Understanding Is Sketchy, Prevention Largely Guesswork…
Dementia, including Alzheimer’s Disease (AD), is the most serious health threat facing seniors. Today’s blog will use the terms dementia and Alzheimer’s interchangeably, because AD accounts for 60 to 80% of all dementia.
Dementia is a Significant Threat
Consider the following:
- Dementia is rampant: among people 65 and older, one in nine have dementia; for those 85 and up, more than one in three.
- We cannot prevent dementia or arrest it.
- Doctors cannot treat dementia or cure it.
- And it kills: AD is the #6 cause of death in the US. (In 2020 only, AD was #7 because COVID-19 jumped in as the #3 killer.)
- Death from other leading diseases is declining, but the death rate from dementia has risen 145% since 2000.
Evidently, if you are otherwise healthy and live a long life, there’s a good chance that you will acquire dementia, and will die from it.
Moreover, the problem is growing worse as our population ages. During the next 40 years, the US population will grow by 22%; however, the number of people with Alzheimer’s will more than double, increasing by 130%.
What We Need To Know About Alzheimer’s and Dementia
Here are the main sections of today’s blog:
– What Do We Know About Alzheimer’s?
– Cell Cleanup as a Cause of Dementia
– Everything is Complicated
– Cutting Through the Confusion
– A Scorecard for Alzheimer’s Research
– The False Conclusions from Correlation
– Correlations That Don’t Give Clear Guidance
– Correlations That Give Good Advice
If you want to skip some of the details, you can jump ahead to the section “Correlations That Give Good Advice” for current guidance from experts.
What Do We Know About Alzheimer’s?
During the last two months, I have seen more than 90 stories about Alzheimer’s research! Therefore, scientists must know something about dementia. What do they know?
As noted above, Alzheimer’s Disease accompanies most dementia. And the distinctive features of AD are the accumulation of “plaques” outside the neurons in the brain, and “tangles” inside the neurons. The plaques consist of fibers formed from protein fragments called beta-amyloid (Aβ). Inside neurons, tau proteins, which are normally soluble, assist in memory and stabilize nerve cell shape. When they become insoluble they join to form twisted strands called tangles. When plaques and tangles form they are generally accompanied by the death of neurons and damage to brain tissue.
So plaques and tangles accompany dementia. Does that mean that they cause dementia?
Not necessarily. Some people who have plaque buildup are not demented at all. And tau proteins, before they form tangles, show malfunctions not only in people who later acquire dementia, but also in those with repeated head trauma.
There’s a normal process called aptosis by which the body breaks down and eliminates cells that are no longer functioning properly. Perhaps it’s OK to have plaques and tangles so long as the body keeps them “cleaned up.” Or perhaps plaques and tangles are simply visible evidence that senescent cells of all kinds are building up due to a failure of aptosis.
Cell Cleanup as a Cause of Dementia
All this suggests the following: that failure of cell cleanup is the underlying cause of AD, echoing earlier work at Mayo Clinic. Recent research links aptosis directly to dementia:
- Proteins are made up of amino acids. Normally the amino acids in living things occur only in a pattern called “left-handed.” But when proteins stick around too long their amino acids can spontaneously convert to a mirror image “right-handed” form that the body’s processes cannot recognize. Thus if proteins don’t recycle in a timely way, that can directly lead to cell malfunction.
- Clonal hematopoiesis is a blood condition in which as many as one-half of the blood cells may be clones of a single mutated stem cell in the bone marrow. Clonal hematopoiesis is dangerous because it can lead to cancer and heart disease. However, it is highly protective against AD, reducing risk by 30 to 40%. The mutated blood cells are found in the brain and it’s possible they are especially effective at cleaning up dementia plaques.
- It’s known that sleep disorders are a risk factor for AD and dementia. And recent work shows that sleep disturbance interferes with the cleanup of amyloid-beta in the brain.
However, if dementia is caused by plaques and tangles, and those in turn are caused by insufficient cleanup of senescent cells, what is causing the breakdown of the cleanup process? So far, we are simply trading one puzzle for another. We don’t have a complete theory to pull it all together.
Everything is Complicated
Everything mentioned so far is complex, and poorly understood. However, you shouldn’t assume that we even know all of the problems. Here are two additional mysteries:
- AD may be caused by, or accelerated by, viral infection leading to inflammation in the brain. Because COVID-19 infection is associated with inflammation and “long-Covid” cognitive problems, that’s one more reason to get vaccinated. However, the data is still incomplete.
