[ed. note: Michael Jorrin, who I dubbed “Doc Gumshoe” years ago, is a longtime medical writer (not a doctor) who writes for us a couple times a month about health issues and trends. He does not typically focus on specific investment opportunities, but has agreed to our trading restrictions… as with all of our authors, he chooses his own topics and his words and opinions are his alone]
I don’t know about you folks out there in Gumshoe Nation, but I get the strong feeling that most people don’t want to talk about Alzheimer’s disease (AD). It just looms over us. We have seen people who have succumbed to AD, and the picture is not pretty. And there is a general sense that medical science doesn’t have a whole lot of ammunition on hand to combat it. But never fear, Doc Gumshoe is not going to devote this piece to reiterating the disappointing news items about Alzheimer’s. Instead, I’m trying to accentuate the positive and latch on to the affirmative, but without totally eliminating the negative.
The generally gloomy view is at least in part a result of a widespread expectation that there should be “miracle cures” for all manner of diseases and conditions. The absence of such a cure is equivalent to failure. We hear that medical science and Big Pharma have utterly failed in their quest to find a cure for cancer. If the only indication of success were a “miracle cure,” a drug or treatment that stopped every form of cancer and resulted in decades of totally disease-free survival for all patients, then, indeed, all efforts have resulted in failure. But as I have repeatedly stated in these pieces, remission rates for many cancers, including the most common cancers, have improved significantly, and many millions of people, here and elsewhere, are enjoying symptom-free lives due to these many non-miraculous treatment modalities. I do not consider that a failure.
But negative news keeps trickling out. For example, it was announced a few days ago that Novartis, Amgen, and the Banner Alzheimer’s Institute are going to work together on a program aimed at preventing AD by means of a drug in a class called BACE inhibitors, which I discussed in a previous post about AD, back on December 21, 2015. BACE 1 (beta-site amyloid precursor protein cleaving enzyme 1) is thought to lead to the formation of beta amyloid in the brain, which in turn is thought to lead to the cognitive disability that characterizes Alzheimer’s. Therefore, inhibition of this enzyme should prevent or delay the symptoms of AD. However, previous trials of BACE inhibitors have not been successful, and the news of this collaboration was generally met with a distinct lack of enthusiasm. In fact, even before any results were announced, failure was anticipated.
This kind of response gets around and shapes people’s views. Quite naturally, lots of us are concerned about the possibility that we will develop Alzheimer’s disease. Any time we forget anything, we think, is that the dreaded Alzheimer’s plague getting ready to strike? A few days ago, for no reason whatever, I was trying to remember the name of the woman who sang “Monotonous” in the show “New Faces of 1952.” It was of no importance, of course. I was hardly going to cheat by resorting to Google. I tried to put it out of my mind, but it kept nibbling at me. I could hear the song in my head – “I met a Rajah, amusing fool, when on my way to Istanbul, bought me the Black Sea for a swimming pool.” After a couple of days of intermittent itching, her name popped into my head – Eartha Kitt! Excellent! I am not slipping into Alzheimer’s, at least, not yet.
Then along came a piece of genuinely good news. Persons who experience occasional memory lapses or blanks and are aware of their episodes of forgetfulness are not any more likely to develop dementia than the rest of the population. The behavior that is much more likely to be a precursor of dementia is forgetfulness that the person is not aware of. They go about their lives happily unaware of what they have forgotten. The blanks in their minds do not cause them any distress. I remember that for years I had to struggle to remember the word “refractory,” and had to recollect it by thinking of surfaces – those that absorb light, those that are transparent, those that reflect, and – aha! – those that refract! That certainly troubled me. Was I slipping into dementia? Would I have to poke and prod at the contents of my noggin to bring to mind the words I needed? But apparently that type of forgetfulness affects great numbers of people who do not go on to develop dementia. The mechanism of ordinary forgetfulness is similar to minor traffic nuisances in the network of neurons. The destination is there, but the street is temporarily obstructed because the school in the middle of the block is having a street fair. One has to find another route, as I did with “refractory.”
Obstructions in the neuronal pathways leading to “Eartha Kitt” or “refractory” do not come close to what happens in Alzheimer’s, which is more like an epic snowstorm that clogs all the roads and streets and eventually – over years – renders them impassable. The person with Alzheimer’s is unable to recall simple everyday words – the wife of a good friend would forget the word “floor” and helplessly point downward to try to indicate what she was talking about. And the avenues that convey the signals that tell us to eat and breathe also become obstructed by this blizzard in our brains, with fatal results. The brain blizzard that blocks the way to simple words eventually also clogs other brain functions – no mail deliveries, no ambulances or fire trucks, no food deliveries to the grocery store.
