A New Mutation That Protects Against Alzheimer’s Disease
By: Gunnar De Winter
Tags: Biology, Science, Health, Genetics, Neuroscience

A New Mutation That Protects Against Alzheimer’s Disease

With an aging global population, Alzheimer’s disease is a growing healthcare burden. Maybe help lies in our genes.

(Pixabay, 9415012)

Alzheimer genes

Alzheimer’s disease is a progressive brain condition associated with cognitive, memory, and behavioral problems. The disease is linked to plaques and tangles in the brain — protein clumps that appear to wreak havoc in the blob encased by our skulls.

There are genetic risk factors, and several genes seem to be involved. Perhaps the most well-known one is the gene APOE. One version of this gene, APOEε4, is associated with a significantly increased risk for Alzheimer’s.

However, this does not mean we’re powerless.

Several lifestyle factors can influence the risk for developing Alzheimer’s regardless of your genetic predisposition. Activity — both mental and physical — can reduce your risk. Physical exercise is good for you, including for your brain. But mental exercise matters too. Reading, writing, playing games, learning a new language, making music… All these activities seem to protect you against Alzheimer’s.

Diet matters as well. People who eat a Japanese or Mediterranean-styled diet, seem to have a lower risk for Alzheimer’s. On the other hand, people with a high intake of saturated fat and refined carbohydrates, appear to increase their risk of developing the disease. This food-brain link has spurred some to explore preventing Alzheimer’s with gut microbes.

To go over all the aspects of daily life that may offer (perhaps only slightl) protective benefits would take us too far, but here are twelve things you can do to reduce your risk for dementia in general.

Protective genes

Fragment of APOEε4 (Wikimedai commons, Ajpolino)

Above, we mentioned genes that increase your risk for Alzheimer’s disease. But there are also gene versions that might protect you. For example, the APOEε4 version of the APOE gene increases your risk (but genes are not destiny, so do not despair!). The APOEε2 version, on the other hand, could shield you against Alzheimer’s.

A recent study now identified a new protective gene variant: the APOE3 Christchurch (R136S) mutation.

What’s even more interesting is that this mutation was identified in a member of a family afflicted by a very strong genetic background of increased Alzheimer’s risk. In fact, this person carried a mutation in the PSEN1 gene that is strongly correlated with early-onset Alzheimer’s disease. Her family members with the same PSEN1 mutation developed the first signs of the disease in their forties.

The person in the study shared the exact same mutation, lived a similar lifestyle, yet only started to show the first signs of Alzheimer’s well into her seventies. A PET scan of her brain showed that she had more amyloid in her brain (often considered to be an important diagnostic tool for Alzheimer’s) than any of her family members.

What’s going on here?

Genome sequencing revealed the APOE3 Christchurch mutation. It’s not entirely clear how this mutation does what it does, but there are two clues:

The mutation impairs APOE’s ability to bind and remove fat. It protects against Alzheimer’s, but increases the risk for cardiovascular problems.

The mutation impairs APOE’s ability to bind to heparan sulfate proteoglycans, which are molecules that coat cells. In fact, this mutation had the lowest binding ability to the proteocglycans of all APOE’s.

Point number two might be the big one.

The authors note:

HSPGs [heparan sulfate proteoglycans] have been suggested to promote amyloid-β aggregation and neuronal uptake of extracellular tau, and APOE binding may be necessary for some of these effects.

The clumps of misfolded tau protein that are thought to be correlated with advanced Alzheimer’s disease appear to rely on APOE binding with the cell-covering proteoglycans, something the newly identified gene version is very bad at.

The hope, of course, is that:

…interventions that safely and sufficiently edit APOE, lower its expression, or modulate its pathogenic functions relating to HSPG interactions could have a profound impact on the treatment and prevention of Alzheimer’s disease.

Take care of your brain.