From where I sit, it seems to me that the entire landscape of Alzheimer’s disease (AD) has changed, and changed quite significantly.   The litany of announcements from pharmaceutical companies big and small revealing the unfortunate news that yet another promising agent for the treatment of AD has failed to meet its objectives in a clinical trial and is being withdrawn from the “race” to approval, is familiar and increasingly depressing.   The most recent and perhaps most disappointing of these were the failures of two BACE-1 inhibitors, one in a Phase III trial, the other in a Phase IIb/III trial.   I have discussed those two drugs, and, especially, their highly promising mode of action, in a previous encyclical, and there will be more to say later on in this one.

These failures, along with the many, many other failures to launch an effective drug for the treatment of AD, have had a dampening effect on AD research.   For example, AD deaths have increased by 145% in the years from 2000 to 2017.   Meantime, cancer deaths were declining; age-adjusted cancer mortality in the US declined by 26% from 1991 to 2015.   But venture-capital funding for cancer during those overlapping years was much higher than for AD – $16.5 billion for cancer in the past 10 years versus $1.0 billion for AD.   

You can’t exactly blame the moneybags guys for their reluctance to bet on a proposition where the odds are at least 20 to 1 against scoring a hit.   Those odds are calculated based on the fact that only four (five if you count a combo) drugs are FDA approved for AD, versus the hundred-plus flops.   And the odds are probably even worse, considering that none of the approved drugs do more than slightly delay the progression of dementia, and a couple were already approved for Parkinson’s disease.   So, if financial gain is the supposed motivation for investing in AD research, you can see why research into new drug development is slowing down.

However, AD continues to receive considerable support from the Federal government.   An additional $350 million were just added to the NIH budget specifically for AD research, bringing the total AD funding for the year 2020 to $2.8 billion.   Overall, despite opposition From Above, Congress increased NIH funding for 2020 by about $3 billion, bringing the total funding to $42.1 billion.

Much of that funding supports scientific research into Alzheimer’s rather than specific drug development.   And there’s a great deal of that going on.   According to PubMed, there are more than 149,000 papers on AD, and according to the Clinical Trials registry, more than 2,000 clinical trials in various phases.   What we’re not seeing are clinical trials of drugs in later phases with the objective of treating dementia in persons with established Alzheimer’s disease.

Before we get into the details, here’s an overview of the impact of AD in the US and the world.

• 5.7 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 200,000 persons under 65 years of age.
• One in ten people 65 years old or older has Alzheimer’s dementia.   That percentage increases with age; 32% of people 85 years old or older have AD.
• Almost two-thirds of Americans with AD – 3.4 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 2025, 7.1 million Americans are predicted to have AD, and by 2050, the number is predicted to be 13.8 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, rather to higher prevalence of conditions and circumstances which contribute to AD and dementia.   We’ll go into some of those later in this post.
• According to the Alzheimer’s Association, the 2019 costs to the nation associated with AD will be about $277 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 about $24,000.   For patients without AD the cost estimate is about $7,500.
• These costs don’t figure in the huge economic impact of AD on caregivers, often the immediate family members of the person with AD.
• AD is the 6^th leading cause of death in the US. 
• The death rate in the 5 other leading causes of death in the US – breast cancer, prostate cancer, heart disease, stroke, and HIV – have all declined between the years 2000 and 2015, while the death rate from AD has increased by 122%.   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.    

So, considering that Alzheimer’s disease is perhaps the most severe health threat to Americans and that drug development to manage this threat to our health, and indeed to our lives, has just about totally stalled, why is there not a vigorous public outcry to do something about it?   It’s almost old stuff when presidents of the US proclaim vows to defeat cancer, but when it comes to AD, mum’s the word.

Perhaps it’s because Alzheimer’s mostly affects older folks.   It’s intuitively okay to accept AD as a natural consequence of aging, whether or not it’s an accurate assessment.   And it also seems to be ethically much more justified to spend dollars on medical treatment of diseases that mostly affect children than on diseases of the elderly.   Money spent on preserving the life of an 8-year-old child buys more life-years than an equivalent sum spent on extending the life on an 80-year-old geezer.      

