Alzheimer’s Disease is a devastating neurological condition affecting 24 million people worldwide. It is the most frequent form of dementia with a heritable risk that is not wholly understood. A study published in the Journal of Neuropathology & Experimental Neurology has identified a new risk gene that was previously overlooked.

Alzheimer’s disease is caused by brain cell death and the formation of Tau plaques in the brain. It comprises of symptoms that worsen over time, usually starting with memory problems. The typical age of onset is 65 and over.

The study focused on Late Onset Alzheimer’s Disease (LOAD) using autopsied brain samples and Whole Exome Sequencing to identify a variable gene region implicated in the disease. The variable region was near two genes, MUC6 and AP2A2. Although the region is within MUC6, it affects the expression of AP2A2 – which is expressed at higher levels in the brain.

Variable regions or Variable Number Tandem Repeats (VNTR) are areas of the genome with a short > 6 base pair sequence repeated. The length of these VNTRs fluctuates between individuals, and the length is inherited through the germline. VNTRs are difficult to identify with normal sequencing methods and are usually overlooked for technical reasons. 

By analysing 119 autopsied subjects and over 10,000 genomes from the Alzheimer’s Disease Sequencing Project, the length of this VNTR was found to be associated with the severity of Tau plaques in neocortical regions. The longer region also correlated with decreased expression of AP2A2. The lack of AP2A2 expression may signal a role in combatting plagues and neurofibril formation – another hallmark of Alzheimer’s.

This genetic variant hints at a possible biochemical pathway in the brain involved in the formation of Tau plaques – leading to a potential therapeutic target. The length of the VNTR was also speculated to be the reason why some individuals are more vulnerable to neurodegenerative diseases caused by Tau.

The identification of a VNTR implicated in affecting Alzheimer’s highlights the importance of more thorough sequencing techniques to not overlook these variable, and valuable, regions.

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