Early-Onset Alzheimer's and Genetic Mutations

Approximately 5-10% of AD cases are classified as early-onset, typically manifesting before the age of 65. The mutations in PSEN1, PSEN2, and APP genes are primarily responsible for these cases. A notable variant, PSEN1 E280A, is particularly prevalent among a population in Antioquia, Colombia, tracing back to a single Spanish conquistador from the 1700s.

Currently, around 1,200 individuals carry this mutation, revealing concerning statistics: - Median age of onset for asymptomatic pre-MCI: 35 years - Median age for symptomatic pre-MCI: 38 years - Median age for MCI: 44 years - Median age for dementia: 49 years - Median age at death: 59 years

Yet, within this group, a few individuals display unexpected resilience. For instance, one woman with the protective APOE3 Christchurch mutation maintained cognitive health into her seventies.

Meet Another Resilient Case: RELN-COLBOS A recent study unveiled a brother-sister duo who exhibited surprising longevity in their cognitive abilities, particularly the brother. The sister faced cognitive decline at 58 and was diagnosed with dementia by 61, passing away at 73. The brother, however, remained cognitively fit until 67, experiencing language decline by 72, and ultimately dying at 74 from pneumonia. His brain was donated for research posthumously.

Despite having amyloid plaques similar to other carriers, his brain displayed significantly fewer tau tangles in key areas, particularly the entorhinal cortex, suggesting a unique protective mechanism.

Researchers identified a new gene variant in the RELN gene, termed RELN-COLBOS, which may contribute to this protection. RELN is responsible for coding reelin, a protein that plays a crucial role in neuronal plasticity and cell interactions in the brain. Recent hypotheses indicate that diminished reelin signaling may contribute to AD.

The RELN-COLBOS variant functions as a hypermorph, indicating enhanced activity compared to the standard gene type. While the increase in activity is subtle, it may still have significant implications for brain health.

In animal studies, male mice carrying the COLBOS variant exhibited an uptick in cerebellar neurons and reduced tau hyperphosphorylation, though these effects were not noted in female mice. This raises questions about gender differences in genetic protection against AD.

The researchers concluded that enhancing the protective RELN pathway, especially in the entorhinal cortex, could hold therapeutic potential in combating tau-related neurodegeneration and cognitive decline associated with Alzheimer's disease.

The first video titled "Healthy Aging and Alzheimer's Disease: Detecting the Genes that Protect Us" delves into the genetic factors influencing resilience against Alzheimer's, offering valuable insights into ongoing research.