New Genetic Variant Provides Protection Against Alzheimer's Disease

A new case of a patient with a genetic predisposition for developing early-onset Alzheimers disease has sparked new research questions. This can lead to even more powerful and persuasive ideas about cause and treatment.

Clinical assessments led by an international team of investigators have identified a new genetic variant that protects from Alzheimer’s disease. The variant occurs in a different gene than in a case from the same family reported in 2019 but points to a common disease pathway.

Genetics of Alzheimer’s disease
There are numerous genes that have been discovered that are associated with Alzheimer’s disease and indicate increased risk, aiding genetic counseling and better care.

‘The newly identified genetic variant points to a pathway that can produce extreme resilience and protection against Alzheimer’s disease symptoms.’

Tweet it Now

Insights from their findings published in the journal Nature Medicine also pinpoint a region of the brain that may provide an optimal treatment target in the future.

Rare Gene Variant Shielded a Man from Devastating Form of Alzheimer's Disease

The case that caught the investigators’ attention involved a family member of the world’s largest-known kindred with a genetic variant called the “Paisa” mutation (Presenilin-1 E280A). Carriers of this variant usually develop mild cognitive impairment at a median age of 44 and die from complications of dementia in their 60s ().

This team of investigators previously studied a woman from this family who remained unimpaired until her 70s and whose case was reported in 2019. In the new study, they describe a case of a male carrier of the Paisa mutation who remained cognitively intact until age 67.

Extraordinary cases like this one illustrate how individuals and extended families with Alzheimer’s disease can help advance our understanding of the disease and open new avenues for discovery.

Dementia - Types, Causes, Symptoms, Diagnosis, Treatment
Dementia has become a very big concern as we have an aging population across the world. Dementia is also terrifying to us because of its disturbing symptoms and limited treatment options.

The insights we are gaining from this second case may guide us on where in the brain we need to look to delay and stop disease progression and will help us form new hypotheses about the series of steps that may lead to Alzheimer’s dementia.

Opening Door for the Prevention and Treatment of Alzheimer’s Disease

Researchers ruled out the presence of the genetic variant in the male patient. The team performed genetic and molecular analyses to identify other variants that could have been protecting him from Alzheimer’s disease.

The most promising candidate was a new and rare variant, never before reported in the Reelin gene. The team named it Reelin-COLBOS. This shows that Alzheimer’s protection can take different shapes and that perhaps a therapy can be successful just by targeting key brain structures.

World's Youngest Case of Alzheimer�s Disease
Standard cognitive tests designed to detect memory loss verified a 19-year-old boy’s probable diagnosis of Alzheimer’s disease.

Reelin is a protein with a pivotal role in the regulation of brain cell development and function. Previous reports have linked mutations in Reelin to diseases like autism, schizophrenia, epilepsy, and bipolar disorder ().

The patient’s scan also revealed amyloid-beta plaque burden was high and he had tau tangles in some regions of his brain, his entorhinal cortex had notably very limited tau pathology. The entorhinal cortex plays a critical role in memory and learning, and its degeneration is known to lead to cognitive impairment and dementia.

Early-Stage Alzheimer�s Disease Can be Detected Using a Molecule in Urine
Recent research suggests that biomarkers in urine can help identify the early stages of Alzheimer’s disease

Studies in a mouse model also showed that the Reelin-COLBOS variant protected against tau pathology. As investigators pursue gene therapies that may in the future deliver treatments that can modify or manipulate gene expression, understanding what region of the brain to focus on for delivery will become increasingly important.

Many treatments for Alzheimer’s disease, including drugs recently approved by the U.S. Food and Drug Administration and other drugs currently in clinical trials, target reducing amyloid plaque buildup ().

The study’s results point to potential new avenues for treatment because the two patients with protection had extremely high levels of amyloid in their brains and yet they were protected.

Alzheimer’s disease remains a devastating disease with an immense global burden, and this work opens the door to further investigation into how this resilience pathway may lead to an effective therapeutic strategy.

References:

Pre-dementia clinical stages in presenilin 1 E280A familial early-onset Alzheimer's disease: a retrospective cohort study - (https://pubmed.ncbi.nlm.nih.gov/21296022/)
Genome-Wide Association Identifies a Common Variant in the Reelin Gene That Increases the Risk of Schizophrenia Only in Women - (https://journals.plos.org/plosgenetics/article?id=10.1371/journal.pgen.0040028)
Resilience to autosomal dominant Alzheimer’s disease in a Reelin-COLBOS heterozygous man - (https://www.nature.com/articles/s41591-023-02318-3)

Source-Eurekalert