Alzheimer’s Disease 2018: The Lay of the Land

Doc Gumshoe catches up on progress in the Alzheimer's fight

By Michael Jorrin, "Doc Gumshoe", August 15, 2018

Is this going to be good news, or bad news, or somewhere in between?   On balance, I would say good news, simply because the research and investigation is going on at an intense pace.   Currently there are 1,903 clinical trials underway at some stage, in the US and all over the world. When I first wrote about Alzheimer’s, back in 2014, that number was 1,286, so that’s a significant uptick.   

The huge majority of the drugs in those clinical trials are in the earliest phases; however, 32 drugs are now in Phase 3 trials, with several different targets including amyloid plaque, neurotransmission, insulin/glucose, Tau protein, and others.   Another 58 drugs are in Phase 2, with those same targets plus vascular issues, inflammation, and neuronal/synaptic growth. 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 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.   

In my opinion, this does not 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 blizzard of amyloid plaque or 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 that 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.

What I would consider to be bad news, possibly the worst news imaginable, is if were the case that the medical / scientific community had come to the conclusion that Alzheimer’s disease and dementia are normal and inevitable signs of aging, like grey hair and wrinkles, and that there wasn’t much to be done about it.   But clearly, the general view is that AD will turn out to be manageable in some way – either treatable, or perhaps preventable.

Obviously, some of the impetus for this activity is a desire to locate the pot of gold, and a very rich pot that would be.   If a drug company happened to hit on an agent that significantly delayed the dementia that accompanies AD, just about everyone on the planet would be pretty interested when they got to be about 60 years old.   So even if pharma companies don’t have a clear path or a logical mechanism of action, they may be willing to pursue the slightest hint that a particular molecule may be the key to stopping AD.

Here are the figures on AD as of this year:

  • 5.7 million persons in the US are currently diagnosed with AD – about 400,000 more than in 2015.   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 – 3.4 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 which contribute to AD and dementia.   
  • According to the Alzheimer’s Association, the 2018 costs to the nation associated with AD will be about $277 billion.   Of this amount, $186 billion will be covered by Medicare and Medicaid. The annual mean cost to Medicare/Medicaid per AD patient is $24,122; the cost per patients without AD is $7,415.    Unless there is a treatment breakthrough, total annual 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.   There appears to be a huge difference between US states in the mortality rate due to AD.   Alaska has the lowest AD mortality, 9.1 deaths per 100,000 population. South Carolina has the highest, 50.1 deaths per 100,000 population.   The US overall rate is 34.4 deaths per 100,000 population.
  • 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.

When people think about Alzheimer’s disease, dementia is the defining characteristic.   But not all forgetfulness or absent-mindedness is dementia or related to Alzheimer’s disease.   Being unable to summon up the name of a person you met at a party, or not remembering the precise word you want, or misplacing your cell phone, are not signs that you’re succumbing to AD.   People with early AD who have memory lapses frequently forget that they had memory lapses in the first place.   As time goes on, they may become confused, angry, sometimes apathetic, frightened, and paranoid. They wander, easily get lost, and may fail to recognize a spouse or a child.   Ultimately, large parts of their brains essentially stop functioning. A common cause of death in AD patients is that they lose the capacity to swallow food; when they are fed, the food, rather than going down the esophagus into the stomach the way it’s supposed to, instead is aspirated into the lungs, leading to choking or pneumonia.   When the brains of AD patients are examined on autopsy, they are frequently greatly shrunken. Large parts of the brain have actually been destroyed by the disease.

As you can see, the stakes are extremely high.

A stumbling block

There are many obstacles in the path to getting a potential AD drug through clinical trials and regulatory approval and, finally, to market.   One of the most stubborn is simply recruiting enough subjects in the needed clinical trials to arrive at a meaningful result. Consider the requirements: the study subjects need to have confirmed AD, not simply show signs of dementia.   But the dementia should not be so advanced as to make it difficult to detect improvement in these subjects. At first glance, those should not be insurmountable obstacles. Whereas formerly, AD could only be confirmed with certainty based on autopsies, it is now possible to confirm AD based on brain scans.   So why don’t we just examine everybody who gets to the age of 60 by means of PET (positron emission tomography) scans and analysis of cerebral spinal fluid? That would identify a lot of people with early stage AD, likely before many of them became significantly demented, so it would be possible to test a drug to see if it delayed or stopped the progression of dementia.   

At first glance, that sounds like a rational plan.   After all, women get mammograms to avoid breast cancer and men get PSA tests to avoid prostate cancer.   The difference is that we can provide assurance to those women and men that by means of early testing, they can avoid the worst consequences of those cancers with a high degree of certainty.   But we cannot reassure 60-year olds that, if they take those brain scans, we have the means to help them avoid AD and dementia. So why on earth should they submit themselves to brain scans and having samples of their cerebrospinal fluid tested, if there’s no clear treatment as a result?   And, do they really want to learn the dismal news?

