Exploring new avenues to treat Alzheimer’s

Neurological disorders viz., Parkinson’s, Alzheimer’s Disease, Epilepsy, Stroke, Autism, etc. are the primary cause of disability worldwide. These neurological disorders are the second most prominent cause of death globally. The total number of deaths is reported to have increased by 39 per cent in the last 30 years. Alzheimer’s disease is the sixth-leading cause of death worldwide.

Alzheimer’s Disease (AD) is a neurodegenerative disorder pathologically characterised by amyloid-beta (Aβ) aggregation and neurofibrillary tangles (NFTs) deposition. AD patients are struggling with cognition related to non-memory. The non-memory aspect includes navigation deficit, troubled vocabulary, and impaired judgment. The three main types of AD include early-onset Alzheimer’s reported before the age of 60. Late-onset Alzheimer’s is reported after the age of 60. The third type of AD is Familial Alzheimer’s disease (FAD). This is hereditary and comprises less than one per cent of cases.

Alzheimer’s disease is a complex condition with multiple factors contributing to its development. Current treatments target only one aspect of the disease and are effective primarily in managing symptoms during the early stages. Recognising the need for more comprehensive approaches, the Indian Council of Medical Research (ICMR) has supported my research project titled, “Development of multitargeted adamantyl analogues for Alzheimer’s disease treatment’. This project aims to design, synthesise, and evaluate novel multitargeted compounds to address various facets of Alzheimer’s disease. The findings from this research are expected to shed light on the potential benefits of multitargeted molecules in managing the disease.

Generally, the two strong hypotheses being advocated in the pathogenesis of AD are based on protein ‘plaques’ and ‘tangles’ that hamper the usual cognitive activity of the brain. Several efforts have been made to design therapies that interfere with these structures. AD is a major amyloidosis, with two types of amyloids deposited in the brain. These are amyloid beta (Aβ) forming aggregates which constitute plaques and cerebrovascular amyloid angiopathy and tau protein which forms NFTs, dystrophic neurites, and neuropil threads. The senile or neuritic plaques and NFTs are the characteristic lesions found in different areas of the brain i.e. temporal lobe and cortical area.

The current treatment protocol for AD provides only symptomatic relief for initial one to two years without addressing the elementary pathogenetic factors responsible for the disease. Therefore, the disease continues to progress with the existing therapies.

Currently, the monoclonal antibody Aducanumab has been approved by the FDA. However, the approval was criticised by the scientific community due to its insignificant effect on the improvement of memory.

In the ICMR-funded project on multitargeted adamantyl analogous, the specific targets considered are Acetylcholine, Aβ and NMDA receptors. These targets are well-validated for the Alzheimer’s treatment. Furthermore, these targets are involved in the primary pathogenesis of disease. The development of multifunctional drugs with the ability to provide symptomatic treatment along with the modulation of pathogenic factors such as Aβ aggregation and oxidative stress is one of the major goals of the present study.

This research contributes to potential therapeutic interventions in the future by checking the suitability of multi-targeted molecules for the treatment of AD. Furthermore, it will also develop novel molecules acting on these targets. Once the preclinical study is completed, the presented result may be used for further drug discovery and clinical trial studies.

The Indian Council of Medical Research (ICMR) has funded his research project, “Development of multitargeted adamantly analogous for the treatment of Alzheimer’s disease”.