[ed. note: Michael Jorrin is a longtime medical writer who writes about health and medicine a couple times a month for our readers, usually without a specific investment focus — though it so happens that today’s topic, Alzheimer’s, is also subject to at least one current heavily-hyped investment pitch. I like to call him “Doc Gumshoe” (he’s not a doctor), he chooses his own topics, and his words and opinions are his own.]

This is not primarily going to be about drugs currently in development by small biotechs – or by Big Pharma, for that matter – that promise to cure Alzheimer’s disease or even significantly reverse the consequences of the disease. I’m aware that many individuals and organizations are looking for ways to do precisely that, and I’m optimistic – but modestly optimistic. This post will stick to what’s known about the fundamentals of Alzheimer’s disease (AD) and what new information has been gained on that front. Then, we’ll survey some specific candidates for treating AD in another post in the next few weeks.

First, let’s see if there are any important changes in the AD landscape since Doc Gumshoe first wrote about it back in 2013. The short answer is, not much. Here are the numbers:

• 5.3 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.
• About two-thirds of Americans with AD – 3.2 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 which contribute to AD and dementia. We’ll go into some of those later in this post.
• According to the Alzheimer’s Association, the 2015 costs to the nation associated with AD will be about $226 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.
• 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 6th leading cause of death in the US.
• 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.

The health-care community obviously recognizes the impact of AD, not only on individual patients and their caregivers, but on the commonwealth. At the same time, equally obviously, the health-care community recognizes the opportunity for – may we put it delicately? – significant financial benefits accruing to whatever entity comes up with treatment modalities that are genuinely effective. This applies especially to pharmaceutical companies, that are inevitably aware of the more than 5 million Americans, as well as many millions more on the planet, who are eagerly waiting for something – anything! – that will slow their cognitive decline. Witness the 1,765 clinical studies currently registered with the National Institutes of Health Clinical Trials Registry, ranging all the way from recently instituted trials, some of which are not yet recruiting subjects, all the way to trials that have been completed and are now in the process of evaluating and releasing their results.

Do we know any more about the disease process?

We know a great deal about what happens in the brains of people with AD. What we don’t know for sure is which of the changes that are observed in the brains that have been examined, either on autopsy or by neuroimaging, are the underlying causes of the changes in cognition and behavior that characterize the disease itself.

By now, just about everybody has heard of the connection between amyloid plaque and Alzheimer’s disease, and amyloid beta (Aβ) and Tau protein are surely familiar to Gumshoe denizens. Even the distinction between the two forms of Aβ, the 40 and 42 amino acid versions, frequently referred to as Abeta 40 and Abeta 42, is making its way into news snippets. Unfortunately, it is not known for sure which of all these entities is the chief culprit in the clinical disease. The highest and most eminent authorities do not see eye to eye.

And AD does not appear to be the kind of disease that can be treated without a good understanding of the pathophysiology. It’s not like rubbing arnica on a bruise, or taking an aspirin for a headache. To treat AD, the disease process itself has to be understood and addressed directly.

AD is a perfect example of the intimate connection between mind and body. The cognitive deficits that characterize AD are almost certainly directly due to brain changes, and not to a troubled adolescence or an unresolved issue with one’s mother. AD is physiological in origin, not psychological. We know this not only because of the observed brain changes, but because the progress of the disease involves a great deal more than just memory and cognition.

The popular view of AD is that the disease mostly affects memory. People forget things – names and words at first; then, as the disease progresses, they forget what it is they forgot. They get lost – at first, perhaps on their way home from the grocery store. Then they get lost in their own homes. They wander around without knowing where they are, or how they got there, or why. They lose their ability to carry out even the simplest tasks. They don’t recognize their closest friends, their children, their spouses. They see without really seeing.

However, the loss of brain function goes beyond memory and cognition. The brain controls everything in our bodies. Right now, as I am typing on my computer, it’s my brain that is guiding my fingers so that they tap the right keys. I don’t have to think actively to tell my left index finger to tap the letter “t.” All that goes on in my brain without active thinking. “Active thinking” is what is going on right in my brain right now, as I figure out where this piece is going and what I’m going to say next. My brain tells my fingers what to do on autopilot, as it were.

