This edition of the epistles of Doc Gumshoe won’t be entirely about Alzheimer’s, but there are Alzheimer’s-related news items that jump to the top, based on timeliness, if nothing more.

When Doc Gumshoe last wrote about what was happening on the Alzheimer’s front, a big chunk of the piece was the FDA’s surprising – and in my view, misguided – approval of aducanumab (Aduhelm) for the treatment of Alzheimer’s. Misguided, thought I, because the benefit it brought was marginal, and also because of the cost, which was projected to be $56,000 per year for each patient treated. A number of experts pointed out that because Aduhelm had received the seal of approval from the FDA, Medicare would have to cover it, and the cost would be passed on to all Medicare subscribers.

On Friday, November 12, the Centers for Medicare and Medicaid Services (CMS) confirmed the prediction that the cost of Aduhelm would indeed be borne by all Medicare subscribers. They announced that in 2022 the standard monthly payment for Medicare will increase to $170.10, up from $148.50 in 2021. A CMS official said that about $10 of the premium is due to the costs of Aduhelm. The balance is due to general increases in health care costs, and to catch-up from the expiration of an act of Congress that had limited the increase in Medicare Part B premiums on account of the COVID-19 pandemic.

Back in July, here’s what I wrote about the cost of Aduhelm and the impact on Medicare:

“A major concern about aducanumab’s approval is its price. The drug would be given monthly by infusion, and the estimated price is about $56,000 per year. It has been estimated that if just one-third of the eligible patients with Alzheimer’s disease were prescribed aducanumab/Aduhelm, the cost to Medicare would be about $112 billion per year, which is far more than Medicare spends on any other medication. If all 5.8 million Medicare-eligible adults with Alzheimer’s took the drug, it would cost $334.5 billion — or nearly half the budget of the entire Department of Defense.”

The nonprofit research organization Altarum estimates that by the mid 2020s, Aduhelm will constitute more than 1% of all health spending in the US, and could increase total prescription drug spending by more than 8%. This is based on the assumption that of the nearly 6 million persons diagnosed with Alzheimer’s in the US, only about 1 million – those with early and mild symptoms – would be prescribed Aduhelm.

The basis of the FDA’s approval of aducanumab was that it removed some amyloid beta (Aβ) from the brains of clinical trial subjects and, at least in one of two trials, resulted in a very, very slight slowing of cognitive decline. Another factor, which was disclosed after the FDA made its pronouncement, is that about 40% of the patients in the two Phase III studies experienced brain inflammation.

What some researchers in Alzheimer’s disease consider as hopeful is that the approval of aducanumab will spur more research into BACE inhibitors, BACE being beta (β) secretase, the enzyme that cleaves amyloid precursor protein (APP), which results in Aβ accumulation in the synaptic space between neurons, and the inhibition of the transmittal of neurotransmitters across this space. Since the transmittal of neurotransmitters from one neuron to another essentially constitutes brain activity, Aβ accumulation preventing this activity has been considered to be, if not the, at least an, essential cause of AD.

A number of BACE inhibitors have been developed, and most of them have been duds. The main defect in these agents is that they have great difficulty in passing through the blood-brain barrier in enough concentration to be at all effective. But it is certainly within the limits of possibility that a BACE inhibitor that easily crosses the blood-brain barrier will be developed and have a major effect on Aβ deposits and, hopefully, cognitive decline.

Are there any recent positive findings about Alzheimer’s?

If by “positive” we mean something like the discovery of a drug that definitively halts the progression of Alzheimer’s, the answer – unfortunately – is “no!”

But from where I sit, anything that is learned about the essential mechanism through which Alzheimer’s wreaks such damage is a positive finding, in the sense that the more we understand about the disease process, the better our chances of interrupting or reversing that process.

A couple of such findings have recently emerged. One came from the University of Cambridge (in the UK) where researchers have learned that the progression of Alzheimer’s is considerably different from what had been thought. (Meisl G. SciAdv 10/28/2021) They accept the premise that the combination of Aβ and tau protein is what messes up brain activity. This combination is now referred to as the “aggregate.” It has been assumed that the disease process consisted of the spread of the aggregate from a single location in the brain to multiple locations.

“The thinking had been that Alzheimer’s develops in a way that’s similar to many cancers: the aggregates form in one region and then spread through the brain,” said Dr. Georg Meisl from Cambridge’s Yusuf Hamied Department of Chemistry. “But instead, we found that when Alzheimer’s starts there are already aggregates in multiple regions of the brain, and so trying to stop the spread between regions will do little to slow the disease.” Clearly, the objective has to be to prevent the formation of the aggregates in the first place, rather than trying to stop the spread.

