Systemic Inflammation, Infection, ApoE Alleles, and Alzheimer Disease: A Position Paper

Alzheimer disease (AD) includes inflammatory processes in the senile plaques and surrounding glia, with increased expression of acute phase proteins such as C-reactive protein (CRP) and IL-6. Increased IL-6 expression during normal brain aging suggests a link of age-related inflammation to the onset of AD during aging. Blood levels of CRP and IL-6 are also associated with higher risk of Alzheimer disease and cognitive decline during aging. Some infections are known to induce inflammation and amyloid deposits. For example, HIV induces the deposition of the same beta-amyloid as in Alzheimer disease. The ApoE4 allele may increase HIV-associated dementia, in addition to its well-known effect on accelerating the onset age of AD. Many other adverse effects of apoE4 are recognized, which suggested the hypothesis that apoE4 persists in human populations because of balancing selection (Charlesworth-Martin hypothesis). The apoE4 allele was acquired during human evolution and may have conferred initial advantages in pathogen resistance. As evidence for this hypothesis, apoE4 carriers have less severe liver damage during hepatitis C infections. As human lifespan lengthened and cognitive and cardiovascular health became more important, the apoE3 allele spread, while the E4 allele was maintained in all populations by balancing selection.