My brain also tells my heart to beat and my lungs to inhale and exhale. It focuses my eyes and directs them to where the ash tree outside my office window is rapidly dropping its leaves. When I put food in my mouth, it tells my jaws when to chew and my gullet when to swallow.

In people with AD, all of this brain activity gradually slows. Eventually, it stops. People with AD perish because they no longer breathe or swallow food. When patients with advanced AD are fed, the swallowing reflex may not function. Food, instead of passing into the esophagus and the stomach, slides into the trachea and the lungs. AD leads to brain death that is more complete than the brain death of some hospitalized persons who are pronounced “brain dead.”

The effects of loss of brain function in AD patients are far, far different from the kinds of memory lapses that affect most people. I am not immune from memory lapses, although by and large my memory is excellent. But there are certain words that I frequently fail to find when needed – the word for a particular shade of yellow-green, for example. Several years ago, when driving in the countryside with my wife, I tried to summon up that word to describe the early spring greenery. I could not remember it, and neither could she. We both struggled with it and eventually moved on to talk about something else. A couple of weeks later, it popped into my head. Chartreuse! And immediately, I had a flood of associations: the sweet liqueur by that name, made by Carthusian monks. The Stendhal novel, La Chartreuse de Parme. The word “chartreuse” may be translated as “charterhouse,” which is what Carthusian monasteries were called in English. How could I forget it? But, not only did I forget it that one time, I have forgotten it many times since, and when I forget the word “chartreuse,” I also cannot summon up the name of the Stendhal novel, or the liqueur, or anything else connected with it. I blame that particular lapse on something like a granny knot in the synapses that link the relevant neurons. I do not think that I am succumbing to AD.

Which is it – amyloid beta or tau protein?

That’s the current controversy, or, should I say, subject of discussion. There’s no doubt that both of these substances are present in the brains of patients with AD. The question is, which one is responsible for the pathology? Or, should I say, which one is principally responsible for the pathology, and, more to the point, which one should be the target of therapies designed to slow or reverse the progression of AD?

The amyloid plaque hypothesis is the senior contender, by about a century. A German physician named Alois Alzheimer – yes, the disease was named after him – had a patient named Auguste Deter, who became severely demented when she was 50 years old. Her husband, Karl Deter, a railroad engineer, placed her in a hospital for mental patients and epileptics where she came under the care of Dr Alzheimer, who followed her until her death in April of 1906. Dr Alzheimer obtained permission to examine Frau Deter’s brain and found it to be pervaded by a dense whitish substance, which he identified as a form of amyloid. Amyloid had been identified and named in the late 19th century by Rudolph Virchow, who thought that it was akin to starch and named it “amyloid” after the Latin name for starch, “amylum.” But amyloid is not starch – it is made of amino acid chains (polypeptides) that have tangled and twisted themselves into insoluble masses.

Attributing the symptoms of AD to the presence of amyloid is entirely reasonable. The brains of AD patients are found, on autopsy, to be greatly shrunken. It made intuitive sense that this dense foreign substance should in some way be harmful to brain function.

But it’s considerably more complicated, of course. Amyloid by itself may not be the problem. The famous Nun Study, which began in 1986 and followed nearly 700 nuns who had agreed to donate their brains upon their deaths, came up with evidence that required closer examination of the amyloid plaque hypothesis: to wit, the correlation between amyloid plaque and severe dementia was not as strong as had been predicted. Many of the nuns whose brains were suffused with amyloid plaque had lived well into their 90s with little or no loss of cognitive function. The strongest correlation with dementia was a characteristic that researchers called “linguistic density.” Most of the nuns, on entry into their religious order, composed autobiographical essays, which remained on file. Researchers evaluated these for choice of words, sentence length, complexity, liveliness of expression, and fluency of thought. Of the participants whose essays were considered to lack “linguistic density,” an extraordinary 80% went on to develop severe dementia in their old age. In contrast, of those whose essays did demonstrate linguistic density, only about 10% demonstrated severe dementia.

