Alzheimers Disease: The Brand--a blog about economics, science, and humanity

Indefatigable truths...

12/7/2020

The full blog is here on data & donuts but there are sufficient followers receiving these posts that might miss out.

There are 46 million Americans with Alzheimer's disease in their brain right now, but no symptoms. --Richard Isaacson
I have two blogs. One is sort of a repository for information. I don’t pay for that one and at times I think it may have run its course but then I think of something else I want to park over there. The name of it is Alzheimer’s Disease: The Brand and there is plenty of value over there but also plenty I have learned.

For example, you really need to do your homework. The hard tedious bits. I long advocatedthe work of Dr. Dale Bredesen and I am not exactly recanting but it never occurred to me to look at the data he cited from the literature in support of the claims made in his writings.The person that dug into the findings and the data in the resources cited by Dr Bredesen was Dr Peter Attia. I have listened to his podcast and read his posts for years. He has evolved into more of a pay to play model for some of his podcast show notes and communications so I was unable to locate the conclusion. Regardless I still follow many of the earlier recommendations simply because they still make sense.

An article in The Washington Post, Atypical forms of dementia are being diagnosed more often in people in their 50s and 60s caught my attention. All gloom and doom and no grounding in the granularity needed to describe the known heterogeneity of Alzheimer’s Disease.

My dad had Alzheimer’s disease likely because of head trauma in a car accident years before we were able to make the probable diagnosis. So with uncertainty regarding any long term benefits from the lifestyle recommendations in the literature I decided to focus my attention on longevity and prevention--the focus of The Drive.

Here is a direct link to the podcast Alzheimer’s disease prevention--patient and doctor perspectives

Measuring what we choose to measure...at all costs

3/2/2020

I teach people how to formulate a data question and the downstream ramifications and skills aligned with collecting, tidying, analyzing, and communicating the ensuing narrative.

What we measure is a choice, which reflects implicitly our value system--Measuring What Counts The Global Movement for Well-Being

I repeat the description of my role in the diverse health ecosystem because it evolves along with everything else. As an avid reader, I am intrigued by the depth of resources freely available but even more so as a data analyst. Free and non-proprietary data abounds. If you have crafted a well designed question, there should be more than a single database for curating insights or empathy. In a perfect data collaboration I would prefer if clients learned about non-proprietary data and invested in the data literacy of their team. Better investment, better outcome, and lower cost--efficiencies abound.

I haven't been writing consistently about Alzheimer's disease lately because to be honest, it often feels like shouting into a black hole.

Gina Kolata from the New York Times writes, "But the studies of anti-amyloid drugs completed so far have repeatedly failed. Companies have spent billions of dollars on the drugs. Some, like Pfizer, have gotten out of the race altogether.
Many researchers say they are not yet ready to give up.
The disease, they note, always progresses in the same way: Amyloid accumulates in the brain and then a tangled, spaghetti-like protein, tau, appears and neurons die."-- An Alzheimer's Treatment Fails: "We Don't Have Anything Now"

This line graph below at best shows the decline in clinical trial trends in seeking a cure or treatment.

I am ecstatic to share a JAMA article, In Alzheimer Research, Glucose Metabolism Moves to Center Stage that provides a robust discussion pointing towards metabolic derangement and the more likely candidate for modifying or preventing Alzheimer's disease in aging populations.

A powerful force in discussions around anti-aging and peak performance is Peter Attia MD. He has a great podcast called The Drive which often yields a depth in discussions necessary to have a granular appreciation of fact-based medicine. I point you to this episode specifically but there are many--Francisco Gonzalez-Lima, Ph.D: Advancing Alzheimer's disease treatment and prevention - is AD actually a vascular and metabolic disease?

Stay tuned...

I am not the type to tell you I told you so but...

5/17/2019

We seem to be forgetting what the science tells us. Perhaps it's the giddy enthusiasm or hope associated with being the first one to break the curse of an Alzheimer's disease cure. But let me remind you, we are not able to diagnose Alzheimer's disease. Not yet. We can speak in probabilities, probable Alzheimer's is as close as we can go. Yes there are biomarkers and brain tissue biopsies but if we don't know the causative pathway--what are we measuring exactly?

