The newest crop of amyloid-targeted drugs to prevent or reverse Alzheimer's disease includes several that are in clinical trials and may soon be available to patients. In this Special Report, Johns Hopkins reviews potential new treatments for Alzheimer's disease.
Preventing or reversing the buildup of amyloid plaque and neurofibrillary tangles in the brain remains the central focus of Alzheimer’s disease research and drug development. Unfortunately, finding an effective treatment has been elusive and frustrating, often leaving researchers still questioning the true nature of Alzheimer's.
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A nagging issue remains whether the plaques and tangles themselves cause the brain cells to die or if they develop as a protective response to another source of damage and are simply indicators of cell death. This issue becomes even more urgent as the Baby Boomers approach prime time for the development of Alzheimer’s disease. Without effective prevention and treatment strategies, Alzheimer’s cases are expected to skyrocket within the next 20 years, a plight that could overwhelm medical and social services.
Certain amyloid-targeted advances in drug development show promise: Several drugs in later-stage clinical trials are somewhat effective in removing amyloid plaque, while other amyloid-related approaches are starting to be investigated.
- Tramiprosate (Alzhemed). This drug is the farthest along in clinical trials. Research suggests that it binds to soluble beta-amyloid and prevents the formation and deposit of amyloid plaques in the brain. Alzhemed also dampens inflammation, which promotes the buildup of amyloid plaques. Preliminary results suggest a modest, if any, benefit.
- R-flurbiprofen (Flurizan). Related to the nonsteroidal antiinflammatory drug flurbiprofen, Flurizan inhibits production of beta-amyloid. This drug is in late-stage clinical trials and, if approved, would be used early in the course of Alzheimer’s disease. It does not appear to show any benefit for moderate or severe Alzheimer's.
- Alzheimer’s vaccine. An earlier experimental “vaccine” for Alzheimer’s called AN-1792 was abandoned after it caused brain inflammation in several study participants. Several newly developed vaccines target smaller portions of the DNA in the beta-amyloid protein, not the whole protein. Researchers are hopeful that this approach will prove safer. Human trials are just beginning.
- Enzyme inhibitors. Beta-secretase and gamma-secretase are enzymes involved in snipping beta-amyloid fragments from their parent protein (beta-amyloid precursor protein, or APP). These are the fragments that can stick together and form amyloid plaques. Researchers are exploring several ways to block beta- or gamma-secretase in hopes of preventing the formation of toxic beta-amyloid fragments.
- SORL 1. Researchers believe this gene is involved in the intracellular transport of the amyloid precursor protein that is split in half by enzymes to produce beta-amyloid. Abnormalities in SORL 1 appear to increase the risk of late-onset Alzheimer’s disease. Perhaps a drug that blocks the gene will decrease beta-amyloid production.
- Retromer complex. This group of proteins is found abundantly in the hippocampus. Like SORL 1, the retromer complex transports the amyloid precursor protein. Malfunctions in the complex allow beta-amyloid to build up in cells.
