A Columbian woman in her 70s should have, by all indications, developed Alzheimer’s disease by her mid-40s. However, she remained to be healthy despite being at an increased risk of developing the disease. This raised the curiosity of researchers who performed a series of tests to reveal not only did she possess one of the 3 hallmark mutations of Alzheimer’s disease; she also carried a rare genetic mutation which has protected the woman from developing Alzheimer’s.
When thinking of genetic mutations, our minds immediately associate them with an increased risk of developing a disease or disruption in normal development. Mutations are rarely considered to be the cause of a positive effect, which in this case proves to be true. In some circumstances, mutations can in fact lower the risk of developing certain diseases. (Please read my previous article ‘Is aducanumab really a game change in the fight against Alzheimer's disease?’ to read more on the pathology of Alzheimer’s disease)
Early-onset Alzheimer’s disease is linked to the mutation of 3 defining genes; APP, PSEN1 and PSEN2. APP encodes for amyloid precursor protein, a transmembrane protein which can impact synaptic plasticity. A mutation in this gene can eventually lead to neurotoxicity. PSEN1 and PSEN2 encode for Presenilins, which are components of gamma-secretase complex. This complex is involved in the survival of neurons, synaptic mechanisms and memory. Mutations in these genes can result in neuronal toxicity. Having any of these 3 mutations can increase a person’s risk of developing early-onset Alzheimer’s disease, which happens to be the case for the Columbian woman.
This woman comes from a family that dominantly inherits Alzheimer’s Disease. She was part of an Alzheimer’s Prevention Registry in Columbia which monitored the progression of the disease in a group of people. Many retained the trademark Alzheimer’s signs, whereas this woman never did. Researchers showed that in 3 decades, the most the woman developed was mild cognitive impairment. Although this is a warning sign for Alzheimer’s, it is very possible that this woman may never suffer from dementia.
This grabbed the attention of researchers at Harvard University who, with the consent of the woman, conducted tests. The results from her brain imaging revealed that she retained the highest amyloid beta burden compared to everyone else in the cohort. This characteristic is undeniably consistent with the onset of the disease. The downstream effects of higher levels of amyloid would normally lead to inflammation and eventual degeneration and destruction of neurons. The imaging also showed that regions of the brain that should have been affected by these high amyloid levels were indeed healthy.
It was only after her entire genome was sequenced that the Christchurch mutation was found (named after the city in which it was first identified). This mutation consists of a single base pair switch that alters the protein produced by the gene APOE (Apolipoprotein E) found on chromosome 19. APOE is involved in the handling of fats in the body, including cholesterol. We all have 2 copies of the APOE gene, which consists of 3 variants of the gene. For each of us, the combinations of the APOE gene variants differ.
They could be the same and they could be different. This means that there are 6 possible combinations of the genes and it is these combinations which influence a person’s risk of Alzheimer’s disease, whether that is an increased risk, an average risk or a lower risk. The Christchurch mutation consists of both copies of the APOE gene being mutated and has shown to mitigate the effects of high amyloid levels in the brain.
This mutation has protected this woman from developing Alzheimer’s and has counteracted the downstream effects of the EOAD mutation that she also carries. The subsequent mechanisms of the Christchurch mutation could play a role in inspiring future treatments for Alzheimer’s and maybe even bring researchers one step further to finding a cure. Research into a treatment or cure for Alzheimer’s is still ongoing. With the exception of a Biogen’s new drug (Aducanumab) which is still in clinical trials, there are few targeted treatments that act as a prevention or inhibitor of the disease.
In the last year, significant progress has been made which could open up treatment options for Alzheimer’s patients, allowing for more patients to be treated, or even combination therapies to be developed. Following this case, which was published on November 4th, 2019 by Journal Nature Medicine, it is clear that understanding the disease is only one part of the puzzle in finding a successful treatment.
Future research into the disease should be carried out across diverse populations as some mutations are more prevalent in certain ethnicities. By expanding research we could discover much more and may find a cure for Alzheimer’s disease.