Moving Beyond the Shadow of Alzheimer’s Disease
 
A century ago, small pox, polio, and almost any form of cancer was a deadly and incurable threat.  Today. for all practical purposes, small pox and polio are extinct, while a growing list of cancers are preventable and treatable. But meanwhile, Alzheimer’s disease, has replaced these as a source of fear for an aging global population.

Alzheimer’s disease is a degenerative brain disease and the most common cause of dementia.  The characteristic symptoms of dementia are difficulties with memory, language, problem-solving and other cognitive skills that affect a person’s ability to perform everyday activities.  These difficulties occur because neurons in parts of the brain involved in cognitive function have been damaged or destroyed.  In Alzheimer’s disease, neurons in other parts of the brain are eventually damaged or destroyed as well, including those that enable a person to carry out basic bodily functions such as walking and swallowing.  People in the final stages of the disease are bed-bound and require around-the-clock care. And, ultimately, Alzheimer’s disease is fatal.

Worldwide, at least 44 millionpeople have Alzheimer’s or a related dementia. But the precise number is difficult to assess because only 1-in-4 people with Alzheimer’s disease have been diagnosed.

In the United States the number of Alzheimer’s victims is estimated at around 5.5 million. It is the 6th leading cause of deathin the United States and is the only one of the 10 leading causes of death that cannot be cured, prevented or even slowed.  10% of Americans over the age of 65 have Alzheimer’sand one-third of Americans over age 85are afflicted with the illness.

There was an 89% increase in deaths due to Alzheimer’sbetween 2000 and 2014. And as of 2017, someone in the United States developed Alzheimer’s every 66 seconds.

Between 2017 and 2025 every state is expected to see at least a 14% rise in the prevalence of Alzheimer’s.  And by 2050, it’s estimated there will be as many as 16 million Americansliving with Alzheimer’s unless we discover a way to cure, prevent or slow the disease.

And the crisis will only grow as American’s age.  In 2031, when the first wave of baby boomers reaches age 85, it is projected that more than 3 million people age 85 and older will have Alzheimer’s.  Worse yet, the number of Americans living with Alzheimers dementia is projected to increase to 11.6 million by 2040 and about 7 million of those will be 85 years or older.

Typical life expectancy after an Alzheimer’s diagnosis is 4-to-8 years.

Obviously, the human suffering for victims and their families is enormous; but so are the economic costs. In 2017, the global cost of Alzheimer’s and dementia was estimated to be $605 billion, which was equivalent to 1% of the entire world’s gross domestic product.  Meanwhile, Alzheimer’s cost the United States $259 billion.  Aggregate cost of care by payer for Americans age 65 and older with Alzheimer’s disease and other dementiastotaled $113 Billion from Medicare, $41 Billion from Medicaid, $44 Billion out-of-pocket, and $29 Billion from other sources.  Worse yet, by 2050, costs associated with dementia, in the United States alone could be as much as $1.1 trillion a year.

And this does not even count the lost productivity of Alzheimer’s sufferers or the millions of unpaid person-hours provided by family and friends.  The economic value of the care provided by unpaid full-time and part-time caregivers of those with Alzheimers disease or other dementias was $217.7 billion in 2014, the most recent quantification of this data.  Notably, more than 1-in-6 Alzheimer’s and dementia caregivers had to quit work entirelyeither to become a caregiver, in the first place, or because their caregiving duties became too burdensome.

Given the personal and economic implications of Alzheimer’s and other dementia, it’s not surprising that it’s one of the most vibrant areas of medical research.  As of the end of first quarter 2018, there were 105 treatments in various stages of trials with the FDA.  And yet, the enormous amount of intellect, technology and funding devoted to this area has, to date, failed to deliver a cure, or even a means of delaying the disease.

So, what’s going on?
 
The fact is that the mechanisms behind the genesisof Alzheimer’s and its progressionhave proven very difficult to understand. Consider the role of beta-amyloid protein.