Some possibly good news about Alzheimer’s
The discouraging statistic that has rocketed about the news media is that an overwhelming proportion of all the proposed drugs to treat Alzheimer’s disease fail in the clinical trial stage. The usual headline is “99.5 % of Alzheimer’s drugs fail!” So, in that context, what good news could there possibly be?
An organization called “ResearchersAgainstAlzheimer’s” has a more hopeful perspective. Here’s their “Statement of Beliefs:”
“We have heard some say that Alzheimer’s disease is an inevitable part of aging. Others have claimed that it simply cannot be prevented or effectively treated anytime soon. Still others believe that we simply cannot afford to do what it would take to stop the disease. They are all wrong.
As men and women of science, we are united by a simple but bold belief: It is possible to prevent and effectively treat Alzheimer’s disease within our lifetimes, but only if our nation does what is necessary:
- Set an aggressive goal of stopping Alzheimer’s disease by 2025, because it will focus the energies of the research community;
- Invest significant resources in Alzheimer’s disease research and innovation, because our commitment to cures must match the scale of the challenge;
- Institute reforms to accelerate the drug pipeline and deliver therapies to patients faster, because the ultimate goal of research is to bring help to those afflicted, and to prevent the disease from afflicting future generations.
If government, private industry, and the research community unite with a common goal and purpose backed with the necessary leadership, resources and incentives, the power of scientific research can be unleashed to unlock new possibilities, to deliver new cures – and to prevent and treat Alzheimer’s disease.”
Their website lists 17 founding members from prestigious institutions, including Johns Hopkins, Rush, Cleveland Clinic, Washington University in St Louis, Indiana University, Baylor, University of Tokyo, Oxford, Mayo Clinic, Harvard Medical School, University of Pennsylvania, University of Southern California, University of California San Francisco. So let’s grant them a degree of legitimacy.
And what they have most recently announced is an unexpected surge in the number of new AD drugs. For example, there are now 58 drugs in Phase 2 clinical trials, and 32 in Phase 3 clinical trials. Two of these are projected to get FDA approval in 2018. These are masitinib, which is the main product of AB Sciences in Paris, and brexpiprazole (Rexulti), from Otsuka Pharmaceuticals and Lundberg. Masitinib is a tyrosine kinase inhibitor, and it targets the formation of tau protein in the brain, which is one of the two postulated causes of AD. Brexpiprazole is a dopamine receptor agonist. It is a successor to aripiprazole (Abilify), which is widely used in mental illnesses such as schizophrenia, but also to address behavioral issues stemming from depression. The expectation for brexpiprazole is that it will help to manage behavioral symptoms such as aggression in AD.
Other drugs, such as TRx0237, from TauRX Therapeutics, and Belsomra, from Merck, both of which have been discussed in previous Doc Gumshoe sermons about AD, are expected to launch in 2018. The projected launch dates for those 32 drugs in Phase 3 trials extend to 2025.
As for the 58 drugs now in Phase 2, the projected launch dates for almost all of these begin in 2022 and go all the way to 2028. Some of these drugs are already approved for other diseases and conditions, and the trials in these drugs are to learn if they might have some kind of beneficial effect on AD. Overall, the drugs target a comprehensive range of the putative pathophysiologies of AD.
For the 32 drugs now in Phase 3 trials, the targets are as follows:
Amyloid plaque 13 drugs (45% of total) Neurotransmission 11 drugs (34%) Insulin/glucose 2 drugs (6%) Tau protein 2 drugs (6%) Other 4 drugs (13%)
And for the 58 drugs in Phase 2:
Amyloid plaque 10 drugs (17% of total) Neurotransmission 17 drugs (29%) Insulin/glucose 4 drugs (7%) Blood/vascular 3 drugs (5%) Tau protein 7 drugs (12%) Inflammation 2 drugs (3%) Neuronal/ synaptic growth 5 drugs (8%) Other 10 drugs (17%)
What sticks out for me is a certain shift in focus – more interest in tau protein and less in amyloid plaque, but also new areas of interest, such as inflammation (a hugely popular topic these days) and also the growth of neurons and the synapses that link them. Although some of the drugs being investigated would aim to do no more than alleviate some of the symptoms, a respectable proportion of the research is directed at the root causes of AD.