As I see it, the prevailing view of AD separates the symptoms, primarily dementia, from the underlying causes, whether those might be the notorious amyloid beta (Aβ) or tau protein tangles, also called neurofibrillary tangles, or something entirely different.   Essentially, the people working on Alzheimer’s have come to realize that those underlying causes can appear many years before any symptoms of dementia manifest themselves.   Another complication emerges, notably that many elderly people (and many not so elderly!) exhibit traits of forgetfulness entirely unrelated to AD.   

The result is that by the time a diagnosis of AD based on symptoms is firmly established and other forms of dementia are ruled out, it appears that Alzheimer’s dementia may be irreversible.   The brain is already severely clogged with amyloid beta or tau protein tangles, or possibly both, and there are no handy brain-clearing instruments or substances.    

The situation is further complicated by the reluctance of people to undergo procedures that might lead to a diagnosis of Alzheimer’s, whatever these procedures might be.   Indeed, if a diagnosis of AD does not lead to a course of treatment that significantly improves the symptoms, why would anyone be willing to be subjected to diagnosis?   The outcome of the diagnostic procedure is certain to be bad news.   In the case of a positive diagnosis, it’s “Yes, you have Alzheimer’s disease, but we can’t do anything to stop it.”   And if the diagnosis is negative, it’s “No, you don’t have Alzheimer’s disease.   You’re just an old-timer who is losing his marbles.”   A lousy verdict either way.

In contrast, diagnostic procedures to detect many of the most common deadly diseases or conditions are downright attractive.   Women don’t regard mammograms as pleasant experiences, but since mammograms have become widely accepted procedures (at least in most of the developed world) breast cancer mortality has plummeted.   The same relationship holds true for many diseases.   Most people accept these diagnostic procedures with a relatively optimistic frame of mind: if the outcome is positive – for example, the patient really does have breast cancer – effective treatment is available.   And if the outcome is negative – no sign of breast cancer – it is received as good news.   That is not the case with attempts to diagnose Alzheimer’s disease once it has taken hold.   But a means of predicting AD in persons in whom the disease has not yet become established might be more attractive, especially if there are ways to stave it off.        

The basic premise of much current research is that once the brain has been invaded by those substances that gunk up the works, whether those are Aβ or tau tangles or something else, nothing seems to works to clear out the gunk.   However, it might be possible to take steps to protect the brain from the gunk and keep it functioning as well and as long as possible.   Thus, the focus of the scientific/medical/ pharmaceutical complex, with few exceptions, appears to be on finding means of detecting AD sooner or identifying the individuals most at risk for developing AD.

Predicting Alzheimer’s Disease

The simplest avenue to predicting AD would be a biomarker – some kind of tell-tale substance whose presence, whether in the blood or another bodily fluid, would suggest that the individual was on a path that would lead to Alzheimer’s.   A test to detect such a biomarker could then be routinely included in a blood test, for example, and could then be an accepted part of a general physical examination.   When a person has a physical exam, he/she is not being specifically evaluated for the risks of developing any particular disease, but the blood test will provide information to predict whether the individual being tested is at risk for a number of diseases/conditions.   What that means is that a person doesn’t have to wait until he/she gets lost on the way to the grocery store to be evaluated for AD.   The results of the simple blood test would constitute a simple warning sign: “AD may be on the way for you, and you should try to take steps to avoid it.”   

Such a test may be on the way.   A study, presented at the Alzheimer’s Association International Conference 2019 found that the presence of certain bodies in the blood was highly associated with the development of AD about four years before the emergence of symptoms.   The study was conducted by the National Institute of Aging in Baltimore, and it studied a group of 128 individuals who had eventually developed AD and 222 age- and sex-matched controls who had remained cognitively normal.   Blood samples had been collected from these persons at the start of the study, and the median time from the collection of the samples to the onset of AD was 4.07 years.

The specific bodies in the blood that predicted AD were extracellular particles, shed by all cells.   The finding was that the diameters of the phosphorylated tau and phosphorylated insulin receptor substrate particles were significantly higher in the preclinical samples of individuals who would eventually develop Alzheimer’s disease than in those who did not develop AD.   

