The survival graphs above show the grim toll of dementia on life span at two different ages at diagnosis, ages 60’s or 80’s. It really hasn’t changed for decades, and is confirmed in other countries. In contrast, the second graph shows that breast cancer survival has improved steadily, in 5-year intervals from the mid-1980s, over 30+ years [>160K patients, median age 64.]
And in the past 5 years or so, FDA has approved over 200 cancer drugs, but only one Alzheimer Disease (AD) drug, aducanumab.
An eminent cancer doctor once asked in private (to paraphrase): why are they going after a “thing,” beta-amyloid, and not a “process,” like tumor progression? When did we ever do that? [K. Herrup’s 2021 book How Not to Study a Disease gives a neuroscientist’s personal insights and view of that history].
To be fair, AD BACE inhibitor trials tried to change the pathway of beta-amyloid production. One agent failed for toxicity and lack of efficacy, but actually diminished beta-amyloid, at least on PET scans and in spinal fluid (verubecestat, NEJM 2019). Lanabecestat had a similar trial outcome (JAMA Neurol 2019).
Of course, the FDA has stated that for aducanumab (Aduhlem ™), diminishing beta-amyloid on PET scans might be a surrogate of effectiveness, and even with controversial evidence of efficacy, it was enough to approve aducanumab, despite its own toxicity.
Let’s not dwell on the minor success shown by AChEIs, or the many amyloid-centered therapy failures (viewpoints published in 2022: “Had Enough, Eh?” and a review of two decades of AD clinical trial failures). So far, tau protein trials have also failed, and the Cochrane Dementia Reviews lists failed agents such as steroids, anti-inflammatory NSAIDS, and natural products.
“Hope springs eternal” (A. Pope, 1733) for innovative researchers. Of course “Those who cannot remember the past are condemned to repeat it” (G. Santayana, 1905), even though some failed anti-amyloid antibodies are now being revived [commentary D. Knopman, Mayo, 2022] for the hope of FDA approval, following aducanumab’s lead.
Recent news has reported the assumption of good results from lecanemab and implications for CMS funding. There is the 2022 pipeline report (143 new drugs in development, J. Cummings) and an opinion of an approach “past Aduhelm,” (H. Fillit); others have proposed combination trials.
Persons living with dementia and families are still desperate now for a breakthough agent, despite the optimism in the news, one that produces a really tangible, life-improving result. Perhaps lecanemab’s purported results will be dramatic, but they may also be modest; other pipeline agents could be 5 or 10 years in the future.
Can the approach and strategy in cancer research accelerate a breakthrough? Or is the best hope for here and now just wishing for serendipity to find a game changer?
Cancer therapy in some ways is brutally simple: “lumps belong in the lab” was the approach touted by one cancer surgeon, i.e. cut out what you can see. Then try to “burn” what you don’t see or can’t get, with radiation therapy. Chemotherapy, with its cellular poisons, historically came later.
More dramatic impacts have been shown with marrow transplantation (HDC-HSCT), protein kinase inhibitors or CAR-T / immunotherapy / checkpoint inhibitors to slow or halt cancer progression; they can make a difference in previously precarious situations. None is a guaranteed cure.
And even if the cancer is halted, there is normal tissue recovery and healing, along with rehabilitation for serious damage. One would expect the same process for a dementia “cure,” perhaps even harder work to repair lost physical and cognitive skills.
But oncology doesn’t always “win”. Even aggressive oncologists are bedeviled by primary brain cancer, which may progress despite all sorts of therapy. The 5-year survival rate for adults in the US with a cancerous brain tumor is only about 36%. More specifically, persons with wild-type glioblastomas have a median survival of about 12 months (JAMA Oncol 2022).
There are many neurologists and neuroscientists working in AD and dementias, with brilliant work and insights over the last several decades. Except for childhood meningitis perhaps, and mRNA agents for SMA, progress in brain / dementia therapies seems to lag behind success stories in other fields and other parts of the body.
One common analogy is that the brain is a problematic Black Box, very complicated with hidden inner workings.
The early days of chemotherapy were at least 70 years ago now, when cancer pathophysiology was just as mysterious. There was also an urgency then, and willingness to try just about anything, so things got started; both features still persist. Urgency and a myriad of therapeutic approaches seem to be missing in AD clinical trials.
But this oncologist / blogger won’t presume to prescribe a strategic approach for dementia. If AD therapy approaches can’t glean anything from oncology, from its innovative clinical trial programs (“Pick the Winner,” “I-SPY,” Phase II/III studies with neoadjuvant arms), to its multi-model approach, perhaps a mixed metaphor can help:
It’s World Series time; can the games be seen as clinical trials? Even the best batters fail ~70% of the time. Some skill and luck is needed to combine hits together and score runs. Many theorists think the real secret to winning is having ace pitchers who can halt any damage from the other team’s batters.
Even the Cubs, who used to be “lovable losers” for over a hundred years, finally won the WS in 2016. Was it the combination of skills on that team, their pitchers halting their opponent’s damage, or the management’s strategy and bedside, er, fieldside decision making? Opinions abound, but that Game 7 one-run, tenth-inning win spread joy all the way to this household’s devoted Cubs fan, despite her Reisberg FAST level 6 then.
Does the picture below remind anyone of a plaque or tangle?
