[Ed. note: Michael Jorrin, who we like to call “Doc Gumshoe,” is not a doctor, he is a longtime medical writer who contributes pieces for us that we hope give a good background or perspective on medical issues (and marketing) for those of us who are as overwhelmed with “live to 150” promises as we are with “get rich” promises. His comments, thoughts and opinions are his own. You can see all of his commentaries here. This time, he’s writing about a disease that touches almost every American at some point — and that is the focus of thousands of researchers (and investors) who are searching for cures and treatments.]
Most likely, you all know the bad news, which I will put right up front so the rest of this piece can be at least moderately upbeat.
- 5.2 million persons in the US are currently diagnosed with Alzheimer’s disease (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.
- AD is the 6th leading cause of death in the US.
- The prevalence of AD increased by 68% between 2000 and 2010.
- The cost of AD in the US in 2013 was $203 billion, of which $107 billion was borne by Medicare and $35 billion by Medicaid. (Those figures are billions with a b!)
- These costs don’t figure in the huge economic impact of AD on caregivers, often the immediate family members of the person with AD.
- At present, there is no cure, and the most effective treatments do nothing to stop the progress of the disease, but only slow it.
However, the health-care community is by no means throwing in the towel. Currently there are 1,286 clinical trials under way in Alzheimer’s disease. This includes trials that are now only recruiting subjects all the way to trials that have been completed, but have yet to report the results. About two thirds of these (based on my quick survey of the National Institutes of Health Clinical Trials Registry) have to do directly with treatment, and the rest have to do with procedures that may impact the management of AD in some way.
Alzheimer’s Disease and Alzheimer’s Dementia
The popular assumption is that this is a distinction without a difference – the growth of those notorious plaques in the brain interferes with vital brain function, and people slowly lose memory, fail to recognize their most immediate family members, lose the ability to perform even the simplest tasks, stop breathing and digesting food, and die. This assumption is entirely reasonable, but in fact there are important distinctions between the disease and the dementia, and these differences can, and we hope, will, have a crucial impact on the future management of this disease.
A Bit of History
Although some old folks remain, as the pleasing expression goes, “sharp as a tack” until they are very old indeed, it has been commonly accepted since just about the dawn of time that some elderly people lose some of their mental acuity. This was commonly attributed to “hardening of the arteries in the brain.” However, Alzheimer’s disease has been recognized as a separate disease entity for over a century. A German physician named Alois Alzheimer had a female patient named Auguste Deter, who became severely demented starting at about age 50, an unusually early onset for senile dementia. Dr Alzheimer carefully followed Auguste for about 5 years, from 1901 to her death in 1906, and then he obtained permission to examine her brain, which he found had been invaded by a dense, whitish substance. Alzheimer recognized that the substance was a form of amyloid, which had been identified and named in the 19th century by the eminent scientist Rudolph Virchow. Virchow, by the way, mistakenly thought that this substance was related to starch, and named it “amyloid” after the Latin for starch, amylum. However, amyloid is not starch, but a protein, composed of chains of amino acids.
For most of the 20th century, the diagnosis of Alzheimer’s disease was applied only to persons who developed the symptoms of dementia prior to old age. Persons who developed those symptoms in old age were described as being affected by “senile dementia.” While there are many possible causes of the loss of mental capacity, old age by itself is not one of them. For about the past 30 years has it been recognized that AD is a principal cause of dementia regardless of age at onset.
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, 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.
What Happens in the Brain in Alzheimer’s Disease?
AD is only diagnosed definitively on autopsy. That does not mean that all persons who are presumed to have died with AD have autopsies performed, only that an examination of the brain of an AD patient is the only way to confirm for certain that the patients indeed had AD. What the pathologists are looking for is the kinds of deposits in the brain that have been found in the patients with Alzheimer’s dementia. But here’s where the confusion begins.
There are basically two proteins that build up in the brains of AD patients, and both are thought to interfere with brain function. One is called beta amyloid (Aβ), and the other is called tau protein.
