Approximately 50 million people worldwide are living with Alzheimer’s or a related form of dementia — a disease that destroys the neurons, dissolves the memories, and erases the identities of tens of millions around the world, all while loved ones can but watch on helplessly as this horror unfolds.
This is Auguste — the first person officially diagnosed with Alzheimer’s disease.
Suffering from severe memory impairment and disorientation, she was taken to a medical asylum in Frankfurt in 1901. When asked by doctors what name was, she would respond “Auguste.” When instead asked questions any more cognitively demanding — her age, where she was, or even her husband’s name — she simply could not answer.
“I have lost myself, so to say.”
Such was the response Auguste would continually offer when asked to recall even the most basic details of her life.
Puzzled, doctors watched on as her condition continued to worsen. Just 5 years later, Auguste had passed away. Doctors were later bewildered to find strange plaques and tangles in Auguste’s brain when performing an autopsy. Strangest of all, though, is the troubling reality that if Auguste had been alive today, the medical community could offer her little to no more help than doctors were able to provide 120 years ago.
An Urgent Medical Challenge
Since 1901, medicine has advanced significantly, from the discovery of antibiotics and crucial antiviral drugs to the development of stem cell therapy. However, we’ve made extremely little progress in addressing Alzheimer’s disease (AD)— all while the number of people believed to be living with the condition today surges every single year.
Between 2000 and 2010, encouraging progress has been made in mitigating or stabilizing the number of casualties inflicted by today’s leading causes of death, from heart disease to cancer. The number of Alzheimer’s-related deaths, however, has seen quite the opposite: a 68% increase during this same period.
Today, 50 million people suffer from the disease. And while this figure is expected to exceed 150 million by 2050, trials for Alzheimer’s drugs can’t seem to stop failing.
Hope to live past the age of 85? There is almost a half chance (45%) that you will find yourself stripped of the opportunity to interact meaningfully with your grandchildren by Alzheimer’s disease.
Beyond simply destroying the memory, thinking, and cognitive functioning in millions, the disease asserts a significant financial toll. In the United States alone, Alzheimer’s care costs $200 billion every single year.
This figure is expected to increase more than fivefold by 2050 as the baby boomer generation ages, at which point Alzheimer’s care would cost more than current federal government spending on K-12 public education, veteran care, housing assistance, and infrastructure combined.
Indeed, whilst a recent ground-breaking study from researchers at the Rush Alzheimer’s Disease Center (RADC) attributes more than 500,000 deaths in 2010 to Alzheimer’s, the disease receives a mere fraction of the research funding dedicated to cancer and other diseases.
A 2013 snapshot of NIH funding indicated that Alzheimer’s research received just $550 million/year — 0.275% of the annual cost of Alzheimer’s care.
Simply put, Alzheimer’s disease represents one of the biggest medical and social challenges of our generation— one we ought to address urgently.
Diagnosis is Late and Expensive
At the moment, there is no single diagnostic test for Alzheimer’s. Upon referral, physicians must first rule out conditions that can have similar symptoms, before relying on cognitive tests and brain imaging scans to diagnose the disease. As a disease for which no cure currently exists, the most the medical community is currently able to do following diagnosis is prescribing medication to temporarily alleviate symptoms.
There are two main problems with these status quo practices of diagnosing Alzheimer’s. Besides clinical assessment, brain imaging and lumbar puncture represent the two most commonly used medical procedure to detect changes in the brain caused by AD. However, these methods are expensive, invasive, and frequently unavailable in many countries.
Though costs vary wildly, current estimates peg the cost of β-amyloid positron emission tomography (PET) imaging tests at approximately $5,000; despite this extreme cost, the brain imaging test is non-invasive — considered almost a necessity for rapid, scalable, and safe diagnosis.
The alternative? A lumbar puncture (also called a spinal tap) — a test which removes a sample of cerebrospinal fluid (CSF) from the spine. Although these tests are less cost-intensive at a price point of $1,000, they involve invasive and burdensome procedures. Reliant on advanced medical equipment at a hefty price tag, PET and spinal tap tests are therefore frequently unavailable in many countries around the world.
