A rare gene protected a man from disease
A man from Colombia was found to have an unusual genetic mutation that caused him to develop early-onset Alzheimer's disease (AD). However, another gene kept him healthy for many years.The newly discovered genetic variant protects against a particularly devastating form, early-onset AD. The so-called presenile variant develops before the age of 65 and is characterized by rapid progression of deterioration of memory, intellectual activity and higher cortical functions. The discovery gives scientists hope for finding new treatments that will prevent or slow the progression of this and other forms of Alzheimer's disease.
The genetic variant discovered is the second gene variant that protects against autosomal dominant Alzheimer's disease (ADBA), a form of AD caused by an inherited genetic mutation. People with ADBA begin to show signs of dementia at about age 40 and rarely live to be 60.
The focus of the new study was a man from a Colombian family whom scientists followed for several years. He is a carrier of the genetic mutation that causes ADBA. However, he showed no signs of early dementia and remained healthy until the age of 60. He did not develop a mild form of Alzheimer's disease until age 72. He died at 73 from causes unrelated to dementia.
Scientists sequenced the man's genes and compiled a list of genetic variants or specific versions of genes that may have protected him from developing AD. The RELN gene particularly intrigued the scientists. It turned out that the protein it encodes binds to the same cellular receptors as the protein produced by the well-known APOE gene. One variant of the APOE gene increases the risk of Alzheimer's disease, in part by causing the formation of amyloid plaques, clusters of mislaid proteins that are thought to be a hallmark of AD.
The researchers studied the effect of the RELN gene on cells in laboratory cups and in mice and found that the variant worn by the man actually causes the protein that encodes RELN to bind more closely to its receptor. This effect appears to help the RELN protein stabilize the tau protein. Recall, it forms tangles in the brain, which serve as another telltale sign of Alzheimer's disease.
The patient had fewer tau clumps in the brain compared to other Alzheimer's patients, but the pathology remained in some parts. A deeper study of the gene variant and how it protects against early-onset AD is the scientists' next step.