If early stage AD is what we want in our study subjects, maybe we could just enroll people at the very first sign of dementia, when they forget the name of the capital of Upper Volta or the composer of the opera Hansel and Gretel.   But do those individuals actually have AD?   The likely answer is “No.” Older people do indeed forget things, perhaps because the hundred trillion neurons in their noggins are already crammed with a lifetime of details to remember.  And if they should happen to ask their doctors whether they might be succumbing to AD, chances are their doctors would reassure them that, indeed, incidents of forgetfulness are by no means certain indicators that AD was closing in, and that they need not over-worry.   Their doctors have good reason to take that course. One is that minor forgetfulness is very common as the years roll on. But perhaps an even more fundamental reason is that even if these doctors did suspect early AD, they cannot at this point recommend any really effective treatment.  So primary care providers are not likely sources of clinical trial subjects.

A result of this has been to skew the studies in AD towards treating subjects in whom the disease has already resulted in significant dementia.   A positive outcome in these studies would be that a significant percentage of the patients taking the study drug would experience a significant improvement in cognition.   A somewhat less positive outcome in these studies would be if patients on the study drug experienced significantly less decline in cognition than patients on placebo. In other words, the study drug stops or at least substantially slows the progression of dementia.   That’s not nothing, but it’s by no means equivalent to restoring Grandma to “sharp as a tack.” And, so far, at least, clinical trial results with positive outcomes of that type have been exceedingly rare.

An underlying issue is that it’s at least possible that the brain damage done by the progression of Alzheimer’s disease in terms of cognition is to a large degree irreversible.   The specific mechanism that underlies AD is at this point subject to investigation, and no consensus has been reached whether the culprit is the toxic form of amyloid beta (Aβ) or the proliferation of Tau protein in the form of neurofibrillary tangles, or perhaps still something else.   I am not at this point going to go back and delve into the details of the conversion of the usual shorter form of Aβ into the toxic longer form or the arguments in favor of one mechanism or another. (If you want a bit more on that subject, the three previous Doc Gumshoe tracts on AD are in the archive.)   But it’s certainly possible that many of the clinical trials in drugs that are intended to slow or possibly reverse the progression of dementia in subjects with established AD and considerable dementia may be doomed to failure, because they may be targeting a mechanism that in fact has nothing to do with the progression of dementia.   

The focus of AD studies should ideally be on identifying patients with preserved cognition, but who are highly likely to become demented if the AD disease process continues unchecked.           

One study in particular, currently underway, focuses precisely on such patients.

The Crenezumab Project in Colombia

Why in Colombia?   It happens that there’s an extended family in Colombia who have an extraordinarily high rate of developing Alzheimer’s disease.   About 5,000 persons have been found who share the same ancestry; they are all descended from the same individual who came from Spain in the 18th century.   What makes this group of people unique is that about half of them have a mutated gene, labeled PSEN1 E280A (“presenelin 1”), which results in the deposition of extremely high quantities of the toxic Aβ very early in life – as early as their mid-twenties.   Many members of this unfortunate family develop full-blown Alzheimer’s dementia in their 40s. This correlation is thought by most researchers in the field to be the strongest evidence yet that it is Aβ that causes Alzheimer’s dementia, and not one of the other putative causes.

A clinical trial, enrolling about 300 of the members of this family, will investigate whether starting treatment very early can prevent the formation of toxic Aβ and also prevent dementia.   As of February of 2017, 252 subjects had been enrolled in the trial. The trial will run 260 weeks (5 years), so we cannot expect results any time soon. The trial will be placebo-controlled, and will compare two groups of family members who possess the mutated gene, as well as a third group, who do not possess the mutated gene.   If persons in the placebo group begin showing signs of dementia, they will be crossed over to drug treatment. A detailed description of this trial was published in March 2018. (Tariot PN, Alzheimer’s Dement 2018 Mar 8;4:150-160)

The study drug in this trial is crenezumab, from Genentech.   Crenezumab is a monoclonal antibody, a subtype of immunoglobulin G4, and it was selected for the study from a large number of candidate drugs because it is less likely to cause immune reactions leading to edema in the brain.   It is an antibody both to the 40- and the toxic 42-amino acid Aβ chains.

The trial is funded in part by NIH, but primarily by Genentech, which obviously has a great deal to gain by its success.   It has been classified as a registration trial by NIH, meaning that if it meets the objectives of significantly preventing the onset of dementia in these subjects who are currently healthy, crenezumab is likely to be approved by the FDA.   The trial is part of the Alzheimer Prevention Initiative and is also supported by the Banner Alzheimer’s Institute.