The whole enterprise – a total of 90 drugs either in Phase 2 or Phase 3 – represents a colossal economic wager, as well as a huge outpouring of hope. This does not happen without a considerable underpinning of optimism. The pharmaceutical companies backing those 90 drugs include just about every outfit I’ve ever heard of, as well as many that I’ve never come across. The outlook is entirely contrary to the gloomy picture painted by sweeping statements about the failures of clinical trials in AD.
In my opinion, this does not so much hold out promise of a single “magic bullet” that will cure or reverse AD, removing it forever as a subject of concern. Instead, what it looks like is the confident expectation that a range of approaches will essentially render AD much more manageable. Some of the mechanisms may indeed slow the deposition of the amyloid plaque or the neurofibrillary tangles which are now thought to be the underlying pathologies of AD. Others may encourage the formation of more new neuronal pathways in our brains, so that despite the blizzard, some avenues continue to be open. This happens all the time anyway; that’s how we form new memories and new associations. But perhaps that function can be assisted.
All in all, the optimistic projection is not that a nuclear device can accurately target and obliterate the capital of Alzheimer’s, but that a concerted campaign from air, land, and sea, will defeat this formidable foe. Or, for a different simile, a really powerful and effective armada of snowplows to keep the streets and roads clear.
Can Alzheimer’s disease and dementia be prevented?
The answer, at least according to an enormously ambitious paper published in Lancet this past July, seems to be “yes,” at least to some degree (Livingston G. Lancet 2017 DOI: http://dx.doi.org/10.1016/S0140-6736(17)31363-6). A couple of years ago, Lancet formed a group to address dementia, initially called the Dementia Care Commission, but now renamed the Dementia Prevention, Intervention, and Care Commission. The work of that group is reported in that Lancet paper, which runs almost two hundred pages. I’m not going into it in any great detail right now, but let me just put a few of the premises and findings in perspective.
An important point of departure is that Alzheimer’s is not synonymous with dementia. The type of dementia associated with AD is different from other types of dementia, as in dementia resulting from trauma or a cerebrovascular incident. The physiologic features of AD do not automatically result in dementia in every case. Those AD features include the notorious amyloid beta and tau protein, and also Lewy bodies in the brain, which are mostly associated with Parkinson’s disease. Persons with these elements in their brain frequently demonstrate characteristics of dementia, but not invariably. In a previous Doc Gumshoe piece about AD, I described a famous study in nuns, which found a strong link between the language they used in the essays they wrote when they first entered the nunnery and the likelihood of becoming demented in their later years. The analysis was not highly sophisticated. It simply measured the length of words and sentences. The nuns whose essays, composed for the most part when they were in their early twenties, employed longer words and sentences, were for the most part less likely to present symptoms of dementia fifty or sixty years later. The nuns in this study had also given permission to have their brains examined on autopsy, and it was found that many nuns who had many of the physiologic features of dementia in their brains, finished their lives in a totally lucid state.
The Lancet paper identified a number of what they termed “Population Attributable Factors” (PAFs) which they thought were responsible for as much as 35% of the incidence of dementia. The study was based in part on observation of about 10,000 adults in the UK.
An important concept, not only in the Lancet paper, but in other investigations of the incidence of dementia, is the concept of cognitive reserve. This sounds fairly obvious – if you have more reserve of any faculty, including cognition, you can afford to spare more of that faculty than a person that has less of it to start out with. And the data seem to support this concept. For example, several factors may affect cognitive reserve, either positively or negatively. Early life education and later life cognitive training boost cognitive reserve, while peripheral hearing loss diminishes cognitive reserve because of the lack of stimulating input that persons with hearing loss experience.
The Lancet paper separates those modifiable risk factors according to periods in an individual’s life. In early life, poor education (i.e., no schooling beyond 11th grade) may account for 8% of dementia incidence, while in the middle years, the principal PAFs are hearing loss (9%), hypertension (2%) and obesity (1%), and in late life the PAFs are smoking (5%), depression (4%), physical inactivity (3%), social isolation (2%), and diabetes (1%). It’s highly likely that a number of those risk factors overlap; for example, high-school dropouts are far more likely to be smokers than are college graduates, and hypertension, obesity, physical inactivity, and diabetes certainly do tend to go together. Other data, by the way, tend to corroborate the Lancet conclusions, e.g., a 19% increase in midlife obesity in China was accompanied by a similar increase in the incidence of dementia. Cause and effect? Coincidence?
