Man With Rare Genetic Mutation Shows Unprecedented Resistance to Alzheimer’s

by Staff Writer
May 17, 2023 at 11:05 AM UTC

Mutation in a patient with ADAD may protect against Alzheimer's.

Clinical Relevance: A newly discovered genetic variant could provide therapeutic clues for Alzheimer’s disease

  • A patient with a never-before-seen genetic mutation is only the second patient to show exceptional resistance to a rare form of Alzheimer’s known as ADAD.
  • Despite heavy plaque buildup in the brain, the man remained cognitively healthy until his late sixties.
  • The mutation, named RELN-COLBOS, appeared to mitigate tau pathologies particularly in the entorhinal cortex, a brain region associated with memory and sense of time.

 

A Colombian man, carrying a never-before-seen genetic mutation, is only the second case ever recorded of having an exceptional resistance to a specific type of Alzheimer’s disease called autosomal dominant Alzheimer’s disease (ADAD.) 

ADAD is an autosomal, or inherited, form of Alzheimer’s characterized by cognitive decline starting as early as 30 years old. Genetic mutations in specific genes like PSEN1, PSEN2, or APP are the suspected cause. A person with the mutation has a 50 percent chance of passing it on to their children.

The Case Study

As described by a recent paper in the journal Nature Medicine, the man did not start showing signs of cognitive problems or memory loss until around the age of 67. At age 70, doctors diagnosed him with mild cognitive impairment and his language skills worsened. By age 73, he progressed to moderate dementia and required assistance with daily activities.

The patient was discovered as part of a research effort known as Colombia–Boston biomarker research study, or COLBOS. Brain imaging tests performed by Harvard researchers at Massachusetts General Hospital revealed high levels of amyloid plaques in his brain, which is a hallmark of Alzheimer’s. 

His sister also carried the same genetic mutation. She was diagnosed with severe dementia at age 64 which progressed to end-stage dementia by age 72. Her cognitive slide began at the age of 58—earlier than her brother but later than expected for someone carrying the same mutation. Other health issues contributed to her death at the age of 73.

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Underlying Mechanisms

Genetic analysis confirmed that the patient carried the PSEN1-E280A gene mutations linked to ADAD. Both he and his sister also had a variant in the RELN gene called RELN-COLBOS. RELN is a gene related to tau phosphorylation, a process implicated in Alzheimer’s disease. 

Specifically, the H3447R variant in the C-terminal region of the RELN gene affects how RELN interacts with proteins on cell membranes. It binds more strongly to a molecule called heparin and interacts differently with a protein called neuropilin 1 (NRP1). This suggests that the RELN-COLBOS variant has altered interactions with certain molecules and may contribute to its protective effects.

Overall, the man had a larger build up of brain plaques compared to others of the same age and with similar mutations. But imaging revealed fewer tau tangles in his entorhinal cortex, an area tied to memory, navigation, and perception of time. Tau sparing in this region may help guard against dementia, the authors speculated.

Additional lab experiments in cells and mice showed that the RELN-COLBOS variant increased the phosphorylation of a protein called Dab1. In mice carrying a similar genetic change, the researchers observed increased phosphorylation of Dab1 in the cerebellum.

Genetic Variant and Resilience

Researchers compared the patient in the current study with a woman diagnosed with ADAD in an earlier study. They reported her mutation on a different gene called apolipoprotein E (APOE). Despite dense brain plaque, she maintained intact cognitive abilities for almost 30 years beyond the expected disease onset.

Understanding the mechanisms involved in RELN-mediated protection could have therapeutic implications, the researchers proposed. They also said their findings highlight the importance of exploring the entorhinal cortex.

“The genetic variant we have identified points to a pathway that can produce extreme resilience and protection against Alzheimer’s disease symptoms,” co-senior author Joseph Arboleda-Velasquez, associate professor of ophthalmology at Mass Eye and Ear, said in a statement.

He added: “These are the kinds of insights we cannot gain without patients. They are showing us what’s important when it comes to protection, and challenging many of the field’s assumptions about Alzheimer’s disease and its progression.” 

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