Tuesday, September 20, 2016

Witness my Life: A Psychotherapist's Journey to Healing

Witness my Life: A Psychotherapist Journey to Healing

Why is it that people participate in research?

A new method of recording and documenting perspectives from a community perspective, called photovoice, has started generating interesting results. Photovoice is where community members are provided with a camera, video or voice recorder to document events at the community level. Photovoice was developed in 1992–by Caroline Wang of the University of Michigan, and Mary Ann Burris, at Women's Health at the Ford Foundation, Beijing, China--for rural women in Yunnan Province, China to advocate for new policies and programs. This method has been producing some amazing documentaries on homelessness among teenagers, illegal drug trade, as well as images of dementia. And the motivation for participating in this kind of documentation is that it seems we want someone to be a witness to our life. Not to judge it, or even be part of it, but just to witness our trials and tribulations. Perhaps an affirmation, that because someone sees our lives nearly as close to as we experience them, that somehow, then, we matter. Perhaps it is seen as some form of non-judgmental validation. All of those screaming social network sites are but another expression of this desire for others to witness our lives.  In this case of witnessing, it is a form of benevolent narcissism.

Albert Camus wrote about this in 1956, in one of his most understated novels, The Fall. This story tells of a confession to a stranger. It takes place in a bar called Mexico City in Amsterdam, by the protagonist of the story Jean-Baptiste Clamence. From his success as a wealthy Parisian defense lawyer culminating on an unidentified crisis which brings about a vague fall from grace. After making some broad and general confession to a stranger in a bar, Jean-Baptiste Clamence ventures out into the night one last time. We are meant to assume that his last act is suicide. Jumping off one of the may bridges in Amsterdam. But the point of the novel is that the only way to bring meaning to the suffering of living, without a god, without objective truth is if there is some recognition that we exist. 
Jean-Baptiste Clamence’s confidant, an unknown character, becomes his final witness to his life. The Fall was awarded the 1957 Nobel Prize in Literature and was Camus’ final piece of fiction until he died in a car crash. The book’s complexity allows for different interpretations and for me it has been the fact that we are ultimately responsible for everything. By your activity or inactivity, we choose to support an outcome. But such an interpretation is too shallow for a deeply complex and ambivalent story.  We might be responsible for our actions, but then there is no morality to pass final judgement. Our final judgement is to have a witness. Good or bad actions do not matter if there is no one to witness it.

Maria Arman with the Karolinska Institutet in Solna, Stockholm, Sweden, in her book, Bearing witness: An existential position in caring has one of the closest meaning to this interpretation of witness. That witnessing is part of the definition of who we are. As social beings, our awareness of self is influenced (if not completely defined) by what and how we think others are defining us.  A basic assumption in caring, or being empathic is to be present for the other person. To bear witness for someone, to share their awareness is to share their burden. But there is more to witnessing, because by sharing an awareness you are affirming their journey through life.

The philosopher Emmanuel Lévinas defines an encounter with another person as a privileged experience. The proximity of the other person is the acknowledgement of being real. In a world where images are held as real, and truth is negotiated, the idea that I matter is a consoling balm on the rawness of my ever changing world.
To be a witness you share a physical space and experience the same perspective with another person. You share, verbally, emotionally or spatially a mutual reality. There is a convergence where you become the other person as much they become you. This is the healing of witnessing. Developing such a relationship is a willful act on your part. Witnessing is an affirmation that we have passed through life. No judgment about good or bad outcomes. There is a validation of my presence, and my journey. A memorable tune, a remembered story, a shared intimacy. All experiences that when witnessed can assert my place in this world. That although there might be nothing else but my experiences, that for one brief moment, that internal and closed trove has been acknowledged.

Isn’t this what psychotherapy is all about? If Sigmund Freud in 1905, the father of psychotherapy, was not so misguided as to suggest that because learning stops at age 50, older adults are not good candidates for psychotherapy, perhaps we would be able to see the effect of witnessing in alleviating despair. As psychotherapists try to instill trust, the experience of witnessing remains the bedrock for affirmation of one life.

 © USA Copyrighted 2016 Mario D. Garrett

Thursday, September 8, 2016

If Alzheimer’s disease was Treated like Cancer

The 2016 Cancer Moonshot, headed by Vice-President Joe Biden, the most potentially funded-health research enterprise in the USA just issued a set of 10 recommendations for cancer research. The Blue Ribbon Panel of expert advisers suggested basic steps in research that are very similar to the steps we should be taking in dementia research if we are serious about a cure. What would these Blue Ribbon Panel of expert advisers advise on dementia? Perhaps something along the following lines below:

