Psychiatry in Florida, and she asked me if I had any recommendations to prevent her from developing AD. I prepared the following statement for her, which she published in the LIAF-Line.

LIAF-Line – Newsletter of the Long Island Alzheimer’s Foundation – July 2002
The Top Ten Treatments for Preventing Alzheimer's Disease - J. Wesson Ashford, MD, PhD

Research is rapidly uncovering information for the treatment and prevention of Alzheimer's disease (AD).

While much discussion about cause is still speculative, there is mounting evidence to support several ideas about how the disease develops. Though there is never enough evidence to prove any scientific theory, there is frequently enough evidence to discuss a particular idea with patients and to make practical recommendations. In the field of AD, there are several such issues that can now be brought to the clinic setting. Here are ten recommendations based on current experience treating AD patients and on the associations between AD and other dementing disorders. Other suggestions are based on scientific hypotheses with only preliminary evidence.

1) Take your blood pressure regularly and be sure that the systolic pressure is always less than 130. (Note, 2024–this recommendation to keep blood pressure under control is still considered a primary issue.) This recommendation is based on the association between stroke and AD. There are several articles relating high blood pressure to poor memory and a higher incidence of AD, particularly in association with certain genes. There is also some evidence that patients taking diuretics for their elevated blood pressure develop less AD. So, keep track of your blood pressure and, if necessary, make sure that it is well treated.

2) Watch your cholesterol; if your cholesterol is elevated, get treated with "statin" drugs. (Note, 2024–there is some controversy about statins, and more research is needed, particularly with respect to APOE genotype.) Cholesterol levels are related to arteriosclerotic vascular disease, which is in turn related to heart disease and stroke. So, this is a good idea in any case. Pertaining to AD, there is recent evidence that brain cholesterol plays an important role in memory and is controlled by Apolipoprotein E (produced by the APOE gene), which may be associated with 50% of the AD risk. Further, two recent studies have suggested that individuals taking “statin” drugs are less likely to get AD. While these findings would not warrant prescription of statin medication without cholesterol elevation, clearly these data give individuals with elevated cholesterol another reason to take their prescribed medications. A diet free of animal fat may also help lower cholesterol levels, and low animal fat diets may be associated with a lower AD risk. However, there are also reasons to eat deep water fish (tuna, salmon, swordfish, etc.), which contain oils thought to be good for the brain. (Note, 2024–dietary recommendations along these lines have become a major part of current AD prevention recommendations, similar to the Mediterranean and MIND diets.)

3) Exercise your body and mind regularly. (Note 2024–there are now numerous studies which demonstrate the benefit of exercise to reduce AD risk, potentially even frequent, short durations of exercise.) Many studies extol the virtues of exercise, and while there are no specific links between exercise and AD, there are links between exercise and health and cognition. People can get smarter by exercising. So, there is a logical recommendation to exercise to reduce the risk of AD.

But, beyond this, there are recent theories linking insulin to AD. The blood insulin level peaks about an hour after you eat. If you exercise about 30 minutes after you eat, even just walking for about 15 minutes, you might reduce your peak insulin level and leave the insulin degrading enzyme to do its other task of breaking down the harmful amyloid-beta that forms fibrils in the brains of AD patients.

There is some recent evidence suggesting that keeping your mind active can also delay onset. While this evidence can be challenged in various ways, it makes sense to continue seeking intellectual stimulation throughout your life. (Note, 2024–note that the second part of this recommendation, including socialization, has been supported with substantial evidence.)

4) Wear your seat belt; wear a helmet when riding a bicycle or participating in any activity where you might hit your head. Many reports show a relationship between head injury and AD, so playing it safe can help reduce this factor. (Note, 2024–a related large issue has become contact sports or sports in which head injury is frequent, with specific concern about “CTE”, chronic traumatic encephalopathy. Also, the relationship with traumatic brain injury, especially those injuries associated with blasts, particularly related to firing weapons and military combat, is being recognized as a potentially serious contributor to brain damage and cognitive impairment.)

