Mutations in DNA leading to brain diseases.
A man carrying a genetic mutation known to cause early-onset Alzheimer’s disease postponed development of dementia until age 72. His story may hold clues for researchers developing drugs to treat Alzheimer’s and other diseases.
The patient was part of a large Columbian family with hereditary Alzheimer’s disease that generously allowed a joint team of researchers, including investigators from the University of Antioquia in Columbia, Massachusetts General Hospital and the Schepens Eye Research Institute of Massachusetts Eye and Ear, to study their 1,200-person kindred with genetic testing, brain imaging and thorough examination of their brain tissues after death, according to the journal Nature Medicine.
The patient in question carried a mutation in a gene called preseni-lin 1 (PSEN1) that is known to cause mild cognitive impairment (MCI) by a median age of 44 and dementia by 49 years. However, he was cognitively intact until age 67 and did not develop MCI until 70 or mild dementia until 72.
The answer to why this man was able to stave off the disease for so long is found, at least in part, in his genes. In addition to the mutation that causes Alzheimer’s, this man also carried a newly described mutation in the RELN gene, called Reelin-COLBOS, which appears to provide protection from Alzheimer’s disease. His sister, with the same hereditary risk, was found to have a mutation in a different protective gene. She avoided cognitive decline until age 58 and dementia until 61.
It is well known that patients with Alzheimer’s disease have a buildup of proteins called amyloid in their brains. It has been thought that groups of amyloid proteins, called plaques, cause the disease, and many drugs for Alzheimer’s disease have targeted amyloids. But this case revealed that both brother and sister had high levels of amyloid plaques in their brains and yet were not exhibiting signs of cognitive decline or dementia.
Examining how the protective mutation operates gives new insights into what may cause Alzheimer’s disease. The protective Reelin-COLBOS mutation plugs into a receptor in the cells of the brain, diminishing the activation of a protein called tau, known to form tangles in brains with Alzheimer’s disease. Of note, imaging of this man’s brain showed that although he had a lot of amyloid plaques, he had very few tau tangles in a region of his brain called the entorhinal cortex. If a mutation in another gene, called APOE, plugs into that receptor instead, it increases tau activation, speeding up the development of those tangles and cognitive decline.
This new genetic information may change the way researchers think about and develop treatments for this disease.
Female chemist at work in laboratory.
This approach has already been successful in other areas of medicine. For example, a woman with very low cholesterol was found to carry genetic mutations from both parents that caused her astonishing LDL cholesterol level of 14. Researchers studied this rare mutation and how it worked and used that information to create a medication to treat patients with very high cholesterol.
The same may someday be true for Alzheimer’s. Finding, understanding, replicating and mimicking the actions of protective mutations may be key to creating more precision medicines and fending off the onset of Alzheimer’s and other diseases.
