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Overview of Alzheimer’s Disease and Novel Treatments Targeting Beta-Amyloid Deposits

Posted in Alzheimer's Disease, Etiology, Neurodegenerative Diseases, Pharmacotherapy and Cell Activity, tagged Acetylcholinesterase, Alzheimer's Disease, Beta-Amyloid, FDA, neurodegenerative diseases on October 7, 2023| 1 Comment »

Overview of Alzheimer’s Disease and Novel Treatments Targeting Beta-Amyloid Deposits

Reporter: Sharada Kittur, Research Assistant 1, Synthetic Biology in Drug Discovery

Alzheimer’s disease (AD) is a common type of dementia. People diagnosed with this disease suffer memory loss. Severe forms of the condition prevent the patients from responding to the environment. Alzheimer’s disease patients may also experience difficulty completing basic tasks, decreased or poor judgement as their executive function competence declines. Frequent changes in mood, personality, or behavior. AD is the 7th leading cause of death in the United States, and the 5th leading cause of death for adults aged 65 and over. Unlike cancer and heart disease, whose death rates are declining, the number of people struggling with Alzheimer’s disease is projected to increase in the coming years.

Currently, there are no cures for the disease. Many of the drugs on the market target only symptoms of the disease. The key mechanism of action (MOA) of AD drugs is inhibiting acetylcholinesterase. Acetylcholinesterase (AChE) is an enzyme that breaks down a neurotransmitter called acetylcholine (Ach), which is an important factor for memory functions. On average, Alzheimer’s disease patients have lower concentrations of acetylcholine. In order to treat this biomarker, scientists found molecules that can inhibit AChE, and reduce the breakdown of acetylcholine, thus improving the memory of patients with Alzheimer’s disease by enabling average levels of Ach. Some examples of AChE inhibitors currently on the market are

donepezil,
rivastigmine, and
galantamine.

One of the main causes of Alzheimer’s disease is believed to be the buildup of beta-amyloid plaques in the brain. Beta-amyloid is a toxic protein that is normally produced in small amounts in the brain. Then microglia, a type of macrophages in the nervous system, clear out the beta-amyloid deposits. In patients with Alzheimer’s disease, the microglia can’t clear away the beta-amyloid, and this obstructs neural function and attacks neurons. The cause of the microglia’s malfunction is still unknown, but it could be due to a gene called TREM2, that tells the microglia to clear the beta-amyloid proteins. When TREM2 doesn’t function properly, the microglia collects all of the beta-amyloid, but isn’t able to dispose of it. It then releases inflammatory chemicals, which increase the production of the amyloid precursor protein (APP). This also increases the production of β-secretase and γ-secretase, enzymes that form beta-amyloid by breaking down APP. This further exacerbates the problem.

On July 06, 2023, the Food and Drug Administration (FDA) fully approved Leqembi (lecanemab-irmb) to treat Alzheimer’s disease. Leqembi is a monoclonal antibody that specifically targets beta-amyloid proteins in the brain. It binds to the beta-amyloid proteins and clears them. This is very promising as in placebo-controlled clinical trials, it significantly decreased the beta-amyloid deposits in 18 months, and delayed cognitive decline by 5.3 months. It’s the first beta-amyloid targeting drug that was approved by the FDA as a Traditional Approval.

Leqembi is not a cure, however. It significantly slows down the mental function deterioration of the patients, but hasn’t been shown to fully maintain it at the current level over time. In addition, Leqembi has many side effects, such as headaches, and presents amyloid-related imaging abnormalities (ARIAs). ARIAs can cause swelling and bleeding in parts of the brain, but they should be temporary for most patients. Severe ARIAs only occur in a very small percentage of patients.

As researchers make progress in understanding the complex causes of Alzheimer’s disease, new treatments that are developed can help improve the lives of millions of people worldwide.

SOURCES:

“Alzheimer’s Association Welcomes U.S. FDA Traditional Approval of Leqembi: Full Details.” Alzheimer’s Disease and Dementia, Alzheimer’s Association, 6 July 2023, www.alz.org/news/2023/lecanemab-leqembi-traditional-fda-approval-full#:~:text=CHICAGO%2C%20July%206%2C%202023%20%E2%80%94,confirmation%20of%20elevated%20amyloid%20beta.

Smith, Tyler. “How Well Does Leqembi Work to Fight Alzheimer’s? First FDA-Approved Alzheimer’s Drug Offers Both Promise and Challenges.” UCHealth Today, 11 Aug. 2023, www.uchealth.org/today/how-well-does-leqembi-fight-alzheimers-first-fda-approved-alzheimers-drug/

Wang, Shaoxun, et al. “Is Beta-Amyloid Accumulation a Cause or Consequence of Alzheimer’s Disease?” Journal of Alzheimer’s Parkinsonism & Dementia, U.S. National Library of Medicine, 17 Nov. 2016, www.ncbi.nlm.nih.gov/pmc/articles/PMC5555607/

“What Happens to the Brain in Alzheimer’s Disease?” National Institute on Aging, U.S. Department of Health and Human Services, 16 May 2017, www.nia.nih.gov/health/what-happens-brain-alzheimers-disease#:~:text=In%20a%20person%20with%20Alzheimer’s,beta%2Damyloid%20and%20tau%20proteins.

“What Is Alzheimer’s Disease?” Centers for Disease Control and Prevention, Centers for Disease Control and Prevention, 26 Oct. 2020, www.cdc.gov/aging/aginginfo/alzheimers.htm#:~:text=Alzheimer’s%20disease%20is%20the%20most,thought%2C%20memory%2C%20and%20language.