This is the first time that human data has been used to track which processes control the development of Alzheimer’s disease over time. It was made possible in part by the chemical kinetics approach which allows the processes of aggregation and spread in the brain to be modeled, as well as advances in PET scanning and improvements in the sensitivity of other brain measurements.

Scientists are now able to observe the basic molecular mechanism of aggregate formation at the molecular level in real time and in real patients. It has been observed that neurons are fairly good at preventing these aggregates from forming, but ways may be found to make them more effective. This could be a decisive step in stopping the progression of Alzheimer’s disease.

Another possibly promising finding

This one links the absence of dementia in persons with extensive aggregate deposits (Aβ and tau protein) to the myocyte enhancer factor 2 (MEF2) gene family. As has been observed many times previously, many individuals have similar levels of that noxious brain sludge that is thought to slow the transmission of neuronal impulses, but without experiencing dementia. The factor to which that has generally been attributed has been termed “cognitive resilience,” and, as we have discussed in previous posts, cognitive resilience is usually attributed to things like education and continuing mental engagement.

This research was carried out by scientists at the Massachusetts Institute of Technology in Cambridge. (Barker SJ. SciTranslMed 11/3/2021;13,618). In two cohorts totaling about 1,000 people, cognitive resilience was highly correlated with expression of MEF2, as well as with many of the genes it regulates. MEF2 also was more active in the brains of mice exposed to a cognitively stimulating environment. These mice performed better in learning and memory tasks.

The MIT research made use of data from a study that Doc Gumshoe has referred to in the past – the study in nuns, which compared their use of language in the narratives that they wrote when entering the convent in their youth with their cognitive function in old age. The finding was that the novices that wrote complex sentences and used long words remained cognitively sharp in their old age in comparison with those sisters who had used simpler language. The study included post-mortem examination of their brains, and revealed that these aged nuns had elevated levels of amyloid beta and tau, but nonetheless remained cognitively sharp.

The finding that is revelatory is that cognitive resilience may have physiologic connections. It is not clear whether the lifestyle that leads to cognitive resilience may also favor the expression of MEF2, or whether MEF2 favors those cognition-enhancing activities.

The lead author of the study, Dr Li-Huei Tsai, said that the findings suggest that enhancing MEF2 activity could help protect against dementia. Because MEF2 affects other types of cells and cell processes, more research is needed to make sure that activating it would not have adverse effects. The group hopes to identify how MEF2 becomes activated and plans to examine the effects of other genes MEF2 controls.

Here’s an update on the current Alzheimer’s disease picture. It been slightly revised since Doc Gumshoe’s most recent update this past July.

• 6.2 million persons in the US are currently diagnosed with AD. That’s diagnosed with AD; an equal number are thought to have undiagnosed AD, perhaps in the early stages.
• This includes nearly a quarter of a million persons under 65 years of age.
• One in nine people 65 years old or older has Alzheimer’s dementia. That percentage increases with age; 36.4% of people 85 years old or older have AD.
• Almost two-thirds of Americans with AD – 3.6 million – are women. The chief reason for this large imbalance is that women’s life expectancy is about 5 years greater than men’s life expectancy, and it’s in those 5 years that the incidence of AD increases steeply.
• AD prevalence is expected to increase as our population ages. By 2030, 8.5 million Americans are predicted to have AD, and by 2050, the number is predicted to be 16 million.
• The prevalence of AD and other dementias is about twice as high in African Americans and about one-and-one half times as high in Hispanic Americans as it is in non-Hispanic whites. The reasons for this are not entirely clear. The disparity is not thought to be due to genetic differences, but rather to higher prevalence of conditions and circumstances which contribute to AD and dementia.
• According to the Alzheimer’s Association, the 2021 costs to the nation associated with AD will be about $355 billion. About half of this cost will be paid by Medicare, and another significant chunk by Medicaid. Unless there is a treatment breakthrough, total costs may reach $1.1 trillion by 2050.
• Annual Medicare costs per patient with AD are estimated to be $26,358. Out-of-pocket costs are $11,571. As noted earlier, the likely addition of Aduhelm to the roster of Medicare-approved drugs will drive these costs even higher.
• These costs don’t figure in the huge economic impact of AD on caregivers, who are often the immediate family members of the person with AD. In 2020, these caregivers provided about 15.3 billion hours of care, valued at nearly $257 billion.
• AD is the 6th leading cause of death in the US.
• Among people aged 70 or older, about 61% of those with AD will not make it to age 80. This is twice as high as the death rate in people without AD.
• The death rate in the 5 other leading causes of death in the US – breast cancer, prostate cancer, HIV, and especially heart disease and stroke,– have declined since the year 2000, while the death rate from AD has increased by 145.2%. At present, there is no cure, and the most effective treatments do nothing to stop the progress of the disease. At best, they slow it. This, may I note, is not unlike some cancer treatments that have been deemed moderately successful.

