Back in 1987, it was discovered that the neurofibrillary tangles of PSP, like those of Alzheimer’s disease, are made of the tau protein with too many phosphate groups attached. That prompted great optimism that the two diseases could eventually share a single treatment to slow or halt the abnormal accumulation of tau.

At the time, I was a young assistant professor working on my first PSP research project — at the behest of my department chairman. It was the first epidemiological survey on that disease and my boss’s plan was for me to turn my attention to other things after that study was over.  But the new insight that the orphan disease of PSP and a huge, public health problem like AD shared an important molecular similarity helped keep part of my research effort focused on PSP.  Suddenly, it seemed a much more solvable problem than before, and one where a novice researcher like me could get in on the ground floor.

Soon thereafter, enough PSP/AD commonalities have emerged to prompt many Pharma companies to use people with PSP as a “test bed” for their new, potential blockbuster, AD drugs. Why not simply use patients with AD?  Because:

1. The diagnostic criteria for PSP were better than those for AD in avoiding false-positive diagnoses in the patient group;
2. The PSP Rating Scale worked better as an outcome measure for PSP than any AD-related scale did for AD; and
3. PSP progressed faster than AD, allowing studies to be smaller and shorter, hence less expensive; and d) because a treatment directed at the tau protein might work better in a “pure tauopathy” like PSP than in AD, where another protein, beta-amyloid, accompanies tau in the brain and may affect tau’s susceptibility to the study drug in unknown and unmeasurable ways.

Then there’s another reason, which belongs in a different category and is relevant mainly in the US: If the experimental drug helps PSP only modestly (or with important side effects) it might well be approved by the FDA just because there was nothing else that worked at all. Then, Medicare, and by extension the private insurance companies, would likely agree to cover it because PSP is so rare, with about 20,000 people in the US.  But if the drug had the same lackluster benefit and important side effects in AD, with about 7 million sufferers, Medicare and insurance companies might refuse to cover it for that condition for purely financial reasons.

But back to the science:  More recently, researchers have discovered important differences between PSP and AD — enough to seriously reconsider the “test bed” strategy.  For example:

1. The “prion-like” spread of tau through the brain proceeds more rapidly in PSP than in AD, and in a very different set of brain areas.
2. PSP starts in the brain’s glial cells, while AD starts in neurons.
3. The part of the brain cells’ “garbage disposal” mechanism presenting the most promising drug targets differs between PSP and AD. 
4. Perhaps most dramatic, the new technique of cryo-electron microscopy, which can image a single tau molecule, has shown important differences between PSP and AD in how that protein mis-folds on itself.  That means that a drug could bind to tau in PSP but not in AD, or the reverse. 
5. A practical issue related to ease of trial design: Newer imaging techniques and blood or spinal fluid tests have permitted much more accurate diagnosis and tracking of AD, while those tests are not (yet) useful in PSP.

BUT: A new discovery just published this week may re-unite PSP and AD, along with frontotemporal dementia and Parkinson’s disease, as diseases that could share the same neuroprotective treatment.  The commonality is a type of “long, non-coding RNA.” For more on that potentially groundbreaking – and definitely oddball — molecule, see the next post.