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Alzheimer's-linked gene missing in man with healthy brain

18 August 2014
Appeared in BioNews 767

A man without a working copy of a gene thought to be necessary for healthy brain function - and linked with Alzheimer's disease - has a 'grossly normal cognitive status', researchers have observed. Targeting this gene in people at-risk for the disease could help to protect them against it.

The 40-year-old African American does not have a working copy of apolipoprotein E (apoE) - a gene that has been implicated in Alzheimer's disease for over twenty years. But despite this, he has normal cognition and memory.

In healthy people, the gene produces a protein - also called apoE - which controls cholesterol levels. People who have the apoE4 version of the gene are at increased risk of developing Alzheimer's disease. Because it is found in the central nervous system, and due to its association with the dementia, apoE had previously been thought to be necessary for healthy brain function and questionable as a drug target.

The apparently normal brain function of the 40-year-old man seems to contradict these ideas. The findings could even indicate that, for people with the apoE4 version of the gene, minimising the amount of the apoE protein in the brain could decrease the risk of developing Alzheimer's disease.

'Surprisingly, with respect to central nervous function, it appears that having no apoE is better than having the apoE4 protein', wrote Dr Angel Mak of the University of Califormia, San Francisco, and colleagues in their report of the patient.

Similarly, analysis of his brain scans and cerebrospinal fluid levels, both of which can be used in the identification of Alzheimer's disease, revealed a perfectly healthy profile.

Professor Joachim Herz, who co-authored an editorial accompanying the case report said in an interview with CBS News that 'an Alzheimer's treatment that reduced brain apoE would theoretically have no or little cognitive side effects'.

However, there could be physical side effects. The faulty gene has caused the man to develop abnormally high cholesterol levels, and he has large, painful build-ups of fat beneath the skin on his hands, elbows and ears.

'It would obviously not be beneficial to reduce the risk for Alzheimer's disease if in the process we increase the risk for cardiovascular disease', said Professor Herz.

Another issue is the man's age: people who appear to be perfectly healthy in terms of their cognition and neurology at 40 could still go on to develop Alzheimer's disease later in life. It isn't yet clear how the absence of apoE might affect the man's brain as he gets closer to the peak onset for the disease - around 65.

Several apoE-targeted treatments for Alzheimer's disease are already in the early stages of development, and have been tested with some success in mice. But other studies have shown less success and it could be a long time before the approach is deemed suitable to trial in humans.

The research article and associated editorial were both published in the journal JAMA Neurology.

Delete ApoE Gene, Set Back Alzheimer’s, and Preserve Brain Health?
Genetic Engineering and Biotechnology News |  12 August 2014
Effects of the Absence of Apolipoprotein E on Lipoproteins, Neurocognitive Function, and Retinal Function
JAMA Neurology |  11 August 2014
Gene Long Linked to Alzheimer’s Memory Loss Is Innocent
Bloomberg |  12 August 2014
Is Apolipoprotein E Required for Cognitive Function in Humans?
JAMA Neurology |  11 August 2014
Man's rare condition may lead to new Alzheimer's treatments
CBS News |  12 August 2014
Normal cognition in patient without apolipoprotein E, risk factor for Alzheimer's
EurekAlert! (press release) |  11 August 2014
Tactic in Alzheimer’s Fight May Be Safe, Study Finds
New York Times |  11 August 2014
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