Christchurch discovery holds promise for Alzheimer’s disease –

A discovery made at the Christchurch Clinical School of Medicine 33 years ago may provide the key to treating Alzheimer’s disease.

In the last month interest in the Christchurch discovery has gone viral. International news agencies, including the New York Times and BBC, as well as the world’s leading science journals have all published stories talking about how the decades old research in Christchurch is linked to Alzheimer’s disease.

The renewed interest is due to a ground-breaking study that was published in Nature Medicine on a special 73-year-old Columbian woman. She has avoided early-onset Alzheimer’s disease, even though genetically she was highly susceptible to getting dementia in her forties.

The researchers linked her surprisingly good brain health to a mutated protein first identified by Christchurch scientists in 1986. The current work points to a real possibility of treating Alzheimer’s disease.

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This is big news because there are currently no effective treatments for this cruel disease. Patients with Alzheimer’s disease are slowly robbed of their memories, the ability to think and do simple tasks, and eventually their personality.

Alzheimer’s disease ranks third, behind cancer and heart disease, as the cause of death for older people.

Back in 1986, the Christchurch team of medical researchers was fascinated by cholesterol and heart disease. They had little interest in Alzheimer’s disease.

The Christchurch researchers wondered why some people have high levels of cholesterol and fat in their blood and why this led to an increased risk of premature heart attacks.

Then one day a patient with extraordinarily high cholesterol and fat in his blood turned up in a clinic run by Ed Janus​ and Robin Fraser at Christchurch Hospital.

These doctors noticed that the man had an abnormal blood protein. The protein, called ApoE, was known to transport cholesterol and fats around the body. To figure out exactly why the protein was abnormal, these curious clinicians turned to scientists in the Christchurch Clinical School of Medicine.

The scientists were Steve Brennan, Robin Carrell​ and a PhD student Mark Wardell. They were skilled at studying the structure and function of proteins, and identifying possible mutations in proteins.

Professor Tony Kettle of the  University of Otago, Christchurch, has honoured retired researchers.

Professor Tony Kettle of the University of Otago, Christchurch, has honoured retired researchers.

Given the technology of the time, they were faced with a challenge resembling molecular Cluedo. The puzzle could only be solved with a detailed understanding of chemistry and adept critical thinking skills.

Together they isolated the abnormal ApoE protein, identified its molecular defect, and traced it to a specific genetic mutation. The team called this mutated protein ApoE Christchurch.

They suggested that ApoE Christchurch would not stick to cells as well as the common forms of ApoE. Their study was published in the Journal of Clinical Investigations in 1987.

Time would show that the mutated ApoE is exceedingly rare. But it gave insight into how cholesterol and fats are moved around the body. The Christchurch study was funded by a small grant from the New Zealand Heart Foundation.

In recent years, other researchers have been studying a Columbian family that is the world’s largest known family of individuals with early-onset Alzheimer’s disease.

About 20 per cent of the 6000 people in this extended family have a fast and highly predictable disease trajectory. The affected family members show up with mild memory problems in their early 40s and rapidly progress to dementia over the next five years.

The researchers were puzzled by a 73-year-old woman in this family who, based on her genetics, should have developed Alzheimer’s disease 30 years earlier. Yet she has only mild cognitive impairment. She has some problems remembering recent events but no evidence of dementia.

Alzheimer's cause plaques between nerve cells in the brain.


Alzheimer’s cause plaques between nerve cells in the brain.

Remarkably though, when her brain was scanned, she was found to have very high levels of plaque typical of Alzheimer’s disease. But she has few tangled proteins in her brain, which are another classic sign of the disease. She also has little brain degeneration.

These findings made the researchers even more curious. They dug deeper and examined all of her genes for possible mutations that might explain her good health.

The automated techniques they used turned up one important mutation. It was the presence of ApoE Christchurch.

The researchers showed that ApoE sticks to sugary molecules that coat brain cells. Forms of ApoE that are associated with Alzheimer’s disease stick strongly, while those least associated with the disease stick less well. ApoE Christchurch barely sticks at all.

This finding is reminiscent of the earlier results from Christchurch. They speculate that when ApoE sticks to brain cells it allows the toxic tangled proteins in affected cells to spread to healthy brain cells.

In this way, ApoE may seed the demise of individual brain cells and slowly destroy the brain. The researchers are now keen to find out whether drugs can prevent ApoE sticking to brain cells, just like ApoE Christchurch.

There is now real hope in finding a treatment for Alzheimer’s disease.

When the Christchurch team of scientists made their prescient discovery in 1986, they could not have known that three decades later their work would become world famous and important.

They could not have dreamt that their findings may eventually contribute to the treatment of Alzheimer’s disease.

These researchers are now retired. They can feel justifiably proud that through their curiosity, clever application of the technology available at the time, and wise use of limited funding, they have firmly placed a key piece in the jigsaw puzzle of health and disease.

* Tony Kettle is a research professor at the University of Otago Christchurch.


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