Beyond high costs and global inaccessibility, these tests fail to take advantage of the long presymptomatic phase which characterizes AD, in which neuropathology gradually accumulates. Indeed, It is now well established that the pathophysiological process of Alzheimer’s disease begins decades before the first symptoms develop. Detecting this pathology at the earliest possible stage offers the best chance of effective treatment — a strategy which all forms of current diagnosis are simply unable to accomplish.
An ideal form of Alzheimer’s diagnosis, therefore, would not only need to be more economical, readily available, and easily administered, but should also capitalize on the neuropathological changes which characterize AD — changes which take place decades before current tests are able to detect.
The Failed Amyloid Hypothesis
Consider the defining features of Alzheimer's disease: conspicuous changes in both behavior and brain histology. In particular, the AD brain can be microscopically characterized by the combined presence of 2 classes of abnormal structure: extracellular amyloid plaques and intraneuronal neurofibrillary tangles. Both of these hallmark symptoms comprise highly insoluble, densely packed filaments.
The soluble building blocks of plaques are amyloid-β (Aβ) peptides — proteolytic fragments of the transmembrane amyloid precursor protein. Neurofibrillary tangles, on the other hand, are abnormal accumulations of a brain-specific, axon-enriched microtubule-associated protein called tau that collect inside neurons.
Accordingly, since the behavioral symptoms of Alzheimer’s disease correlate with the formation of plaques and tangles, they are therefore a direct consequence of the accumulation of amyloid-β peptides and tau pathology, as concisely summarized below:
In early 2018, two high-profile clinical trials of drugs for Alzheimer’s disease ended in disappointment. These drugs joined an ever-growing graveyard of potential AD treatments that have failed to deliver tangible benefits. Indeed, a recent study found that out of 244 promising compounds for Alzheimer’s, only one received approval. This gives Alzheimer’s disease drug candidates one of the highest failures rates of any disease area — 99.6%, compared with 81% for cancer.
The development of the vast majority of these failed drug candidates was guided by an idea that has dominated Alzheimer’s research for the past 30 years: the amyloid hypothesis, which refers to the assumption that accumulation of amyloid-β is the main cause of the disease.
Researchers proposed that when amyloid-β clumps together to form deposits in the brain, it triggers neurodegenerative processes that lead to the loss of memory and cognitive ability that is observed in Alzheimer’s disease. The sequence of pathogenic events leading to AD as proposed by the amyloid (cascade) hypothesis is illustrated below:
From there, amyloid-β naturally becomes a target, both for therapeutic treatment and diagnostic detection. “If you can deal with the peptide, then you can treat the condition,” researchers once posited.
This assumption, though, is at the very heart of the reason why so many Alzheimer’s drugs have failed. Despite extensive federal, foundation, and pharmaceutical funding in amyloid research, the protein’s causal role remains unclear. Indeed, published literature indicates that up to 40% of people in their 70s have amyloid deposits, without exhibiting any decline in memory or cognitive ability. perhaps, researchers now ponder, amyloid deposits are not themselves causal but rather are part of the wider brain’s injury response.
“In the past we’ve seen other big amyloid-β-targeted drugs fail, but the excuse was that maybe they weren’t so potent at reducing amyloid-β in the brain... Here, the Phase 1b data is clear that it was effective at reducing amyloid-β, so you have to question whether targeting amyloid beta can ever be effective.” − Phil Nadeau
In fact, recent research published in the journal Molecular Psychiatry points to the early accumulation of tau — the other hallmark pathology of Alzheimer’s — as a better predictor of AD-related memory decline than an accumulation of amyloid plaque.
The Promise of Tau Markers
Normally, tau helps assemble and maintain the structural scaffolding of brain cells. However, various molecular changes can cause the protein to turn toxic. Toxic tau misfolds, just like how a pair of earphones might tangle into a messy knot instead of remaining neat and parallel.
In this contorted state, tau appears have a causal effect on the misfolding of other tau proteins, which then clump together to wreak further havoc.
Tau was long thought to be a secondary actor in giving rise to Alzheimer’s disease. But with decades of focus on amyloid-β having failed to significantly help patients, researchers are increasingly turning to the tau pathology as a potential target.