  1. Establish a network for direct patient involvement; engage patients to contribute their comprehensive dementia profile data to expand knowledge about what therapies work, in whom, and in which types of dementia.
  2. Establish a dementia immunotherapy clinical trials network devoted exclusively to discovering and evaluating immunotherapy approaches.
  3. Develop ways to overcome dementia’s resistance to therapy, through studies that determine the mechanisms of misfolded proteins, in addition to the Beta Amyloid and Tau Protein.
  4. Create a national ecosystem for sharing and analyzing dementia data so that researchers, clinicians, and patients will be able to contribute data, which will facilitate efficient data analysis.
  5. Intensify research on the major drivers of early onset dementia; improve understanding of the genetic component of early onset and use new preclinical models to develop inhibitors that target them.
  6. Minimize dementia treatment's debilitating side effects; accelerate the development of guidelines for routine monitoring and management of patient-reported symptoms to minimize debilitating side effects of dementia and its treatment.
  7. Reduce dementia risk and dementia health disparities through approaches in development, testing, and broad adoption of proven prevention strategies.
  8. Mine past patient data to predict future patient outcomes; predict response to standard treatments through retrospective analysis of patient specimens.
  9. Create dynamic three-dimensional maps of human dementia evolution to document the genetic lesions and cellular interactions of each neuropathological event  as it evolves from a preclinical to advanced dementia.
  10. Develop new enabling dementia technologies to characterize neuropathology and test therapies.

For a complete summary of the faults with Alzheimer’s research and why we need a similar Blue Ribbon Panel of expert advisers of Alzheimer’s disease:

Humayunn Niaz Ahmed Peerzaada/Flickr
Source: Humayunn Niaz Ahmed Peerzaada/Flickr
Garrett MD & Valle R (2016) A Century of Confusion in Researching Alzheimer’s Disease. Dementia: The International Journal of Healthcare 2(2), 13-22.

Garrett MD, Valle R (2015) A New Public Health Paradigm for Alzheimer’s Disease Research. SOJ Neurol 2(1), 1-9.

Garrett MD & Valle RJ (2016).A Methodological Critique of The National Institute of Aging and Alzheimer’s Association Guidelines for Alzheimer’s disease, Dementia and Mild Cognitive Impairment. Dementia: The International Journal of Social Research and Practice,15(2) 239–254. DOI: 10.1177/1471301214525166

Garrett MD (2015) Politics of Anguish: How Alzheimer's disease became the malady of the 21st century. Createspace. USA

© USA Copyrighted 2016 Mario D. Garrett

Wednesday, July 13, 2016

The Death of Biological Determinism

In May 2016, in a short eight-page report in Nature Biotechnology, Rong Chen, Stephen Friend and Eric Schadt from the Icahn School of Medicine at Mount Sinai, New York, and their colleagues reversed our ideas about genetic determinism. This small revolution proved to be radical because by association, this also unhinges biological determinism—the belief that biology determines all your traits.

What they did is to apply scientific methods to commonly held beliefs about disease. Usually genetic investigations focus on a group with disease by trying to find genes that are different in this group from the rest of the population. By comparing this group with a control group they hope to single out the gene that causes this difference. Sometimes geneticists hit lucky and find only one gene that is different between the two groups. In such circumstances this single gene follows Mendelian laws in how it affects people. Mendelian laws are named after the monk Gregor Johann Mendel.

Between 1856 and 1863--before genes were discovered in the early 1900s--Mendel was working on cultivating some 29,000 pea plants. He noticed that peas seem to acquire their characteristics from both parents in a mathematical fashion, with some traits being more dominant than others. Mendel discovered the mathematics of heritability.

He defined for every characteristic—a phenotype, an expressed genetic trait—there are two parts determining how that characteristic is expressed. Now we know that two alleles compose a gene that determine a physical trait. Mendel’s observations developed three basic laws:
·      Alleles can be either dominant or recessive, with the dominant allele always imposing its influence over the recessive.
·      Alleles separate during cell formation so that recessive and dominant allleles are received by different cells.
·      Alleles have different and unique characteristics that are unrelated to other elleles.

Using this method, scientists have identified 584 Mendelian diseases: where one gene causes a specific disease. Most of genetic studies are based on this methodology. But such methodology remains flowed in reasoning. Just because a group had a specific gene, and a control did not, does not define a causal relationship. The syllogism is wrong. Just because all As have Bs does not mean that all Bs have As.

Such fault in reasoning in our genetic understanding of Mendelian diseases was exposed by Rong Chen and his colleagues who performed a comprehensive screen of 874 genes in 589,306 genomes—individuals—with 874 implicated genes. This comprehensive study led them to identify 15,597 candidates where their genes did not match the expression of the disease. After rigorous elimination of candidates for various technical and theoretical reasons, a final list of 13 candidates remained. All these individuals had either both pairs of a recessive gene, or one of a dominant gene that causes one of eight type of Mendelian disease. These Mendelian childhood disorders would normally be expected to cause severe disease before the age of 18 years: cystic fibrosis, Smith-Lemli-Opitz syndrome, familial dysautonomia, epidermolysis bullosa simplex, Pfeiffer syndrome, autoimmune polyendocrinopathy syndrome, acampomelic campomelic dysplasia and atelosteogenesis.

There are three possible interpretations of this outcome. That the Mendelian diseases identified were in fact incorrectly defined and there might be other genes involved. Secondly, that these individuals are resilient—in ways unknown--to the disease. The third possibility being that there are other factors—including genetic factors as well as epigenetic influence--that determine whether genes express into a disease--genotype expresses into a phenotype.

The overarching outcome of this study is however the importance of logic/reasoning and the scientific method. Science is nothing but method. The results of scientific work are always incomplete since science is not about the outcomes but about the method. In gerontology this study contributes to a continuing appreciation of how genetics might be the road map, but we are in fact the drivers of our journey through life.