Fortune magazine early this year stated, "Few spaces in the life sciences have fathered failure to the extent that experimental Alzheimer’s drugs have. In the past year alone, at least a half-dozen Alzheimer’s drug hopefuls from major pharmaceutical companies bit the dust. What’s more, there’s an ongoing debate about what should be the main focus area—amyloid plaque, some other biological marker, or a combination strategy?"--Alzheimer's: A Trail of Disappointment for Big Pharma.

The headlines dazzle in the wake of failure after failure of drugs applauded in early phase clinical trials--doomed when Phase III results fizzle. I like Derek Lowe and read his In The Pipeline take on drug discovery and pharma.

I’m not going to do some sort of victory dance, because (once again) this is bad news for Alzheimer’s patients and for their families. I know that I have written many times that I thought this program would fail – I was cautious in 2015, cautious earlier last year, and much more than cautious just a few weeks later. My views on amyloid antibodies are well known, for the little that’s worth. I had no real expectations that aducanumab would work, despite all the attempts at positive spin over the years, and by golly, it doesn’t work. That doesn’t make me a prophet – I think any objective observer would have to have come to the same conclusion. Biogen and Eisai put themselves into this situation, although they definitely made it worse by trying to pretend that things were going differently than they have for every single other amyloid antibody program ever. They have all failed. One after another, again and again.--Derek Lowe

The one area of research deserving of attention points toward metabolic derangements. A recent book, Diabetes Mellitus: A Risk Factor for Alzheimer's disease includes a chapter The Full Spectrum of Alzheimer's disease is Rooted in Metabolic Derangements that Drive Type 3 Diabetes.

Aging leads to atrophy and reduced function of most organs throughout the body, including the brain. Lifestyle choices have measurable positive and negative effects on aging such that healthful eating habits and regular physical and mental exercise help preserve cognitive function, whereas poor lifestyle choices accelerate physical and functional aging.

Furthermore, aging is the most consistent and dominant risk factor for neurodegeneration. One of the main difference between aging and neurodegeneration is that with aging, the brain exhibits modest degrees of atrophy and functional loss over a period of years, whereas in AD, the declines are swifter and relentless, driving formerly fully functioning people to eventual end-stage vegetative states.

These concepts suggest that lifestyle measures that either curtail or exacerbate the aging process may also modulate risk and rates of developing AD as well as other neurodegenerative diseases--S.M. de La Monte

Next month I will be attending a program sponsored by The Johns Hopkins Institute for Basic Biomedical Sciences. It will be a "day long immersion in science and medicine." If you are a writer, journalist, blogger, or public information officer you can register here Mysteries of the Mind--Understanding Mental Health and Addiction June 10th, 2019.

I am looking forward to a related presentation on Alzheimer's disease, Engineering the Future of Medicine: Predicting Alzheimer's disease.

Computational medicine, as defined by JHU, "...is an emerging discipline devoted to the development of quantitative approaches for understanding the mechanisms, diagnosis and treatment of human disease through applications of mathematics, engineering and computational science."

Watch this space for related topics and a run-down of the discussions.

Find me on twitter @datamongerbonny

Do you have a brain? Well then, you are at risk for Alzheimer's...

10/2/2018

I still dramatically arch an eyebrow when cures or proclamations in general are made about Alzheimer's disease. But when Peter Attia, MD weighs in--he has my attention. I am confident that you are able to Google with the best of them so hope you will do your due diligence and appreciate the insights and appropriate level of granularity he is able to deliver. I mention him here and here if you are short on time.

The Peter Attia Drive podcast with Richard Isaacson, MD is long and in depth. Peter knows you are easily distracted and his team produces stellar show notes for quick reference. My schedule of 2 to 3 hour trail runs were made for the hypnotic focus of the format. Think of what you thought you knew--now consider it a palimpsest--seek the critical thoughts and evidence based logical thinking and change your mind...okay this sounds a little fandom-y but when you are surrounded by blather and self-aggrandizing listicles of how to be this or that--the truth can be like manna.

I like to think of charts and graphics like little arguments. They are to be read, not briefly scanned or summarized without thought or reason. The poster below is mentioned in the podcast and I thought to expedite this post I would topically introduce it to you for your edification and review.