The Nun Study did not chuck the amyloid theory into the dustbin. It continued to be recognized that amyloid played a role in some form; it remained to be determined just what form that might be. But it strongly suggested that the human brain has a great deal of what one might term “redundant” capacity; brains that are choked with amyloid can still manage to work pretty well.

A problem with the amyloid hypothesis, which is quite common in medicine, is that while the association between a physiologic condition and a disease, as described by a group of symptoms, can easily be established, determining that the condition is the real cause of the disease is not so easy. Part of the reason is that quite often the physiology is only investigated in persons with the symptoms. In the case of AD, the brains of persons who died with severe dementia have been carefully examined on autopsy, and amyloid depositions have been identified. But how many brains of persons who died without severe dementia have been similarly examined?

Now that there are other methods of investigating the brain, it has become increasingly clear that there’s quite a bit more to it.

It is now understood 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. Res miranda!

And in those synapses there is amyloid precursor protein, a portion of which contains the amyloid beta peptide sequence. This is generally true of 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 number of drugs in clinical trials seek to address this process, including the BACE inhibitors, which we’ll discuss in detail in the next installment.

The role of tau protein

Tau proteins are not in themselves toxic. They are present in the brain and central nervous system, particularly in neurons. Their normal function is related to the structural stability of axons, which are microtubules extending from neurons, connecting neurons to the central nervous system. Tau is one of several microtubule associated proteins (MAPs). (Note, axons are not dendrites – a neuron has only one axon, whereas it can have many thousands of dendrites.)

Tau is one of a number of phosphoproteins, meaning that there are phosphate radicals attached at various sites on the protein structure. Normal – i.e., non-toxic – tau has about 30 phosphate radicals attached, but some tau proteins have many more potential sites for attachment of phosphate radicals. When more of these phosphate radicals are attached, the tau protein is said to be hyperphosphorylated. It is hyperphosphorylated tau that is thought to be a causative factor in the brain changes linked to Alzheimer’s dementia.

The hyperphosphorylation of tau can result from mutations, and also possibly from other interactions, such as with enzymes. The presence of hyperphosphorylated tau can result in the formation of dense tangles within the neuron and the axon, interfering with the vital link between neurons and the central nervous system, choking off essential nutrients, and resulting in death of the neuron. This would have an evident consequence to mental function of any kind.

There may also be a link between Aβ and hyperphosphorylated tau. In normally functioning cells, proteasomes degrade superfluous and deleterious proteins. Aβ appears to inhibit the activity of the proteasome in clearing the hyperphosphorylated tau. Thus there is reason to believe that Aβ and tau may be co-conspirators in the pathogenesis of Alzheimer’s disease.

There are similarities and differences between amyloid and tau. Both are proteins that occur naturally in the brain, and, in their natural state, do not produce harmful results. Both may undergo changes due to physiologic processes. The extraction of the specific amyloid beta peptide sequences, whether the 40- or 42-amino acid versions, from the amyloid precursor protein, is done through the agency of certain enzymes. The hyperphosphorilation of tau may also be related to enzymatic action.

But the key difference between Aβ and hyperphosphorylated tau is that Aβ dwells outside the neurons, most crucially in the synaptic space, but also elsewhere in the surrounding brain area. Tau dwells inside the neurons, particularly in the axon, creating tangles that block the neuron’s essential connection to the central nervous system, resulting in the death of the neuron.

It certainly seems likely, at this stage in the process of delving into the causes of AD, that the answer to the “which is it” question is “both.” Aβ messes up the links between neurons, while Tau kills the neurons from within. And if both Aβ and Tau are causative factors, it makes sense that treatment might need to target them both in order to be maximally effective.

Risk factors for Alzheimer’s disease

Understanding risk factors is a vital step in combating a disease. We may be able to avoid or alter some of them, and researchers can determine a connection between the risk factor and the disease, and target that in devising a treatment strategy.

