Major Cause of Age-related Memory Loss Discovered

Scientists say they have discovered a protein deficiency in the brain that is a major cause of age-related memory loss, according to a study published online in the journal Science Translational Medicine.

The researchers, from Columbia University Medical Center (CUMC), say this discovery offers the "strongest causal evidence" that age-related memory loss and Alzheimer's disease are individual recognizable conditions. The study, conducted on postmortem human brain cells and in mice, revealed that the hippocampus in the brain - a region that plays an important part in memory, lacks a protein called RbAp48 in those who experience age-related memory loss. The finding suggests that a deficiency of this protein is a cause of memory loss, but more importantly, the researchers say this form of memory loss is reversible. They began conducting this current study in order to seek direct evidence that Alzheimer's disease is a completely separate condition from age-related memory loss. Previous research has suggested that Alzheimer's disease hinders a person's memory by affecting the entorhinal cortex (EC) in the brain. The EC is a region that provides important pathways to the hippocampus. According to the study authors, it was thought that age-related memory loss was an early sign of Alzheimer's, but they add that recent evidence suggests age-related memory loss is a separate process that affects the dentate gyrus (DG). This is a subregion in the hippocampus that has direct input from the EC.

RbAp48 gene discovered: For the study, the researchers conducted microarray (gene expression) analyses of postmortem brain cells from the dentate gyrus of eight people aged 33 to 88, who were all free of brain disease. As a control, they also analyzed brain cells from the entorhinal cortex, given that the EC brain structure is unaffected by aging, the researchers say. From this, 17 candidate genes were found that could be linked to aging in the DG. The gene RbAp48 showed the most significant changes, with its expression deteriorating as the study subjects aged. The next step involved genetically inhibiting the RbAp48 gene in the brains of healthy young mice. The mice demonstrated the same form of memory loss when tested by object recognition and water maze memory tests. However, their memory returned to normal when the RbAp48 gene was switched off. Functional MRI (fMRI) scans were conducted on the mice who had the RbAp48 gene, which showed a specific effect in the DG, similar to the effect seen in fMRI scans of aged mice, monkeys and humans, the researchers say. They add that the effect of the gene on the DG also showed defects in molecular mechanisms usually found in old mice. Once again, when the RbAp48 gene was switched off, the DG profile shown in the fMRI scans and molecular mechanisms returned to normal.