The differences between the test results in the group that developed AD and the group that did not indicated that the test would have a high degree of sensitivity (81.8%) and specificity (85.8%).   The total area under the curve, indicating overall predictive efficacy, was 89.6%    

The lead researcher, Dimitrios Kapogiannis MD, notes that these results, while highly encouraging, are by no means the end of the journey.   Kapogiannis pointed out that there are several other particles that may also be specific markers for AD, and it may be possible to add some of these to the assay and arrive at a test that is more accurate than the sum of its parts.   (Kalogiannis D. JAMA Neurol  2019 Jul 15)

A possibly relevant finding in this study was that the two cohorts had similar quantities of other substrate particles which were similar in diameter as well.   One of the substrate particles that were similar both in quantity and diameter were Aβ 42, which is the form of Aβ that has been postulated as a causative factor in Alzheimer’s disease.   But the study found no differences between the quantities or diameters of those particular particles between the individuals who went on to develop AD and those who remained free of AD.   The study authors came to no conclusions regarding this finding and the question of Aβ as the underlying cause of AD.   Nor did they suggest that their findings provided support for the alternative theory, that the true cause of AD is related to tau proteins.   In any case, it is one more bit of evidence that needs to be considered in establishing the cause of AD.

Other bits of evidence that need to be weighed include the continuing series of failures in the trials of keenly anticipated Alzheimer’s drugs of the class known as BACE inhibitors.

What does the failure of BACE inhibitors say about the amyloid beta 42 hypothesis?

We now know that our brains normally contain considerable quantities of a substance called amyloid precursor protein (APP).   It is not inside the neurons, nor yet in the dendrites extending from the neuron, but in the spaces between the dendrites, across which the signal from one neuron is transmitted to another neuron.   The signal is in the form of a neurotransmitter, usually a chemical that passes through the dendrite, across the synapse, is received by another dendrite, and travels to a receptor neuron.   Our brains contain billions of neurons; each neuron can have as many as hundreds of thousands of dendrites, and the total number of synapses in our brains is thought to be in the neighborhood of a hundred trillion.   

And in all of those synapses there is amyloid precursor protein, a portion of which contains the amyloid beta peptide sequence.   This is true of all normal, well-functioning synapses.   What happens in the formation of the particular toxic plaques that result in AD is that enzymes cleave APP, leaving the amyloid beta (Aβ) segments.   Two protease enzymes take part in this process – beta (β) secretase and gamma (γ) secretase.   β-secretase (BACE) does the bulk of the work, and γ-secretase applies the finishing touches.   

It now appears that there are two versions of Aβ.   One is a sequence of 40 amino acids; the other one is just two amino acids longer.   These are now labeled Aβ 40 and Aβ 42.   The ratio of Aβ 40 to Aβ 42 in plaque is usually about 9 to 1, but there is evidence suggesting that when the proportion of Aβ 42 increases, the toxicity of the plaque increases.   Increased quantities of the Aβ 42 peptide appear to shift the behavior of the entire Aβ pool towards obstruction the transmission of information across synapses – in other words, towards dementia.

A class of agents that showed early promise, but has since been disappointing, targets BACE, the enzyme that cleaves amyloid precursor protein (APP), thus resulting in Aβ accumulation in the synaptic space between neurons, and inhibiting 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.   Several agents inhibiting the action of that enzyme have been in various stages of development for a number of years.   

Most of these agents are in a class called monoclonal antibodies (mAbs), and they are derived from various sources.   Researchers identify antibodies that have emerged in response to various challenges, some in mice (murine) or other animals, some in humans.   These antibodies are then cloned and produced in the laboratory.   The process of creating mAbs is basically the same whether the antibodies are in response to an immune process, as in rheumatoid arthritis, to a cancer, or, in the case of AD, to the enzyme that does most of the work of cleaving Aβ from the precursor protein.    