Beta-amyloid protein attacks and destroys synapses, the connections between nerve cells in the brain.  This results in memory loss, dementia and ultimately death. Overproduction of beta-amyloid is strongly linked to development of Alzheimers disease.  So, this has become a natural focus of much research.  But, unfortunately, many drugs targeting beta-amyloid have failed in clinical trials.

Why?

Researchers at Kings College London recently discovered a vicious “feedback loop” underlying brain degeneration in Alzheimers disease.  In the new study, published in the journal, Translational Psychiatry,they found that when beta-amyloid destroys a synapse, the nerve cells make more beta-amyloid driving yet more synapses to be destroyed.  The result is a vicious positive feedback loop, in which beta-amyloid drives its own production.  Once this feedback loop gets out of control it is too late for drugs which target beta-amyloid to be effective.  This could explain why so many Alzheimers drug trials have failed!

This work highlights the intimate link between synapse loss and beta-amyloid in the earliest stages of Alzheimers disease and the importance of early therapeutic intervention.

The researchers also confirmed that a protein called Dkk1, potently stimulates production of beta-amyloid and is central to this positive feedback loop.  And, while it is barely detectable in the brains of young adults, its production increases as we age.

And that’s why this research may represent a huge tipping point in our battle against Alzheimers.  Instead of targeting beta-amyloid itself, this research indicates that targeting Dkk1 could be a better way to halt the progress of Alzheimers disease by disrupting the vicious cycle of beta-amyloid production and synapse loss.

And most importantly, this work has shown that we may already be in a position to block the feedback loop with a drug called fasudil, which is now used in Japan and China for stroke treatment.  The new research convincingly demonstrates that fasudil protects synapses and memory in animal models of Alzheimers, and at the same time reduces the amount of beta-amyloid in the brain.

The researchers found that in mice engineered to develop large deposits of beta-amyloid in their brains as they age, just two weeksof treatment with fasudil dramatically reduced the beta-amyloid deposits.

In addition to being, a safe drug, fasudil appears to enter the brain in sufficient quantities to potentially be an effective treatment against beta-amyloid.

Research is now expected to advance rapidly to a clinical trial in people with early stage Alzheimers disease to determine if fasudil improves brain health and prevents cognitive decline in humans.

These and other breakthroughs indicate accelerating progress. Realistically, we may be, for the first time, on the precipice of curing,preventing or at least slowing, Alzheimer’s disease.  However, simply discoveringa game-changing treatment is not enough to eliminate the suffering and economic hardship for Americans.

According to a recent RAND Corporation study, the U.S. health care system lacks the capacity to rapidly move a treatment for Alzheimers disease from approval into wide clinical use, a shortcoming that could leave millions of people without access to such transformative care once such a breakthrough is available. And since Alzheimer’s is a progressive disease, it must be treated beforeit does serious damage; treatment delayed is, effectively, treatment denied.

As the RAND report explains, the primary problem is that there are too few medical specialists to diagnose patients who may have early signs of Alzheimers and confirm that they would be eligible for therapy to prevent the progression of the disease to full-blown dementia.  Other shortcomings include a relatively low number of specialized diagnostic scanners and too few infusion centers to deliver treatments to patients.

Researchers estimate that as many as 2.1 million U. S. patients with mild cognitive impairment could develop Alzheimers dementia over a two-decade period while waiting for evaluation and treatment, even after approval of an effective therapy by the U. S. Food and Drug Administration.

According to RAND, little work has been done to get the medical system ready for such an advancement. So, even while there is still some uncertainty about if and when an Alzheimers therapy will be approved, health care leaders need to begin thinking about how to respond to such a breakthrough.
 
The RAND research assumed that a therapy is approved for use beginning in 2020 and screening would begin in 2019.  Under such a scenario, about 71 million Americans aged 55 and older would have to be screened for signs of mild cognitive impairment.  After follow-up examinations and imaging to confirm evidence of Alzheimers, the RAND study estimates 2.4 million people could ultimately be recommended for treatment.  The question they sought to answer was, “What are the implications for America’s current health care system related to:

- the supply of dementia specialists,

- the supply of scanners used to identify Alzheimers abnormalities in the brain, and

- access to so-called “infusion centers,” which would deliver the treatment.”