What is a prospective cohort study? The prospective part of the study describes subjects enrolled into a cohort or group that have not yet developed the outcome of interest. None of the subjects in the study below actually have been "diagnosed" with Alzheimer's disease--read the study design for clarity. Longitudinal (over a period of years) studies are needed to observe and identify potential risk factors or associations with disease outcomes.

There will never be a monotherapeutic cure for Alzheimer's disease. Prove me wrong but I can't imagine it and to date over 99% of research in the field have been consistent with this hypothesis. The investigators of the study are examining multiple AD, dementia, and vascular risk scales and their response to multi-modal interventions. Secondary outcomes include measures of blood biomarkers and cognition.

The two genotypes are ApoE (epsilon 2, epsilon 3, and epsilon 4) and MTHRF C677 1298c:

MTHFR A1298C = heterozygous mutation (one mutation)
MTHFR C1298C = homozygous mutation (two mutations)
MTHFR C677T + MTHFR A1298C = a compound heterozygous mutation

The point is to notice the stratification of variations in response for blood biomarkers and cognitive tests (figure listed in Results). The green blocks signify "significant" improvement over 6 months. I need a confidence interval here to be convinced p<.05 indicates anything of note or if there are meaningful clinical outcomes over time but at the very least--there is much to consider for additional investigation.

“Anyone with a brain is at risk for Alzheimer’s.” —Richard Isaacson

The folly of human conceits...

6/8/2018

There is perhaps no better demonstration of the folly of human conceits than this distant image of our tiny world--Carl Sagan

The similarities between space travel to Mars and the latest attempts to discover a blockbuster monotherapeutic cure for Alzheimer's disease are (or should be) self evident.

On the space exploration frontier get those check books out to the tune of ~ 19 billion dollars. Can you even imagine what we could do to mitigate the environmental challenges here on home-station earth? Water toxicity and air quality need significant attention and funding as we roll back to the era of "lakes on fire." What about solar energy or other eco-friendly reforms targeted to agriculture and antiquated "right-to farm" policies? In my state of NC hog farming is decimating water supplies and air quality--the industry owns everything but the "waste" so the farmer is left with a whatever works mentality, hence the lakes of hog waste.

Let's pivot back to Alzheimer's disease. The Research Portfolio Online Reporting Tools or RePORT from National Institutes of Health (NIH) provides estimates of funding for various research, condition, and disease categories. The spend per year for Alzheimer's disease and associated dementias exceeds a billion dollars by the US government and a 2.5 billion dollar investment by Pharma each year.

Are we naive enough to believe that investing 3.5 billion into R&D for what is ostensibly a complex cascade of metabolic derangements and pathologic senescence will yield a worthwhile outcome at the patient level? Again think about the upstream possibilities of investment in social determinants of health and healthy aging. Aging is not just about getting "old". It is about infrastructure and much larger frameworks.

After the Fact is a podcast from the Pew Charitable Trusts. A recent bonus episode, How Today's Generations are Changing the World describes the 6 generations currently sharing the planet and how by midcentury there will be 2 billion elderly people and 2 billion young. This first ever combined statistic will represent 40% of the world population. If we keep a narrowed focus on solving diseases of aging with monotherapeutic cures instead of how to address "labor supply, family structures and finances, demands on health and welfare services, housing", education, transportation and other variables with downstream impact on health what becomes of our society?

I was fascinated to learn of the organic evolution of neuroscience as a discipline. The randomization of how medicine evolved from holistic to a discipline chunked out by organ systems is weird and counterintuitive. Read an interesting article about Mapping Change in Large Networks for a detailed discussion of not only the visualization below but about an interesting methodology applicable across data questions--"methods are general to many types of networks and can answer questions about structural change in science, economics, and business."

My point remains--neuroscience is a relatively young discipline...

I work with data to solve complex problems. I find the data by listening and participating in political discussions about health policy, economics, medicine, and health law/healthcare. A deep understanding is needed to identify which variables are needed to add a 360 perspective for the best way forward.

Before we get excited and committed to discovering water on new planets--let's stop polluting the water here on earth. Our ancestral selves will be thankful...

