By age 43, Ofelia, who lived in the hills north of Medellín, Colombia, could no longer hold down a job because of the mistakes she made. She started collecting garbage and bringing it home for no apparent reason. She lost the ability to write words; all she could manage were senseless doodles. She died in 1996 at the age of 44, just as science was uncovering the cause of her early-onset, rapidly progressing dementia.
That cause — a hereditary genetic mutation known as E280A — is at the heart of science journalist Jennie Erin Smith’s deeply researched book, “Valley of Forgetting: Alzheimer’s Families and the Search for a Cure.” The gene becomes known as the “paisa mutation” because, as Smith explains, “paisa” in Colombia refers to people from the mountain region that includes Medellín and the surrounding villages. And it’s among these paisa that E280A has made its home, an inheritance that traces back to four sisters who lived in the region during the late 18th and early 19th centuries and that has been handed down to thousands of families in the region.
BOOK REVIEW — “Valley of Forgetting: Alzheimer’s Families and the Search for a Cure,” by Jennie Erin Smith (Riverhead Books, 384 pages).
E280A is not a risk factor for early Alzheimer’s; it is nearly a guarantee of it. Carriers start showing signs of cognitive decline in their 30s and 40s, and often die in their 50s. “Valley of Forgetting” is their story. As Smith unpacks the decades-long investigation of inherited Alzheimer’s, the genes behind it, and the research of possible treatments, she also brings readers inside the world of the families whose fate is intertwined with this wayward and irreversible change in their DNA.
One could argue that any book about Alzheimer’s disease is important. Just about 7 million Americans age 65 and older are living with the disease, the most common form of age-related dementia. Globally that figure climbs to an estimated 57 million people with dementia.
The disease is costly both financially and emotionally. By one account, caregivers for people living with some form of dementia spend about 23 hours per week providing the intense support this role entails. An estimated $42 billion in private research has gone toward developing a treatment for Alzheimer’s disease since 1995. And U.S. taxpayers have spent nearly $4 billion into research dedicated to acquired cognitive impairment, a broad category that includes damage stemming from strokes and infections, but also irreversible neurodegenerative conditions such as Alzheimer’s.
Yet despite all of these numbers, little progress has been made in developing an effective treatment or in laying out proven preventive measures. In other words, Alzheimer’s disease is a massive, seemingly intractable problem, and any books that help unravel why and how this epidemic persists have a place in the canon.
“Valley of Forgetting” is a special addition to that bookshelf. Though journalists have reported aspects of this story over the years, it has not been told in full, nor with such depth, poignancy, and gripping relevance for both scientific research and society at large. In Smith’s deft hands —including in a piece she wrote for Undark in 2019 — the story of E280A demonstrates, in no uncertain terms, that scientific research is never just about the research or the data. It is about humanity — as a motivator but also as a compass.
Alzheimer’s disease is a massive, seemingly intractable problem, and any books that help unravel why and how this epidemic persists have a place in the canon.
The story centers on Francisco Lopera, a charismatic and thoughtful Colombian neurologist who, himself a paisa, earns the trust of hundreds of carriers of the mutation and their loved ones. After co-discovering the E280A mutation in 1995 with neurologist Kenneth Kosik and geneticist Alison Goate, Lopera founds Grupo de Neurociencias de Antioquia, a research institution dedicated to furthering the scientific understanding of the gene and to running clinical trials of drug candidates.
Together with numerous talented researchers — like Francisco Piedrahita, a scientist who had lost several family members to E280A-caused Alzheimer’s — Lopera leads experimental drug studies in which all the participants are local villagers. He also conducts long-term epidemiologic studies of families carrying the gene and laboratory investigations of autopsied brains from locals who died from its disease.
But Smith doesn’t shine the spotlight on the scientists alone. Instead, she brings readers into the living rooms, kitchens and bedsides of the families — the daughters who have lost mothers, aunts, and grandparents to the ravishes of E280A; the mothers and sisters who are wondering if a moment of forgetfulness signifies the start of the disease; the son who knows to make clicking sounds to assure his mother that he is still nearby.
At one point, Smith attends prayers mourning the death of a woman named Camila, who died from Alzheimer’s at age 55. She was the sixth sibling in her family to succumb to the disease, and Smith is struck by the nonchalant response to that fact among the mourners. “That six siblings should be dead before age sixty did not impress the people who had gathered here,” she writes. For the mourners, early-onset Alzheimer’s is simply “another way to die.”
