[Dr. R. Hodes presenting amyloid and tau PET scan images from Quiroz et al, in patients from Columbia with genetic early onset Alzheimer's, NIH, 2018, photo: Andrew Propp for Fogarty/NIH on Flickr, US Govt work].
Is there a new Act III in the “rivalry” between scientists working on abnormal proteins in Alzheimer’s Disease (AD)? New tau imaging and other studies have made tau newsworthy, while uncertainty about the status of anti-amyloid therapy persists. And perhaps some rivalry goes back to 1907!?
Five years ago, Alzforum news was describing “The Feud, Act II,” about the relative importance of amyloid and tau: “For some, scientists are starting to decipher how the proteins might influence pathology and—why, hello!—the old rivalry between Aβ and tau resurfaces. (In truth, the religious war of yesteryear lives on only as fodder for some media stories; most scientists agree both are important.)”
Since then several anti-amyloid clinical trials have failed, monoclonal antibodies and BACE inhibitors; at least one anti-tau therapy also failed. Aducanumab, an amyloid monoclonal, reportedly met stopping rules for clinical futility, but re-analysis by the investing company was evidently convincing enough for it to apply to the FDA for marketing approval. That whole process has been a bit controversial.
Why do people get clinical dementias in the first place? Looking at dementia brains over 100 years ago, Dr. Oskar Fischer of Prague and Dr. Alois Alzheimer of Munich, some say from “rival” academic groups, independently described microscopic abnormalities in papers circa 1907. African-American psychiatrist Solomon Carter Fuller is said to have made similar discoveries in that time. (Alzheimer died of heart failure in 1915, Fischer died decades later in a concentration camp).
Science progressed, and molecular studies found that tau is a protein found in abnormal “neurofibrillary tangles” (NFT) within neurons, whereas amyloid beta is a smaller protein found in abnormal aggregates or “plaques” outside of neurons, much as Fischer and Alzheimer (and Fuller?) described.
Over 110 years later, we still are waiting for disease-modifying therapy based on any theory (including the cholinesterase pathway and ideas about inflammation). By 2018, it seemed that the amyloid and tau camps were coalescing, and the histories of the amyloid and tau hypotheses were nicely summarized by Patricia Thomson on the StressMarq blog. She mentions the rivalry, sometimes jokingly called “Tauists vs. BAptists” [BA for beta-amyloid]. The NIA/AA Research Framework (2018) does mention using PET scans for both proteins moving forward, but seems to emphasize amyloid (tau imaging has evidently improved since then).
This year, two papers (from some of the same authors) discuss some tau findings that were a bit confusing for AlzheimerGadfly. The first discusses both “brain resilience” (better brain structure on imaging) and “cognitive resilience” (better performance) in MCI or mild AD patients with positive amyloid and tau (flortaucipir) PET scans: women and younger age were better for structure. Cognitive resilience correlated with education and better structure. Resilience is the hopeful idea that one can somehow persevere despite a bad looking tau PET scan, but then how good would the PET scan be? Hmmmm.
The second paper touts an improved tau PET imaging agent (RO948), with better specificity for Alzheimer’s. The authors suggest the new agent may not be that good in MCI or early AD, but since tau seems to continually accrue in dementia, they imply its best use might be in confirming AD, even as standalone imaging, once the diagnosis can be made clinically. If I read it correctly, the new agent is no better than MRI though, at looking at the interesting medial temporal lobe (hippocampus/memory region). Hmmmm.
What’s the real point? Anti-tau clinical trials using oral agents by the TauRx company failed. Abnormal tau is seen in other conditions, like Chronic Traumatic Encephalopathy (CTE) in football players and other athletes, so a good therapy might have a wide application. To that end, Cummings et al have summarized the anti-tau “pipeline” in an article; most are still in Phase I/II trials. But are tau and amyloid just tombstone markers, scars from damage already done by something else?
What really counts is finding disease-modifying therapy for Alzheimer’s and other dementias; one supposes history will tell us if these rival theories are even relevant to that end. Perhaps the spark of rivalry is just a joke, but the prolonged lack of clinical progress is no joke.
Some have asserted that the emphasis on the Amyloid Cascade Hypothesis did not allow other ideas to flourish. Readers of this blog will know that the prime counter-example of research strategy in medicine is oncology, with its multiple theories and multiple therapies. Let’s hope some current competition in AD work, for funding if nothing else, will somehow accelerate clinical progress.
While we’re waiting, maybe we need a serendipitous game changer to appear. So perhaps “Hacking the Brain” is next? At least it will be the subject of another AlzheimerGadfly post!