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Thursday, 7 November 2019

Genetics of a Colombian woman offer new clues to fight against Alzheimer's disease

A woman with an Alzheimer-causing mutation and a large accumulation of beta-amyloid (in red) in her brain has maintained good cognitive health for decades. | Aaron Schultz

The search for new treatments to fight the dreaded Alzheimer's disease has gained new momentum in recent years. And sometimes, nature brings its own clues. In 2016, Harvard researchers analyzed the brain and blood of a 73-year-old woman from Medellin, Colombia, who had a genetic mutation that caused many in her family to develop dementia in old age. But for decades, she had naturally avoided the disease. The researchers therefore tried to understand how this was possible. In a new study, they report that another rare mutation (well known as a risk factor for Alzheimer's disease), that of the APOE gene , may also have protected it.

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Although the researchers can not prove that this mutation alone has prevented the disease, their study again draws attention to the possibility of preventing or treating Alzheimer's disease by targeting the APOE protein gene . An idea that, according to some researchers, has already spent too much time in the spotlight.

This is a very special case, " says Yadong Huang, a neuroscientist at the Gladstone Institutes in San Francisco, California, who did not participate in the research. " It could open up a very promising new avenue in both research and therapy ."

The gene for APOE , the most potent genetic risk factor for Alzheimer's disease, exists in three common forms (alleles). A variant called APOE2 reduces the risk of the disease. The most common variant, APOE3 , does not influence risk. APOE4 (allele 4) increases the risk; about half of people with the disease have at least one copy of this variant.

Researchers have long considered targeting APOE with therapies. To this end, a team from Cornell University will soon begin a clinical trial to "infuse" the APOE2 protective gene into the cerebrospinal fluid of people with two copies of APOE4 .

Protein APOE: genes still too little understood

However, many unanswered questions about  APOE prevented it from becoming a priority drug target. APOE protein binds and transports fats and is abundant in the brain. But "she's doing so much in the brain that's confusing," says Eric Reiman, neuroscientist at Banner Alzheimer's Institute in Phoenix and co-author of the new study, published in Nature Medicine.

APOE4 appears to promote the formation of sticky plaques of beta-amyloid protein, which obstructs the brain in Alzheimer's disease. But the powerful anti-amyloid drugs have largely not benefited patients participating in clinical trials. Some researchers have found no reason to try APOE- targeted therapy , which just seemed like "an anti-amyloid treatment for the poor," says Reiman.

On the left, the two theories explaining Alzheimer's disease: the amyloid hypothesis and that of ApoE (both producing a cognitive decline). Right: Due to stress or injury, the ApoE gene can express itself. This causes overproduction of the ApoE4 protein, which will alter the function of neurons and neuronal mitochondria, leading to learning and memory impairments. Credits: L. Mucke et al. (2012), adapted by T. Lombry


A special case that could change everything about APOE

But the case of the Colombian woman (the research team keeps her name confidential) suggests other ways that APOE can affect the risk of developing Alzheimer's disease. The woman in question participated in a study conducted by researchers from the University of Antioquia in Medellín, which tracked about 6,000 members of her extended family.

Approximately one-fifth of them had a mutation causing Alzheimer's disease in a gene for a protein called presenilin 1 ; these carriers usually developed dementia in their late forties. However, the woman did not show the first signs of the disease until she was 70, even though she was carrying the mutation. " It's really a special case ," says cell biologist Joseph Arboleda-Velasquez of Harvard Medical School in Boston.

At Harvard, a woman's brain positron emission tomography revealed greater amyloid accumulation than any other member of the scanned family. " It was very striking, " says Yakeel Quiroz, clinical neuropsychologist at Massachusetts General Hospital and Harvard Medical School.

However, the team found no evidence of major neuronal damage and minimal accumulation of another feature of Alzheimer's disease: misfolded tau protein.

Whatever protection the woman had, she did not depend on the fact that the brain was free of amyloid. Her case argues instead for the idea that tau plays a "pivotal role in the clinical manifestations of Alzheimer's disease," says Jennifer Yokoyama, a neurogenetician at the University of California at San Francisco.

A rare mutation in the APOE gene

Sequencing of the genome revealed two copies of a rare mutation in the APOE gene . Discovered for the first time in 1987, the mutation, known as the "Christchurch mutation," occurs in a region distinct from those that determine the APOE2 , 3 , or 4 status of a given person. The Colombian woman wore the neutral variant, APOE3 .

Previous research had revealed that the mutation of Christchurch, as the mutation APOE2 , impairs the ability of APOE to bind and eliminate fat, which sometimes leads to cardiovascular disease.

The researchers also found that this mutation prevented APOE from binding strongly to other molecules called heparan sulfate proteoglycans (HSPGs), which cover neurons and other cells "like a carpet," says Guojun Bu, a neuroscientist at Mayo Clinic of Jacksonville, Florida, who studied the interaction between these molecules and APOE.

APOE2 can also affect the ability of the protein to bind to HSPGs. But the way this mechanism protects against the disease is unclear. A likely clue is the research of neuroscientist Marc Diamond and colleagues at Southwestern Medical Center at the University of Texas at Dallas, suggesting that toxic tau protein relies on HSPGs to promote cell-to-cell propagation. Perhaps the less APOE is related to HSPG, the more difficult it is for tau to spread.

However, more studies will be needed to understand if this relationship exists, Diamond warns. The Christchurch mutation could have protective effects unrelated to HSPGs. It is also possible that other genetic mutations (such as Christchurch) have protected the woman.

If the impediments to normal APOE binding had really spared it from Alzheimer's disease, future treatments could be aimed at mimicking this effect. An antibody or small molecule could cling to the APOE protein to interfere with binding; Gene editing could change the structure of APOE to mimic the mutation of Christchurch. Or, a "gene silencing" approach could reduce the production of APOE.

Reiman hopes that the new study will rally researchers to pursue APOE- related treatments . Quiroz, Arboleda-Velasquez and others also published an article (in pre-print) on November 2 showing that people with two copies of APOE2 have a much lower risk of developing Alzheimer's than previously estimated (about 99% of less than people with two copies of APOE4 ).

" When it comes to finding a treatment that could have a profound impact on the disease, APOE may be among the most obvious targets, " concludes Reiman.


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