Why Treating Alzheimer's Is So Difficult?

Pharmacy
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In 1906, Alois Alzheimer examined the brain of a patient after she died from “a mysterious illness” with symptoms of dementia. He found the presence of amyloid plaques and tangled bundles of fibers inside the brain.

Alzheimer’s disease is a progressive neurodegenerative disease associated with memory loss and cognitive decline. Main biomarkers of AD is amyloid beta plaques depositions and tau protein tangles accumulation.

Lot of drugs that were discovered for the treatment of AD never made it to the market , many of the drugs failed in the phase 3 clinical trials.

Examples of such drugs :

  1. Aducanumab : Developed by Biogen , it is a monoclonal antibody aimed to remove the accumulated amyloid plaques. it was the first drug that was actually targeting the cause of AD, before that all the therapies were working in brain to release chemicals to improve memory.

This drug was approved in US by FDA in 2021 initially, but later other agencies rejected it like EMA because of inappropriate way of reporting the end points and stating the superiority of the drug .It showed clearing of plaques but no improvement in the symptoms of AD. FDA was also questioned later for their incompetency and way of approving a drug. This drug also reported bleeding and ARIA (amyloid-related imaging abnormalities) in one treatment arm of the clinical trial.

This drug itself require a separate post but anyone interested can read through this link.

  1. Semaglutide

We know this is the drug used for diabetic patients, as it is a GLP-1. But researchers thought that may be semaglutide can help with alzheimer’s because as we know it can help with inflammation , neurodegeneration that usually occurs when body is insulin resistant and hyperglycemia causes neuropathy and cardiovascular complications.

Novo Nordisk conducted two major Phase 3 trials:

  • EVOKE

  • EVOKE+

These tested oral Semaglutide in patients with early symptomatic Alzheimer’s disease. Around 3,800 patients participated over about 2 years.

There were improvement in biomarkers such as tau tangles , inflammatory signals but this not translated into improvement in the clinical symptoms. Later novo nordisk discontinued the further trials.

Drugs such as Donanemab , Simufilam are examples of such drugs that were developed to treat AD but could not clear all the checkpoints.

This also raises an interesting query that although these drugs were acting on the amyloid and tau that are considered to be cause of AD and were helping to clear it , but this didnt improve the symptom that is memory loss which can point at that may be we still need to understand more about the pathophysiology of this disease , may be we need to target something else “MAY BE”

What are your thoughts on this ?

MBH/PS

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@deepika.rwt well explained and after taking the exact prescribed guidlines but still in this condition leads very low recovery or result

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Very insightful post. The repeated failure of Alzheimer’s drugs despite clearing amyloid and tau suggests that AD is likely more complex than we currently understand. It raises an important question whether these proteins are the true cause or just one part of the disease process. More research into the underlying pathophysiology is definitely needed.

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Would like to get a clear explanation on amyloid beta plaque deposition and tau protein tangle accumulation.

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Definitely more research into the pathogenesis of Alzheimer’s disease and memory loss process is needed to create drugs that can act to reverse the disease or stop it from progressing further.

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