These families are typically poor, scraping together an income however they can, including selling lottery tickets and clothing in the waiting room of Neurosciencias during their clinical trial appointments. Aside from a cure for Alzheimer’s, the greatest wish the families express to the researchers is for adult diapers. “In the advanced stages of Alzheimer’s, a patient could go through several diapers per day, and they were expensive,” Smith writes.
Many of the women Smith profiles suffered abusive relationships, both romantic and familial. One woman, Paula, recalls eating out of garbage cans as a child. All of this — the scientific and personal challenges — takes place against the backdrop of gang-driven violence that terrorized Colombians during crucial years chronicled in the book, particularly the late 1990s and early 2000s. “Lopera and his group worked out of a hospital system whose daily bread was carnage,” writes Smith, “where assassins would break into recovery rooms to put more bullets into an enemy who’d just been painstakingly sewn up.”
Smith embeds herself with her sources, moving to Medellín in 2017 to follow the Alzheimer’s Prevention Initiative Colombia trial, or API Colombia. The trial was a clinical investigation of crenezumab, a monoclonal antibody that Lopera, Kosik, and others hoped could thwart the brain-damaging activity of E280A. Lopera joined forces with scientists funded by the U.S.-based Banner Alzheimer’s Institute to run the trial — that institute contributed funding to the study, along with the National Institutes of Health and Genentech, which manufactured crenezumab — a collaboration that brought together excellent scientific minds along with egos and different understandings of the patient population.
“That six siblings should be dead before age sixty did not impress the people who had gathered here,” Smith writes. For the mourners, early-onset Alzheimer’s is simply “another way to die.”
Those complications seem like a luxury, though, juxtaposed with the perilous lives of the E280A families. At one point, a woman named Daniela, who had lost her mother to Alzheimer’s, moves in with Smith, giving us an intimate view of Daniela’s struggles — grieving for her mother, watching her aunt descend into the same disease, scrambling for an income, moving away in the hope of building a life that then fails to materialize, and contemplating suicide if she turns out to be a carrier.
“Maybe it’s cowardly, I don’t know,” Daniela tells the physician who ran the Neurociencias brain bank, as she recalls her mother’s state at the end of her life. “The way they end up is just” — she cannot finish the sentence without tearing up.
That inner turmoil leads Daniela on a quest to be tested for the E280A mutation, something that Lopera refuses to disclose to the families, a source of tension throughout the book. “The way I see it, if I have the gene, my life plan won’t include being a mom,” Daniela tells Smith. “If I end up never knowing, and all this time I never had the gene, I’ll have wasted my chance.”
In some respects, we already know how the story ends. No drug has made a significant impact in the prevention or treatment of Alzheimer’s disease, including that linked to E280A. API Colombia ended in 2022 with no sign of clinical benefit. That outcome is especially crushing because of the tight bond forged between the researchers, the trial participants, and the thousands of villagers who had donated blood and given their time to the effort for years.
Woven throughout the story are a multitude of nuances and dynamics that illustrate the extent to which science is never just about science. There’s the way in which Neurociencias becomes central to the lives of the E280A families. There’s the tension between research teams who all have an interest in the autopsied brains from E280A carriers. And there’s the continued push — rooted in the unproven hypothesis that Alzheimer’s is caused by the build-up of amyloid plaques in the brain — to keep agents like crenezumab in the drug development pipeline despite the absence of meaningful benefit after decades of research.
Smith seems ambivalent about the future of Alzheimer’s research. As the grip of the amyloid hypothesis continues to weaken, new opportunities are opening up for research pathways. And researchers are continuing to scrutinize the brain from an E280A carrier who did not develop Alzheimer’s until her 70s, hoping for clues about genes that might counteract the disease. Yet API Colombia was followed with a trial for another anti-amyloid drug to be tested on E280A carriers. “Was this the best that could be done for the families?” Smith asks. “Or was it a way to keep the research gears turning and money and data flowing with so few alternatives available?”
The many individuals and families Smith writes about can be hard to track in places. But the confusion is balanced by the awareness of the hundreds, perhaps thousands of individuals not included in Smith’s account whose already difficult lives exist in a state of watching and waiting for concerning symptoms to appear, and who can break that spell only by refusing to have children.
Their intimate relationship with Alzheimer’s in all its stages and expressions is at once empowering and heart-wrenching. It is this in-between state that drives Daniela, whose entire life has been overshadowed by E280A, to move to Spain. “Daniela wanted to know how it felt to be, as she put it, “the absolute master of myself,”’ Smith writes.
Jessica Wapner is a widely published journalist, writer, and producer. She is the author of “The Philadelphia Chromosome” and “Wall Disease,” and the reporter and co-host of the podcast One Click.