Neurology

Editors' note: Revisiting protein aggregation as pathogenic in sporadic Parkinson and Alzheimer diseases


Despite genetic data from families harboring APP mutations in Alzheimer disease (AD)—or SNCA gene multiplication in familial Parkinson disease (PD)—Dr. Espay et al. emphasized the limited evidence that implicates these protein products in the pathogenesis of sporadic cases of AD/PD. Instead, the authors argued, such proteins may be epiphenomena or could represent the nervous system response to cellular stress. Using established Bradford Hill criteria to determine a cause-and-effect relationship of these proteins and their respective diseases, the authors challenged the “age-old” notion that such proteins play a proximate role in disease pathogenesis. By summarizing the available evidence, the authors concluded “human studies of protein aggregation in AD and PD do not meet a minimum set of Bradford Hill’s criteria to support a causal role.” Dr. Nelson respectfully disagrees with the conclusions drawn by the authors, citing evidence that nondemented patients with “preclinical” disease already exhibit abnormal protein deposits in the CNS, whereas demented patients without histopathologic evidence of AD or PD demonstrate pathology consistent with other degenerative conditions. As such, abnormally misfolded and aggregated proteins are more likely to be deleterious rather than protective or reactive. In response, Dr. Espay et al. emphasize the lack of evidence supporting the benefit of antiaggregation therapy (so far) in the treatment of patients with preclinical disease. Targeting these proteins, or preventing their aggregation, may fail to address the occult, proximate causes underlying these conditions. Although the jury may still be out regarding this chicken or the egg dilemma, it stands to reason that we should consider alternative hypotheses in the pathogenesis of sporadic AD or PD, if only to avoid perpetuating confirmation bias.

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