Read more about healthcare at the intersection of health policy, health economics, medicine, and healthcare:

The Science of Health versus The Science of Disease

3/19/2018

A few years ago I was looking for data. Not a strange occupation as I make my living as a data informed analyst and medical writer. But I always felt there had to be something driving the increase in chronic diseases in the general population. Not only the upward climb in reported rates of dementia but across the board. It seemed there was something. I thought maybe food policy was to blame. There are a lot of potential correlations to be examined. Why isn't this a larger priority?

I suggest in a profit making healthcare system--what would be the point? When rent-seeking is the status quo why would we want to identify potential causative factors?

Economists have a name for these activities: they call them rent seeking, getting income not as a reward to creating wealth but by trapping a larger share of the wealth that would otherwise have been produced without their effort. Those at the top have learned to suck out money from the rest in ways that the rest are hardly aware of - that is their true innovation.--The Price of Inequality, Joseph E. Stiglitz

Rent-seeking describes competition between companies to confer advantages involving unproductive use of resources resulting in advantage to the firms. Instead of making a better product at a lower price, companies seek benefits by influencing policy. Examples include lobbying the government for taxing, spending and regulatory policies without returning any benefits to the consumers.

I know we are comfortable assigning blame to the pharmaceutical companies but when we grab the low hanging fruit we show a disregard or ignorance to the "corporate health-care middlemen".

As the drug industry has come back down to earth, the returns of the 46 middlemen on the list have soared. Fifteen years ago they accounted for a fifth of industry profits; now their share is 41%. Health-insurance companies generate abnormally high returns, but so do the wholesalers, the benefit managers and the pharmacies.

In total middlemen capture $126 of excess profits a year per American, or about two-thirds of the whole industry’s excess profits. Express Scripts earns billions while having less than $1bn of physical plants and no disclosed investment in R&D.

This year the combined profits of three wholesalers that few outsiders have heard of are expected to exceed those of Starbucks.
The dark view is that pockets of rent-seeking have become endemic in America’s economy.

Wherever products are too complex for customers to understand, and where subsidies and complex regulation add to the muddle, huge profits can opaquely be made. Remember mortgage-backed securities?--The Economist, Which firms profit most from America’s health-care system

I have about a 3.5 hour drive to the coast and like to listen to my podcast queue. I was listening to Rich Roll and his guest Zach Bush, MD discuss glyphosate and the increase in chronic disease associated with the widespread use of Round-Up weed killer. Look at the red line on the charts below. Interesting to say the least. I am planning on digging a little deeper into current data but as far as hypothesis generation goes--It looks worth examining.

If you want a deeper dive into the discussion I suggest clicking on the podcast. Zach Bush is one of the few triple board certified physicians. His compelling quote is an important one to remember "The politicians are not the solution. You and I are the solution as consumers".

Alzheimer's and race: social, political, or biologic proxy?

2/14/2018

What is going on here? A well-funded "volunteer" non-profit should do better. What is race a placeholder for? I am certain they know that risk is not determined by pigment. If there are social determinants of health--give them voice. If there are biologic measures, name them.

We can only connect the dots we collect

1/14/2018

The news that Pfizer is re-allocating budget away from Alzheimer's disease and Parkinson's disease is newsworthy. It is likely a smart move. The complexity of chronic metabolic derangement in older age combined with potential discoveries of mysterious lymphatic systems hidden within the dura mater should point to "innovation" away from a monotherapeutic cure.

It is not sufficient, he argues, to simply collect and store massive amounts of data; they must be intelligently curated, and that requires a global framework. “We have all the pieces of the puzzle — now how do we actually assemble them so we can see the big picture?”--The Mathematical Shape of Big Science Data--Jennifer Ouellette

Standard methods of analyses have required a hypothesis. Unfortunately the focus appears to be too narrowly tuned on the role of tau protein and/or plaques. I would argue that small molecule solutions appear to be the preferred status quo even in the face of enormous financial loss and personal tragedies. I am patiently waiting for the game changer--but will it be a blockbuster drug?

Extracting insights from the shape of complex data using topology describes a method to analyze large complex data by using geometric representation. The advantage is the ability to identify smaller groups often over-looked in analyses allowing deeper stratification compared to standard methodology.