The news about these agents has been mostly bad:

• Solanezumab, from Eli Lilly, failed to meet its primary end-points in terms of cognition and activities of daily living in a Phase III trial.   
• Bapineuzumab, from Johnson & Johnson/Pfizer, was supposedly scrapped three years ago, for a similar Phase III trial failure.   Although brain imaging showed positive changes in Aβ deposition, the patients taking bapineuzumab did not demonstrate clinical improvement in cognition and activities of daily living.   
• Ganterenumab, from Roche, has also been scrapped, or at least interrupted.   Ganterenumab is hampered by the risk of an adverse effect known as ARIA (amyloid-related imaging abnormalities), which can lead to dangerous swelling of the brain, thus there is a reluctance to push the dose, and effective dosing levels may not have been reached in clinical trials.   
• Crenezumab, from Genentech/Roche in partnership with AC Immune, also failed to meet endpoints in a Phase II trial, but reported some improvement in cognition in patients with mild AD.  

The most recent BACE inhibitor flops were particularly resounding.   Merck’s verubecestat demonstrated a significant reduction in the levels of Aβ in the brain of patients with early Alzheimer’s, but this reduction was not accompanied by any beneficial effect on cognition.   The Phase III trial compared two groups of patients taking 12 mg and 40 mg of verubecestat with patients taking placebo.   At the end of 104 weeks of treatment, both groups of patient taking verubecestat had worse scores on tests evaluating cognition than did patients taking placebo.   The test used was the Clinical Dementia Rating Scale-Sum of Boxes scores, with higher scores indicating worse cognition and daily function.   The mean scores in placebo patients was 1.58, while the 12 mg and 40 mg verubecestat patients’ means scores were 1.65 and 2.02 respectively, suggesting not only that verubecestat treatment worsened cognition, but that higher doses worsened cognition more than lower doses.   

Looking at the estimated rate of progression leading to dementia, again the number of events considerably favored the placebo group, with an estimated 19.3 events per hundred patient years, compared with 24.5 and 25.5 events leading to dementia in the 12 mg and 40 mg verubecestat cohorts.

A Phase 2b/3 trial in another BACE inhibitor, atabecestat, from Janssen, was terminated because participants taking the study drug had seriously elevated levels of liver enzymes.   Interim scores of the Preclinical Alzheimer’s Cognitive Composite Score also suggested greater cognitive decline in the atabecestat cohort than in subjects taking placebo.       

A major setback in the BACE inhibitor arena was the suspension of two clinical trials in the drug aducanumab.   In March of this year Biogen and Eisai announced that they would end the Phase III ENGAGE and EMERGE trials of aducanumab in early AD.   An analysis demonstrated that the two trials had no chance of meeting their primary endpoints, those being the slowing of cognitive decline as measured by the abovementioned Clinical Dementia Rating Scale-Sum of Boxes.   A total of 3,200 patients had been recruited worldwide for these trials.

Workers in the Alzheimer’s field were disappointed, but perhaps not surprised.   John Hardy, of University College in London, wrote “This tells us that the removal of amyloid in people with disease is too late.   Amyloid is a disease trigger   Once the neurodegenerative disease process is up and running, it’s up and running.”

David Holzman, of Washington University, St Louis wrote, “I think Aβ is still a good target for the primary and maybe secondary prevention trials of AD, before tau and inflammation have started driving the disease.” 

These flubs do not mean that the strategy of preventing or slowing Aβ accumulation is a failure.   However, a problem with the entire mAb class is the difficulty these molecules have in passing the blood-brain barrier.   For example, the crenezumab molecule is huge – it consists of about 20,000 atomic units, with a weight of 144.88 kiloDaltons.   As a result, the concentration of the antibodies within the brain is only about 0.1% of the concentration in the serum – or, to put it another way, to get enough concentration in the brain, the serum concentration has to be about 1000 times higher.   This invariably entails a risk of adverse effects, so researchers are understandably highly reluctant to escalate the dose.   No one at this point can be certain that beta-secretase does not play significant roles elsewhere in the body, so huge doses of any BACE inhibitor may be chancy.       