“Amyloid hasn’t been as successful as we hoped… Tau has really emerged as a [potentially] more relevant target… There’s certainly a lot of smoke around this fire.” − Jang-Ho Cha
Recent research investigating changes in tau arising early in sporadic forms of Alzheimer’s has suggested that tau pathology appears approximately 21 years before the first noticeable symptoms of Alzheimer’s develop — findings which provide evidence that tau changes may be a vital biomarker of early AD.
Although this research has promising implications for the long-term development of tau-based, disease-modifying therapies for AD, there is a pressing need for inexpensive, easily accessible, non-invasive tests for the diagnosing Alzheimer’s disease today. Indeed, a novel, tau-based testing technology could in turn support drug development by helping to identify the right people for clinical trials and by tracking the impact of therapies being tested.
“There is an urgent need for simple, inexpensive, non-invasive and easily available diagnostic tools for Alzheimer’s… The possibility of early detection and being able to intervene with a treatment before significant damage to the brain from Alzheimer’s disease would be game changing for individuals, families and our healthcare system.” − Maria C. Carrillo
Furthermore, the accumulation of tau decades before symptoms develop bodes well for the ability of tau-based testing to detect Alzheimer’s in its presymptomatic stage.
In addition to detecting the condition as early as possible, ideal tau-based diagnostic testing also ought be highly accurate, inexpensive, non-invasive and easily available, in order to avoid the pitfalls of the inadequate forms of diagnosis that are presently available, including PET brain imaging and CSF spinal tap tests, alongside traditional manual clinical assessment.
Introducing Taufold
Taufold is a simple blood test for Alzheimer’s. The test measures changes in the blood/plasma levels of p-tau217 — a specific form of tau found in tangles — to detect the disease, decades before symptoms appear.
Moreover, as a blood-based test, this form of diagnosis harbors potential to detect Alzheimer’s just as accurately as current procedures, but at just a faction of the cost. And as one of the most common types of medical test, the blood samples you might take throughout your life need only screen for just one additional blood component to facilitate the detection of Alzheimer’s as early as possible: p-tau217 levels.
“Blood tests like P-tau217 have the potential to revolutionize Alzheimer’s research, treatment and prevention trials, and clinical care.” − Eric Reiman
Discriminative Accuracy of Plasma p-tau217
The cornerstone of the value of any blood-based test is its diagnostic accuracy — in this case, both for discriminating between patients who either have Alzheimer’s already or those who would end up developing the disease and those that wouldn’t, as well as for differentiating neuropathologically defined AD dementia from other tauopathies (neurodegenerative diseases for which tau protein deposition is a predominant feature).
To begin with, prevailing research (Palmqvist et al., 2020) sheds light on the correlations between plasma tau phosphorylated at threonine 217 (p-tau217) concentration and total tangle density score in Alzheimer’s. As seen here, there is a clear correlation between increasing levels of p-tau217 and the recorded tangle density score in patients with AD, while non-AD participants recorded no statistical difference (shaded areas indicate 95% confidence intervals around the regression lines):
With respect to the discriminative accuracy of plasma p-tau217 for Alzheimer’s versus other neurodegenerative diseases, this same research paper observed plasma tau phosphorylated at threonine 217 (p-tau217) concentrations across the different diagnostic groups. As illustrated in the figure below, plasma p-tau217 was found to strongly differentiate clinically diagnosed AD dementia from other neurodegenerative disorders:
That is to say, heighted levels of plasma p-tau217 detected in Taufold’s blood test strongly attest to the presence of Alzheimer’s disease, as opposed Parkinson’s disease, Vascular dementia, or any number of other neurodegenerative diseases.
The other major form of accuracy the test ought to demonstrate entails the ability to reliably distinguish between participants who do indeed exhibit neuropathologically defined AD or will develop the disease, and participants who did not demonstrate diagnostic levels of AD histopathology. The figure from the aforementioned study highlights receiver operating characteristic (ROC) curve analyses of plasma p-tau217 and other biomarkers using tau–positron emission tomography (PET) positivity in the temporal meta–region of interest (ROI) as the reference standard:
These analyses demonstrate that beyond merely correlating with cerebral tau tangles, plasma p-tau217 levels discriminated abnormal vs normal tau-PET scans with significantly higher accuracy than plasma p-tau181, plasma NfL, CSF p-tau181, and CSF Aβ42:Aβ40 ratio, alongside MRI measures.