They found bottleneck’s in the capacity of all three areas of the health care system that are needed to cope with the surge in demand triggered by an effective Alzheimers therapy.

As a result, RAND estimates that wait times to complete all three stages of the diagnostic and treatment process would be 18.6 months in 2020, shrinking to 1.3 months in 2030 as the system develops more capacity and the surge in demand declines.

To summarize, Alzheimer’s disease continues to take an enormous toll on the happiness, health and finances of human beings, here and around the world.  And, despite decades of research, any commercially available means of curing, preventing or slowing the disease, is still a few years away. But, for the first time, breaking the vicious-cycle that has thwarted previous trials appears to be possible using an existing solution that is safe, effective and affordable.  Assuming trials of this or other therapies are successful, the big challenge is driving the reallocation of health care resources needed to make the game-changing technology, available to everyone who needs it in time to make a difference.  Meanwhile, research shows that there are individual decisions we can make while we’re waiting for a breakthrough solution to become available. Collectively, these factors improve our chances of avoiding this devastating threat, entirely.

Given this trend, we offer the following forecasts for your consideration.

First, as soon as 2019, clinical trials of fasudil and other drugs targeting Dkk1 in humans will provide a better way to halt the progress of Alzheimers disease by disrupting the vicious cycle of beta-amyloid production and synapse loss.

Efficacy in mice, has already been proven by the team at King’s College London.  More importantly, commercial use in Japan and China, means that Phase I trials for toxicity and side-effects have already been performed and documented. Therefore, the new “fast-track human trials” will focus immediately on identifying dosage levels and confirming its efficacy in humans.  Assuming, fasudil qualifies under the recently implemented “Right to Try” law, some American patients diagnosed with Alzheimer’s may have access to it by sometime in 2020.

Second, to address the current shortage of neurologists and geriatricians, primary care physicians and nurse practitioners will be trained to conduct initial screening for mild cognitive impairment indicative of early-stage dementia.

In addition, the Rand Report anticipates that some primary care physicians and general psychiatrists could become certified in dementia care to allow them to provide advanced testing and treatment. Similarly, AI-based screening also may play a role in identifying those who need diagnostic brain scans.
 
Third, government and private institutions will aggressively work with medical technology companies to deploy affordable PET-scan machines, as well as alternatives.

Today, PET scans are the only FDA-approved diagnostic to confirm brain changes caused by Alzheimers.  Tau-PET scans, in particular, accurately identify 90-to-95 percent of people who go on to develop Alzheimer’s, while minimizing false positives.  Rand suggests mobile PET scan clinics as a way to target a wider commmunity.  Other options, including tests that diagnose the illness using cerebrospinal fluid, could be used to reach more patients, at a lower cost.

Fourth, once a treatment and a pool of diagnosed patients emerges, infusion centers will ramp-up capacity quickly while treatment in physician offices and home infusion will become commonplace.

Fasudil is an intravenous drug and most of the other treatments under development for Alzheimers are biologic drugs that must either be injected or infused. According to the RAND report, the third potential bottleneck is a shortage of infusion centers where patients could receive medications.  Long-term, a combination of home infusion, primary care offices and infusion centers approach will meet the needs of the public quickly and affordably.
 
Fifth, more people will adopt routine use of low-dose aspirin, as an inexpensive way of delaying or preventing the onset of Alzheimer’s disease.

Researchers have long known of the lower incidence of Alzheimer’s among those who consistently take low-doses of aspirin. New research published in The Journal of Neuroscience, now indicates that a low-dose aspirin regimen could reduce Alzheimers disease pathology.  How?  Aspirin decreases amyloid plaque pathology in mice by stimulating lysosomes, the components in animal cells which help clear cellular debris.  The research adds Alzheimer’s prevention to aspirins established uses for pain relief and for the treatment of cardiovascular diseases.