Certain of the AD risk factors we cannot avoid or modify, especially age and family history. Others, maybe. A risk factor that one might consider difficult to modify by the time that AD begins to figure as a threat to most people is education: people with less education are more likely to develop AD. This has been observed within families and in people with similar genetic traits: the family member who dropped out of high school is more likely to develop AD than the one who went on to college.

But education later in life, and continuing mental activity, also appears to lessen the risk of dementia. It’s hard to say whether this is a “use it or lose it” phenomenon, or whether keeping those mental circuits active in some way impedes the clogging up of the neural circuits. Another likely mechanism is that education actually creates more neural circuits, so that if one gets blocked, the connections can still be established through other routes. My personal guess is that it’s a bit of each.

All of the usual cardiovascular risk factors increase the likelihood of developing AD: smoking, obesity, diabetes, elevated cholesterol, high blood pressure. Those are modifiable risk factors, so that’s good news. The crucial question is whether it does any good to modify those risk factors once the symptoms of dementia have appeared. The most the authorities will say is, “it can’t hurt.”

The cardiovascular risk factors and perhaps educational differences are likely to be what account for the considerable differences in AD prevalence between non-Hispanic whites, Hispanics, and African-Americans. A 2009 analysis of several data sets concluded that in African-Americans the prevalence of AD or other dementias is approximately twice that in non-Hispanic whites, while in Hispanics the prevalence is approximately one-and-one-half times that in whites. Another study found that about 10% of white persons aged 75 to 84 years had AD or another dementia, while in African-Americans that prevalence was about 20%; in persons over 85 years those numbers were approximately 20% in whites versus about 58% in African Americans. “Other dementias” is a vexing term which could include dementia with Lewy bodies, often associated with Parkinson’s disease; also frontotemporal lobar degeneration, which is the most common dementia after AD and can only be distinguished from AD on autopsy.

Another category of risk factors for AD is traumatic brain injury. A moderate brain injury doubles AD risk, a severe brain injury quadruples it. Trauma resulting in loss of consciousness for 30 minutes or longer is classified as moderate; however, repetitive injuries resulting in shorter blackouts can have the same consequences for developing AD dementia. The most common cause is auto accidents, which I know we all try to avoid anyway, but that’s another reason. And, of course, notoriously these days, football and boxing. Although I’m afraid some of those guys may be demented to start with.

And then there are genetic factors, specifically one of the apolipoprotein genes. Apolipoproteins are vital participants in our physiologic function. One of the things they do is glom onto insoluble lipid particles and surround them with a soluble protein, so that they can be transported in the circulatory and lymphatic systems. The apolipoprotein genes relevant to AD are the three APOEε genes – APOEε2, APOEε3, and APOEε4. APOEε3 is the most common and, as far as is known, has no relevance in terms of AD. APOEε2 is present in about 10% to 20% of the population; people with that gene seem to have a lower incidence of AD. APOEε4 is thought to be a culprit in AD. About 20% to 30% of the population has at least one copy of APOEε4, and about 2% has two copies. Up to 65% of persons with AD have at least one copy of APOEε4; it appears that the gene at least doubles the likelihood of developing AD, and perhaps triples it. Persons with two copies of APOEε4 tend to develop full-fledge Alzheimer’s dementia at a younger age than persons with one copy.

And, finally, there are a very few cases of AD that appear to be directly due to genetic mutations, either in the gene for the amyloid precursor protein that we mentioned above, or genes for proteins labeled “presenelin 1” and “presenelin 2.” Individuals inheriting those genes are certain to develop AD, frequently at a young age, as early as 30. These unfortunate individuals are of enormous interest to researchers treating AD because they constitute a population in which early treatment can be evaluated in clinical trials. In my previous piece on AD, back in 2013, I described a project in Colombia in which the drug crenezumab would be tested in a group of about 300 blood relations who possess this gene. The ultimate objective of studies in this group will be to see whether treating persons who are genetically fated to develop the disease, but in advance of any disease symptoms, can delay or prevent the onset of clinical disease. A trial with crenezumab enrolling some persons in this cohort who had already developed symptoms of cognitive impairment failed to meet its endpoints, but this does not mean that the population with genetic mutations does not continue to be of great interest to researchers, even though hopes for crenezumab appear to have dimmed.