Standard methods are reliant on hypothesis validation and the underlying assignment of sound models or hypothesis. Topological Data Analysis (TDA) discussed in more detail at the link--describes a method where a defined hypothesis is not required to explore the shape of the data in breast cancer databases.

I know plenty of colleagues and science-minded people anxiously waiting for a drug they can begin taking today to avoid Alzheimer's disease in their twilight years. The message of prevention has fueled many a drug pipeline and although mediocre symptom alleviation strategies have somehow squeezed past the FDA there are things we can do right now. Granted we are learning how to analyze data from outside clinical trials and perhaps the most data savvy are hesitant to propagate the less profitable and less "sciencey" claims--we should be paying attention.

Potential for primary prevention of Alzheimer's disease: an analysis of population-based data

"After accounting for non-independence between risk factors, around a third of Alzheimer's diseases cases worldwide might be attributable to potentially modifiable risk factors. Alzheimer's disease incidence might be reduced through improved access to education and use of effective methods targeted at reducing the prevalence of vascular risk factors (eg, physical inactivity, smoking, midlife hypertension, midlife obesity, and diabetes) and depression."--The Lancet Neurology volume 13, issue 8, August 2014

Your best defense against dementia may be a brisk walk

Why don't we hear about prevention outside of pharmaceutical hype? Physical exercise as a preventive or disease-modifying treatment of dementia and brain aging and any of the books or articles about Blue Zones should be written about right alongside the earnest efforts of small molecule cures.

“Now we have this new multimodal data [gleaned] from biological systems and human social systems, and the data is gathered before we even have a hypothesis.” The data is there in all its messy, multi-dimensional glory, waiting to be queried, but how does one know which questions to ask when the scientific method has been turned on its head?--The Mathematical Shape of Big Science Data

*"We can only connect the dots we collect"--Amanda Palmer

Shining a light on memory formation and system thinking...

12/21/2017

Everyone is hurling content over the pay-wall. In a time when we should be diffusing knowledge, the monetization beckons and many move deeper into their echo chamber.

That is why my favorite read has been QuantaMagazine. Light-Triggered Genes Reveal the Hidden Workings of Memory saved my morning.

I am a big Systems Thinker and you should be too. The cost of being a one-dimensional thinker plays out in the latest R&D efforts in Alzheimer's disease. Believe it or not--we are still funding the failed hypotheses of decades earlier.

Adaptive Phase II Study of BAN2401 in Early Alzheimer’s Disease Continues toward 18-Month EndpointCriteria for Success at 12-Month Analysis of ADCOMS Not Met
Study to Remain Blinded Per Protocol until Final Readout of Comprehensive 18-Month Data

Study 201 (ClinicalTrials.gov identifier NCT01767311) is a placebo-controlled, double-blind, parallel-group, randomized study in patients with prodromal or mild Alzheimer’s disease (collectively known as early Alzheimer’s disease) and with positive biomarkers for brain amyloid pathology.

Indulge me in a brief tangent. A recent podcast shuffled my thinking. Debbie Millman is a powerhouse design expert with a broad range of interests and talents. Design Matters is a juggernaut source of creativity and ideas but underneath the hood are powerful conversations and observations about words, artistry, and engagement.

I thoroughly enjoyed a recent interview with Richard Saul Wurman--the founder of TED. Let me clarify. I enjoyed the banter as I ran 6 miles on a trail--I would not have wanted to be interviewing him. A tad bit belligerent and fussy but a riveting partner on a crisp fall morning. He talks about questions. We don't ask the right questions. He wants more from the media. For example, to just report the magnitude of an earthquake tells us nothing. If we know nothing of the depth, infrastructure, or a host of other variables we are unable to contextualize. I believe him. I lived in California and experienced both the Loma Prieta in 1989 and Northridge in 1994. Weaker magnitude earthquakes can have far more devastating consequences depending on building codes, tidal surges, and a host of other characteristics.

Here are a few questions for what is listed in Clinical Trials.gov for the latest clinical trial report from NCT01767311. I do research and data analytics for a living but the website is intended for patients, family members, health care professionals, and other members of the public easy access to information on clinical studies on a wide range of diseases and conditions. Again, there isn't any data available yet that I can find.