Is there a link between statins and dementia? 


Let me lead off with a quote from Dr JoAnn Manson, chief of the Division of Preventive Medicine at the Harvard-affiliated Brigham and Women’s Hospital.

“I think that the relationship between statins and cognitive function remains controversial. There’s still not a clear conclusion whether they help to prevent dementia or Alzheimer’s disease, have neutral effects, or increase risk. While the science in this area is a little murky, one thing is clear: If your health care provider is recommending statins and saying that you are a candidate, the benefits of taking it are very, very likely to outweigh any risks.

Statins also decrease inflammation, which has been implicated in Alzheimer’s disease and some other forms of dementia. While you would expect that statin use would reduce the risk of cognitive decline and dementia because statins lower cardiovascular risks and the risk of stroke, it hasn’t been clearly shown to be the case.”

The question whether statins might possibly have some adverse effect on cognition stems from reports dating back to 2012 that some statin users had complained of short-term cognitive deficits after using statins. The FDA listed these as possible effects of statins. A recent analysis published in the British Medical Journal looked at the results of 62 clinical trials in more than 120,000 participants with an average follow-up period of four years. The conclusion was that statin use was linked with a small increase in symptoms such as muscle pain, liver dysfunction, kidney problems, and eye conditions. Cognitive deficit was not one of those symptoms.

In a recent study, researchers looked at data on statin use among 18,446 people, ages 65 or older (Zhou Z. J Am Coll Cardiol 2021 Jun 29;77(25):3145-3156. Over a period of almost five years, people who took statins weren’t any more likely than non-users to have dementia. The same was true when it came to other changes in cognition, memory, language, executive function, or a measure called psychomotor speed, which measures how quickly someone can process information. They also found no differences between lipophilic and hydrophilic statins.

That particular finding is especially relevant regarding the possible link between statins and dementia. Lipophilic statins are more easily able to dissolve in fat, whereas hydrophilic statins dissolve more easily in water. Therefore lipophilic statins would – at least theoretically – be more likely to cross the blood-brain barrier, since the brain contains abundant fatty tissue, and result in cognitive issues. However, the JACC study found no such link.

The lipophilic statins are simvastatin (Zocor), fluvastatin (Lescol), pitavastatin (Livalo), lovastatin (Altoprev), and atorvastatin (Lipitor). The hydrophilic statins are either rosuvastatin (Crestor) or pravastatin (Pravachol). Non-statin cholesterol-lowering drugs include ezetimibe (Zetia), alirocumab (Praluent), and bempedoic acid (Nexletol).

Many clinicians have pointed out that people should not stop taking statins, because elevated cholesterol has definitively been demonstrated to be a risk factor for cognitive decline as well as a risk factor for heart attacks and strokes.

Muscle aches and leg cramps have been linked with statins. Persons experiencing these effects might consider switching to a non-statin agent – of course, with the advice of their physician. Another possible agent that has been reported to provide relief from leg cramps is CoQ-10.

And, while we’re discussing lipids, here’s something else.

Adding pecans to their diet appears to reduce lipid levels in some at-risk individuals

This was based on a small study conducted by Liana Guarneiri, a PhD candidate at the University of Georgia. The study recruited 52 persons, aged 30 to 75 years, and assigned them to three groups, as follows:

• One group was composed of 16 persons who kept to their regular diet, but added pecans.
• A second group of 18 persons substituted pecans for foods of equal caloric content from their regular diet.
• A third group of 18 were assigned to a nut-free diet.

At baseline and at the conclusion of the trial at 8 weeks, all subjects had a high-fat breakfast and then had blood drawn over a period of 4 hours to determine changes in blood lipids.

• Low-density lipoprotein cholesterol (LDL-C) decreased 14 mg/dL in the group that just added pecans to their diet and decreased 9 mg/dL in the group that substituted pecans, but increased 6 mg/dL in the non-pecan-eating roup (P<0.01)
• Triglycerides decreased 14 mg/dL in the group that just added pecans to their diet and decreased 13 mg/dL in the group that substituted pecans, but increased 27 mg/dL in the non-pecan-consuming group (P<0.001)

Guarneiri noted that previous studies have shown that eating pecans had a positive effect on blood lipids among people who were healthy. The focus of her team’s current study was to determine if pecan consumption would also help people at risk of cardiovascular disease by reducing blood lipid levels.

