The amyloid cascade hypothesis is widely accepted as central to Alzheimer disease pathogenesis. It proposes that abnormal production of beta amyloid protein is the cause of Alzeimer disease and that the neurotoxicity is due to beta amyloid itself or its oligomeric forms. The authors suggest that this may not be the cause of Alzheimer disease because demonstrating such toxicity requires micromolar concentrations of beta amyloid, while their levels in brain are a million times lower in the picomolar range. Instead, they suggest that Alzheimer disease probably results from the inflammatory response induced by extracellular beta amyloid deposits, which later become enhanced by aggregates of tau. The inflammatory response, which is driven by activated microglia, increases over time as the disease progresses. The authors suggest that therapeutic attempts may continue to fail as long as the central role of inflammation is not taken into account.

Non-steroidal anti-inflammatory drugs (NSAIDs) have significant sparing effect on Alzheimer disease which suggests that the anti-inflammatory approach to disease modification is a useful one. Biomarker studies have indicated that early intervention may be necessary, especially since disease onset occurs more than a decade before the appearance of clinical symptoms. By combining biomarker and pathological data, it is possible to define six phases of disease development, each separated by about 5 years. Phase one can be identified by decreases in amyloid beta in the CSF and phase 2 by increases of tau in the CSF plus clear evidence of amyloid beta brain deposits by PET scanning. Phase 3 shows slight decreases in brain metabolic rate by PET-FDG scanning. Phase 4 is characterized by minimal cognitive impairment (MCI) and small decreases in brain volume by MRI scanning. Clinical diagnosis of Alzheimer disease is reached in phase 5, and phase 6 represents advanced Alzheimer disease requiring institutional care. The authors conclude that use of anti-inflammatory agents early in the disease process is a therapeutic opportunity for useful future development.

McGeer PL and McGeer EG: The amyloid cascade-inflammatory hypothesis of Alzheimer disease: implications for therapy. Acta Neuropathol. [Epub ahead of print, September 20, 2013].

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