2018 was another year of failure for drugs to improve Alzheimer’s disease (AD) or dementia.  While 59 new agents were approved by FDA last year, including cannabidiol for epilepsy, an agent for a rare amyloid neuropathy (not AD amyloid beta), and many cancer therapies, none improved cognition in dementia.  The last FDA approval for AD was in 2014, for a one pill combination of two much older drugs, donepezil and memantine, so there has been nothing really new, nothing disease-modifying, for many years.

On the other hand, a 2018 abstract showed that caregiving training (see below) may be a way to decrease or delay institutionalization of patients, reminiscence therapy got an astute, sophisticated writeup (see below also), and there was some funding news.

Last year started with the publication of the clinical trial results of solanezumab, an immunotherapy against AD amyloid.  While it was a clinical failure, and did not improve patients, it did show some effects against its target, as measured by specialized PET scans and spinal fluid “biomarkers.”

My first editorial remark:  I am not a neuroscientist, just a caregiver with experience with cancer trials; I’ve seen lots of patients’ scans or other “biomarkers” improve while enduring new agents, only to have the cancer worsen later.  The solanezumab data is like another AD monoclonal antibody trial, bapineuzumab, in that it improved biomarkers but failed to substantially improve humans (rodents seem to do much better, I guess).  Followup of the bapineuzumab trial (2018 publication) seems to be showing that some subjects had unexpected shrinking of the hippocampal area of the brain, thought to be a memory center.

Verubecestat is an agent, formulated for humans as a pill, that improved AD biomarkers in rodents and other animals.  Also anti-amyloid-beta, this agent works along biochemical pathways in a different approach than the antibody agents listed above.  Sadly, this failed to improve human subjects and was associated with some adverse events.  Still, I applaud all those involved in these clinical trials, from subjects to investigators to investors, who are trying.

BAN2401, an agent in clinical trials, got some press this year, touted at the Alzheimer’s Association International Conference mid-year.  I liked the trial in 2017 because it seemed to have improved cognitive testing routines, even though originally thought to be a failure.  It seemed resurrected at the meeting in Chicago, but by October some its research methodologies were called into question in a serious way.  Evidently, the companies involved were not giving up.

February 2018 saw the FDA publish a new “draft guidance” to help drug companies get “accelerated approvals” of AD therapies.  They had previously changed AD guidance about five years ago, with no results.  This time, they proposed creating drug approval criteria for subjects with no discernible dementia (as clinically defined) but who had “biomarkers” of probable on-coming dementia, with specialized scans or body fluid lab tests, all to be yet determined.  I editorialized on this development, published here and in the Federal Register, wondering if it would really help.  It would certainly create a new market for such an agent.

So, if drug therapy didn’t come to fruition, what can one do?  Well, several groups have worked hard to improve the quality of life of people with cognitive problems.  Kenowsky and Reisberg at NYU have developed an intense program that seems to decrease and delay moves from a domestic setting to a nursing home.  While it is a small subject group, they had a followup report in abstract form last year showing their program decreased emergency room visits, too.

The New Yorker piece by Larissa MacFarquhar, The Comforting Fictions of Dementia Care, includes the statement: “In dementia care, everybody lies.” Although it’s ostensibly a piece about reminiscence therapy, it explores ethical issues and touches on subjects from improv comedy to theater to a philosophical thought experiment proposed by Robert Nozick.  Amazing read.

Caregiving seemed to get more recognition in 2018.  If one does a search for caregiving reviews on PubMed.gov, there seem to be 14/16 hits that are related to dementia caregiving in English.

Late last year, US Congress approved some budget items that brought AD spending at the National Institutes of Health (NIH) over $2B for the first time.  They did spend $1.4B the previous year.  Cancer gets about $6B, but there does seem to be a difference in the way money gets spent (even our little Ph2-Ph3 childhood cancer investigational unit got trickle down funding from NIH).  I have a tongue-in-cheek posting about what the $1.4B was spent on, and how some of the $2B might be spent clinically.

Big names were associated with AD fundraising, from Bill Gates and the late Paul G. Allen (in the past), to the Chan-Zuckerberg Initiative.  Most of the pledged funding is to go to developmental basic research, perhaps with big data approaches, etc.  There wasn’t much focus on clinical research, the harder, messier, and many times more frustrating end of the spectrum.

Second editorial: Cancer clinical trials featured combinations of agents before molecular mechanisms of action were elucidated, over 60 years ago.  Today, a woman with HER2+ breast cancer might get two different antibody therapies, along with chemo.  Except for combinations of donepezil (and  agents in the same class) and memantine, combination trials with multiple amyloid antibodies and other therapies seem rare for AD.

Institutional big names, the National Institute of Aging and the Alzheimer’s Association, put their heads together (in a manner of speaking) and came up with a roadmap of sorts for research going forward:  NIA-AA Research Framework: Toward a biological definition of Alzheimer’s disease.  It proposes defining dementia in the living with biomarkers, using the “AT(N)” nomenclature for Amyloid, Tau and Neurodegeneration (imaging and biofluids).

My own comments, in a letter to the editor of the same journal, was accepted last May, but I understand will appear soon.  I’ll post it when available.

Let’s hope for a breakthrough 2019!

(public domain image from Maxpixel.net)