The second leading cause of death worldwide, neurodegenerative diseases, resulted in 9 million fatalities annually. Of these several conditions under the umbrella term neurodegenerative diseases, Alzheimer’s disease (AD) is the most prevalent condition. It claims 28.7 million disability-adjusted life years and 2.4 million lives every year. With 500,000 new cases reported annually, Alzheimer’s disease is one of the most common disorders observed in the elderly population globally.
According to a 2023 survey, 1 in 9 Americans older than the age of 65 are diagnosed with Alzheimer’s, the 6.7 million diagnoses account for over 10% of the country’s population. Physiological changes in the patient’s central nervous system and gradual deterioration of condition over time negatively impact the overall well-being of the patient as well as that of their caretakers.
With researchers worldwide dedicating themselves to the awareness and management of neurodegenerative conditions, a new therapeutic molecule was discovered. In a study by Mass General Brigham analyzing potential therapeutic targets for Alzheimer’s disease, researchers discovered a monoclonal antibody. The study was inspired by a case study wherein a natural genetic variant of the ‘APOE’ was observed in a 70-year-old woman in Colombia. She was part of a family at unusually high risk of developing early-onset Alzheimer’s disease. Her genetic variant, APOE Christchurch (APOE3Ch), protected her cognitive ability for almost three decades.
Results showed that genetic variation or manipulation of this gene induced extreme resistance against Alzheimer’s disease. The resultant therapeutic developed used a molecule that mimicked the nature of the genetic variant and was processed for preclinical testings. Like the previous molecule, the compound produced by investigators from Massachusetts General Hospital in collaboration with Mass Eye and Ear targets abnormal tau proteins. Alzheimer’s disease can be characterized by the appearance of amyloid beta plaque on the brain scans. Tau proteins are a family of proteinaceous molecules that form these amyloid beta plaque buildups.
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Published in the reputed journal Alzheimer’s and Dementia: The Journal of the Alzheimer’s Association on October 4, 2023, this study identified an APOE genetic variant called APOE3 Christchurch. A researcher of the study, Claudia Marino, said, “remarkably, the subject with extreme protection against Alzheimer’s disease who carried the APOE Christchurch variant had a similar clinical presentation with much lower tau accumulation despite severe amyloid pathology”. Scientists have developed specific synthetic antibody molecules that are designed to target the interactions between ApoE and heparan sulfate proteoglycans. This molecule was able to replicate the protective mechanism observed in the APOE3 Christchurch genetic variant successfully.
The researchers used in silico protein modeling techniques to predict the compatibility of the several antibody crystal structures with the target protein. An antibody, called 7C11 was able to obtain the desired results efficiently. It was able to inhibit pathological interaction, providing some protection against Alzheimer’s disease. Further validations were then conducted to calculate effective doses and methods of delivery to obtain optimum results.
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