- What about “mild cognitive impairment” (MCI), which many people experience in their 70s. Is that a precursor to full-up dementia? That would seem logical, but in fact it turns out not to be true. A study showed that MCI does not predict dementia, and in fact MCI often disappears as its recipient ages. (And, we previously noted that early dementia tests are faulty unless they are calibrated with same-gender data.)
Cutting Through the Confusion
Let’s back off from these confusing, fragmentary results. Suppose that we are confronting a new, mysterious disease, “X”? Here are some reasonable steps to diagnose and eventually conquer it:
- Define the symptoms of “X” clearly.
- Measure how “X” progresses, for good or (often) for ill.
- Look for correlations between the disease and any other human characteristics: genetics, age, diet, exercise, medical condition and so on.
- See whether some characteristics have predictive value: that is, does their presence predict the future onset or progression of disease X?
- Can we reduce the probability of incurring X by changing something in people who have not yet caught it?
- When people have caught X, are there medicines or treatments we can give them that will slow or eliminate the disease? We don’t want to inadvertently injure the patients, so we have to step very carefully. Surely, we must be certain that the treatment will do no harm. We may test it on animal “models” before risking it with humans. And the human tests must be double-blind, and eliminate as many confounding factors as possible.
- We also need a theory that explains how the disease arises and how we can conquer it. It’s not essential to fully understand a disease to treat it – after all, we can treat many cancers by surgery, radiation and chemotherapy without knowing their exact mechanism. However, a theory that makes testable predictions that turn out to be true could be tremendously powerful in guiding all the steps listed above.
A Scorecard for Alzheimer’s Research
Alzheimer’s was first described in 1901. What has medical science accomplished since that time, along the lines outlined above?
Item 7: We have flunked out on developing a theory. We have pieces of a theory, in which we know that some changes in the brain accompany behavior showing dementia. And we are learning more all the time about how one change in the brain affects another. However, we don’t know which changes actually cause dementia, nor how to interrupt that process.
Item 6: What about treatments? Only one treatment for Alzheimer’s has been approved by the Food and Drug Administration, aducanumab, whose trade name is Aduhelm. The approval is limited to people with only mild cognitive impairment, a condition which as noted above often cures itself. FDA’s approval is controversial because this medication does not cure or stop the progression of dementia. It causes serious side effects yet evidence of its effectiveness is, to many experts, uncertain. Other drugs have been tried but none with convincing results. Thus to date, research also flunks the test of generating valid treatments.
Item 5: We believe, based on correlations and their predictions, that following a healthy diet, exercising and controlling your weight will reduce your likelihood of contracting dementia. However, an experiment to prove this hypothesis would require many years and a large number of people willing to follow a very strict life protocol. In addition, it’s difficult to have a control group for comparison, because the test subjects know what actions they are taking or not taking. Thus their reported symptoms may be distorted by their expectations. For these reasons, we cannot say for certain that the activities recommended to fend off AD will actually have any significant effect.
We’re in better shape with items 1 through 4:
Item 1: The definitions of AD have evolved through the years. However, at any given time we have a good idea what we mean by having this disease.
Item 2: And the progression of AD has been unfortunately often observed and is well known.
Items 3: Many people have looked for and discovered correlations between dementia and one or another measurable factor. However, as we keep saying, correlation does not mean causation.
Item 4. Fortunately, some of the correlations seem to also have predictive value. That does not yet prove causation, but when we don’t have a good theory to explain things, predictive value does make causation more plausible.
Thus, 120 years of research have equipped us with only 4 of the 7 factors listed above. And 4 out of 7 is a pretty poor scorecard.
The False Conclusions from Correlation
It’s worth a brief digression on the way that correlations lead us astray. Correlations are sometimes hyped as if they proved something. However, they may be false, causing people to engage in behavior that is either irrelevant or even harmful to their health.
Here’s an example: A UK study found that people over 50 who drink several cups of coffee or tea daily had a 28% lower risk of getting dementia. These results are consistent with earlier research. Some folks who read about this would conclude that adding coffee to a non-coffee diet reduces your risk, but that is not at all what the study showed.
