Alzheimer’s disease (AD) is characterised by the accumulation of amyloid plaques in the brain, sticky clusters of proteins that damage neurons involved in memory, reasoning and other cognitive processes. In a new study published in the Nature Medicine journal, researchers show how a little-known gene called Reelin protected against the development of Alzheimer’s dementia in a man carrying the presenilin 1 E280A mutation. This finding has the potential to inform future therapies to build resilience against AD and cognitive decline. The COLBOS study follows the world’s largest known family group of people with autosomal dominant AD: an inherited, genetic form of AD that leads to the development of dementia by the age of 50, on average.
The causative mutation, called PSEN1-E280A, leads to defective processing of amyloid proteins, and their accelerated accumulation in the brain. The man who was the subject of the Nature Medicine research carried this mutation, and had extremely elevated amounts of amyloid plaques in his brain. However, unlike his relatives who also share the PSEN1-E280A mutation, he lived without dementia until his early 70’s. To find out why, a team of researchers led by Yakeel Quiroz (Harvard Medical School, USA) and Francisco Lopera (University of Antioquia, Colombia) carried out detailed clinical examinations and genetic analyses, identifying a promising variant in a gene called RELN (Reelin). This little-known gene encodes a protein that helps control the actions and processing of tau, another biological driver of dementia and a drug target that is currently being evaluated in clinical trials.
A tantalising clue from the Nature Medicine study: postmortem evaluation of the brain showed much lower levels of tau in a small area of the brain called the entorhinal cortex. Situated in the medial temporal lobe deep within the brain, the entorhinal cortex is a central hub for communications with the hippocampus, supporting the consolidation of memories, navigation, and perception. To understand how Reelin might be exerting its protective effects, Prof. Quiroz and colleagues used animal models and laboratory research tools to study its impact on brain cells, and on biological processes such as tau phosphorylation. These studies revealed that Reelin can influence the phosphorylation of tau proteins, limiting their ability to form tangles that prompt cognitive decline. Reelin also binds to receptors for a protein called APOE, and its competition for access to these receptors may also help protect the brain from AD. Further studies are now ongoing to refine this new disease mechanism, and pinpoint options for targeted drug development.
Read the Nature editorial about this research: https://www.nature.com/articles/d41586-023-01610-z