ADAPTIVE PHASE II STUDY OF BAN2401 IN EARLY ALZHEIMER’S DISEASE CONTINUES TOWARD 18-MONTH ENDPOINT

1.Criteria for success at 12-month analysis of The Alzheimer's disease Composite Score (ADCOMS) not met but study is still continuing. I am curious about the in-house developed endpoint ADCOMS to measure efficacy.

Assessment of safety reasons for stopping were not met--but what were the safety signals? Amyloid related imaging abnormalities (ARIA)? What were the interoperability scores for results?

2. Original primary outcomes was a 12-month time frame and now the current status 18 months (submitted 9.17.2015)

3. Secondary outcomes include hippocampal volume, composite clinical score (ADCOMS), and brain amyloid measured by amyloid PET.

4. The Bayesian design is a responsive design allowing "automatic changes to the design during the study, including adaptively changing the subject allocation ratio to treatment arms with higher probabilities based on the results of interim analyses in order to more efficiently identify the effectiveness and optimal dose regimen of BAN2401."

What do we really know about "diagnosing" patients for participation? What is the inter-operator variability for different assessments of cognition? If we are using PET scan and other imaging to define AD or dementia we are making a BIG leap that this is the causative agent. Given the history of evidence, Bayesian priors should point in a different direction, no?

The ADCOMS measures what investigators want it to measure. Composite study end points should focus separately on safety and effectiveness outcomes, and design separate composite end points to match these different clinical goals. Instead ADCOMS includes 4 Alzheimer's Disease Assessment Scale–cognitive subscale items, 2 Mini-Mental State Examination items, and all 6 Clinical Dementia Rating—Sum of Boxes items (memory, orientation, judgment and problem solving, community affairs, home and hobbies, and personal care)

Now if we return to Nobel laureate Dr Tonegawa we see research findings that red areas of hippocampus are essential for creating new memories but the short-term recall depends on a specialized area in green called the subiculum. This generates new ideas and what we might learn from measures of hippocampal volume as secondary endpoints.

How memories are indeed formed would be a smart place to start. How do we know what actually is responsible for cognitive decline of the scale observed in Alzheimer's disease and other dementias? Metabolic derangement definitely has a role but the solutions are bigger and need a system thinking approach...the brain demands it.

50 million dollar investment in Alzheimer's disease: but can we disrupt the persistent paradigm?

11/13/2017

Bill Gates is making a bold move. I like his commitment--both financial and personal as well as his search for " a lot of ideas." I hope he hasn't spent the last year in the R&D drug focused echo-chamber because if he has, my enthusiasm will wane--quickly.

"You have a nearly 50 percent chance of developing the disease if you live into your mid-80s. In the United States, it is the only cause of death in the top 10 without any meaningful treatments that becomes more prevalent each year. That trend will likely continue as baby boomers age, which means that more families will watch their loved ones suffer from cognitive decline and slowly disappear. Despite this growing burden, scientists have yet to figure out what exactly causes Alzheimer’s or how to stop the disease from destroying the brain."--Why I'm Digging Deep Into Alzheimer's, Bill Gates

Publications by the Alzheimers Association perpetuate myths assigning race or ethnicity as a risk factor. If you read on, statements like this are pushed beneath sensationalized talking points, "Variations in health, lifestyle and socioeconomic risk factors across racial groups likely account for most of the differences in risk of Alzheimer’s and other dementias by race." Why race? Are we looking for biologic differences or the impact of social determinants? There is one race. The human race. I don't know what you think skin color will add to our search for answers. We need the granularity of genetic variants or we need the social constructs and political implications of how we answer questions of race in our society--but also in the field of medicine.

I sincerely want to see approaches outside the capitalistic forces upstream from disease but are we ready to change policy? Should we be gobsmacked that so many of us will suffer from dementias in our 80s? The insult of toxic air, agri-business, poor food policy, wealth inequality, poor education, food deserts, unequal access to healthcare, subsidized low nutritive school lunches, lack of attention to mental health, low literacy, and more should come to bear towards the end of any lifespan.

These chronic diseases are metabolic derangements and diseases of lifestyle and we seek pharmacologic cures? One monotherapeutic cure to unravel a life time of medical-industrial complex exposure and the politics of not only race but disease?

What could go wrong?

Social Correlates of Health: What if the bear comes home every night?

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