More Work Needed for Alzheimer’s Disease Therapeutic Targets
For many years, characteristic misfolded protein tangles called amyloid plaques used to diagnose Alzheimer’s disease (Alzheimer’s) were the therapeutic target for Alzheimer's medication development.1 In the last few years, a widely anticipated medication was being tested that many hoped would be a breakthrough in Alzheimer’s treatment. The medication, aducanumab, did reduce plaques in people with mild or developing Alzheimer's. However, in subsequent trials, improvement in symptoms was not detected in participants with moderate Alzheimer’s.2 Clearly, researchers had missed something.
The common scientific maxim is “correlation does not equal causation,” but amyloid plaques are so characteristic of Alzheimer's that they became the focus of treatment development for years. But the existence of plaques does not necessarily mean they are the causative agent. Perhaps, they are a result of some other, undiscovered step that initiates disease progression, eventually ending in loss of memory and cognitive function.3 To find a better therapeutic target for treatment, scientists will need continued work to discover the mechanisms causing the disease.
There are plenty of candidates, and whether Alzheimer's is the result of a specific phenomenon, or a combination of factors is still unknown. Some scientists suspect it is multifactorial and any treatment will need to tease out the specifics. In addition to amyloid plaques, there are also structures called neurofibrillary tangles consisting of misfolded tau proteins. It is possible there are complex interactions that occur between the two and characteristics of the aging brain.
In fact, some researchers are studying metal ions like copper and iron in the brains of people with Alzheimer’s. One type of gene, APOE ε4, seems to increase the risk of Alzheimer's, but confounding factors are not well understood. There is evidence that other Alzheimer’s associated genes may also play a role. Some studies point to lifestyle factors like exercise and diet as having an impact on the risk of developing Alzheimer's. Other dementias can be related to vascular health. At present, one possibility scientists are studying is the influence of neuroinflammation and oxidative stress in the brain – could those processes, over time, lead to plaques and tangles?4
By attacking the problem on two fronts–trying to discover the science behind it and noting which interventions have positive outcomes in Alzheimer’s patients–the inciting mechanisms of Alzheimer’s disease will hopefully be discovered, and an effective treatment developed.
- Hassan NA, Alshamari AK, Hassan AA et al. Advances on therapeutic strategies for Alzheimer's disease: from medicinal plant to nanotechnology. Molecules 2022;27:4839. doi: 10.3390/molecules27154839.
- Delrieu J, Bateman RJ, Touchon J et al. The future of AD clinical trials with the advent of anti-amyloid therapies: an CTAD Task Force Report. J Prev Alzheimers Dis 2022;9:393–399. doi: 10.14283/jpad.2022.48.
- Plascencia-Villa G, Perry G. Neuropathologic changes provide insights into key mechanisms related to Alzheimer disease and related dementia. Am J Pathol 2022:S0002-9440;00206-1. doi: 10.1016/j.ajpath.2022.07.002.
- Behl T, Kaur I, Sehgal A et al. The road to precision medicine: eliminating the "one size fits all" approach in Alzheimer's disease. Biomed Pharmacother 2022;153:113337. doi: 10.1016/j.biopha.2022.113337.