Tangles of tau protein are found in the nucleus of brain cells, and one school of AD researchers holds to the theory that it is this protein that is responsible for the failure of brain cells.
The beta amyloid theory has more adherents. The identification of Aβ is relatively recent; for a long time researchers just thought the amyloid deposits themselves – the whitish deposits identified a century ago by Dr Alzheimer – were the culprits, but they have learned since that the culprit is only a subset of the amyloid, where the amino acids that make up amyloid are folded in a certain way, which they labelled beta amyloid. And another twist – it now appears that the particularly toxic version of Aβ consists of sections that are cut into snippets that are just two amino acids longer than the usual beta amyloid sections, which are 40 amino acids long. The 42 amino acid beta amyloid sections are the ones that are thought to be damaging to brain function.
Both of these proteins affect brain function in different ways. The tau protein tangles appear to destroy the brain cells from within, while the beta amyloid surrounds the brain cells, interfering with communication among cells and eventually killing those cells Could one or both of these processes be responsible for the characteristic Alzheimer’s dementia? That’s what the researchers are trying to sort out.
There is a genetic component in AD, although, except in very few cases, the genetic component is a risk factor, but not determinative. There is a specific variant of the apolipoprotein gene, APOEε4, which is present in as many as half to three-quarters of people with AD; however, many individuals with this gene do not develop AD, so it’s not possible to establish a one-to-one correlation between APOEε4 and AD. It’s a strong risk factor, but no more than that.
Another genetic link is between Down syndrome and AD. Individuals with Down syndrome have one extra chromosome which bears a gene that stimulates the production of the precursor protein from which beta amyloid is made. By the time they are adolescents, the brains of Down syndrome patients have a large quantity of Aβ plaques, very much like the brains of persons with Alzheimer’s.
Markers of Alzheimer’s Disease
We’ve said that the only sure way of confirming Alzheimer’s disease is examination of the brain on autopsy. However, there are other ways of looking at the brain, especially PET (positron emission tomography) scans and examination of cerebral spinal fluid. PET scans can reveal deposits of tau protein and amyloid plaque, but not distinguish between normal and toxic Aβ. Spinal fluid can be examined microscopically for tau protein and toxic Aβ. Using these two modalities can give investigators a pretty good idea of what’s going on in the brains of people with possible AD.
Targets for Alzheimer’s Disease Treatment
What this information provides to the clinical researchers that are looking for a way to attack Alzheimer’s disease and prevent Alzheimer’s dementia is potential targets in the disease process.
- The Aβ chains themselves are an obvious target, and researchers have looked for similarities between these and other protein chains which have been found to be susceptible to attack.
- Another potential target is the genetic link that increases the creation of Aβ chains from the precursor peptide.
- Yet another is the enzyme, beta secretase, that does the cutting down of the precursor amyloid protein, creating the toxic 42 amino acid beta amyloid.
- There is evidence suggesting that it is not the Aβ itself that does the damage, but small, soluble fragments that separate from the chain, attacking the brain cells. Thus, an agent that increases the stability of the Aβ might actually reduce its toxicity.
All these, and many more targets are avenues for research.
Before we delve into AD research, we should note that there is at least one other theory, with highly qualified proponents. This theory proposes that the cause of AD is none other than inflammation, which is well known to be at the root of many other pathologies in the body, including rheumatoid arthritis and many of the autoimmune diseases. Proponents of this theory point to free radicals, which in particular attack the energy-producing parts of brain cells and impede their function. They suggest that beta amyloid growth is a protective response to free radical invasions, and that attempts to interfere with Aβ might do more harm than good.
A certain amount of research is going on in the free radical area, but the most ambitious research is directed against beta amyloid.
Two research projects in particular deserve more detailed discussion. Both of these are in populations of persons who do not have full-blown Alzheimer’s dementia, but either have early signs of Alzheimer’s disease detected by brain scans, or whose genetic characteristics and family history put them at high risk for developing AD. The objective of both projects is to find out if an early attack on the disease process can delay – or perhaps even prevent! – the development of dementia.