Sixth, exercise will become increasingly popular as more people associate it with a reduced risk of Alzheimer’s disease, along with other brain-related benefits.

A study published in the journal, Science,finds that physical exercise can "clean up" the environment in the brain, allowing new nerve cells to survive and thrive and improving cognition in those with Alzheimers. The researchers found that while drugs and gene therapy can also activate neurogenesis in the hippocampus, exercise is better because it turns on the production of BDNF, a chemical which helps the new neurons to survive. As with aspirin, its benefits related to Alzheimer’s are simply a bonus on top of other well-established health benefits. And,

Seventh, beginning around age 50, those who aggressively manage their blood pressure will be less likely than their peers to develop Alzheimer’s and MRI will play a big role in detecting those patients most at risk, while there is time to act.

A new study published in Cardiovascular Research, indicates that patients with high blood pressure are at a higher risk of developing dementia.  This research also shows, for the first time, that an MRI can be used to detect very early signatures of neurological damage in people with high blood pressure, before any symptoms of dementia occur.   It is well known that the vast majority of cases of Alzheimers disease and related dementia are not due to a “genetic predisposition,” but rather to chronic exposure to vascular risk factors.  The clinical approach to treatment of dementia patients usually starts only after symptoms are clearly evident.  However, it is becoming increasingly clear that when signs of brain damage are manifest, it may be too late to reverse the neurodegenerative process.  The results indicated that hypertensive patients showed significant alterations in three specific white matter fiber-tracts.  Hypertensive patients also scored significantly worse in the cognitive domains ascribable to brain regions connected through those fiber-tracts, showing decreased performances in executive functions, processing speed, memory and related learning tasks.  Obviously, this provides an important new pathway for prevention, while we wait for a cure.  But, more importantly, using MRI systems for early-stage diagnosis may help reduce the diagnostic bottleneck identified by the RAND Corporation.

References
1. Alzheimer’s Association Report.  Joseph Gaugler, Ph.D., Bryan James, Ph.D., Tricia Johnson, Ph.D., Allison Marin, Ph.D., and Jennifer Weuve, M.P.H., Sc.D.   2018 ALZHEIMER’S DISEASE FACTS AND FIGURES.

https://alz.org/media/HomeOffice/Facts%20and%20Figures/facts-and-figures.pdf

2. Rand Corporation Reports.  Jodi L. Liu, Jakub P. Hlavka, Richard Hillestad, and Soeren Mattke. Assessing the Preparedness of the U.S. Health Care System Infrastructure for an Alzheimers Treatment.

https://www.rand.org/content/dam/rand/pubs/research_reports/RR2200/RR2272/RAND_RR2272.pdf

3. Cardiovascular Research, 2018. Lorenzo Carnevale, Valentina D’Angelosante, Alessandro Landolfi, Giovanni Grillea, Giulio Selvetella, Marianna Storto, Giuseppe Lembo, and Daniela Carnevale. Brain MRI fiber-tracking reveals white matter alterations in hypertensive patients without damage at conventional neuroimaging.

https://academic.oup.com/cardiovascres/article/114/11/1536/5033438

4. Translational Psychiatry.   Christina Elliott, Ana I. Rojo, Elena Ribe, Martin Broadstock, Weiming Xia, Peter Morin, Mikhail Semenov, George Baillie, Antonio Cuadrado, Raya Al-Shawi, Clive G. Ballard, Paul Simons, and Richard Killick.  A role for APP in Wnt signalling links synapse loss with β-amyloid production.

https://www.nature.com/articles/s41398-018-0231-6

5. JAMA. 2018.  Ossenkoppele R, Rabinovici GD, Smith R, et al.  Discriminative Accuracy of [18F]flortaucipir Positron Emission Tomography for Alzheimer Disease vs Other Neurodegenerative Disorders.

https://jamanetwork.com/journals/jama/article-abstract/2702872