My first laboratory job was right after earning my Master鈥檚 degree, and it was on a research project on Alzheimer鈥檚 disease. I had to test DNA samples from participants for a particular form of the gene APOE. We get one copy of the gene from our mother and another from our father, and this gene like all others comes in different flavours. People who had a very specific form of the APOE gene, I learned, were predisposed to Alzheimer鈥檚 disease.
Here we are, exactly twenty years later. My own career has changed significantly, and my supervisor at the time is retiring. Have we made any progress in detecting Alzheimer鈥檚 disease before it manifests?
Actually, yes. Progress has been slow, and the field has been marred by what appears to be scientific fraud. But alongside expensive and invasive tests for Alzheimer鈥檚 disease, there is now a simple blood test that performs really well.
In honour of biomedical scientists鈥� aversion to creativity, it is called p-Tau217.
Not all dementias are Alzheimer鈥檚
More than are estimated to currently have dementia, and although it鈥檚 easy to think that Alzheimer鈥檚 disease and dementia are the same, Alzheimer鈥檚 disease is only the most common type of dementia.
Dementia is a significant decline in our thinking abilities, usually involving memory and language problems, and this deterioration interferes with independence and activities of daily living, like getting dressed and going to the bathroom.
Alzheimer鈥檚 disease鈥攚hich develops over years without symptoms before manifesting as mild thinking issues, until it progresses to dementia鈥攊s a horrible affliction, but we鈥檙e not all equally susceptible to it. Age is the biggest risk factor. A family history of dementia also predisposes you to it, although inherit the condition from their parents.
Some genes have indeed been tied to the condition, like APOE. One form of the gene, called the 蔚4 (epsilon four) allele, increases your odds of developing Alzheimer鈥檚 disease by ; if both copies of APOE are of the 蔚4 variety, your odds go up by a factor of eight to twelve. But this genetic test is binary: either you have these alleles or not. It does not change over time. (This test is , as it does not give the doctor significant, additional information and false positives and negatives cannot be avoided.)
While we still do not really know what causes the disease, a look under the microscope has revealed two telltale signs that scientists have tried to exploit for both diagnostic and therapeutic use.
Plaque attack
The first hallmark of Alzheimer鈥檚 disease that is invisible to the naked eye is plaque. Not dental plaque, but aggregates of a specific short protein called amyloid beta (A尾). In our neurons, a forefather of A尾 pokes through the membrane of these cells, like a flower emerging from the ground. When this precursor protein is cut in a particular way by molecular lawnmowers, one of the fragments is called A尾, and in the brains of deceased patients who had Alzheimer鈥檚 disease, pathologists can see these fragments gathering together like snowballs in between neurons. It鈥檚 a gradual process while we鈥檙e alive, as single A尾 units join each other in packs of five or six, before their size turns them into 鈥減rotofibrils,鈥� which themselves grow to become actual plaques.
Even though Alois Alzheimer himself described the existence of these plaques back in , whether they cause the disease or are simply a consequence of it remains hotly debated today. But the plaques are there, and so they have acted as a lightning rod for research efforts.
Unfortunately, almost every attempt at developing a treatment that clears up this plaque has ended in failure. So far, two therapeutic antibodies (which bind to amyloid beta) have been approved in the United States for use in patients with Alzheimer鈥檚 disease: lecanemab (Leqembi) and donanemab (Kisunla). Their benefits are modest and their approval was not . (These drugs have not been approved by at this moment.)
Despite these therapeutic shortfalls, those plaques are clearly tied to the disease. Interesting fact: people with Down syndrome who reach middle age . Why? Because they have a third chromosome 21 and the gene that encodes the A尾 precursor protein is on that very chromosome. They get an extra dose of it, which magnifies their risk for the disease and speeds up its development.
A couple of decades ago, there was strong evidence that A尾 causes Alzheimer鈥檚 disease, but investigations have revealed probable fraud.
In 2006, a paper was published that seemed to prove that smaller, soluble aggregates of A尾 called oligomers caused memory issues in rats. These specific oligomers, called A尾*56, became, as a pun on the name, the 鈥渟tar suspect鈥� for Alzheimer鈥檚 disease. This paper has been cited in other papers nearly 2,000 times, according to Web of Science. Last year, it was with the blessing of all but two of its authors. Its figures showed 鈥渟igns of excessive manipulation.鈥� The data, it seems, had been doctored.
As was argued in an on this scandal by Charles Piller for Science, scientific fraud is not benign: it misleads researchers who waste time while patients suffer.
This doesn鈥檛 invalidate the fact that A尾 is there in the brains of people with Alzheimer鈥檚 disease. Some scientists, however, are denouncing what they call the 鈥渁myloid mafia,鈥� who discourage researchers from pursuing other potential explanations for the disease, like immune problems or issues linked to metals our bodies need, like zinc, copper, and iron.
In fact, the recent breakthrough in diagnosing Alzheimer鈥檚 disease has little to do with A尾 but with another important feature of the disease.