The Solanezumab Project
Solanezumab is an Eli Lilly (LLY) drug (LY2062430) which targets beta amyloid formation. It is a monoclonal antibody (mAb) which binds to the Aβ precursor, preventing, or at least minimizing, the formation of the toxic Aβ chains that are thought to be damaging to brain cells. Currently there are eight clinical trials in progress with solanezumab. One, funded by Lilly, will enroll 2,100 subjects ages 55 to 90, in 39 locations in 11 countries. A second trial, funded in part by the National Institutes of Health, will enroll 1,000 subjects ages 65 to 85.
The Lilly trial will run for 80 weeks and is focused on patients diagnosed with mild AD. The objective is to test whether solanezumab will slow the cognitive and functional decline of these patients. A previous trial of solanezumab, which studied patients with mild, moderate, and severe AD, was considered to have failed to meet its objectives. However, people from Lilly point out that the study design obligated them to consider the entire patient population as one group, and, indeed, in the entire patient population, the destructive effects of AD were not slowed. But in patients with mild AD, there was considerable slowing of cognitive decline. Patients taking the drug had about one-third less decline than those taking placebo. So the current Lilly trial will study only patients with mild AD, and try to determine whether solanezumab delays their decline into dementia.
The more interesting trial is the NIH trial. This trial, smaller and about twice as long-running, will enroll a different type of subjects. These are people who at this point show no signs of Alzheimer’s dementia, but whose PET scans show signs of the invasions of beta amyloid that are thought to be the hallmarks of Alzheimer’s disease. The NIH has selected solanezumab as the trial drug, and the hope is that by starting treatment well before dementia symptoms have appeared, the destructive effects of AD can be prevented. The primary investigator in this trial is Dr Reisa Sperling, director of Alzheimer’s research at Brigham and Women’s/Massachusetts General Hospital in Boston, and she points out that the beta amyloid invasions can start as early as ten years before the appearance of any signs of dementia, so why not start preventive treatment at that point?
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, labelled “presenelin 1,” that results in the deposition of extremely high quantities of the toxic beta amyloid 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 beta amyloid 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 beta amyloid and also prevent dementia. 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.
The study drug in this trial is crenezumab, from Genentech. Crenezumab is also 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 in the brain leading to edema. It is an antibody both to the 40 and 42 amino acid beta amyloid 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.
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 beta amyloid and 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 an underlying cause for the disease. What this might be, who knows.
The Nun Study
And now for something completely different. The Nun Study began in 1986 as a study in aging and disability. The study population, as you will have guessed by now, consists of elderly nuns, members of an order called the Sisters of Notre Dame. When the study began, it had 678 participants between the ages of 75 and 103, with a mean age of 85. A principal reason for studying nuns, rather than a mixed population, is that many of the factors that may lead to differences in study outcomes don’t apply in a population of nuns. The nuns in the study (besides all being female) are all non-smokers, drink little if any alcohol, have the same marital and reproductive history, and have basically lived similar lives.
And one more factor of crucial importance in this study is that all the participants agreed to donate their brains for post-mortem examination.
Finally, there was information in the archives of the Sisters of Notre Dame that led to an exceedingly interesting correlation. When the young women entered the order, mostly in their early 20s, they wrote autobiographical essays. Sixty years later, these essays were examined as part of the Nun Study, and assessed for a characteristic termed “linguistic density,” which summed up a number of features of their writing including choice of words, sentence length, complexity, liveliness of expression, and fluency of thought. The extraordinary finding was that of the participants whose essays were evaluated as lacking in linguistic density, over 80% went on to develop Alzheimer’s dementia in old age. But in those whose essays were not considered lacking in linguistic density, about 10% developed dementia. Note that in comparison with the reported 45% prevalence of dementia in persons age 85 and older, the 10% figure for those nuns is a success story.
