Man with Genetic Predisposition for Alzheimer’s Has Another Mutation That Delayed Disease’s Onset

Early-onset Alzheimer’s affects people younger than age 65. The disease often strikes when a patient is in their 40s or 50s. A particular genetic variant, called the paisa mutation, leads people to get this earlier form of the disease. However, a new study has found a man with this genetic variant, but who also has a second gene mutation that appears to have staved off the disease for many years.

Research recently published in the journal Nature Medicine is the latest paper from Francisco Lopera at the University of Antioquia in Colombia. Lopera has spent several decades following a 6,000-member extended family often inflicted with the paisa mutation. Many of the family members have developed Alzheimer’s in their 40s or earlier.

However, one male relative impacted by the mutation didn’t develop dementia until age 67, despite having high levels of Alzheimer’s hallmarks amyloid plaques and tau protein in his brain. At the same time, there was one area of his brain related to memory and navigation – the entorhinal cortex – which had low levels of tau. Upon investigation, researchers found that he also had a mutation in gene coding for the reelin protein, which is linked with brain disorders including schizophrenia and autism.

To further understand how the protein may impact Alzheimer’s, the researchers genetically engineered mice with the same mutation, finding that in these mice, the tau protein was chemically modified and couldn’t cluster around neurons as easily.

The researchers noted that the mutated reelin protein binds to the same receptors as the APOE protein, which is another risk factor for Alzheimer’s. In 2019, the team encountered another woman with the paisa mutation who also had an APOE mutation and developed dementia 30 years later than average. Her brain had very high levels of amyloid, as well.

The researchers say these findings suggest that a stronger reelin protein or a weaker APOE protein could provide protective benefits against Alzheimer’s, and this information could be used in future treatments.

However, more research is needed, and the study authors write, “Because the comparative neuropathology was conducted in a relatively low number of cases, the results should not be considered definitive and they are only helpful as informative to generate hypotheses.”

The full study can be found here.