The amyloid cascade hypothesis states that amyloid-beta accumulation is the key event in Alzheimer disease neurodegeneration. However, recent data put this model into question. Knopman DS et al (Ann. Neurol. http://dx.doi.org/10.1002/ana.23816) recently compared cognitively normal elderly human subjects with amyloid-beta deposition (with or without neuronal injury) to individuals with neuronal injury but no amyloid-beta deposition.  The first group was classified as having preclinical Alzheimer’s Disease. The second group (lacking amyloid-beta deposition) was designated as having suspected non-Alzheimer pathology (SNAP).

However, in the SNAP group, 10% of subjects converted to mild cognitive impairment (MCI) or dementia within one year. This does not fit the classical amyloid cascade hypothesis stages of (1) amyloidosis first, then (2) presence of both biomarkers of neuronal injury and amyloid-beta, (3) and third, appearance of subtle cognitive impairment.

It was noted that the 10% conversion rate within a year (for the SNAP group) was not markedly different from that seen in the preclinical Alzheimer’s Disease group. The authors concluded that the initial appearance of brain-injury biomarkers in cognitively normal people may not depend on amyloid-beta amyloidosis. New views which replace the classical amyloid cascade hypothesis now suggest that amyloid-beta, tau and possibly other pathologies may be partly independent of each other. Examples include amyloid-beta-independent neuronal injury in apolipoprotein-E4 carriers. Further work is warranted.

Chételat G: Aβ-independent processes – rethinking preclinical AD. Nature Reviews Neurology [Epub ahead of print, February 12, 2013; doi:10.1038/nrneurol.2013.21]

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