One of the authors of the paper, Lon Schneider of USC, commented that the findings of the Lancet Commission partly contradict the conclusion of an NIH committee in 2010 that pronounced that there were no measures to prevent AD. He acknowledged that it would not be possible to confirm these findings through controlled studies – it would hardly be ethical to assign one cohort in a randomized trial to smoke cigarettes and the other cohort to abstain, so that 50 years later the incidence of AD in the two cohorts could be compared. But the data strongly support the concept of prevention as a way of reducing dementia risk.
The Lancet paper places the factors into three main sets, as shown in the diagram: one set includes the factors that affect cognitive reserve; a second set includes factors that affect brain inflammation; and a third set includes factors that contribute to cerebrovascular damage. There is overlap between the sets, and the single factor that affects all three sets is exercise.
Can we reduce the risk of dementia/Alzheimer’s disease by dietary changes?
You will have noticed that one of the factors thought to reduce the development of dementia is adherence to the Mediterranean diet, which is widely thought to be beneficial in the management of diabetes, hypertension, and elevated cholesterol. There have been several studies attempting to find a relationship between dietary intake and the incidence of Alzheimer’s disease. What can be said of these studies in general is that they did indeed find relationships between what we eat and the brain changes that are thought to lead to AD; however, their findings don’t amount to a complete formula for an AD- or dementia-protective diet.
Perhaps the strongest evidence relates to some antioxidant nutrients, including in particular vitamin E and vitamin C, which have been shown, at least in animal studies, to protect the brain from damage due to inflammatory and oxidative mechanisms. Three prospective human studies assessed the relationship between those nutrients and the risk of Alzheimer’s disease – one in Chicago, one in Rotterdam, and one in New York City. The Chicago and Rotterdam studies found a significantly lower risk of AD in individuals with a higher intake of vitamin E; the New York study did not find that association, but it happened that the vitamin E intake in subjects in the New York study was very much lower than in the Chicago or Rotterdam cohorts, so that may have accounted for the difference. The relationship between vitamin C intake and AD was much less robust than with vitamin E; only the Rotterdam study found a link.
It needs to be emphasized that none of those studies found a link between vitamin E and vitamin C supplements and a reduced risk of Alzheimer’s. To the extent that a reduced risk was detected in relationship with vitamin E intake, it was only as a result of the presence in the diet of foods that were rich in vitamin E. A possible reason for the absence of beneficial effect with vitamin E supplements is that those supplements usually consist only of alpha-tocopherol; however, gamma-tocopherol is more abundant in the diet, and it has been suggested that the combined intake of all eight forms of tocopherol reduce oxidative stress and inflammation more than alpha-tocopherol alone. We are told that the foods richest in vitamin E are vegetable oils, nuts (especially almonds), seeds, and also whole grains, eggs, and some fruits and vegetable such as avocados, apples, and melons.
Dietary fats, especially transfats, may significantly increase the risk of Alzheimer’s, but the evidence concerning fats in general is somewhat contradictory. It’s intuitively attractive that cholesterol in the vascular system in the brain cannot be good for cognition, and a study in Japan showed a strong relationship between cholesterol levels and the deposition of amyloid plaques in the brain. The study followed 147 adults for up to 15 years before their deaths, and then performed autopsies on their brains. Those whose total cholesterol levels were more than 224 mg/dL were seven times more likely to have amyloid plaques than those whose total cholesterol was below 173 mg/dl. The link between elevated LDL-cholesterol, greater than 155 mg/dL and amyloid plaque was even more robust, by a factor of eight, over those whose LDL-C level was below 106 mg/dL.
Omega-3 (Ω-3) fatty acids may also reduce the risk of AD-related dementia, in particular docosahexaenoic acid (DHA) which happens to be a major component of membrane phospholipids in the brain. Patients with established AD have been found to have lower levels of Ω-3 fatty acids than the general population, and one fish meal per week was associated with a 60% lower risk of developing AD in both the above-mentioned Rotterdam and Chicago studies. However, as with the vitamin E and C supplements, no studies to date have found an association between fish-oil capsules and a lower risk of developing AD. You actually have to eat the fish!