Chen, R., Shi, L., Hakenberg, J., Naughton, B., Sklar, P., Zhang, J., ... & Sleiman, P. (2016). Analysis of 589,306 genomes identifies individuals resilient to severe Mendelian childhood diseases. Nature biotechnology.

© USA Copyrighted 2016 Mario D. Garrett

Monday, June 20, 2016

How Mild is "Mild Cognitive Impairment"?

As we get older, we start having a constant fear that our lapses in memory are the beginning of Alzheimer’s disease. After cancer, Alzheimer's disease has taken hold as the number one fear among Americans.  We all have memory lapses, at any age. But when we are older we tend to be more aware of these lapses in memory and we become more fearful when we forget.  We try and add humor in order to alleviate this fear. We say things like it’s a senior moment, a brain fart, a mental hiccup, misfiring neuron, and my favorite synaptic lapse. Despite the humor the fear persists.

The problem is that although all those with Alzheimer’s disease started off experiencing memory loss, not all those that have memory loss will develop into Alzheimer’s disease. In fact even with documented memory impairment you are more likely to have some other underlying condition than Alzheimer's disease. Unfortunately what we call Mild Cognitive Impairment (MCI), the term used to refer to these bouts of memory lapses, is itself not well understood.

There are problems measuring memory loss using MCI. When we refer to “cognitive” we should be referring to our mental processes that should include perception, judgment, reasoning, AND memory. However, MCI is most often just limited to memory. So if you have a failing memory then it is assumed that the rest of your cognitive abilities are similarly diminished. This is not only not true but also simplistic. The second issue with this method of defining your mental capacities is the assumption that there is an average or normal level of memory and that this level is stable. This is of course not true. From experience we know that we have good days and bad days, at any age. Memory is not a static library but an active engaging process that is vulnerable to many external factors, particularly emotional trauma. Memory can become compromised during episodes of grief, retirement, an upcoming medical operation or divorce among many other situations that distracts our ability to remember past events.. This is made worse by lack of sleep, which accompanies stressful times, and is one of the biggest issues with older adults.

In addition, being retired means that you can take little naps during the day. But this results in not feeling sleepy at night, or getting up in the early hours of the day. Sleep deprivation not only affects your memory but also changes your mood, balance and appetite.  In some cases, sleep disorders are due to changes in our brain, such as the reduction in melatonin, but we can do something about this, as we will discuss later on.

But perhaps the biggest culprit that affects our memory is medication. Medication among older adults is perhaps the single most significant cause of problems. Such iatrogenic diseases--problems caused by bad medical practices--remains a hidden problem among older adults. Medication can have drastic effects on memory. Even if you have been taking the same medication for some time, your body processes chemicals differently as you age. Especially if you have recently started taking additional medications or substances. In particular, nearly all sleeping pills, over-the-counter antihistamines, anti-anxiety medications and antidepressants can have negative effects on memory. Medications that you might be taking for other existing conditions can also start having negative effects on your memory such as some medications used to treat schizophrenia, and pain medicines used after surgery.

Identifying the cause of your memory lapses is important because it means that you can reverse these problems. Some memory problems can also be related to vitamin B1 and B12 deficiency, easily checked with a blood test. Some health issues, such as thyroid, kidney, or liver disorders also can lead to memory loss. In addition, some herbal medicines, recreational drugs and also the use of alcohol will negatively effect memory.

These are all likely culprits for why your memory has gotten worse. Rather than jumping to the conclusion that you have Alzheimer’s disease. Unfortunately, nearly all websites that offer advice on memory loss--despite the caveat that not all memory loss leads to Alzheimer's disease--invariably end up with a definition of Alzheimer's disease. It is important to think of these other ways that your health can be changed rather than resigning yourself to saying that it is Alzheimer’s. Especially since Alzheimer's disease is so passive a disease. At least by approaching it as a lifestyle issue  you retain control, you can change your condition.

A recent study by Dale Breseden from southern California has successfully reversed clinically diagnosed Alzheimer’s disease. Breseden did this not with some magic potion or a new drug, but with some simple behavior strategies, involving diet, exercise and social/physical activities. This recent study reported how an intervention included:

Cutting out all simple carbohydrates and reducing wheat products and processed foods, while increasing consumption of vegetables, fruits and non-farmed fish;
Fasting 12 hours before bedtime and 3 hours between dinner and bedtime;
Yoga and meditation for 20 minutes a day;
Exercising for at least 30 minutes a day, 4-6 days a week;
Taking melatonin each night (used to ease insomnia), and increasing sleep to 7-8 hours;
Taking methylcobalamin (a form of vitamin B), vitamin D3, fish oil and CoQ10 supplements each day; and,
Increasing oral hygiene through use of an electric flosser and electric toothbrush.

Using this comprehensive life-style change, Bredesen saw nine out of the 10 patients improve within 3‐6 months. These improvements were sustained for two-and-one‐half years from initial treatment. The one person who did not improve was because their dementia was so great that he forgot to carry out the exercises. Not surprisingly, this life-style change was found to have a positive impact on multiple other chronic illnesses in addition to Alzheimer’s disease. Memory loss is unlikely to be due to Alzheimer’s disease, but use this as an indication that you need to address some of your life-style patterns and aim to live a healthier life. There is nothing mild about Mild Cognitive Impairment but it does not mean its a death knell.

