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Rare Mutation in Colombian Woman Reveals New Targets for Alzheimer's Research and Treatment

In This Article

  • In 2016, a 73-year-old Colombian woman with familial early-onset Alzheimer's disease had her brain and genome examined to determine the factors that protected her from cognitive impairment for decades past the expected age of clinical onset
  • The woman carried a presenilin 1 mutation, which causes Alzheimer's disease (AD) by the age of 50 and was found in over 1.000 members of her extended family
  • Researchers from Massachusetts General Hospital found that the woman also carried two copies of a rare mutation in the APOE gene known as Christchurch, which prevents APOE from binding to certain molecules

Analysis of the genome of a 73-year-old Colombian woman has opened a new avenue for Alzheimer's disease (AD) research and treatment.

A team of researchers led by Yakeel T. Quiroz, PhD, a neuropsychologist and director of the Familial Dementia Neuroimaging Lab and the Multicultural Alzheimer's Prevention Program at Massachusetts General Hospital, Joseph Arboleda-Velasquez, MD, PhD, assistant scientist at Schepens Eye Research Institute of Mass Eye and Ear, and colleagues reported that a mutation in the well-known Alzheimer's risk gene APOE may have protected the woman's cognition and functional independence for decades longer than expected.

Surprisingly, the results of positron emission tomography scans of the woman's brain showed more amyloid buildup than in any other family member, but showed no major damage to neurons and minimal buildup of the misfolded protein tau. The woman also carried the Alzheimer's-causing presenilin 1 (PSEN1) mutation, but did not develop mild cognitive impairment for thirty years past the expected age of clinical onset for people with a PSEN1 mutation.

Genome sequencing revealed that the woman carried two copies of an APOE3 mutation known as Christchurch, which prevents APOE protein from binding strongly to heparan sulfate proteoglycans (HSPGs). Researchers posit that HSPGs facilitate the spread of tau protein, which happens less as the Christchurch mutation decreases the ability of APOE to bind HSPGs.

The amount of amyloid buildup in the woman's brain may also indicate that her protection from cognitive impairment did not depend on the breakdown of amyloid in the brain.

While the relationship between the Christchurch mutation, HSPGs, tau buildup and neurodegeneration remains unclear, researchers say that the findings of the case study could serve as a foundation for future treatments that mimic the effects of the mutation on the binding effects of APOE.

Learn more about the Multicultural Alzheimer's Prevention Program

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