In a first of its kind human genome study, researchers have identified 13 new rare genomic variants associated with Alzheimer’s disease.
The lesser-known gene mutations may hold critical information about the biology of the disease and can lead to the development of new drugs for the devastating neurological condition, according to researchers from the Massachusetts General Hospital (MGH) in the US whose study has been published in the Alzheimer’s & Dementia: The Journal of the Alzheimer’s Association.
The new gene variants are linked with the functioning of synapses—the junctions that transmit information between neurons—development of neurons and neuroplasticity—the ability of neurons to reorganise the brain’s neural network.
“This paper brings us to the next stage of disease-gene discovery by allowing us to look at the entire sequence of the human genome and assess the rare genomic variants, which we couldn’t do before,” said lead author Dmitry Prokopenko from MGH’s McCance Center for Brain Health.
The results are published in “Rare gene variants are the dark matter of the human genome,” said Rudolph Tanzi, director of the hospital’s Genetics and Ageing Research Unit.
Of the three billion pairs of nucleotide bases that form a complete set of DNA, each person has 50 to 60 million gene variants—and 77 per cent are rare, he added.
Notably, Tanzi and colleagues co-discovered genes that cause early onset (prior to age 60) familial AD (that is, a form that runs in families), including the amyloid protein (A4) precursor (APP), and the presenilin genes (PSEN1 and PSEN2). Mutations in these genes lead to accumulation of amyloid plaques in the brain, a hallmark of AD.
The next 30 AD gene variants that were discovered are primarily linked to chronic inflammation in the brain (or neuroinflammation), which also increases the risk for this cognitive disease. However, loss of synapses is the neurological change that is most closely correlated with the severity of dementia in Alzheimer’s disease, yet no clear genetic links between the disease and these vital connections had previously been identified, as per the study.
Identifying less-common gene mutations that increase the risk for AD is important because they may hold critical information about the biology of the disease, said Tanzi.
This study was supported by the Cure Alzheimer’s Fund and grants from the National Institutes of Health.