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Two neurologists published a review. cell Discuss Current status of Alzheimer’s disease treatmentincluding drugs in early development, treatments in clinical trials, and currently prescribed treatments.
Monoclonal antibodies, whose names end in -mab, have become the go-to approach for pharmaceutical companies seeking to develop anti-Alzheimer’s drugs. These treatments aim to attack and remove amyloid-beta plaques in the brain. They were built on the amyloid cascade hypothesis, the idea that Alzheimer’s disease is caused by the well-known buildup of plaques. .
While these treatments have been successful in mice, they have largely failed in humans until very recently.Aducanumab received accelerated approval in 2021, but many in the Alzheimer’s disease research community consider this approval controversial . Resenemab has shown clinical success in slowing the progression of Alzheimer’s disease and received accelerated FDA approval in January and full approval in June.
-mab drugs have unique challenges in development because they are based on the immune system. One common side effect of many new monoclonal antibodies is a form of brain swelling known as ARIA, which is more likely to occur in people who carry the dreaded APOE4 allele. The APOE4 allele is the same allele that is highly associated with increased risk of Alzheimer’s disease. .
Additionally, the problem with even the best alpha-mab drugs is that they only slow the rate of decline by about 30%, even when given to people in the early stages of Alzheimer’s disease progression. . Alpha-mab remains the only direct Alzheimer’s disease treatment that has made it through the clinical trial process, but clearly a different approach is needed.
Is it Tau time?
Although it has long been known that misfolded, insoluble tau aggregates are a precursor to Alzheimer’s disease, the effects of targeting tau remained unclear.First-generation tau therapy, which removes all forms of the protein, turns out to be ineffective . After examining the results of Alzheimer’s disease monoclonal antibodies and their various effects on tau, these researchers hypothesize that directly targeting tau may have no effect at all.
However, second-generation anti-tau therapies that target only toxic variants of the protein are in early clinical trials. .One of these potential treatments was found in one of these early trials to reduce tau in the human brain, but its clinical efficacy is not yet clear . The National Institutes of Health will test tau-based treatments in combination with anti-amyloid therapy in the upcoming Alzheimer’s Tau Platform Trial.
Amyloid-beta plaques in Alzheimer’s disease are often accompanied by other biomarkers, such as TDP-43. which is itself part of frontotemporal dementia, and alpha-synuclein , a protein associated with Parkinson’s disease. The authors note that these factors influence the progression of Alzheimer’s disease and may be the reason why some treatments are less effective than they would otherwise be. They also note that Alzheimer’s disease involves a global loss of proteostasis.
In this context, the authors point out that therapeutics targeting proteostasis mechanisms may simultaneously affect multiple related pathologies. . The protein maintenance protein ubiquitin and related compounds such as the ligase TRIM11 have been highlighted as potential targets for such approaches. It has been noted that many other protein-related neurological disorders are specific to certain mutations, while other mutations are protective.
The authors point out potential problems with -mabs becoming part of standard treatment. Combining amyloid and non-amyloid approaches would increase the risk of ARIA and other adverse events, making it difficult to discontinue existing Alzheimer’s drugs and get people to participate in placebo-controlled studies. Furthermore, the need to test multiple drug combinations significantly increases the cost and time required for testing.
Umbrella approaches with multiple arms and basket approaches used in cancer treatment have also been proposed. In the umbrella test, one arm can be stopped if no effect is seen. Basket trials use the same compound to test for multiple types of neurodegeneration, potentially reducing costs and increasing efficiency.
Ultimately, the authors are optimistic about the future of Alzheimer’s disease treatment. If combination therapy can wipe out its hallmark amyloid beta and tau buildup, restore protein levels to normal, and remove amyloid aggregates inside and outside cells, it could potentially halt Alzheimer’s disease and prevent the creeping dementia associated with it. Dew. He took the lives of many people and himself.
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