MEDELLÍN, Colombia – Aliria Rosa Piedrahita de Villegas carried a rare genetic mutation that had all but guaranteed she would develop Alzheimer's disease in her 40s. But only at age 72 did she experience the first symptoms. Her dementia was not terribly advanced when she died from cancer on Nov. 10, a month shy of her 78th birthday.
Neurology investigators at the University of Antioquia in Medellín, led by Dr. Francisco Lopera, have followed members of her extended family for more than 30 years, hoping to unlock the secrets of early onset Alzheimer's disease. In that time, they encountered several outliers, people whose disease developed later than expected, in their 50s or 60s. But none was as medically remarkable as the woman they all knew as Doña Aliria.
In recent years, Piedrahita de Villegas traveled to Boston, where investigators at Massachusetts General Hospital conducted nuclear imaging studies of her brain as part of an ongoing study of this Colombian family, the largest in the world with genetic early onset Alzheimer's. In Boston, it was discovered that Piedrahita de Villegas had exceptionally large quantities of a protein seen in Alzheimer's — amyloid beta — without much tau, the toxic protein that spreads later in the disease cascade. Something had interrupted the usual degenerative process, leaving her day-to-day functioning relatively preserved.
Last year, researchers at Harvard Medical School and the University of Antioquia published the surprise finding that while Piedrahita de Villegas carried a well-known mutation, unique to Colombia, that causes early onset Alzheimer's, she also carried two copies of another rare mutation that appear to have thwarted the activity of the first one.
Since then, investigators have been studying what is known as the Christchurch mutation, a variant on a gene, APOE, that can affect a person's risk of developing Alzheimer's. Thus far, drugs targeting amyloid beta have disappointed in clinical trials. If the protective effect of Piedrahita de Villegas' mutation can be replicated, a new avenue for therapies could open.
Piedrahita de Villegas did not have overly healthy habits that might help her stave off Alzheimer's. She could not resist a good party, her daughters said. Her sweet and chatty nature endeared her to her neighbors, who on Nov. 20 came out in droves to attend a mass in her honor.
Her melanoma diagnosis, delayed by the pandemic, was unexpected. She was assigned to palliative care, and nursed by family members who kept her toenails painted, her jewelry adjusted and her face freshly made up — as she insisted that they do — until the end.
Post-mortem studies to learn how dementia works on the brain have been a pillar of Alzheimer's research since 1906, when Dr. Alois Alzheimer, a German psychiatrist and brain anatomist, shared findings from a patient named Auguste Deter. What Alzheimer discovered in tissue slides of her brain after she died at age 55 distinguished her disease from other dementias. Microscopic seed-like structures permeated her shrunken brain, along with tangles that marked where neurons had died. Later these became known as amyloid plaques and tau tangles, key hallmarks of Alzheimer's disease.
Lopera, head of the neuroscience research group at the University of Antioquia in Medellín, called Piedrahita de Villegas "the Auguste D. of our time," noting that as Deter's brain helped elucidate how damage occurred in early onset Alzheimer's, Piedrahita de Villegas' might help show how that damage could be stopped.
Like most families involved with Lopera's research group, who have lived with early onset Alzheimer's for countless generations, Piedrahita de Villegas' children had agreed to donate their mother's brain for study when she died. The University of Antioquia now holds some 400 brains.
Each brain donation begins in a large funeral home. The arrangement allows the researchers to remove the brain and walk it quickly to their lab a block away, after which the family can proceed with a funeral or cremation.
Among the things that distinguished Piedrahita de Villegas' case from any other like it was that investigators would have genetic, clinical imaging and now autopsy information to work with: a single case, but with a suite of data.
At the University Medical Center Hamburg-Eppendorf in Germany, a neuropathology researcher, Diego Sepulveda-Falla, waited for samples. The key one was a frozen piece of the entorhinal cortex, a pinky-size structure that regulates memory and time perception and the first brain region from which tau begins to spread. Sepulveda-Falla said he would use single-cell RNA sequencing and machine learning to compare samples from Piedrahita de Villegas' brain with those from more than 125 Colombians who had died with the same mutation.
In Santa Barbara, Calif., a cell biologist, Ken Kosik, and his team, who secured a grant from the National Institutes of Health to study tissue from the Medellín brain bank, awaited further samples. On some, they would perform single-cell RNA sequencing, which can reveal how specific genes are expressed in brain cells. Kosik and his colleagues recently discovered the chemical receptor involved in the spread of tau from cell to cell, a receptor earlier found to interact with the APOE gene, which affects Alzheimer's risk. The sequencing results could shed light on how one of Piedrahita de Villegas's two rare mutations may have acted against the other.
"She was a very important patient; her story made news all over the world," Kosik said. "We learned a lot from her — and now that she's died, it's on us to make sure we give it a careful look."