Interleukin-1 and the Immunogenetics of Alzheimer Disease

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Abstract
Established genetic causes of familial Alzheimer disease (AD) involve genes for β-amyloid precursor protein (βAPP), presenilin-1, and presenilin-2. For the more common sporadic forms of AD, increased risk has been associated with a number of genes; the most important of which is the ε4 allele of apolipoprotein E. Two recent studies, one clinical and one using postmortem material, now show increased risk for AD associated with certain polymorphisms in the genes encoding the α and β isoforms of interleukin-1 (IL-1). IL-1 levels are elevated in Alzheimer brain, and overexpression of IL-1 is associated with β-amyloid plaque progression. IL-1 interacts with the gene products of several other known or suspected genetic risk factors for AD, including βAPP, apolipoprotein E, α1-antichymotrypsin, and α2-macroglobulin. IL-1 overexpression is also associated with environmental risk factors for AD, including normal aging and head trauma. These observations suggest an important pathogenic role for IL-1, and for IL-1-driven cascades, in the pathogenesis of AD.