A woman from Medillin, Columbia participated in a study led by researchers at the University of Antioquia in Medellín that has tracked roughly 6000 members of her extended family. About one-fifth of them carried an Alzheimer’s-causing mutation in a gene called presenilin 1; these carriers generally developed dementia in their late 40s. Yet the woman didn’t show the first signs of the disease until her 70s, even though she, too, carried the mutation. (Science, Nov 2019)
Despite being a member of one of the largest families afflicted by autosomal dominant Alzheimer’s disease, this woman also inherited two copies of a different mutation, the APOE3 Christchurch (R136S) mutation. Researchers currently think that inheriting two copies of this rare mutation protected this woman from early-onset dementia by inhibiting the binding of a specific sugar compound to the APOE gene.
The patient was flown to Mass General Hospital for imaging tests that revealed an astounding buildup of amyloid plaques in her brain. Her amyloid beta levels were far higher than the levels seen in young mutation carriers who are already cognitively impaired. The presenilin 1 mutation she carriers causes amyloid-beta overproduction. Her doctors described her as very sharp and independent with a brain that is functioning very well compared to people who are 45 or 50. She had only one year of formal education, and it is thought that her cognitive protection came from her biology rather than cognitive reserve.
Family members who inherited only one copy of the APOE3 Christchurch mutation (which is extremely rare on its own) still developed early-onset Alzheimer’s disease. The delay in dementia was only present in the woman who inherited two copies of the rare APOE3 Christchurch mutation. This case study provides a compelling example of an individual with a disease-causing mutation who remained cognitively unimpaired until much later in life. By identifying risk-reducing genes, investigators can take the next steps to understand the mechanism of action of protective mutations.
Dr. Guojun Bu, a member of the Cure Alzheimer’s fund research leadership group, was quoted in the New York Times article: “when you have delayed onset of Alzheimer’s by three decades, you say wow. The research suggests that instead of drugs attacking amyloid or tau, which have failed in many clinical trials, a medication or gene therapy targeting APOE could be promising.” APOE is an important gene for late-onset Alzheimer’s disease risk. A person has the possibility of inheriting three different versions of the gene: APOE2, APOE3, and APOE4. Inheriting two copies of APOE4 greatly increases the risk of developing Alzheimer’s disease. APOE2, on the other hand, lowers the risk of disease.
One of the scientists from the team, Dr. Francisco Lopera, said: “This case is a big window to discover new approaches.” There are several researchers that Cure Alzheimer’s Fund is actively supporting who are interested in the question of APOE and its ability to bind to various sugars and the impact that inhibiting this interaction can have on decreasing the spread of tau throughout the brain.
In a comment on AlzForum, Dr. David Holtzman provided the following opinion: “Since the person has a high amyloid load but less tau pathology, one wonders whether the effect of this ApoE variant is somehow decreasing the ability of ApoE to initiate a microglial-mediated inflammatory response to tau pathology.”
Dr. Holtzman also provided some clues regarding the potential mechanism of action for the protective mutation: “The fact that the ApoE3 Christchurch does not bind to the LDLR receptor of heparan sulfate proteoglycans (HSPG) very well suggests several mechanisms to further explore regarding how ApoE may be modulating inflammation, tauopathy progression, and neurodegeneration.”
Cure Alzheimer’s Fund has supported grants from Dr. Marc Diamond of the University of Texas Southwestern Medical Center in Dallas to study how tau binds to the sugar, heparan sulfate proteoglycan (HSPG). It is thought that tau binding to HSPG helps it spread throughout the brain. One hypothesis is that certain forms of APOE have different abilities to bind to HSPG. The less APOE that binds, the harder it is for tau to spread.
Studies in mouse models from Dr. Holtzman’s lab have suggested that the APOE4 genetic mutation can worsen tau pathology independently of its effect on amyloid. More studies with humans will be crucial to determine whether APOE influences the spread of tau.
In an interview with Science magazine, Cure Alzheimer’s Fund research leadership group member Dr. Marc Diamond said: “It will require much more study to understand if this relationship exists. The Christchurch mutation might have protective effects unrelated to HSPGs; it is also possible that genes other than Christchurch protected the woman.”
For the time being this woman’s story remains a compelling case for a rare mutation providing insights into a potentially protective mechanism in Alzheimer’s disease.
To read the full account of how this mutation was uncovered, please visit the New York Times: https://www.nytimes.com/2019/11/04/health/alzheimers-treatment-genetics.html
For more information on this remarkable case study, please visit Science:
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