The failure of the Aβ-targeted therapies by itself does not mean that the amyloid hypothesis is null and void.   However, it is by now clear that attempting to reduce the formation of more Aβ plaque, once the disease process is under way, will not have any clinical effect.

What about taking aim at tau protein?

Much less capital has been expended on this alternative hypothesis.   The essential difference between Aβ and tau protein is that while the Aβ structures impede communication between neurons by congregating in the synapses, tau protein fibrils cause neuron death by forming tangles in the axons, which are the conduits through which neurons obtain nourishment.   In brief, Aβ does its dirty work outside the neurons while tau protein kills neurons from within.

A leader in the search for an agent that prevents or at least slows tau protein aggregation is TauRX Therapeutics, Ltd, of Aberdeen, Scotland.   TauRX is a biotech spun off from the University of Aberdeen in Scotland, where its clinical trials are being conducted, although its official headquarters are based in Singapore, likely for tax reasons.   Their AD candidates are derived from a parent compound, methylene blue, which has been around for decades, and has been used to treat malaria and methemoglobinemia, a blood disease in which normal hemoglobin is replaced by a form containing ferric rather than ferrous iron, which is less able to transport oxygen.   TauRX’s first formulation based on methylene blue (methylthioninium chloride) was Rember, which has been replaced by a successor, LMTX, formerly labelled TRx0237.   LMTX and Rember have the same mode of action, but LMTX is a stabilized, reduced form of the parent compound in order to improve the drug’s absorption, bioavailability, and tolerability.

LMTX has been evaluated in a number of clinical trials and at several different dosages.   In several of these trials, LMTX failed to meet its endpoints.   However, in trials designated as TRx-015 and TRx-005, further analysis of the results demonstrated that patients who were taking LMTX as monotherapy experienced a significant decrease in disease progression in comparison with placebo, and the level of brain atrophy diminished by 33% and 38% respectively in the two trials.

Both trials also determined that the benefit of the 8mg/day dose, originally intended to be a control, was similar to the higher doses and had fewer side effects. To confirm whether there is a benefit to LMTX as a monotherapy, TauRx is currently running another Phase II/III trial called LUCIDITY to investigate two low doses (8 mg and 16mg) of LMTX vs. placebo. The trial is looking to recruit 375 participants with early Alzheimer’s disease. The primary outcomes of the study include changes in brain function using imaging techniques, changes in cognitive performance, and the number and types of adverse events. Results of the study are expected in December 2020.

What factors increase or decrease the chances of developing AD and dementia?

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, such as depositions of the notorious amyloid beta and tau protein, do not result in dementia in every case.   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 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.       

What presumably protected those nuns who, while having the Aβ deposits in their brains associated with AD, did not become demented, was what might be termed “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.   

An organization in the UK called the Dementia Prevention, Intervention, and Care Commission conducted an extensive observational study in about 10,000 community-dwelling adults.   A conclusion of the study was that as much as 35% of the incidence of dementia could be attributed to what they called “Population Attributable Factors” (PAFs).   The PAFs are risk factors that are subject to modification.

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 11^th 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?  

Possible effect of dietary changes on dementia and Alzheimer’s

In the Lancet paper adherence to the Mediterranean diet is suggested as a way of reducing the risk of AD and dementia.   The Mediterranean diet is generally considered to be beneficial in the management of diabetes, hypertension, and elevated cholesterol, and there is evidence that this diet is beneficial in terms of prevention of the brain changes that are thought to lead to AD.   However, there is no evidence for a comprehensive diet to prevent AD.

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.

But 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.   Which foods are these?   According to nutritionists, the foods richest in vitamin E are vegetable oils, nuts (especially almonds), seeds, and also whole grains, eggs, and some fruits and vegetables such as avocados, apples, and melons.   Doesn’t sound too bad.   

Dietary fats, especially transfats, may significantly increase the risk of Alzheimer’s.   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.   Whether those persons with more amyloid plaques were also actually more demented is not known.