Other findings of interest were that many of the participants who continued to demonstrate good mental function into their 90s, were found on post mortem examination of their brains to have significant depositions of amyloid plaques. Some participants, whose brains had suffered the ravages of amyloid and tau protein and were considerably shrunken when they were examined on autopsy, had nonetheless continued to function, mentally and in terms of activities of daily living, well into extreme old age.
The Nun Study does not suggest that the beta amyloid or tau protein hypotheses are incorrect, or that these deposits are not the root causes of Alzheimer’s dementia. What it does suggest is that the human brain has considerable redundant capacity, and that even when parts of the brain cease to function, other parts can step up to the plate. This is consistent with the experience of rehabilitation of stroke victims, who have lost the use of parts of the brain, but whose brains can be retrained to carry on with the job.
It also suggests that a lifetime of active brain work may be one of the most effective measures against the onset of dementia, whether Alzheimer’s dementia or any other form.
Current Treatment Options
Nothing works well. A handful of drugs are FDA-approved for Alzheimer’s disease, and the best any of them can do is slow the progress of dementia. 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, and 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, The drugs that employ this mechanism are:
- Donepezil (Aricept), developed by Eisai and marketed by Pfizer (PFE)
- Tacrine (Cognex), also marketed by Pfizer, but withdrawn from the market
- Rivastigmine (Exelon), from Novartis (NVS)
- Galantamine (Razadyne), from Janssen, part of Johnson & Johnson (JNJ)
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. Rivatigmine is also approved for Parkinson’s disease.
Another mechanism being tried is the blockade of glutamate receptors in the brain. Glutamate is an exitatory amino acid, meaning that it stimulates neuronal activity, which is necessary for brain function. However, excess glutamate action may overstimulate neurons, leading to premature cell death. The one agent that employs this mechanism is memantine, marketed as Namenda by Forest (FRX), and also sold in a number of supplement forms. Memantine aims to block the N-methyl-D-aspartate (NMDA) glutamate receptor channel, and is reported to be moderately effective in mild or moderate Alzheimer’s dementia.
However, neither the acetylcholesterinase inhibitors not glutamate receptor blockade appears to have any effect on the underlying AD disease process, nor do they reverse the decline of cognitive capacity in patients. The most they can do is slow it down.
So, What Does This Tell Us?
If there’s a message in all this bad news, it’s that waiting until real symptoms of dementia start to manifest is way too late. The Colombia study and the solanezumab study may either support the beta amyloid hypothesis, or they may deal this hypothesis a severe blow. But, as I said earlier, there are 1,286 clinical trials is Alzheimer’s disease, at various stages. These investigate not only ways of stopping or even possibly reversing the brain changes in AD, but other potential ways of managing the cognitive decline. Some of these trials are not specifically drug trials, but other interventions that may support memory and cognition. There are also studies in novel ways to detect AD at ever earlier, and therefore more treatable stages.
I plan to take a close look at some of the most promising drug trials in a future note. I’ll keep you posted.
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I’m keeping track of the many interesting and, in many cases, challenging comments and questions from readers. No surprise, not everyone agrees with me, and that’s not new in my life! I’m going to try to collect and summarize the themes of these challenging comments and address them in an upcoming blog, rather than responding to them separately in the comments section. One of the questions raised by several readers is, what are my credentials for sounding off about this medical stuff? After all, I’m not a real doctor. The quick answer is that I’ve been a medical writer for 30 years, I’ve written lots of continuing medical education material (CME), which is stuff that real docs use to keep their own credentials in running order, and I’ve co-written (with real docs) lots of papers in professional, peer-reviewed medical journals. So I’ll stick up for my capacity to read and understand the medical literature. Of course, the conclusions I draw from what I read are absolutely my own, and I put them out there for you all to take shots at! Thanks for your comments, best to all, Michael Jorrin (aka Doc Gumshoe).
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