New research, led by scientists at the University of Cambridge, suggests spontaneous DNA mutations that occur when a baby's brain is growing in the womb may help explain why so many people develop dementia without having any prior family history with the disease.
The vast majority of patients suffering from dementia, Alzheimer's disease, and Parkinson's disease have no family history of the conditions, making it extremely difficult for doctors to identify those most at risk. Early-onset Alzheimer's disease, for example, is one of the few identifiably heritable types of the disease, yet this only accounts for less than five percent of all diagnoses.
"As the global population ages, we're seeing increasing numbers of people affected by diseases such as Alzheimer's, yet we still don't understand enough about the majority of these cases," says Patrick Chinnery, one of the researchers on the project. "Why do some people get these diseases while others don't? We know genetics plays a part, but why do people with no family history develop the disease?"
The hypothesis is that non-heritable cases of dementia may be influenced by somatic mutations in specific genes known to be associated with neurodegenerative disease. A somatic mutation is a genetic alteration that occurs during cell division, after conception.
The new research examined 173 brain tissue samples using a new technique called ultra high-depth re-sequencing. This technique, when paired with a mathematical model, allowed the researchers to identify somatic DNA mutations from small brain samples and extrapolate those findings across the entire brain.
The results suggest that when an embryo is developing in the womb, certain spontaneous genetic mutations can appear in the developing brain. These mutations ultimately appear as "islands" of brain cells in a developed brain, and as we grow into adulthood can slowly seed the spread of the toxic proteins known to result in neurodegenerative disease.
"These spelling errors arise in our DNA as cells divide, and could explain why so many people develop diseases such as dementia when the individual has no family history," says Chinnery. "These mutations likely form when our brain develops before birth – in other words, they are sat there waiting to cause problems when we are older."
At this stage the conclusion is still reasonably hypothetical, as it is unclear how prominent these somatic mutations are in most common cases of dementia. However, the study does offer a compelling possible answer as to why every case of dementia is expressed differently from patient to patient. If the different somatic mutations are originally seeded during embryonic development in various "islands" of brain cells then the symptomatic progression of each patient would be entirely unique.
The research also suggests certain new treatments that are being designed to target rare genetic forms of neurodegenerative disease may actually be useful for patients without an explicit family history.
"Our data suggests the same genetic mechanisms could be responsible in non-inherited forms of these diseases," explains Chinnery, "so these patients may benefit from the treatments being developed for the rare genetic forms."
The new study was published in the journal Nature Communications.
Source: University of Cambridge