Other factors that affect cognition and dementia

An investigation conducted as part of the Harvard Aging Brain Study found that greater physical activity was associated with slower Aβ-linked cognitive decline.   The physical activity of 182 clinically normal adults, average age about 73 was monitored at baseline using waistband pedometers.   Cognition was measured annually with the Preclinical Alzheimer Cognitive Composite for about 6 years.   There was no association of physical activity with Aβ burden, but even modest levels of physical activity were linked to slower cognitive decline as well as grey matter volume loss.   In both cases, the relationship was highly significant – P <  0.001 and P < 0.002.   (JAMA Neurol. July 16, 2019. doi:10.1001/jamaneurol.2019.1879) 

Traumatic brain injury increases the risk of Alzheimer’s disease, and in some cases markedly ups the risk.   A moderate brain injury doubles AD risk; a severe brain injury quadruples it.   Trauma resulting in loss of consciousness for 30 minutes or more is classified as moderate; however, repetitive injuries resulting in shorter blackouts can have the same consequences for developing Alzheimer’s-related dementia.   The most common cause is auto accidents, but football and boxing can lead to dementia.

We haven’t gotten around to discussing the relationship between AD and the apolipoprotein genes – APOEε2, APOEε3, and APOEε4.   APOEε2 is present in about 19% to 20% of the population, and those lucky folks have a lower incidence of AD,   APOEε3 is the most common form and as far as is presently known, has no effect on the incidence of AD.   APOEε4, on the other hand, is thought to be a culprit in AD.   Up to 65% of persons with AD have at least one copy of APOEε4.   It appears that having that gene doubles the likelihood of developing AD and perhaps even triples it.   Persons with two copies of that gene – one from each parent – tend to develop full-fledged Alzheimer’s dementia at a much younger age than persons with one copy.        

Where do we come out?

As we review the factors that seem to contribute to Alzheimer’s and AD dementia, a profile of the likely victim takes shape.   She (most likely a woman) is poorly educated (a high-school dropout), obese, a smoker, eats mostly junk food, is physically inactive, and perhaps is afflicted with one or more chronic conditions such as diabetes, high cholesterol or hypertension – conditions which, of course, are more prevalent in obese sedentary smokers.   Our victim is also more likely to be African-American or Hispanic.   She might be able to improve her chances of avoiding Alzheimer’s dementia if she lost weight, quit smoking, joined a gym, and so forth.   But that’s a lot harder than it sounds.

In contrast, consider a very good friend of ours, who is highly educated, trim and fit, a life-long non-smoker who successfully manages his type 2 diabetes through diet alone.   Nonetheless, he has Alzheimer’s disease, likely due to his genetic inheritance.   He remains highly active and able to participate in conversations, which he ably steers to avoid the gaps in his cognition.   He is receiving one of the very few drugs approved for AD – there are five in all, including one combination, and none of them make any pretense at reversing the disease course or doing anything more than perhaps slowing progression. 

I can’t think of a single thing that our friend could have done to prevent the development of AD.   There will certainly be individuals like our friend, who, despite all efforts to the contrary including mental and physical exercises and the healthiest possible lifestyle, ultimately go on to develop Alzheimer’s disease.   But they can probably stave it off and gain more years of living while in full possession of their wits.   In fact, that’s the situation for the rest of us.   What we want is for our mental capacities to remain optimal even as our physical capacities dwindle   

But what AD research tells us is that, at least in the case of Alzheimer’s disease, physical and mental capacities are one and the same.   The transmission of information between our brain cells is purely physical, and it is that transmission that constitutes mental activity.   Alzheimer’s impedes that transmission, likely through the growth of some form of crud in our brains.   And because the growth of that crud is physical, there is reason to hope that some form of physical intervention, whether it be a drug (a chemical) or some form of exterior stimulation acting on the physical brain activity, may be able to counteract in some way the effects of the stuff that gums up the works in our brains.   So in spite of the big decline in research aimed at finding effective new treatments, I (speaking as Doc Gumshoe) am keeping up my hopes for something that really works.   

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Thanks to all Planet Gumshoe denizens for reading this lengthy manifesto and for whatever questions / comments you send my way.   Let me know what you want to read about and I will try to oblige.   Best to all, Michael Jorrin (aka Doc Gumshoe)