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What would the failure of this trial mean?   Many knowledgeable observers think that a great deal rides on this trial – much more than the fate of this one drug and the fortunes of Genentech.   If crenezumab significantly slows the deposition of Aβ, but the subjects in the trial nonetheless go on to develop Alzheimer’s dementia, the scientific community will basically have to go back to looking for another underlying cause for the disease.   What this might be, who knows.

A possibly promising clinical trial

The results of this trial were only announced a few weeks ago, at the annual meeting of the Alzheimer’s Association.   It was an 18-month Phase 2 trial in 856 subjects with established Alzheimer’s disease, although in the fairly early stages.   The trial drug is identified as BAN2401, by Eisai (ESALY), comarketed with Biogen. BAN2401 is a humanized version of a mouse monoclonal antibody that binds to a soluble form of Aβ, termed protofibrils, reducing its toxicity, and in some cases preventing those Aβ protofibrils from inflicting cell death on neurons.   

Three different dosages of BAN2401 were evaluated in the trial – 2.5 milligrams per kilogram (mg/kg) of the trial subjects’ body weight, 5.0 mg/kg; and 10.0 mg/kg, each given bi-weekly.   Early results were discouraging, as the subjects receiving the two lower dosages – 2.5 mg/kg and 5.0 mg/kg – actually performed less well on cognitive evaluations than did subjects receiving placebo.

The trial was continued despite these early negative results.   When the full 18-month trial was completed, the subjects receiving the highest dose of BAN2401 – 10 mg/kg bi-weekly – did considerably better than placebo-treated subjects, scoring 30% higher on one cognitive test and 47% higher on another cognitive test.   The conclusion was that in the 161 subjects treated with the highest dose of BAN2401, cognitive decline was slowed significantly in comparison with the placebo cohort.

It has been pointed out that this trial was the first trial that linked an agent that targeted Aβ with any evidence of a beneficial effect on cognition.   No treatment addressing either Aβ or tangles of tau protein has been approved in 15 years, since either of those two putative causes of Alzheimer’s disease was proposed.

The results of the BAN2401 are far from definitive.   One important difference between the subjects who were given the two lower doses and those who received the 10 mg/kg dose that ultimately gave strong signs of being effective is that whereas only about 30% of the subjects in the high dose arm were carriers of the APOEε4 gene, between 73% and 91% of the subjects in the two other arms were carriers of that gene.   That gene is a specific variant of the apolipoprotein gene, and it is present in as many as half to three quarters of persons with AD. Many individuals with this gene do not go on to develop AD, and there is certainly not a one-to-one correlation between APOEε4 and AD.

The APOEε4 gene is a strong risk factor, but no more than that.   Thus, analysts have been reluctant to ascribe the differences between the lower doses of BAN2401 and the 10 mg/kg dose to the presence of the APOEε4 gene in a majority of the subjects that received the lower dose versus its absence in a majority of the subjects that received the higher dose.   That disparity is not determinative, but certainly leads to head-scratching.

The next analysis of the BAN2401 trial will be presented at the CTAD (Clinical Trials in Alzheimer’s Disease), which will be held October 24th – 27th in Barcelona.   As my mother said about a million times, “We’ll just have to wait and see.”

In the meantime, how are Alzheimer’s disease patients treated?

In the forty-plus years since AD was recognized as the most common form of dementia, only five prescription drugs have been approved by the FDA for treatment of AD.   None of those five drugs reverse Alzheimer’s dementia or even stop the progression of dementia. The most they are able to do is slow its progression, and that delay is usually only temporary.   Three of the five drugs are cholesterinase inhibitors. They are:

  • Aricept (donepezil), developed by Eisai and marketed by Pfizer (PFE), which is approved for all phases of AD
  • Exelon (rivastigmine), from Novartis (NVS), which is approved for mild-to-moderate AD and also for Parkinson’s disease
  • Razadyne (galantamine), from Janssen (JNJ),  which is approved for mild-to-moderate AD

The mechanism of action of most of these drugs is inhibition of the enzyme acetylcholesterinase, which breaks down acetylcholine in the brain.   Acetylcholine (ACh) is vital to brain function, enabling the activity of cholinergic brain cells. One of the things that happen in AD is a decline in the numbers of cholinergic brain cells, so any means of increasing the amount of circulating ACh is a potential boost in brain functioning.

Aricept (donepezil) is the most widely-prescribed of these agents, and is the only one approved by the FDA for treating AD patients whose dementia has progressed to advanced stages.   Donepezil is available in a 1