German scientists have identified a rare genetic variation in the RELN gene (encoding the signal protein reelin) in a male, which is associated with the recovery ability of autosomal dominant Alzheimer's disease (ADAD) for over 20 years. This is the second report of this type of resilience, highlighting a new molecular pathway that could potentially increase the resilience of all forms of Alzheimer's disease as a therapeutic target. The relevant research was published on May 15th in the journal Nature Medicine.

ADAD is a rare genetic form of Alzheimer's disease, most commonly due to a specific mutation in the PSEN1 gene (encoding transmembrane transporter Presenilin 1). Its characteristic is early onset cognitive impairment, such as memory loss at a younger age (usually between 40 and 50 years old). A previously reported case described an ADAD woman with a rare mutation called "Christchurch" in the gene encoding apolipoprotein E (APOE), who maintained cognitive impairment for nearly 30 years after the expected age of onset, despite showing signs of Alzheimer's disease in the brain.

Francisco Lopera, Yakeel T. Quiroz, Joseph F. Arboleda Velasquez, Diego Sepulveda Falla, and colleagues at the Hamburg Eppendorf University Medical Center analyzed clinical and genetic data from 1200 individuals with PSEN1 mutations and ADAD tendencies from Colombia. They found that a man, despite carrying the PSEN1 variant of early-onset ADAD, maintained cognitive integrity until the age of 67. The author compared this man with a woman who previously reported delayed ADAD. Both individuals have extensive and abundant amyloid protein pathology in their brains, which is a pathological characteristic of Alzheimer's disease. However, the accumulation of tau protein (a microtubule stabilizing protein in the brain) in the olfactory cortex is limited, and this brain area is typically affected by the early clinical stage of Alzheimer's disease. The author conducted genetic sequencing and found that the second patient had a different type of mutation: a rare new RELN variant (H3447R, known as COLBOS). The author believes that this mutation leads to a RELN ligand (a binding molecule) that may be more effective in limiting tau protein accumulation, but further research is needed to explore this point. The APOE and relin proteins involved in protecting these individuals function as ligands for general cellular receptors, which the authors suggest may imply a common mechanism for tolerating Alzheimer's disease.

Researchers say the discovery highlights a previously unknown molecular pathway that may confer resilience to cognitive impairment on individuals at increased risk of Alzheimer's disease.

Resilience to autosomal dominant Alzheimer’s disease in a Reelin-COLBOS heterozygous man

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.