5) If you have diabetes, make sure that your blood sugar is optimally controlled. Patients with diabetes have a tendency to get vascular disease, and this disease can injure the brain. While there is no clear relation between diabetes and AD, patients who have uncontrolled blood sugars may lose memory and be at greater risk for suffering from dementia.

6) Consult your doctor about treatment for your arthritis pain. There have been several studies indicating that arthritis patients who take NSAIDs (non-steroidal anti-inflammatory drugs) have a reduced risk of AD. Because the risks of these drugs (especially internal bleeding) are so great, they cannot be recommended for routine prevention. However, if you have arthritis, you should seek the advice of your doctor for treatment. Other research suggests that only certain NSAIDs may prevent the development of a toxic protein in the brain that may be a specific cause of AD (amyloid-beta-1-42).

The particular NSAIDs identified with this benefit so far are ibuprofen (Motrin, Advil), sulindac (Clinoril), and indomethacin (Indocin). Indomethacin may be the most potent, and one study suggested that this drug does slow down the course of AD. Ibuprofen is most readily available, and sulindac is the most easily administered and has the fewest side effects. (Note, 2024–NSAID relationship to AD has been supported by epidemiological research, but actual treatment of AD has not been positive, possibly because treatment must begin many years before the onset of dementia, when the pathology associated with amyloid-beta is beginning.)

7) Take your vitamins. There is little reason not to take supplemental vitamins after age 50, and they might even help if you have some transient deficiency in your diet. There is general support to take extra supplements of Vitamin E (400 international units [IU]) and Vitamin C (500 milligrams [mg]) together (once per day for prevention, twice per day if memory problems are present, and three times per day if AD is diagnosed). These recommendations are based on the oxidation/free-radical theory of aging and AD, and one large study which suggested that Vitamin E delayed specific endpoints for AD patients by as much as 6 months. Though far from conclusive, this “neuro-protective regimen” has become a common treatment for AD and is taken by many as a preventive. (Note, 2024–some recent studies have not fully supported this recommendation.)

B12 and folate have also been advocated as brain protective agents. B12 recommendations are complicated because its levels in the body are dependent on an individual's intestinal ability to absorb it. If an individual cannot absorb B12 taken orally, monthly injections must be given (though B12 is absorbed well when taken sublingually). However, these issues need to be discussed with your physician. The RDA for folate is 400 micrograms (mcg) per day, but this dose can be increased to 1 mg per day if memory difficulty is a concern. Here again, because of the complicated relationship between B12 and folate, it's essential to discuss proper dosage with your physician. With recent findings showing a correlation between elevated homocysteine levels and AD, B12 and folate become even more important because of their ability to keep homocysteine in check. Note too that alcohol and caffeine intake and tobacco use increase homocysteine levels. Your doctor may wish to check your homocysteine level.

(Note, 2024–Vitamin D deficiency has become pervasive and related to the development of AD, and this deficiency is easily treated. However, a causal association with AD is not established and absorption and other factors could also explain the relationship.)

8) Discuss sex-hormone replacement therapy (HRT) with your physician (only women for now). (Note, 2024–the use of HRT for women is still of unclear benefit for preventing AD, but there is still some supporting evidence.) There are general recommendations to postmenopausal women to take HRT to reduce the risk of heart disease and improve life in a variety of ways. These hormones might reduce the risk of AD. Although one study suggests treatment of female AD patients with HRT may have more risk than benefit. The issue is of interest because these chemicals seem to enhance the function of many brain cells. This finding raises the question of whether female HRT could help elderly males as well. Certainly, men with prostate cancer should discuss this issue with their physicians.

9) If you have difficulty getting to sleep, consider trying up to 6 milligrams of melatonin at bedtime. (Note, 2024–implementing melatonin use beneficially is somewhat difficult because utility depends on melatonin’s status in the brain and may not be helpful if the level in the brain is adequate. Alternatively, benefit may require high dosing to enforce good sleep. The anti-depressant trazodone is currently the most widely used drug in the US for insomnia, and there is some evidence that this medication, which is the only sedative medication which improves deep sleep, may have an important role in preventing AD.)

Despite little scientific evidence, melatonin, a natural substance produced in the brain, may help initiate and sustain sleep. With aging the brain produces less melatonin, and older people do sleep less. Sleep, however, is good for the body and brain and may help to keep AD pathology from developing.