It takes tau to tangle
While amyloid beta plaques accumulate outside of neurons in the brain, a particular version of the tau protein accumulates inside of them. The Greek letter tau (pronounced with a 鈥渢鈥� preceding a scream of pain) is used to refer to a protein that helps assemble and stabilize the scaffolding inside our cells. It can be dotted with phosphate groups, like a child being given a couple of balloons to hold onto, but in Alzheimer鈥檚 disease, this protein becomes hyperphosphorylated. The child is given too many balloons and gets tangled up with other kids holding on to their bunch of balloons. Inside neurons, these agglomerations of hyperphosphorylated tau proteins are called neurofibrillary tangles and they disrupt the functioning of these neuronal cells.
Researchers have studied the various modifications that tau proteins can undergo, and one of these modifications has recently made it to the top of the list. It鈥檚 called p-Tau217, meaning the tau protein that has a phosphate group on a specific building block called threonine 217. It can be found in the blood of people decades before they show signs of Alzheimer鈥檚 disease.
Identifying good biomarkers is hard. A biomarker is something we can measure in the body that relates to a health condition. It may be a mutation in a gene, or a molecule carried in the blood or secreted in the saliva. It may help diagnose a disease, or predict one that will develop later, or help determine the odds of someone鈥檚 survival, or even guide therapy.
An ideal predictive biomarker for Alzheimer鈥檚 disease will correctly identify everyone who will develop the disease and vice versa: no one who won鈥檛 go on to have Alzheimer鈥檚 should get a positive result and no one who will should be mistakenly reassured. At the very least, these error rates need to be very low. This biomarker should flag people very early on, be non-invasive, and cheap. And if it鈥檚 to be used specifically for Alzheimer鈥檚 disease, it should not be detected when a person will develop a different dementia, like vascular or frontotemporal dementia.
Based on the accumulated data, p-Tau217 . It can distinguish between people who have Alzheimer鈥檚 and those who don鈥檛. It has prognostic value in the sense that higher levels of p-Tau217 in the blood mean a higher risk the person will exhibit symptoms. It seems to differentiate well between Alzheimer鈥檚 dementia and other types of dementia. And it responds to treatment like exercise, meaning that patients who exercise (which has some benefits for Alzheimer鈥檚 disease) see their p-Tau217 levels in the blood go down. A number of approved tests based on p-Tau217 are now commercially available.
So, should we all get tested every year to monitor our chances of developing Alzheimer鈥檚? It鈥檚 certainly : that in the near future, alongside our blood cholesterol levels, we鈥檒l have our p-Tau217 levels checked at the doctor鈥檚 office. But the problem with tests is that they鈥檙e never perfect. When used to screen the entire population, a tiny false positive rate still means a lot of people will freak out unnecessarily. They will be told they will develop Alzheimer鈥檚 disease when in fact they will not, because no matter how robust a biomarker is, it鈥檚 never 100% accurate. This is why the idea of screening everyone for every form of cancer every year鈥攖empting though it may be鈥攊s ill-advised: loads of perfectly fine people will be anxiously sent for more invasive testing like biopsies. Screening needs to be done smartly, which is why there are age recommendations for things like colorectal and breast cancer screening.
This p-Tau217 blood test may be worthwhile for people who have a family history of Alzheimer鈥檚 disease, as current diagnostic protocols are far from perfect. At least people diagnosed with Alzheimer鈥檚 disease based on what a doctor observes in the clinic turns out not to have the disease on autopsy, and people over the age of 85 who were never diagnosed with dementia turn out to have signs of Alzheimer鈥檚 disease in their brain in a postmortem examination. Although lumbar punctures and expensive medical imagery have improved the diagnosis of the disease, we could use a robust blood test.
In the end, though, the big question with early detection is always: so what? What can we do, beyond mentally preparing and getting our affairs in order, if we鈥檙e told that ten years from now, we will probably start exhibiting the signs of Alzheimer鈥檚 disease? Treatments for the disease once manifested are : cholinesterase inhibitors can modestly help with some symptoms, and memantine is used though its benefits are unclear. Two antibodies targeting amyloid beta are approved in many countries (with a third, Aduhelm, having been abandoned after its disputed approval), and vitamin E appears to slow down one aspect of the progression of the disease. As for prevention, there is a saying: what is good for the heart is good for the brain. Being physically active, eating well, staying away from tobacco and alcohol, and managing cardiovascular issues like high blood pressure and high blood cholesterol all seem to help.
The frustrating thing about Alzheimer鈥檚 disease from the research side is how slow progress has been given how debilitating the condition is and the amount of money invested in studying it. We know that amyloid beta and phosphorylated versions of the tau protein鈥攁s well as the protein called neurofilament light chain, which I haven鈥檛 mentioned鈥攁re implicated in the disease, but whether they are culprits or passersby remains vague. We are finally seeing a breakthrough with the use of p-Tau217 for diagnostic use. Let鈥檚 hope it does not become entangled in its own controversy over possible fraud.
Take-home message:
- One of the invisible signs of Alzheimer鈥檚 disease is the formation of specific protein tangles inside neurons in the brain
- A particular version of this protein, known as p-Tau217, has emerged as a reliable marker which can be measured in the blood to predict if someone is likely to develop Alzheimer鈥檚 disease in the future
