Cases of dementia may arise from DNA ‘spelling mistakes’

A study led by researchers at the University of Cambridge believe they may have found an explanation for some dementias: spontaneous errors in our DNA as cells divide and replicate.


The findings suggest that for many people with neurodegenerative diseases such as Alzheimer’s disease and Parkinson’s disease, the roots of their condition will trace back to their time as an embryo developing in the womb.


In common neurodegenerative diseases, toxic proteins build up in the brain, destroying brain cells and damaging brain regions, leading to symptoms including personality changes, memory loss and loss of control.


Only around one in twenty patients has a family history, where genetic variants inherited from one or both parents contributes to disease risk.


“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,” said Professor Patrick Chinnery from the Medical Research Council (MRC) Mitochondrial Biology Unit and the Department of Clinical Neurosciences at the University of Cambridge. “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?”


Researchers examined 173 tissue samples from the Newcastle Brain Tissue Resource, part of the MRC’s UK Brain Banks Network. The samples came from 54 individual brains: 14 healthy individuals, 20 patients with Alzheimer’s and 20 patients with Lewy body dementia, a common type of dementia estimated to affect more than 100,000 people in the UK.


They found ‘somatic mutations’ (spontaneous, rather than inherited, errors in DNA) in 27 out of the 54 brains, including both healthy and diseased brains.


Together, these findings suggest that the mutations would have arisen during the developmental phase when the embryo is growing in the womb.


Combining their results with mathematical modelling, their findings suggest that ‘islands’ of brain cells containing these potentially important mutations are likely to be common in the general population.


“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 Professor 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.”


Reference: Keogh, MJ, Wei, W et al. High prevalence of focal and multi-focal somatic genetic variants in the human brain. Nature Comms; 15 Oct 2018; DOI: 10.1038/s41467-018-06331-w


18 October 2018.