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Brain-tissue slides in Medell\u00edn, Colombia.Credit: Federico Rios Escobar\/New York Times\/Redux\/eyevine<\/p>\n
In 1982, neurologist Francisco Lopera and his colleagues at the University of Antioquia in Medell\u00edn, Colombia, began studying a family for whom Alzheimer\u2019s disease was a fact of life. Members of this family would invariably develop mild cognitive impairment at around 45 years of age. This would typically progress to dementia by the age of 50 as the hallmark protein plaques and tangles of Alzheimer\u2019s accumulated in their brains, and death before their 60th birthday1<\/a>.<\/p>\n Nature Outlook: Alzheimer\u2019s disease<\/p>\n <\/a><\/p>\n The early onset of the disease and its frequent occurrence in this extended family suggested a genetic cause. Lopera\u2019s team, in collaboration with neuroscientist Kenneth Kosik, then at Harvard Medical School in Boston, Massachusetts, found that more than 100 affected people \u2014 all blood relatives \u2014 shared a mutation in the gene presenilin 1 (PSEN1)2<\/a>. Mutations in presenilin genes are the most common cause of early-onset Alzheimer\u2019s, and the Colombian cohort is the single largest group affected, with about 1,200 carriers of the mutation identified to this day.<\/p>\n But in every family, there is someone who goes against the grain. In this case, it is a person whose story challenges scientists\u2019 understanding of Alzheimer\u2019s disease pathology.<\/p>\n In 2019, researchers introduced the world to a woman born in rural Angostura, Colombia, who, like so many of her relatives, carried the PSEN1 mutation. But unlike them, she did not develop Alzheimer\u2019s disease by the age of 50. Even at 72, she was barely showing symptoms. Her name was kept hidden until she died of cancer in 2020, one month shy of her 78th birthday. Today, researchers are still trying to work out why Aliria Rosa Piedrahita followed such a different path \u2014 and whether it might point the way to treatments that can help others.<\/p>\n A golden brain<\/b><\/p>\n Piedrahita used to joke that she had a \u201cgolden brain\u201d, and a scan revealed what she might have meant. Her brain contained extremely high levels of amyloid-\u03b2 plaques, but minimal neuroinflammation. Something else was missing, too. \u201cThe tangles of tau proteins that invariably accompany the plaques spared most of the brain \u2014 particularly those regions associated with clinical dementia,\u201d says Kosik, now at the University of California, Santa Barbara. \u201cRight away we learnt something important,\u201d he says \u2014 that the plaques in her brain were not, in themselves, enough to cause cognitive issues.<\/p>\n Genetic testing showed that PSEN1 was not her only mutated gene. She also carried a mutated form of the gene APOE. One form of this gene, APOE4, is a major risk factor for late-onset Alzheimer\u2019s disease. Two other versions are associated with either lower risk (APOE2) or typically have no effect (APOE3).<\/p>\n Piedrahita had two copies of the most common version, APOE3. However, hers was a rare variant called APOE3 Christchurch or APOE3Ch. This mutation affects how the APOE protein binds to a sugar\u2013protein compound called HSPG, which helps tau to propagate through the brain. APOE3Ch showed the lowest affinity for HSPG of any form of the protein; APOE4 showed the highest3<\/a>.<\/p>\n Animal studies recreated the unusual pattern of proteins seen in Piedrahita\u2019s brain. When the APOE3Ch mutation was introduced into mice that would otherwise develop disease similar to Alzheimer\u2019s, it protected against neurodegeneration. These mice had fewer, less widespread tau tangles, less damage to neurons, and less cognitive impairment4<\/a>. Moreover, reduced binding of APOE3Ch to HSPG triggered degradation of tau by myeloid cells in the brain. \u201cThis may explain why tau seeding and spreading was less,\u201d says David Holtzman, a neurologist and neuroscientist at Washington University School of Medicine in St. Louis, Missouri, and senior author of the study.<\/p>\n A team led by Yadong Huang, a neuroscientist at the Gladstone Institutes in San Francisco, California, explored whether APOE3Ch could also protect against late-onset Alzheimer\u2019s in different model systems. It found that engineering the mutation into the APOE4 gene reduces the accumulation of tau, as well as the neuroinflammation and neurodegeneration that would otherwise be expected5<\/a>. \u201cIt is really striking that the Christchurch mutation can lead to such broad protection,\u201d says Huang.<\/p>\n Basis for treatment<\/b><\/p>\n The mechanisms behind the protective effects of APOE3Ch suggest that blocking the interaction between APOE and HSPG might help to treat Alzheimer\u2019s disease.<\/p>\n![\"\"](\"https:\/\/www.europesays.com\/uk\/wp-content\/uploads\/2025\/05\/d41586-025-01103-1_50851004.jpg\"\/)
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