Although many people claim that melatonin helps sleep a great deal, it may be effective only in those individuals with a significant melatonin deficiency. Further, melatonin is an excellent antioxidant and there is evidence that suggests melatonin and/or sleep may prevent the formation of toxic amyloid fibrils in the brain, which are related to the cause of AD. (Note, 2024–there is increasing evidence that the brain clears toxic proteins, including amyloid-beta, during sleep).

10) If you have significant difficulty with your memory, talk to your doctor about cholinesterase inhibitors. Several drugs from this class, including tacrine (Cognex), donepezil (Aricept), rivastigmine (Exelon), and galantamine (Reminyl), have been approved by the FDA for treating AD patients with mild dementia. While the primary evidence suggests that these drugs have only a modest benefit on cognition, there have been several studies that have suggested that these drugs may slow down the progression of AD. These studies are only suggestive, not conclusive, but many physicians agree with this suggestion based on their own observations. Importantly, if these drugs can slow AD progression, then they may have their biggest advantage very early in the disease course. While doctors are not prescribing these drugs for preventing AD, many physicians are prescribing these drugs beneficially for patients with mild memory problems. It is possible that these drugs may become a central part of preventive therapy for AD in the future. (Note, 2024–while recent, expensive anti-amyloid therapies have been FDA approved and appear to slightly slow the progression of AD pathology, these drugs have not been tested against the substantial disease slowing shown for the cholinesterase inhibitors.)

More options and future directions

There are several treatments in addition to those listed above that have been recommended for AD as treatment or preventive agents. At this point, there is not enough data to make more explicit recommendations. For example, recommendations for Ginkgo biloba remain ambiguous; co-enzyme Q-10 has been recommended but without wide support; and there is not enough evidence that aluminum is associated with AD, but you probably shouldn't cook tomato sauce (or other acidic foods) in an aluminum pot. Alcohol in very low quantities may protect against heart disease and may protect against AD as well, but anything more than minimal use is not wise. Several studies are exploring potential new preventions and treatments for AD. The “amyloid vaccine” is one of the most interesting, but development of this treatment was halted when some of the volunteers trying the treatment developed brain inflammation. (Note, 2024–anti-amyloid drugs have been approved by the FDA recently for slightly slowing the progression of AD, but they can be substantially harmful to the brain, particularly in individuals with an APOE ε4/ε4 genotype.) Also, there may be specific drugs now available that might slow AD pathology. For example, lithium and valproic acid, two drugs used to treat manic-depression, may inhibit a brain enzyme (glycogen-synthasekinase-3-beta), which could prevent the development of neurofibrillary tangles (which is the late AD pathology most correlated with dementia after synapse loss). Many patients with AD, including those in very early phases, have problems with depression and paranoid ideas. These symptoms can and should be treated. (Note, 2024–memantine (Namenda) was approved by the FDA in 2003 and may significantly reduce mortality in AD. And there are links between the inflammation seen in AD and depression and obesity.)

Another critical factor in AD, especially if early treatment can slow progression and delay dementia, is early recognition. Screening tests to be used routinely in doctors' offices for patients over 60 years of age are now being developed and may prompt many patients to get help sooner (Note, 2024–the Medicare Annual Wellness Visit, part of the Change Act passed by Congress, with updates as recently as 2023, mandates screening for cognitive impairment:, which can be efficiently improved with brief clinic screening tests and computerized memory tests, such as MemTrax: At this time, there are many genes being uncovered that appear to be associated with AD. In the future, it is likely that specific individuals will be told not only what their risk is for developing AD, but also how they can modify their life to prevent it completely.

There are so many indications that AD might be prevented that there is hope mounting that we may be able to end this disease in the near future.

(Note, 2024–as the world’s population ages and AD becomes more prevalent, the desperate need for prevention warrants progressively more attention. The purpose of providing these two volumes, the Handbook of Prevention and Alzheimer’s Disease and the Handbook of Intervention and Alzheimer’s Disease, is to bring greater understanding to the field and move these important approaches forward.)