Ongoing clinical research into Alzheimer’s disease is uncovering previously unknown information about the genetic risk factors for the condition — findings that could potentially pave the way for more effective approaches to treatment.
An umbrella term used to describe different progressive brain disorders such as Alzheimer’s disease, dementia is one of the most pressing public health issues of our time.
On a personal level, the symptoms associated with the ongoing decline in brain function are deeply distressing both for those living with the condition and their loved ones. On a national level, dementia costs the UK economy £26 billion each year — and its prevalence is only increasing.
According to the Alzheimer’s Society, 850,000 people currently live with dementia in the UK. By 2025, numbers are expected to reach 1 million. By 2051, that figure is set to soar to 2 million. Every three minutes, someone is diagnosed with the condition.
These statistics are certainly sobering, especially given that there is currently no cure for the illness. Despite the bleak outlook, however, novel studies into the potential causes of dementia are laying the groundwork for improved pharmacological treatment in the future.
As we mark this year’s World Alzheimer’s Day, we take a look at the promising developments taking place in gene therapy and examine whether these breakthroughs could one day lead to preventative treatments for people at risk of developing the disease.
What causes Alzheimer’s disease?
Scientists believe that for most people, Alzheimer’s disease — the most common type of dementia, affecting 62% of those diagnosed — is caused by a combination of genetic, lifestyle and environmental factors that affect the brain over time.
On a chemical level, research so far suggests that the condition is caused by the abnormal build-up of two types of proteins in and around brain cells. These proteins are called a). amyloid-beta, which clump together to form plaques around brain cells, and b). tau, which deposits to form tangles within brain cells.
Though we cannot accurately ascertain what triggers this process, scientists have discovered that changes in the neurochemistry and anatomy of the brain begin decades before symptoms appear.
Early detection is vital. By identifying Alzheimer’s disease years before symptoms appear, clinicians can plan adequate care and start therapeutic interventions as early as possible.
The advent of gene therapy in Alzheimer’s research
Crucially, studies in gene therapy — an experimental therapeutic pathway that introduces genetic materials into cells in order to treat or prevent disease — have found evidence that some people are more at risk of developing the condition than others due to genetic factors.
The apolipoprotein E4 (ApoE4) allele — a version of the ApoE gene which is involved in transporting cholesterol throughout the body — has been identified as the greatest genetic risk factor for late-onset Alzheimer’s disease. People with two copies of the ApoE4 gene are up to twelve types more likely to develop Alzheimer’s disease than those with ApoE2 and APoE3 versions of the gene.
Research by the University of Eastern Finland (in collaboration with the University of Wollongong and the University of Helsinki) has revealed that ApoE4 impairs the function of human brain immune cells called microglia. The study also found that ApoE4 reduces the ability of the cells to migrate and phagocytose pathogenic material. By impeding these vital brain functions, ApoE4 can disrupt homeostasis and decrease protection against pathogens.
According to the Alzheimer’s Association, about 65% of people with the condition have at least one copy of ApoE4. For people born with two high-risk copies, one from each parent, the onset of dementia essentially becomes an inevitability if they live long enough. Evidently, understanding more about the genetic basis of Alzheimer’s disease is an urgent undertaking.
At Weill Cornell Medicine in New York City, a pioneering research team led by Ronald Crystal has been conducting clinical trials on people who have two copies of the ApoE4 gene and mild to severe dementia. By flooding the brain with ApoE2, a version of the gene previously shown to have protective effects against the progression of the disease, researchers hope to slow down Alzheimer’s disease.
It’s worth noting that researchers are wary of positing ApoE4 as the sole cause of Alzheimer’s disease — after all, people with ApoE2 and ApoE3 develop the condition, too. There have also been recent studies investigating a possible neurological link between migraine and Alzheimer’s. However, by continuing to test the ability of the ApoE2 gene to prevent the disease, the gene therapy route does offer hope that we might one day be able to stop Alzheimer’s before it begins.
Hope for the future
Because recent trends in Alzheimer’s research suggest that the disease begins decades before the onset of symptoms, understanding the genetic link seems to be the most promising avenue for further therapeutic research.
Though recent attempts to develop drugs that attack the plaque-inducing amyloid-beta protein have ended in a string of negative trial results, the Financial Times argues that lessons learned from these setbacks are “providing new targets in the fight against the disease.”
Thanks to the results of these trials, scientists now believe that amyloid deposits are the wrong target. Instead, many feel that the tau protein is a better therapeutic target because its dynamics more closely mirror the progression of Alzheimer’s disease than amyloid. For others, data suggests that mitochondrial dysfunction caused by a loss of the NCLX protein is a potential trigger of Alzheimer’s pathology.
Regardless of stance, there exists a concerted effort among the scientific community to uncover novel therapeutic treatments for Alzheimer’s disease. As Dr Mark Mintun, vice-president of pain and neurodegeneration R&D at Eli Lilly, told the FT:
“It is hard to find an example of such a major disease in which pharmaceutical companies and academic scientists collaborate more than we do in Alzheimer’s.”
Indeed, the global CNS gene therapy market is set to grow exponentially in the next decade, galvanising hope that sufficient funding can be secured to accelerate clinical trials and pursue preventative treatments. Finding the therapeutic means to prevent Alzheimer’s disease may seem like a long shot, but with the prevalence of the disease set to grow, doing so is one of the most pressing tasks of our time.
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