Researchers discover genetic variant that could ‘protect against Alzheimer’s by helping to get rid of toxic protein clumps in the brain’
- Variations in the gene MS4A4A boosted levels of receptor TREM2 in spinal fluid
- TREM2 helps remove damaged nerve cells; low levels linked to Alzheimer’s
- Receptor ‘ingests’ the protein amyloid β, causes plaque in Alzheimer’s brain
A genetic variant which may protect against Alzheimer’s has been uncovered by researchers in a potential breakthrough.
Scientists at Washington University in St Louis analysed spinal fluid samples from around 800 participants. Some had the memory-robbing disorder.
They discovered variations in the gene MS4A4A altered levels of a protein heavily linked to Alzheimer’s, called TREM2.
Some variants were linked with either higher levels of the protein, which scientists said appeared to reduce the risk of Alzheimer’s.
Others were linked to lower levels of TREM2, which the results suggested increased the risk of the disorder.
The genes influence Alzheimer’s risk by altering levels of TREM2, a protein (shown stained in red) that is believed to help microglia cells clear excessive amounts of the Alzheimer’s proteins amyloid and tau from the brain. The MS4A4A protein is shown stained in green
TREM2 is thought to ‘ingest’ the proteins amyloid β and tau, which cause the tell-tale plaques in an Alzheimer’s patient’s brain.
The researchers now hope MS4A4A could be a ‘target’ for future Alzheimer’s treatments. It is currently incurable, with existing therapies only being able to temporarily ease symptoms.
Dementia affects 850,000 people in the UK, of which 62 per cent have Alzheimer’s – the most common form, according to the Alzheimer’s Society.
And in the US, 5.8 million people live with the condition, which is set to rise to nearly 14 million by 2050, Alzheimer’s Association statistics show.
TREM2 is known to play a ‘critical role’ in the activation and survival of microglial cells, the researchers wrote in the journal Science Translational Medicine.
Scientists at Washington University in St Louis analysed spinal fluid samples from around 800 participants. Some had the memory-robbing disorder
These are a specialised form of immune cell that removes damaged neurones and maintains the health of the central nervous system.
HOW TO DETECT ALZHEIMER’S
Alzheimer’s disease is a progressive brain disorder that slowly destroys memory, thinking skills and the ability to perform simple tasks.
It is the cause of 60 percent to 70 percent of cases of dementia.
The majority of people with Alzheimer’s are age 65 and older.
More than five million Americans have Alzheimer’s.
It is unknown what causes Alzheimer’s. Those who have the APOE gene are more likely to develop late-onset Alzheimer’s.
Signs and symptoms:
- Difficulty remembering newly learned information
- Mood and behavioral changes
- Suspicion about family, friends and professional caregivers
- More serious memory loss
- Difficulty with speaking, swallowing and walking
Stages of Alzheimer’s:
- Mild Alzheimer’s (early-stage) – A person may be able to function independently but is having memory lapses
- Moderate Alzheimer’s (middle-stage) – Typically the longest stage, the person may confuse words, get frustrated or angry, or have sudden behavioral changes
- Severe Alzheimer’s disease (late-stage) – In the final stage, individuals lose the ability to respond to their environment, carry on a conversation and, eventually, control movement
There is no known cure for Alzheimer’s, but experts suggest physical exercise, social interaction and adding brain boosting omega-3 fats to your diet to prevent or slowdown the onset of symptoms.
A past study suggested variations to TREM2 increase the risk of Alzheimer’s by almost three times. However, TREM2’s exact role in the disease is ‘not well understood’.
To better grasp how it is linked to Alzheimer’s, the team of researchers analysed genes in spinal fluid samples from 813 participants.
Of these, 172 had Alzheimer’s, 221 had ‘late mild cognitive impairment’, 183 had ‘early mild cognitive impairment’, 68 had ‘significant memory concerns’ and 169 were ‘cognitively normal’.
Results revealed variations in the genes MS4A4A and MS4A6A were linked with higher concentrations of TREM2 in the participants’ spinal fluid.
Higher TREM2 levels were then linked to a reduced risk of Alzheimer’s and an older age at the disease’s onset.
Other variants in the gene cluster linked to a greater risk of Alzheimer’s disease were linked with lower levels of TREM2, the researchers said.
‘We observed TREM2 risk variants more often in people who had Alzheimer’s or were mildly cognitively impaired,’ said co-senior investigator Dr Celeste Karch.
‘It turns out that about 30 percent of the population in the study had variations in the MS4A4A gene that appear to affect their risk for developing Alzheimer’s disease.
‘Some variants protected people from Alzheimer’s or made them more resilient while others increased their risk.’
In a second part of the experiment, the researchers overexpressed MS4A4A in human immune cells called macrophages in the laboratory.
This caused TREM2 production to increase, whereas ‘knocking out’ MS4A4A reduced the levels of the protein.
How TREM2 may protect against Alzheimer’s is unclear. The receptor has been linked to increased phagocytosis ‘in the presence of amyloid β’.
Phagocytosis occurs when cells ingest or engulf bacteria, particles or other cells.
‘These results suggest MS4A4A may be a therapeutic target for Alzheimer’s,’ the researchers wrote.
Future studies should look at whether changes to TREM2 concentrations in spinal fluid are correlated with ‘neurodegeneration’ or the presence of amyloid β, they added.
THE WAR ON ALZHEIMER’S: MORE THAN 150 TRIALS HAVE FAILED IN 20 YEARS
Scientists have for years been scrambling to find a way to treat or prevent Alzheimer’s disease, which accounts for around two thirds of the 50million dementia patients worldwide.
But attempts to tackle the brain-destroying disease have been beset with failures.
In March this year the pharmaceutical company Biogen abandoned two late-stage trials of a promising Alzheimer’s drug, aducanumab, which it hoped would work by clearing the brain of sticky build-ups.
After years of research and testing the company decided its prospects looked poor in the end stages of a human trial and pulled the plug, wiping $18billion (£13.8bn) off its own market value.
In January, the firm Roche announced it was discontinuing two trials which were in their third phase of human testing.
It was trying to develop crenezumab, which worked by preventing build-up of plaques in the brain and had already been proven safe, but wasn’t having the desired results.
Between 1998 and 2017 there were around 146 failed attempts to develop Alzheimer’s drugs, according to science news website, BioSpace.
Billions of dollars have been invested in the industry and a successful, marketable treatment would likely make a fortune for the company which gets there first.
Experts have said a difficulty in testing drugs on the right people may be partly to blame – Alzheimer’s is rarely diagnosed before it has taken hold and, by that time, it is often too late or studying people becomes too difficult.
For drugs which try to modify the course of a disease, trials often have to be longer and more in-depth, making them more difficult and costly, researchers wrote in the journal Expert Opinion on Investigational Drugs.
The same researchers added scientists may be struggling to find the correct dose of drugs which could work, and that they may be recruiting the wrong types of people to test them on.