© USA Copyrighted 2016 Mario D. Garrett

Tuesday, March 15, 2016

Reversible Alzheimer’s Disease: The role of normal-pressure hydrocephalus

Between 9 and 13 percent of residents in nursing homes and assisted living facilities are likely mis-diagnosed with Alzheimer’s disease and can be cured. Anthony Marmarou with the Virginia Commonwealth University Medical Center, Richmond, Virginia and his colleagues investigated how common it is to find buildup of fluid in the brain among clients in assisted-living and extended-care facilities. [1]  Known as idiopathic (unknown cause) normal-pressure hydrocephalus (iNPH), this condition mimics the behavior of Alzheimer’s disease. Normal-pressure hydrocephalus occurs when there is a restriction in the spaces that hold fluid deep inside the brain, resulting in pressure build-up. The pressure compresses the soft tissues of the brain restricting its function. The authors found that out of 147 patients between 9 to 14% had NPH depending on the diagnostic criteria used. Among these 17 patients, 11 received shunts and seven of these showed either transient or sustained improvement a year later. Although they were likely diagnosed with Alzheimer’s disease, a year later most were cured.

The symptoms of normal-pressure hydrocephalus are very similar to Alzheimer’s disease. When identified as a distinct disease it is known as the “wet, wild, and wobbly.”  Characterized by urinary incontinence (wet), dementia (wild), and gait dysfunction (wobbly). It is estimated that 1.6–5.4% of those with dementia are affected by iNPH.[2]  If the condition is left untreated—most of these cases are overlooked as Alzheimer’s disease—chronic iNPH patients share overlapping characteristics with Alzheimer’s disease in 75% of the time. It becomes increasingly difficult to differentiate the two the longer that iNPH is left untreated since the NPH syndrome will become Alzheimer’s disease.

Although there is no community-wide study looking at how common NPH is, there are some small sample studies that indicates that it is likely to be very common among older adults 65 years older. [3]  Among older adults in the community, the prevalence is around 1.3%, higher in assisted-living and extended-care residents with 11.6%. A small proportion of patients (2%) show permanent improvement after releasing the pressure in the brain using a shunt. The problem is that there are no easy indicators—including brain imaging—for distinguishing iNPH and Alzheimer’s disease. The images must still be interpreted with clinical features, blood measurements, CSF biomarker measurements, tap test, and CSF drainage results.

Because it is hard to diagnose, iNPH remains under recorded. Many studies report an association between hypertension, vascular disease and iNPH—with strokes and heart attacks being common precursors—so there is a need to look at any vascular disease as a precursor to Alzheimer’s. And the problem is that Alzheimer’s disease is so broad a category that most things that affect the brain and cause behavior changes are likely to be diagnosed Alzheimer’s disease even though it is likely not, such as amyloid deposition, CSF biomarker content, and presence of vasculature diseases. [4] A diagnosis of Alzheimer’s disease is a prescription for lost hope, whereas vascular disease is more likely to be amenable to therapy.

Vascular dementia—where the plaques and tangles are caused by a lack of blood flow in the brain (called cerebral perfusion)—is confused with Alzheimer’s disease most often because both share the same biomarkers and have the same expression. They look the same to the inexperienced clinician. Cerebrovascular disease among adults over 75 years of age is a common condition—36 percent overall, 25 percent for coronary, 58 percent hypertension, and 11 percent for stroke. [5]  It seems likely that because of these co-morbidities, vascular dementia contributes to, and is sometimes mis-diagnosed as Alzheimer’s disease. The silent issue is recognizing how frequently vascular disease promotes dementia.  Contemporary neuroscience still lacks a thorough understanding of exactly what contribution cerebrovascular disease makes to cognitive impairment. [6]

The answer is to move away from the practice of calling anything that disturbs cognition as Alzheimer’s disease.[7] Clinicians need a strategy, a roadmap to differentiate all these different type of diseases because they have different causes. Knowing the cause is the first step to formulating a cure. That is, if we are truly serious about finding a cure for Alzheimer’s disease.

[1] Marmarou A, Young HF & Aygok GA (2007) Estimated incidence of normal-pressure hydrocephalus and shunt outcome in patients residing in assisted-living and extended-care facilities. Neurosurgical Focus, 22(4); 1-8.

[2] Gallia GL, Rigamonti D, Williams MA (2006) The diagnosis and treatment of idiopathic normal pressure hydrocephalus. Nat Clin Pract Neurol 2, 375-381.

[3] Martín-Láez, R., Caballero-Arzapalo, H., López-Menéndez, L. Á., Arango-Lasprilla, J. C., & Vázquez-Barquero, A. (2015). Epidemiology of Idiopathic Normal Pressure Hydrocephalus: A Systematic Review of the Literature.World neurosurgery, 84(6), 2002-2009.

[4] Di Ieva, A., Valli, M., & Cusimano, M. D. (2014). Distinguishing Alzheimer's disease from normal pressure hydrocephalus: a search for MRI biomarkers.Journal of Alzheimer's Disease, 38(2), 331-350.

