The role of brain inflammation in Alzheimer’s disease may be more significant in APOE-4 carriers

For over twenty years, there has been growing evidence of the importance of inflammation in Alzheimer’s disease.  For a comprehensive review of this topic, follow this link to a 2018 paper in Alzheimer’s & Dementia. Briefly, there have been a number of observations that people taking anti-inflammatory medications, particularly those with rheumatoid arthritis, have a modestly reduced risk of getting Alzheimer’s disease. Studies in animal models have shown that brain inflammation has a dual response, protective in the acute reaction and detrimental when chronic. Chronic neuroinflammation activates inflammatory cells in the brain called microglia, exacerbates beta amyloid burden, and increases the production of hyperphosphorylated tau, the toxic form of tau protein found in neurofibrillary tangles. However, trials of anti-inflammatory medications such as ibuprofen in humans have for the most part failed to show significant reduction in risk of getting Alzheimer’s. Recent work has suggested that this damaging effect of inflammation on Alzheimer’s risk does indeed occur in humans but is specific to those carrying the APOE-4 allele. 

This is one more example of the heterogeneity of Alzheimer’s disease. Alzheimer’s disease associated with APOE-4 appears to be a different disease than Alzheimer’s disease in the absence APOE-4. I think this is one important reason that it has been so hard to find an effective medication to treat Alzheimer’s. Anti-amyloid monoclonal antibodies like Aduhelm also appear to be more effective in patients with APOE-4-associated Alzheimer’s disease. I am hopeful that as we learn more about the genetic and biochemical differences in these diseases that we have lumped together as Alzheimer’s, we will finally be able to develop targeted therapies to all of these variants.