Rare genetic mutation delayed Alzheimer's in Colombian man

Several drugs approved by the Food and Drug Administration in the U.S. target amyloid plaques and attempt to remove them from the brain. However, they have only shown little improvement in the cognitive decline in patients.

Rare mutation

Francisco Lopera, a neurologist at the University of Antioquia in Medellín, Colombia has been studying the early onset of Alzheimer's in a family for over 40 years.

Lopera has zeroed in on the "paisa" mutation as the cause for the early onset of dementia in the family that has more than 6,000 members, Nature reported. The members of the family develop Alzheimer's in their forties or even earlier.

However, Lopera and his team also found an individual in the family, a man, who did not develop cognitive decline till the age of 67.

Scans of his brain revealed that there were high levels of amyloid plaques that resembled those of an individual with severe dementia. However, the man showed signs of only mild cognitive impairment.

After analyzing genomes of 1,200 Colombians with paisa mutation, the researchers found that the man had a second genetic mutation, in the gene that codes for the protein Reelin. The protein is known to have a role in the development of schizophrenia and autism, but not in Alzheimer's thus far.

The researchers then genetically engineered mice to have the mutation and found that it resulted in modification of the tau protein and prevented it from accumulating around neurons.

Interestingly, the man's sister also has the same two sets of mutations but developed severe dementia by the age of 64. The researchers suggest that head injuries and other disorders could have likely contributed to her developing cognitive decline earlier.

The mutated Reelin protein binds to another protein known as APOE, which has also been linked to Alzheimer's in previous studies. Both Reelin and APOE also compete to bind to receptors on neuronal cells and it appears that a stronger reelin or a weaker APOE can protect the brain against the disease.

The findings have opened new doors for Alzheimer's research since scientists can now move beyond the amyloid plaques and tau proteins in their bid to reverse the disease. The research was published in the journal Nature Medicine.

Abstract

We characterized the world’s second case with ascertained extreme resilience to autosomal dominant Alzheimer’s disease (ADAD). Side-by-side comparisons of this male case and the previously reported female case with ADAD homozygote for the APOE3 Christchurch (APOECh) variant allowed us to discern common features. The male remained cognitively intact until 67 years of age despite carrying a PSEN1-E280A mutation. Like the APOECh carrier, he had extremely elevated amyloid plaque burden and limited entorhinal Tau tangle burden. He did not carry the APOECh variant but was heterozygous for a rare variant in RELN (H3447R, termed COLBOS after the Colombia–Boston biomarker research study), a ligand that like apolipoprotein E binds to the VLDLr and APOEr2 receptors. RELN-COLBOS is a gain-of-function variant showing stronger ability to activate its canonical protein target Dab1 and reduce human Tau phosphorylation in a knockin mouse. A genetic variant in a case protected from ADAD suggests a role for RELN signaling in resilience to dementia.