[5] Schiller J.S., Lucas J.W. & Peregoy J.A. (2012.) Summary health statistics for U.S. adults:National Health Interview Survey, 2011. National Center for Health Statistics. Vital Health Stat, 10(256).

[6] Jellinger K.A. (2008). Morphologic diagnosis of 'vascular dementia' - a critical update. J Neurol Sci, 270: 1-12

© USA Copyrighted 2016 Mario D. Garrett

Thursday, March 10, 2016

Early Emotional Cascade and Alzheimer’s disease

Saturday, March 5, 2016

Wrong on so many levels: The Amyloid Cascade hypothesis and Alzheimer's disease

Our body, including our brain, is constantly changing. Within each of the 37 trillion cells [1]  there is a constant dynamic activity. A relentlessly hive of activity maintaining, coordinating and enhancing functioning. All of this activity is based on four major molecules—macromolecules—essential for all known forms of life. These are fats, carbohydrates, nucleic acids and proteins. 

Fats and carbohydrates are the source of all energy for the body, while nucleic acids (meaning from the nucleus) and proteins (meaning primary or first) constitute the components of the body.

Nucleic acids hold our genetic material our DNA—Deoxyribonucleic Acid—whose sole purpose is to make and coordinate the production of proteins. DNA is stored in the nucleus while a replica of this DNA called RNA—Ribonucleic Acid—is a working copy of the many parts—called genes—of the DNA. The sole purpose of the DNA and RNA is to hold information that make up all the proteins that our body needs.

RNAs are thought to be earlier versions of DNA, our genetic templates. At some point the strand of information that contains the four nucleotides—chemical codes—must have combined with another RNA strand to form a DNA helix, a more stable and accurate structure. This structure is more stable because each nucleotide, piece of information, is matched on the other side of the double helix—like double entry book keeping, resulting in less chance of making mistakes. This robustness is a necessary feature if you aim to become immortal, as genes are.

Because the DNA is a stable structure, it must however be unwound and transcribed to form copies of RNAs which can then be translated to proteins. Proteins—which are made up of amino acids—function as enzymes, hormones and body tissues. The importance of proteins is expressed by the recent ambition to map all human proteins in the Human Proteome Project. Just because we mapped the genome does not mean very much if you do not know what those codes mean. Proteins are the deciphering tool.

As there are more proteins than genes, the aim to map all proteins is ambitious and much larger than mapping the genome. It is also very complex. The proteome has two additional levels of complexity. While the genome is defined by the sequence of four nucleotides, the proteome is determined by the same genome but then involving the permutations of 20 different amino acids. Each amino acid is defined by a set of three nucleotides on the RNA—a codon. A chain of amino acid is defined as a protein, having varying sequence and lengths. Each variation defines the physical structure, and the structure determines its function. This complexity resides within nearly each of our 37 trillion cells. Cells within specific organs produce specific proteins, although all cells have the capacity to synthesize all proteins.

In our body, most of our cells have a nucleus and a membrane around it—Eukaryotic Cell as apposed to Prokaryotic Cell. Within these eukaryotic cells is a complex factory of activity. Not only have eukaryotic cells evolved to include alien small organs— organelle such as mitochondria which have their own genetic material separate from the cell’s DNA—each cell has a copy of all of our genetic material, our body’s complete template.  How our genes virtually replace or maintain each and every cell as we live, is one of the most intriguing enigmas in science.

The DNA is like a musical record that is being played constantly. Instead of sound, the player—an enzyme, another protein, called ribozyme—makes negative copies of one strand of the DNA. Through a process known as transcription—it produces a negative copy called the RNA. As the DNA is transcribed, a strand of RNA is created within the nucleus of the cell. This RNA strand migrates out of the nucleus wall into the cytoplasm, the main part of the cell. This small negative replica is composed of a string of nucleotides which are “read” three nucleotides at a time—these keys are called codons. To produce protein, the DNA transcribes three types of RNA.

One part defines the type of protein to build, this is the messenger RNA—mRNA. The second RNA strand is a transfer RNA—tRNA—which attaches to a specific amino acid. Like a shopping trolley, it selects individual amino acids as the building blocks of protein. The final structure —rRNA—is the two-part machine called a ribosome, that builds the protein itself. Ribosomes combine the messenger and the transfer RNA according to the code, the codon. As it matches them together it then steals their amino acids. Ribosomes join one amino acid with the subsequent amino acid, creating chains of amino acids. This is the birth of a protein.

