Guess I’m back on the topic of Alzheimer’s Disease research again.
Jennie Erin Smith’s “Valley of Forgetting: Alzheimer’s Families and the Search for a Cure” is very tightly focused on one particular subset of familial Alzheimer’s being studied in Columbia. This particular form of Alzheimer’s is caused by a mutation in the gene presenilin-1 (PSEN1), E280A. A single amino acid change at position 280 leads to altered protein function. E280A is one of the most common causes of early onset familial Alzheimer’s, and the vast majority of carriers all come a single state in Columbia—Antioquia.
Sometimes known as the paisa mutation, in reference to the people from the rural regions around Medellín, E280A has proven to be an excellent candidate for researchers to follow. With a history dating back at least five generations, thousands of subjects, and extremely high penetrance, the Paisa families provide an unprecedented opportunity to discover new biomarkers and protective variants, as well as the ideal population in which to carry out clinical trials. But, as Smith goes to great effort to draw attention to throughout her book, scientific research does not exist in isolation. It’s not just about the data, but the communities it effects.
The high rates of familial Alzheimer’s in the region means that most of the families are impacted. When I said that the the paisa mutation has an extremely high penetrance, what that means is that it’s not just a strong predictor of developing the disease before middle age—it is a damned near guarantee. And you have a 50:50 change of inheriting it if you have one parent with the mutation. Think of Huntington’s disease, but with an even young skew. Even for the non-symptomatic, nearly everyone has a relative that is affected, or has had to stand in some fashion as a caretaker. And it’s not just the fear of losing their family members, but their own uncertainties they have to live with as well. Is your one moment of forgetfulness just that, after a stressful day? Or is it a portent of what’s to come? You’ve spent—especially if you’re a young woman—the better part of a decade caring for a parent or an aunt; will there be anyone around to care for you? And again, especially pressing for younger women in this culture, do you go on and have kids?
The effects of this disease on these communities went mostly unnoticed until the 1990’s when Francisco Lopera, a Colombian neurologist, and a slightly eccentric American from Harvard, Ken Kosik, first characterized the paisa mutation. It was an uphill battle, helped by fellow Columbian Jorge Ossa, who built up a team at the University of Antioquia and helped them secure their very first grant—of $800. They dynamics here are quite fascinating with regards to bringing in Kosik; due to the evolving political situation at the time, the columbian scientists knew they were a bit isolated, and some of them were worried that Kosik might be a bit scared off visiting Medellín. One of Escobar’s lieutenants having just been killed by the police, and they were expecting that retaliation would spill out onto he streets. So to make sure Kosik didn’t get too spooked, they tightly escorted him throughout his trip and nicked all his newspapers so he couldn’t read the news.
Not everyone was super pleased about Kosik’s involvement; Ossa really didn’t know what to make of the man, and was insistent that the project remained “a Colombian project, and not something stolen by the gringos” But overall, the collaboration was a success, and Lopera went on to eventually set up the Grupo de Neurociencias de Antioquia, a whole research institution focused on studying this mutation, providing a brain biobank—and trialing cures.
Smith arrived in 2017, to report on their largest and most expensive trial effort to date: the Alzheimer’s Prevention Initiative Colombia trial, or API Colombia. The drug in question was crenezumab, a monoclonal antibody that targeted the mutant PSEN1. What struck me here is how central to the community the institute became, and how central Lopera was to the institute. Often his works and words were final. One of his choices that had the greatest impact on the young people Smith befriends is his stance on genetic disclosure; Lopera had made it his policy to never to disclose genetic results unless absolutely needed. There are some good reasons for this; Lopera was the opinion that many of the researchers at the institute were not qualified genetic counselors, and having blinded groups makes sense light of the clinical trials. But this meant that they left people in the community living in uncertainty for twenty years.
Another issue that the institute was dealing with was the potential aftermath of the clinical trials; if crenezumab proved to be a success, and the people of Antioquia ended up being the test population that brings that result to light; could they ever benefit from it? Virtually all monoclonal antibody drugs are very expensive; could any of the families access the treatment, if it were to be approved? If any successful drug were to be approved?
I appreciate the amount of legwork Smith has put into this book. While the tangled webs of different families were not always easy to follow, I feel it’s important to put human faces to these stories. It also reinforces something that I’ve ranted about in other reviews of other books: hyper results oriented clinical research is not the be all to end all, and the outcomes you want are not going to be proportional to the amount of money you put in. The Grupo de Neurociencias de Antioquia has done phenomenal work with regards to Alzheimer’s research and has brought in a considerable amount of research dollars, but it’s still important to care for the people from which, over the last forty years, helped generate the data brought in these funds.