The study did not include actual cardiovascular disease outcome measures. The underlying assumption was that elevated low-density lipoprotein cholesterol (LCL-C) increases cardiovascular disease (CVD). However, it certainly does confirm the premise that vegetable fats are healthier than animal fats and consequently should reduce the incidence of CVD events.

At first glance, the study conveys some good news, and certainly no bad news. However, it needs to be put in perspective. The three groups of subjects were fairly small, and there was no information as to what their regular diets consisted of. We can assume that these 52 individuals varied considerably as to their diets, and their willingness to participate in a trial of this kind suggests that their normal diets were indeed fairly normal. Neither the person who insists on a rare steak every night nor the one who is watching his/her weight and trying to subsist on vegetable shakes would have volunteered for the trial. But even within “normal” diets, there is wide variation. We simply do not know what else the study subjects consumed. There is reason for skepticism – at least a little skepticism.

Enough skepticism that Doc Gumshoe, for one, is not going to go around with a little bag of pecans and gobble one down any time he is feeling the least bit peckish. Pecans are delicious, but they’re generally salted, and eating lots of delicious little salted tidbits is a sure way to ingest a whole lot more salt than is good for me.

And, while we’re speaking of salt …

Sodium increases CVD risk; potassium decreases that risk

That is the conclusion of a pooled analysis examining six prospective cohort studies that employed the most accurate and reliable method of measuring both sodium and potassium, specifically 24-hour urine samples. The study was led by Dr Yuan Ma, a research scientist in the Department of Epidemiology at the Harvard T.H. Chan School of Public Health.

The six studies were the Health Professionals Follow-up Study, the Nurses’ Health Study, the Nurses’ Health Study II, the Prevention of Renal and Vascular Endstage Disease study, and the Trials of Hypertension Prevention Follow-up studies. The researchers analyzed the individual sodium and potassium excretion data and the incidence of cardiovascular disease, including coronary heart disease or stroke. The data came from multiple 24-hour urine samples — the most reliable method for assessing sodium intake — that were taken from more than 10,000 generally healthy adults. CVD events were traced for an average of nearly nine years. A total of 571 cardiovascular events were documented during the cohort studies.

Higher sodium intake was significantly linked with higher cardiovascular risk; the higher the intake, the higher the risk. The range of sodium intake as calculated based on excretion was from about 2,000 to 6,000 milligrams per day. For every 1,000 mg per day increase in sodium excretion, the CVD risk increased by 18%. In contrast, for every 1,000 mg per day increase in potassium excretion, the risk of CVD decreased by 18%. These associations were consistent across subgroups, defined by age, sex, baseline hypertension, weight, and years of follow-up.

As I’m sure you know, almost all of our sodium intake comes in the form of salt – sodium chloride (NaCl). The relationship between sodium intake and the risk of CVD has been controversial. This is not because there are data to the contrary, but because in general the food industry puts a whopping amount of salt in their prepared products (not just on pecans), and some scientists sympathetic to the prepared food industry express skeptical views regarding those studies. Previous studies have been also criticized for assessing sodium intake using methods prone to measurement errors, such as spot urine tests. However, physiologic tests have consistently demonstrated that one of the effects of sodium is an increase in blood pressure, as sodium passes through the sodium channels in the arterial wall, triggering contraction and thereby increasing blood pressure. And this increased blood pressure elevates the risk of cardiovascular events, such as heart attacks and strokes.

Potassium has an opposite effect in the body — it can help relax blood vessels and increase sodium excretion while decreasing blood pressure. Rich sources of potassium include fruits, leafy greens, beans, nuts, dairy foods, and starchy vegetables like winter squash. Bananas are an excellent source of potassium, and in our family we rely on them to stave off those agonizing leg cramps that come out of nowhere in the night when we’re supposed to be peacefully asleep.

It’s okay to be a bit overweight

In fact, it might just be better than okay to be a bit overweight.

Dr T. Jared Bunch said, “I observed the obesity paradox in a published study I conducted while studying at the Mayo Clinic. We looked at 226 people who experienced a heart arrest in the community and were resuscitated. What we found was that people that were slightly overweight (BMI from 25-30) had the highest five-year survival at 78%. People who were underweight had a significantly lower survival at 67%, similar to people considered morbidly obese.”

