Neuroinflammation in Alzheimer's disease: from pathogenesis to a therapeutic target

The top-down, reductionist approach of the past three decades has resulted in remarkable progress in identifying genes and proteins involved in Alzheimer's disease (AD), including β-amyloid (Aβ) peptides and tau protein. Recently, a number of genes of the innate immune pathway have been identified as AD risk factors and several microglial proteins have been shown to be chronically activated in AD brains. Together, these observations suggest a crucial role for neuroinflammation in AD pathogenesis and emerging evidence suggests that neuroinflammation is both a cause and a consequence of AD. Epidemiological studies show that long-term users of anti-inflammatory drugs are protected from AD but anti-inflammatory treatment in mild AD patients has not been successful. These observations suggest that anti-inflammatory treatment is likely to be successful if initiated prior to the onset of neurological symptoms. Finally, after the remarkable success of the reductionist approach, a complimentary bottom-up systems approach is necessary to gain a better understanding of the highly complex, multifactorial nature of AD pathogenesis.