Rare gene mutation linked with protection from Alzheimer’s disease
Scientists have linked a rare gene mutation with protecting a woman from developing symptoms associated with Alzheimer’s disease.
Researchers say it could be the first known candidate for a gene that has the potential to be used in the development of interventions to halt the progression of the disease.
Some people who carry mutations in genes known to cause early onset Alzheimer’s disease do not show signs of the condition until a very old age.
Researchers found one such person in a study of 1,200 individuals in Colombia for whom Alzheimer’s disease is extremely likely to develop owing to genetic predisposition.
The woman, from a large extended family with more than 6,000 living members, did not develop mild cognitive impairment until her seventies – nearly three decades after the typical age of onset.
Like her relatives who showed signs of dementia in their forties, the patient carried the E280A mutation in a gene called Presenilin 1 (PSEN1).
This gene has been shown to cause early onset Alzheimer’s disease, according to the research published in the Nature Medicine journal.
Analysis showed the woman had a high degree of brain amyloid pathology, a hallmark of the disease, but did not present with symptoms associated with the disease.
Researchers found she also had a rare variant of the APOE gene, called Christchurch.
They suggest this may have counteracted the detrimental effects of the PSEN1 mutation, which could have protected her against the disease.
In several experiments, they suggested mechanisms by which this mutation may exert its protective effects by impairing binding of APOE to certain sugars – called heparan sulphate proteoglycans (HSPG) – implicated in Alzheimer’s disease.
Co-author Dr Yakeel Quiroz, researcher at Massachusetts General Hospital, said: “This single case opens a new door for treatments of Alzheimer’s disease, based more on the resistance to Alzheimer’s pathology rather than on the cause of the disease.
“In other words, not necessarily focusing on reduction of pathology, as it has been done traditionally in the field, but instead promoting resistance even in the face of significant brain pathology.”
Co-lead author Dr Joseph Arboleda-Velasquez, of the Schepens Eye Research Institute of Massachusetts Eye and Ear, said: “This finding suggests that artificially modulating the binding of APOE to HSPG could have potential benefits for the treatment of Alzheimer’s disease, even in the context of high levels of amyloid pathology.”
Further research with larger samples is required to establish a definitive causal relationship between the mutation and protection from disease.
John Hardy, professor of neuroscience at University College London (UCL), said: “It is interesting that a person with this rare APOE variant has stayed well longer than would be predicted because of her presenilin mutation.
“And it is to be hoped that this spurs research into therapies using APOE because this is a neglected research area.
“It is, however, a single case report and it is prudent to be cautious about over interpreting single patient data.”
Dr Fiona Carragher, chief policy and research officer of the Alzheimer’s Society, said: “This is a rare example where the study of just one person could change the thinking of a whole research field.
“This breakthrough opens up a new and promising avenue of Alzheimer’s research, although further studies with larger numbers are needed.
“We need to understand more about how this protective gene mutation is working to make the brain more resilient to amyloid plaques, but the hope is that this exciting scientific advance could lead to new treatments and take us a step closer towards a cure for dementia.”