Gene Variant Neuro Link
12 September 2023
People with a specific variation in a gene that helps control the immune system are less likely to develop Parkinson’s, Alzheimer's and possibly other neurological disorders, according to a new study led by Stanford University.
Known as DR4, the variant is part of a family of genes that normally help our immune system pinpoint and destroy foreign invaders like bacteria and viruses. Scientists already knew from earlier studies that the DR4 variant seemed to protect against Parkinson's disease, but they have now identified common factors with Alzheimer's too.
The finding was surprising because Parkinson's and Alzheimer's are distinct conditions with different pathological biomarkers in the brain – Lewy bodies for Parkinson's, and abnormal tangles of a protein called tau in Alzheimer's.
The scientists gathered medical and genetic data from dozens of databanks around the world, giving them a diverse dataset that included participants from Europe, Asia, Latin America, and African America. Comparing 176,000 patients with Parkinson's or Alzheimer's disease with just under 2 million control cases revealed that those who carried the DR4 variant were significantly less likely to have either disease – more than 10 percent less likely, in fact.
The researchers then studied data from 7,000 autopsied brains affected by Alzheimer's, finding that those with the DR4 gene mutation had a later onset of symptoms and fewer neurofibrillary tangles, which correlate with the severity of the condition.
Biomarkers of Alzheimer's feature altered versions of the tau protein. One fragment in particular, known as acetylated PHF6 (a-PHF6), is crucial to forming these clumps. Lab experiments revealed DR4 proteins bound strongly to this fragment. Thanks to this robust connection, the immune system recognizes the tangled tau as foreign, and therefore fights it as a virus or bacteria.
Even though the tangles aren't a mechanism for Parkinson's, carrying DR4 correlated with symptoms starting later in that disease too. A smaller analysis of people with motor neurone disease found a similar trend, though results did not reach statistical significance, which researchers attributed to the smaller sample size.
Tens of millions of people around the world are diagnosed with Alzheimer's, while another ten million live with Parkinson's. These numbers will grow as the proportion of the population over 65 increases. Scientists think that people carrying this genetic variant might benefit from an a-PHF6 vaccine that could help to delay the progression of disease or even prevent neurological disease from developing at all.