Consider this: People who drink coffee or tea may have more disposable income than others; those with more income generally have healthier diets and better access to health care, and those factors might give them protection from dementia. Alternatively, coffee and tea drinkers may consume fewer sugary sodas (thereby reducing their risk of obesity and diabetes), or drink less alcohol (thereby reducing damage to their organs); in either case, it’s not the coffee, it’s the indirect effects that may help them.
Therefore, if you don’t currently drink coffee or tea, what will happen if you add those to your diet? If there’s a direct link between caffeine and Alzheimer’s, that addition may give you protection from AD. However, drinking more coffee will not automatically make you richer or healthier. Therefore, if all of the coffee/Alzheimer’s effect is indirect, drinking more coffee won’t help you.
Correlations That Don’t Give Clear Guidance
As noted, looking for correlations (item 3 above) is useful in trying to understand dementia. However, we need to be cautious when using correlations to guide our behavior. Here are examples of factors that correlate with the risk of dementia:
- Heart Health: Higher heart rate and midlife cardiovascular conditions are linked to greater risk of dementia. Higher blood pressure predicts mild cognitive impairment, but not necessarily dementia. Heart disease seems to cause brain dysfunction, especially for those with genetic predisposition.
- Sleep Problems: In general, sleep problems are associated with greater dementia risk. Some blame insufficient REM sleep, others blame insufficient deep sleep. Some say that side sleeping helps clear waste from your brain yet others question that. Others claim that your brainwave patterns during sleep (specifically, “spindles”) can give early diagnosis of dementia.
- Factors Correlated with Higher Dementia Risk: Low vitamin D. Having a spouse with cognitive impairment. Exposure to formaldehyde at work or elsewhere. Having a fluctuating BMI (body mass index).
- Factors Correlated with Lower Dementia Risk: Cataract surgery. Taking fish oil supplements. Drinking coffee and tea. Consuming Blueberries and Garlic (hopefully not together!). Making music. Taking sildenafil (Viagra).
After noting many factors that are associated with either higher or lower risk of dementia, it’s worth pointing out some things that appear to have no correlation at all:
- Many people take statins by prescription to lower their blood cholesterol. Taking statins, or avoiding statins, appears to have no relationship to contracting dementia.
- When otherwise healthy (non-deficient) people take dietary supplements, these appear unrelated to risk of dementia: ginkgo biloba, Omega-3, vitamin E, curcumin, multivitamins and high doses of individual vitamins (selenium, B vitamins, calcium, vitamin D).
Correlations That Give Good Advice
With all the work that’s been done, surely there must be some winners? Some lifestyle advice that may fend off dementia, even though we don’t yet understand it very well?
Yes. There are correlations that seem to have predictive value, and that are consistent with one or another theory of the mechanisms underlying dementia. So here are the factors that experts advise probably cause or protect against Alzheimer’s:
Likely Causes of Dementia: Older Age. Genetics (especially, having the APOE-e4 (apolipoprotein) gene). A family history (not necessarily genetic) of Alzheimer’s. Race and ethnicity (which often is associated with poorer access to health care). Sleep disturbances. Physical frailty. One or more previous instances of ischemic stroke. Multiple chronic diseases in midlife.
Likely Ways to Reduce Dementia Risk: Physical activity. Not smoking. Lifelong learning. Being socially and mentally active. Controlling blood pressure. Having a healthy diet, especially the MIND diet.
Avoid “Long COVID”: The aftereffects of coronavirus infections include effects on the brain similar to impact injuries, and may increase dementia risk. COVID vaccination and boosters certainly reduce the risk of catching coronavirus, and may also reduce the severity of Long COVID, although the latter data is still incomplete. And those who die from COVID-19 have brain changes that resemble AD.
Despite much research, scientific progress has been slow. Thus this list is not very different than one in a previous blog from mid-2014.
- Dementia and Alzheimer’s Disease are serious risks for everyone as they age. These conditions are poorly understood and cannot be cured or even effectively treated.
- Most advice that is publicly circulated comes from observing correlations. We should view it with caution, especially if there isn’t a plausible theory as to why it should work.
- The best ways to reduce risk of dementia are to remain physically and mentally active, to maintain good health, to have a healthy diet and to protect against viral diseases.
- Because of its increasing relevance to an aging population, we should support public and private funding of research to understand and eventually prevent or cure dementia and AD.