For decades, a small Colombian village has been plagued with a disease that’s left residents crippled with little to no memory.
Residents in Yarumal, a town of about 41,500 people in northwestern Columbia, have been suffering from Alzheimer’s disease at a rate much higher than other countries – all due to a genetic mutation.
The mutation, named E280A – commonly referred to as the ‘paisa mutation’ – has been passed down by a gene from a single common ancestor to an extended lineage of 6,000 people in the town and it causes Alzheimer’s in nearly every person that has it.
Located on the 14th chromosome, it leads to a devastating form of early-onset Alzheimer’s and leaves patients suffering from crippling dementia.
Those who have the mutation also have a higher risk of developing Alzheimer’s as early as their 30s. In the US, the average age is 49.
However, after decades of misery, one person’s unique genetic mutation could hold the secret to a cure.
Jennie Erin Smith, author of Valley of Forgetting: Alzheimer’s Families and the Search for a Cure, followed University of California Santa Barbara neuroscientist Dr Kenneth Kosik and Colombian neuroscientist Dr Francisco Lopera as they spent four decades studying Yarumal residents – until they stumbled upon Aliria Rosa Piedrahita de Villegas.
Piedrahita de Villegas, who died at 77 from cancer, was born and raised in Yarumal and had the paisa mutation. However, she spent her entire life without being afflicted by Alzheimer’s, even as her younger family members were plagued by it.
A perplexing case, scientists eventually learned that not only did she have the dementia gene, she had another mutation that actually safeguarded her from the disease.
Thousands of residents in Yarumal, a quaint town, have been suffering from Alzheimer’s disease – showing signs in their 30s and 40s, dying in their 50s – all due to a genetic mutation
Now, experts believe if they are able to understand and replicate the mysterious protective effect observed in Piedrahita de Villegas’s brain, they might be able to prevent the development of the disease in other people.
Dr Kosik recalled: ‘She was so fascinating because she had this mutation that just inevitably leads to Alzheimer’s disease and here she was, 70-something years old and still fine.’
Through her participation in the team’s research and her family’s willingness to donate her brain after her death in 2020, both neuroscientists have been able to make significant progress in understanding potential cures for a disease that affects about 44million people globally.
Alzheimer’s disease is one of the most common forms of dementia and mostly affects older adults. About 7million people in the US 65 and older live with the condition and over 100,00 die from it annually.
The illness begins due to the development of amyloid plaques and tau tangles in the brain – which damage and kill cells.
Amyloid protein molecules stick together in the brain cells, forming clumps called plaques. Tau proteins twist together in fiber-like strands called tangles.
The plaques and tangles block the ability of the brain’s neurons to send electrical and chemical signals back and forth.
Over time, this disruption causes permanent damage in the brain that leads to the development of Alzheimer’s.
The World Health Organization predicts 115million people worldwide will have Alzheimer’s by 2050. Pictured is a brain scan of a 74-year-old patient with the condition
While there is no clear cause of the disease, experts believe it can develop due to genetic mutations and lifestyle choices, such as physical inactivity, unhealthy diet and social isolation.
There is no cure but doctors can prescribe treatments and therapies to try and ease symptoms.
Dr Kosik believes he may have now uncovered previously unknown clues as to how Piedrahita de Villegas managed to evade the disease while her entire family succumbed.
Pictured: University of California Santa Barbara neuroscientist Dr Kenneth Kosik
Along with the UCSB neuroscientist, investigators at Massachusetts General Hospital found Piedrahita de Villegas’s brain had exceptionally large quantities of amyloid protein but nearly no tau protein.
Due to the lack of tau protein, her brain didn’t develop the hallmark tangles of Alzheimer’s disease.
Dr Kosik said: ‘One clue that appeared when researchers examined her brain tissue [was] while Aliria had the same overproduction of plaques that the rest of her family had, the tangles of misfolded tau protein that typically accompany the plaques in Alzheimer’s patients in her were relatively scant, keeping intact things like motor skills and executive function.’
In addition to the paisa mutation, the team also found her DNA carried two copies of another rare gene mutation called apolipoprotein or APOE.
A single parent can pass down the mutation, located on the 14th chromosome – which causes a devastating form of early-onset Alzheimer’s and leave patients suffering from dementia
Also known as the Christchurch mutation, the APOE gene variant allowed her body to produce lipoproteins that protected her brain from Alzheimer’s disease by counteracting the effects of the amyloid protein-caused plaques.
Lipoproteins are molecules made of proteins and fats in the body and they carry cholesterol through the bloodstream to cells.
The two main groups of lipoproteins are called HDL (high-density lipoprotein) or ‘good’ cholesterol and LDL (low-density lipoprotein) or ‘bad’ cholesterol.
Now, scientists are hoping this discovery can lead to treatments or preventatives therapies for people with or at risk of the disease.
Dr Kosik said: ‘The probability of one rare mutation is very small, but a person with two exceptionally rare mutations in the setting of an Alzheimer’s rare mutation, how unlikely is that?
‘She was a very important patient; her story made news all over the world. 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.’