Do the Alzheimer’s risk factors have any implications for treatment?

Aside from the obvious, i.e., play badminton instead of football and don’t crash your car, and what you already know you’re supposed to do regarding those cardiovascular risk factors, there are, I think, some valuable insights here. AD is hard to get a handle on because so many factors can contribute to its onset and development. There’s a fairly vocal contingent that swears that AD is mostly the result of an unhealthy life-style, and the linking of AD with cardiovascular risk factors reinforces that position.

Focusing on persons whose risk factors make them likely to develop AD may also aid in identifying biomarkers for the disease, and permit earlier intervention. And by “intervention” I mean any of the activities that might help, not just drugs. If the individual has hypertension and elevated cholesterol and two copies of APOEε4, don’t wait for her to get lost on the way home from church.

The spectrum of AD risk factors points to a treatment issue that is historically familiar to the health-care community: by the time most persons with AD come to the attention of a health-care professional, the disease has progressed to the point where treatment – even if there were good treatment options – is too late. The same thing could have been said of heart disease at one time. A person could have had elevated blood pressure but have no symptoms, until that first stroke or MI. So a significant part of the effort in combating AD is to find ways of identifying patients earlier. At this time, nobody is talking about population-wide screening for AD. However, the Alzheimer’s Association and the National Institute on Aging, which are part of NIH, have come up with a three-stage definition of AD. Stage one is Preclinical Alzheimer’s Disease; stage two is Mild Cognitive Impairment (MCI) Due to Alzheimer’s Disease; stage three is Dementia Due to Alzheimer’s Disease. They also stress the need to distinguish between what they call Alzheimer’s disease–pathophysiologic (AD-P) and Alzheimer’s disease-clinical (AD-C), in an effort to find ways to address the underlying disease process before symptoms become overwhelming. Here’s a brief quote from the paper describing the diagnosis of preclinical AD:

The concept of a preclinical phase of disease should not be too foreign because medical professionals readily acknowledge that cancer can be detected at the stage of “carcinoma in situ” and that hypercholesterolemia and atherosclerosis can result in narrowing of coronary arteries that is detectable before myocardial infarction. It is widely acknowledged that symptoms are not necessary to diagnose human disease. Type II diabetes, hypertension, renal insufficiency, and osteoporosis are frequently detected through laboratory tests (i.e., biomarkers), and effective treatment can prevent the emergence of symptoms. Thus, we should be open to the idea that AD could one day be diagnosed preclinically by the presence of biomarker evidence of AD-P, which may eventually guide therapy before the onset of symptoms.

The difficulty in the field of AD is that we have not yet established a firm link between the appearance of any specific biomarker in asymptomatic individuals and the subsequent emergence of clinical symptomatology. If we can, however, definitively determine the risk of developing AD dementia and the temporal course of clinical progression associated with AD-P in individuals without dementia or MCI, we will open a crucial window of opportunity to intervene with disease-modifying therapy. (RA Sperling, 2011)

I’ve gone on at considerable length without giving any hints as to what treatment interventions have emerged in the past couple of years that offer genuine hope. There actually have been some, but the prospects are certainly not immediate. Some of the most hyped are probably blarney. Travis kindly sent me a piece about the promise of “orange aspirin,” and I’ll tell you what that is and if it indeed is a miracle drug or maybe something that might help and probably won’t hurt. And there are others, including several drugs that have been used successfully for other indications and “might help, probably won’t hurt” for AD. One of the quirks of finding drugs for really tough diseases is that if there’s even a small benefit in advanced cases, that could imply considerable promise in patients with earlier disease. That’s coming up in the next Doc Gumshoe piece, which I have been working on concurrently with this one.