A protein starts life in the cell as a long chain of, on average, 300 of these amino acids. There are 20 different types of amino acids—nine are called essential that we need to get from our diet and cannot be manufactured. The sequence and number of amino acids determines how the protein chain will fold upon itself once completed. Some proteins provide structure, others transport molecules, while others help cells to divide and grow. The function of a protein is dependent on their folding structure. It is an origami dictated by the sequences of amino acids and the length of the chain.[2]

Back to Alzheimer’s disease

The Amyloid Cascade hypothesis was first articulated in 1992 [3] and became enshrined in the guidelines published by the National Institute on Aging and Alzheimer’s Association (Jack et al., 2011).  The amyloid cascade hypothesis posits that the deposition of the amyloid-β peptide in the brain is a crucial step that ultimately leads to Alzheimer's disease. Amyloid-β peptide is a small protein called a beta (β) that has misfolded and became an amyloid. [4] Amyloid refers to how small proteins interact together by combining and forming a solid insoluble mass—they become hydrophobic, shy of water, because of how they fold. This type of interaction has its own designation as a disease called amyloidosis. These misfolded proteins combine together to create plaques of a million or so amyloid beta molecules. According to the National Institute on Aging and Alzheimer’s Association, these amyloid beta molecules grow until they interfere with the normal functioning of the brain. This is the cause of Alzheimer’s disease. And they have tested and substantiated this theory with mice models. But there is a problem.

The problem

The Amyloid Cascade hypothesis has not been supported by the data on humans. To date most of the treatments tested in human clinical trials are amyloid-β-based drugs, including those that remove amyloid-β. Despite the success of these drugs in removing the plaques from the brains of Alzheimer’s disease patients, the effect on behavior and thinking was negative.  [5]    Patients who had the misfolded proteins removes chemically did worse in tests than before the intervention. [6]

It seems that the clinical expression, the behavior, is not solely determined by increases in misfolded protein. A longitudinal study reported that eight percent of participants who behaved and acted free from dementia—when they died and had their brain examined—were found to have the most severe neuropathology. [7]  Despite having abundant and severe disease—neurofibrillary tangles and senile plaques—they had normal functioning.

Approximately half of clinically demented oldest-old have insufficient neuropathology to account for their dementia. [8]  While approximately thirty to fifty percent of older adults without dementia meet the neuropathological criteria for Alzheimer’s disease. [9]

The reality

The story of errors in making proteins which end up in the brain, as the cause of neurological disease, is incomplete. The repetitive story about the biology is also intentionally simplistic. In reality, science is still too naïve to understand the molecular biology of cells and therefore the biology of Alzheimer’s disease. Although geneticists play with genes and create amazing results, we still do not understand the fundamental nature of biology. And we cannot understand the biology of Alzheimer’s disease before we can understand the molecular biology of cells.

Scientists make simplified determination despite knowing only a very small proportion of the biology of cell functioning. We might have traced most of the dance moves, but we still do not know the music. That symphony that all our cells are all dancing to remains mute. With a complex choreography of steps there remains new ones to identify. We are missing the poetry because of the words, and we are missing the music because of the steps.

Each DNA sequence that contains instructions to make proteins is known as a gene. There are two variants of the same type of gene called alleles. Consider these as the paired dancers, with one being “dominant” over the other. There might be many (more than two) alleles for the same gene. How alleles communicate each other’s protein is unknown, especially how they communicate with alleles from a different gene. Unless we know the music of the dance, all that we can see is that there is communication and we can predict the outcome using a mathematical model. [10] However, prediction does not mean that we understand the mechanism.  

Another perplexity is that the size of a gene may vary greatly, ranging from about 1,000 individual nucleotides (bases) to 1 million bases. Genes that make protein—defined by unique start and stop codons—only make up about 1 percent of the DNA sequence. The rest is—we think—involved in the regulation. Around 99 percent of all genetic material is devoted to coordination.

Coordination of protein production—-how and how much of a protein is made; distribution, equilibrium and maintenance, including protection from viruses, bacteria, aberrant cells and malformations. This is the dance music and it seems that DNA is more invested in the music than the dance.

Regulation is the music of this dance that we see in protein synthesis. The transcription—DNA to RNA—and translation—RNA to protein synthesis—involves constant feedback, ensuring an equilibrium within the whole body. So far we are still mapping steps in the dance. It is a mystery how DNA self-polices itself, but it does. It edits code and monitors outcomes. [11]  For example in gene splicing, the initial messenger RNA is edited by removing introns--and joining exons together. And it does this as a dance. First it identifies the beginning and the end of the intron by its nucleotides. Small proteins (snRNPs), bind to these ends of the intron and forms a loop. The loop is then removed leaving the two remaining exons to link together. In addition to this method, there are alternate splicing methods which create many different variations from the same gene. In 2000 S. Lawrence Zipursky and his colleagues at the University of California, Los Angeles (UCLA) identified that this alternate splicing resulted in "one gene–many polypeptides." From one template (gene) there are multiple ways of generating different proteins. How this is done is a mystery. But we know it is not a simple mechanistic process. This is a rhapsody that constantly repeats itself 37 trillion times in each of our cells.

And looking at this fathomless universe, you have to wonder, where does this leave the Amyloid Cascade hypothesis? If the music becomes faulty, then the dance becomes erratic. And we can see this not in one or two steps, but in a series of steps across the body. 


Protein mis-folding is continuous and “normal.”  The ribosome which reads the DNA to make the proteins makes mistakes in as many as 1 in every 7 proteins.  The gene splicing seems variable. Proteins can misfold through other mechanisms. For example, one of the amino acid might be deformed and eventually effect the whole protein. Or the protein is formed perfect but the conditions inside the cell—e.g. temperature or acidity—make it fold unconventionally. Sometimes the misfold is a required fold.  Perhaps the gene itself is dictating a misfold. We have to be careful with this concept of misfold and errors. These are moral judgments.  Especially when some combination of misfolded proteins--amyloids--are naturally produced to carry out necessary functions in the body.