The findings regarding vitamin E, cholesterol, and fish, and their association with AD-related dementia certainly support the general recommendation of a Mediterranean diet, with its emphasis on fish, vegetables, fruit, grains, and olive oil, as per the Lancet paper’s conclusions.
But those percentages and ratios – 60% lower risk here, seven or eight times lower risk there – may paint an overly optimistic picture. We might assume that by adopting all these dietary and other preventive measures, we could add up the lowered risk factors to the point where our risk of becoming demented would be reduced to zero. Unfortunately, it doesn’t work that way. As Ecclesiastes said, “…but time and chance happeneth to them all.” However, in the view of Doc Gumshoe, who is more of an optimist than Ecclesiastes was, the outlook is considerably more rosy than has been generally presented.
A closer look at the trends
Yes, the overall prevalence of Alzheimer’s, not only in the US, but globally, is increasing. But the main reason for this is that we’re all living longer – in some parts of the world, quite a bit longer. Several specific trends that are in themselves good news about our health may paradoxically result in increases in the prevalence of AD. For example, as discussed earlier, vascular risk factors, including hypertension and diabetes, are associated with increasing risks of AD/dementia. We have seen significant improvements in the treatment of cardiovascular and cerebrovascular disease, and a decline in the incidence of stroke. As a result, we might expect to see a decline in the incidence of AD. But there are some contradictions. There are more persons with subclinical vascular disease being treated with anti-clotting drugs that lessen the likelihood that they will experience a stroke. And we are also seeing significantly improved survival after stroke. These persons, many of whom under different clinical circumstances would likely have died of strokes, may now be more likely to progress to AD/dementia.
A careful paper by Walter Rocca and others (Alzheimer’s Dement. 2011 Jan; 7(1): 80–93) examined some of the factors that would be likely to have an impact on the specific incidence and overall prevalence of dementia in the US. For example, they noted that from 1994 to 2002, in African-Americans over the age of 65 years, the prevalence of hypertension climbed from 73% to 83%, and of diabetes rose 26% to 36%. These increases, as well as the increase in obesity, may have contributed to an increased risk for cognitive decline and dementia, although this negative impact may not become evident for some time.
But, in the past twenty years, we also have seen an increased level of education among adults in the US over 65. The proportion of adults age 65 years or older with a high school diploma increased from 53% in 1990 to 72% in 2003, and the proportion with a college degree increased from 11% to 17% during this time period. Also, the wealth of older adults in the US has risen considerably, from $119,000 in 1989 to $196,000 in 2005 (in constant 2005 dollars). Both of these factors are thought to contribute to declining levels of disability, including dementia.
Another factor that would be likely to reduce the incidence of dementia is that the percentage of people with elevated levels of cholesterol is declining, and there is a strong association between elevated cholesterol and AD/dementia. The figures are surprising. Data from the NHANES report that the overall prevalence of high total cholesterol, defined as greater than 240 mg/dL, has declined from 18.3% in 1999-2000 to 12.4% in 2015-2016. NHANES is the National Health and Nutrition Examination Survey, and their data are considered to be rock-solid.
A curious finding was that elevated cholesterol was much more common in younger than in older people. High cholesterol peaked in men between ages 40-59 at 16.5%, but then declined dramatically in those 60 and over, dipping to 6.9%. (That does not imply that on reaching the sixtieth birthday, cholesterol rates plummeted; more likely that as men reached their senior years they became more conscious of heart health and took steps to mend their previously gluttonous ways.) Prevalence of elevated cholesterol in white women was higher than in white men, while in black, Hispanic, and Asian women, those prevalences were lower than for men of the same ethnicities.
But in terms of the likelihood of developing Alzheimer’s as well as heart disease, the news that the prevalence of persons with elevated cholesterol levels has declined that much is undeniably good!
What does all this amount to?
No, it doesn’t look as though a magic bullet or a miracle cure is about to appear. But the likelihood is that a combination of prevention and treatment that both slows the development and ameliorates symptoms, holds out promise of many healthy and undemented years for most of us.
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And the news continues to trickle out. On November 6, 2017, just a few days ago, a study supported by the National Institute on Aging, which is part of NIH, was published in Alzheimer’s & Dementia. This study, based on brain autopsies, found a strong, probably causal relationship between glucose levels in the brain and the severity of amyloid plaques and tangles. Doc Gumshoe will look at it more closely and report back. In the meantime, keep those comments coming! Many thank and best to all, Michael Jorrin (aka Doc Gumshoe).