Characterizing a person’s weight as normal or overweight (and so forth) is commonly done by calculating that person’s body-mass index, or BMI, which we all certainly know about. As a reminder, BMI is an attempt to attach a specific numerical figure to a measure of body fat. The figure used is the ratio of the weight of the body in kilograms to the square of its height in meters.

In adults, BMI ranges are classified as follows:

BMI ranges above 35.0 are generally referred to as “morbid obesity,” implying that severe health consequences would result.

Dr Bunch, however, referred to another Mayo Clinic study that bore out the conclusions of his study. The study looked at results from 40 different studies in 250,152 subjects. The lowest risk of all types of mortality as well as heart-related mortality was in persons considered to be overweight. In fact their risk of death was 12% lower than in those considered to be of normal weight. The highest risk of death was in the underweight subjects – 37% higher than in those persons considered normal weight. Even their risk of CVD-related mortality was 45% higher than in those that were of normal weight.

It was not until people had a BMI above 35 that there was a clear increased risk of CVD-related mortality (80% increased risk) compared to normal weight people. What we have here is a classic “U” shaped survival curve with the highest mortality risks seen at the two higher ends of the curve, in individuals that were severely underweight or overweight. The lowest part of the curve, with the lowest mortality, was in those considered overweight (BMI from 25-29.9), but not obese.

What BMI misses is the proportion of body fat to other components of the body, especially muscle. Many or perhaps most high-performance athletes would be classified as overweight or obese by the BMI standard because of their greater muscle mass.

At the other end of the scale, it’s likely that some persons with a BMI in the underweight category are underweight as the result of a health problem, so it may well be that the low BMI itself would not be the cause of elevated mortality risk, but the reverse – the underlying health problem is the cause of both the elevated mortality risk and the low BMI.

The BMI tool is quick and cheap, while more accurate methods of determining the body’s composition in terms of muscle-to-fat ratio are time-consuming and expensive and therefore probably not appropriate for use during a routine annual physical examination. But in these days where every quick, cheap, routine factoid goes in our electronic medical records, the BMI score could be damaging.

In my own case, when I was checking out after my routine annual physical, I saw that my BMI had crossed the line into the obese category, which I knew was incorrect. When I saw the actual figures the score was based on, I at once spotted the error. The nurse had me at more than two inches shorter than my actual height, which put my BMI over the mark. Why did she make this error? Because she was too short to see the top of the scale I was standing on when she put that bar on the top of my head to measure me. Needless to say, I made a fuss.

Vitamin D might deliver one more benefit

Specifically, vitamin D supplements might lower our chances of developing an autoimmune disease. This came from the analysis of a large clinical trial in about 17,000 adults. Among those who were taking daily vitamin D supplements, there were 123 new cases of autoimmune disease, while among those on placebo, there were 155 cases. If that ratio holds true in the population at large, it would mean that vitamin D supplements reduce one’s likelihood of developing an autoimmune disease by about 22%. That result was judged to be just barely significant (P = 0.045).

That’s not huge, but it’s not nothing. We need to bear in mind that there are no current interventions of any kind that actually prevent the onset of autoimmune diseases. The autoimmune diseases include rheumatoid arthritis, lupus, inflammatory bowel disease, multiple sclerosis, type 1 diabetes (but not type 2), psoriasis, and others.

The data came from analysis of the VITAL trial, whose primary outcome was the effect of vitamin D and omega 3 fatty acids on cancer and cardiovascular disease. No decrease in risk was seen for those conditions. However, the effect on autoimmune disease attracted the attention of the investigators.

The trial was led by Karen Costenbader, MD, of Brigham and Women’s Hospital in Boston. Speaking at the virtual annual meeting of the American College of Rheumatology, she said, “I don’t have to convince this audience of the burden of autoimmune diseases. These diseases affect 5% to 8% of the population, or 15 to 20 million Americans. They are among the top 10 causes of death among women under 65 in the U.S. and the second most common cause of chronic illness.”

* * * * * * *

No mention of COVID-19 in this installment, but clearly it’s not over. The big news, of course, is how quickly Omicron has taken over the media. But that new variant is not the only news of consequence that needs attention. Doc Gumshoe will attempt to provide a meaningful look at the entire picture in his next diatribe. Meantime, thanks for all the comments and keep’em coming. Best to all and stay well, Michael Jorrin (aka Doc Gumshoe)

[ed. note: Michael Jorrin, who I call Doc Gumshoe, is a longtime medical writer (not a doctor) who writes for us about medicine and health a couple times a month. He has agreed to our trading and disclosure restrictions, but does not generally write directly about investments. His ideas, thoughts and words are his own, and you can see all his past pieces here.]