In a nutshell, these findings confirm that p-tau217 can indeed distinguish participants who exhibit AD histopathology from those who don’t extremely accurately. Therefore, the use of p-tau217 levels exhibits all the necessary markers of an accurate diagnostic test.
Special thanks to Palmqvist et al. — the authors of the paper Discriminative Accuracy of Plasma Phospho-tau217 for Alzheimer Disease vs Other Neurodegenerative Disorders, from which several conclusions regarding the discriminative accuracy of Plasma p-tau217 were drawn.
Detection Decades Before Symptoms
Moving beyond the potential for p-tau217-based blood tests to detect Alzheimer’s accurately, this same research presented from scientists in Sweden indicated that changes in blood tau levels could be detected long before symptoms of Alzheimer’s disease appeared.
In fact, in a subgroup of participants these changes could be observed 20 years prior to the estimated onset of the disease — that is, before diagnostic levels of AD histopathology were observed. As such, given that forms of tau protein become abnormal in the very early stages of Alzheimer’s disease, Taufold’s blood-based test could either detect these changes just as early as PET or CSF tests, or decades before the first symptoms develop in some patients.
“Levels of ptau217 correlated with those who later developed the disease, up to 20 years before symptoms were seen.” − Sharon Reynolds
Given the importance of catching Alzheimer’s as early as possible to provide patients with the best possible chance to benefit from treatment, the capability for Taufold’s blood test to detect AD decades before symptoms appear facilitates intervention to delay the onset of the disease and gives patients years to plan for the future.
Strong Economic Incentives
As a blood-based test, Taufold should technically be considered invasive ; however, the equipment used to conduct the test is far less sophisticated than both positron emission tomography technology and the invasive procedures required to administer lumbar puncture tests; all the blood test really requires is simple phlebotomy equipment and a plasma analyser to gauge p-tau217 levels in the resulting sample. Taufold is therefore easily accessible in countries which have blood testing capabilities, but lack the equipment to conduct a PET scan or spinal tap test.
Furthermore, the usage of simpler tools for diagnosis also impacts the projected cost of administering the test. Currently, PET scans and spinal tap tests come at price points of $5,000 and $1,000 respectively. The current cost of a blood test to check for some given blood component (haemoglobin levels or white blood cell count, for instance) is about $200 in the United States. Accordingly, pricing a dedicated Taufold test (that is, a test specifically administered to measure tau levels in plasma) at $240 represents a reasonable, conservative estimate.
A more probable projection, though, is one in which the routine complete blood count (CBC) tests you might take throughout your life simply incorporate p-tau217 levels into the wider portfolio of blood components these tests track. Indeed, complemented with Taufold’s ability to detect the early signs of Alzheimer’s decades before the medically defined onset of the disease, this unique synthesis makes the prospect of detecting the disease years before symptoms develop a reality.
Overall, as a simple, highly accurate, easily accessible, and highly accurate test which detects the disease at the presymptomatic stage, Taufold fully avoids the pitfalls of today’s inadequate forms of Alzheimer’s diagnosis.
Closing Thoughts
Affecting 50 million people worldwide, Alzheimer’s disease represents one of the most significant social and medical challenges of our generation.
Although reasonably accurate in accurately detecting diagnostic levels of AD histopathology, current forms of diagnosis fail to capitalize on the accumulation of tau pathology decades before the onset of the disease. In addition, as frequently sophisticated, inexpensive and therefore inaccessible forms of diagnosis, the inadequate PET scans and spinal tap tests foundational to the old paradigm of Alzheimer’s testing warrant replacement.
Taufold represents a solution in the form of a simple blood test for Alzheimer’s. By measuring changes in the plasma levels of p-tau217, the simple test harbors potential to detect AD decades before the onset of the disease appear at a fraction of the cost of current measures.
In doing so, Taufold advances the state of Alzheimer’s testing to an era in which diagnosis can begin in a doctor’s office years before symptoms even appear — a promising development in the fight against the degenerative disease.