Neal Hammer with the University of Michigan Medical school, and his colleagues, [12] reviewed cases where the amyloid has been shown to be a necessary feature. The authors conclude that “Despite over twenty years of [Alzheimer’s disease] AD research the nature of the toxic species of Aβ has yet to be conclusively identified and little is known about how Aβ polypeptide aggregation begins in vivo.“

We still do not know for certainty how many proteins there are in the body. The Human Proteone Project has so far identified 30,057 proteins. [13]  This figure might be revised to 100,000 unique types of proteins in humans. We also do not know the full extent, how often, and the overall consequence of misfolded proteins.  Aβ can be formed from 18 inappropriately folded versions of proteins naturally present in the body. But there are many more misfolded proteins that we have already identified, more remain to be identified. [14]  One thing that we have learned from nature is that errors are the salvation to immortality. Humans are the product of errors and the immortality of genes relies on the continuation of errors. Perhaps we should refrain from judging nature too early in our knowledge.

Amyloidosis in Alzheimer's disease.

The problem, we are told, is that when proteins fold incorrectly some become amyloids. And this happens so frequently that it becomes a disease all by itself called Amyloidosis. This physical expressions of the disease is determined by the type of protein that is misfolded and the organ or tissue it resides in. [15]  By studying amyloidosis it is now believed that certain misfolded small proteins called “seeds” can induce other proteins to fold—known as the study of proteopathy.  This is exactly what happens with the prion misfolded protein which causes a cascade of prion disease— Creutzfeldt–Jakob disease disease in humans. As with music that orchestrates the dance, the wrong tune will cause multiple wrong steps, and they are related to the same sheet of music. So that, as an example, Alzheimer’s disease is related, both clinically and also statistically, with type 2 diabetes, both seen as diseases of amyloidosis.  The other protein implicated in Alzheimer's disease, tau protein, also forms such prion-like misfolds. There is some evidence that misfolded Aβ can induce tau to misfold, although this might be a symbiotic relationship, one promotes the other.

So the question is why—if the National Institute on Aging and Alzheimer’s Association truly believe in the Amyloid Cascade hypothesis—are they not looking at all of these other diseases of amyloidosis together rather than in silos?

And we know the answer to that question already. [16]

The second question that follows is more fundamental. If all these diseases share a common process, if by addressing the known cause of one can we delay or stop the cause of a secondary disease? Perhaps then, a public health approach to Alzheimer’s disease is warranted. [17]

There is a third and more radical question. If these misfolded proteins are in fact there for a reason and not as a result of error, then what are they protecting us from?

Perhaps we do not know the underlying disease of Alzheimer's yet. There is increasing evidence suggesting that the large amyloid plaques are developed to protect. [18] And science is bearing this out. It could be that although the small misfolds are dangerous because they are small enough to interfere with the workings of synapsis—-by clamping together they become too big to interfere with the small synaptic transmissions. They are likely protecting the brain. Like a scab on a wound.

A research cul de sac might remain as long as we remain in our silos of research. We need to venture out and explore. “Man cannot discover new oceans unless he has the courage to lose sight of the shore.”―André Gide. We need such intellectual honesty to understand the complexity of Alzheimer’s disease and to dig ourselves out of this research cul de sac.

​[1] Bianconi, E., Piovesan, A., Facchin, F., Beraudi, A., Casadei, R., Frabetti, F., ... & Perez-Amodio, S. (2013). An estimation of the number of cells in the human body. Annals of human biology, 40(6), 463-471.
[2] . With two common structures called “alpha helices,” like a slinky and “beta sheets” like folded paper fan–α-helices have 21 amino acids while β-sheets have 30 amino acids. There are many other types of shapes and varying levels of complexity of the final structure.
[3] Hardy, J. A. & Higgins, G. A. Alzheimer's disease: the amyloid cascade hypothesis. Science 256, 184–185 (1992).
[4] Peptides are small proteins consisting of 2 or more amino acids. Oligopeptides have 10 or fewer amino acids. Polypeptides are chains of 10 or more amino acids, while polypeptides having more than 50 amino acids are classified as proteins.
[5] Iqbal K., Liu, F. & Gong, C.X. (2014). Alzheimer disease therapeutics: focus on the disease and not just plaques and tangles. Biochemical pharmacology, 88(4): 631-639.
[6] Boche D., Donald J., Love S., Harris S., Neal J.W., Holmes C., et al. (2010). Reduction of aggregated tau in neuronal processes but not in the cell bodies after Abeta42 immunisation in Alzheimer’s disease. Acta Neuropathol, 120: 13–20.
Gilman S., Koller M., Black R.S., Jenkins L., Griffith S.G., Fox N.C, et al. (2005). Clinical effects of Abeta immunization (AN1792) in patients with AD in an interrupted trial. Neurology, 64:1553–62.
[7] as defined by Braak & Braak stages:
Snowdon D. (1997). Aging and Alzheimer's Disease: Lessons From the Nun Study. The Gerontologist, 37(2):150-156
Snowdon D.A. (2003).Healthy aging and dementia: findings from the Nun Study. Annals of Internal Medicine, 139(5,2): 450–454.
Snowdon DA, Greiner LH, Mortimer JA, et al. Brain infarction and the clinical expression of Alzheimer disease. The Nun Study. JAMA. 1997;277:813-817.
[8] (Crystal et al 2000; Polvikoski et al 2001)
[9] (Crystal et al, 1988; Polvikoski et al, 2001; Katzman et al, 1988; Tomlinson, Blessed & Roth 1970; Dickson et al, 1997).
[10] Hardy-Weinberg principle
[11] Some of these are:
Antisense RNA—asRNA, piRNA, micRNA—inhibits translation of mRNA by physically obstructing the translation of some of the nucleoids, germ cell and stem cell development, sperm production, and epigenetic process.
Natural antisense transcripts (NATs) are regulatory RNA involved in interference and inhibit gene expression (RNAi), alternative splicing, genomic imprinting, and X-chromosome inactivation
Long and Short non-coding RNA—ncRNA— perform multiple tasks related non protein transcription for four-fifths of all genome. The FANTOM3 project identified ~35,000 non-coding transcripts from ~10,000 distinct loci.
There are also parasitic RNA that we inherited from other retroviruses (in most cases.) But the most interesting are those RNAs involved in post-transcription. The message within each mRNA is edited—known as gene splicing—by other types of RNA. How they know what to delete and edit is a mystery. There are also some RNA that modifies our DNA replication.  Not just through epigenetic switches—which does not change the DNA—but through modification of our DNA itself.
[12] Hammer, N. D., Wang, X., McGuffie, B. A., & Chapman, M. R. (2008). Amyloids: friend or foe?. Journal of Alzheimer's Disease, 13(4), 407-419.
[13] Kim et al. A draft map of the human proteome. 2014. Nature. 509, 575-581.
[14]  Misfolded proteins:
1.              ABri
2.              ADan
3.              Amyloid A protein
4.              Amyloid β peptide
5.              Apolipoprotein AI
6.              Apolipoprotein AII
7.              Apolipoprotein AIV
8.              Atrial natriuretic factor
9.              Beta-2 microglobulin
10.            Calcitonin
11.            Crystallins
12.            Cystatin C
13.            Fibrinogen
14.            Fused in sarcoma (FUS) protein
15.            Gelsolin
16.            Glial fibrillary acidic protein (GFAP)
17.            Immunoglobulin heavy chains
18.            Islet amyloid polypeptide (IAPP; amylin)
19.            Keratoepithelin
20.            Lysozyme
21.            Medin (lactadherin)
22.            Monoclonal immunoglobulin light chains
23.            Notch3
24.            Prion protein
25.            Prolactin
26.            Proteins with tandem glutamine expansions
27.            rhodopsin
28.            Seipin
29.            Serpins
30.            Superoxide dismutase,
31.            Tau protein
32.            TDP-43
33.            Transthyretin
34.            α-Synuclein
[15] Amyloidosis Disease:
Primary systemic amyloidosis
Ig heavy-chain-associated amyloidosis
Secondary (reactive) systemic amyloidosis
Senile systemic amyloidosis
Hemodialysis-related amyloidosis
Hereditary systemic ApoAI amyloidosis
Hereditary systemic ApoAII amyloidosis
Finnish hereditary amyloidosis
Hereditary lysozyme amyloidosis
Hereditary cystatin C amyloid angiopathy
Injection-localized amyloidosis
Hereditary renal amyloidosis
Senile seminal vesicle amyloid
Familial subepithelial corneal amyloidosis
Medullary thyroid carcinoma
Neurodegenerative diseases
Alzheimer’s disease
Parkinson’s disease
Lewy-body dementia
Huntington’s disease
Spongiform encephalopathies
Hereditary cerebral hemorrhage with amyloidosis
Amyotrophic lateral sclerosis
Familial British dementia
Familial Danish dementia
Familial amyloidotic polyneuropathy
Frontotemporal dementias
Other diseases
Diabetes mellitus
Sickle cell anemia
[16] Garrett MD (2015) Politics of Anguish: How Alzheimer's disease become the malady of the 21st century. Createspace. USA
[17] Garrett MD, & Valle R (2015) A New Public Health Paradigm for Alzheimer’s Disease Research. SOJ Neurol 2(1), 1-9.
Garrett MD &Valle RJ (2016).A Methodological Critique of The National Institute of Aging and Alzheimer’s Association Guidelines for Alzheimer’s disease, Dementia and Mild Cognitive Impairment. Dementia: The International Journal of Social Research and Practice,15(2) 239–254. DOI: 10.1177/1471301214525166
[18]  D.M. Walsh, I. Klyubin, J.V. Fadeeva, et al.Naturally secreted oligomers of amyloid beta protein potently inhibit hippocampal long-term potentiation in vivo Nature, 416 (2002), pp. 535–539
P.M. Douglas, S. Treusch, H.Y. Ren, et al. Chaperone-dependent amyloid assembly protects cells from prion toxicity. Proc Natl Acad Sci USA, 105 (2008), pp. 7206–7211
© USA Copyrighted 2016 Mario D. Garrett