Primary age-related tauopathy and the amyloid cascade hypothesis: the exception that proves the rule?

Abstract

Extensive data supports the amyloid cascade hypothesis, which states that Alzheimer's disease (AD) stems from neurotoxic forms of the amyloid-beta (Aβ) peptide. But the poor correlation between Aβ plaques and neurodegeneration/cognitive impairment, the spaciotemporal disparity between Aβ and tau pathology, and the disappointing results following several large clinical trials using Aβ-targeting agents are inconsistent with this explanation. The most perplexing inconsistency is the existence of AD-type dementia patients that develop abundant neurofibrillary tangles that are indistinguishable from those in early to moderate-stage AD in the absence of compelling evidence of amyloid toxicity. This neuropathological phenotype, which is distinct from other diseases with tangles, represents a conceptual disconnect, because it does not fall within any previously established category of tauopathy and ostensibly invalidates the amyloid cascade hypothesis. Instead, recent efforts have led to consensus criteria for a new alternative diagnostic category, which presupposes that these tangle-only dementia patients represent extreme examples of a distinct primary age-related tauopathy (PART) that is universally observed, albeit to varying degrees, in the aging brain. The cause of PART is unknown, but sufficient evidence exists to hypothesize that it stems from an Aβ-independent mechanism, such as mechanical injury. Should the PART hypothesis withstand further experimental testing, it would represent a shift in the way a subset of subjects with AD neuropathological change are classified and has the potential to focus and reaffirm the amyloid cascade hypothesis. Emergence of the amyloid cascade hypothesis In 1906, Alois Alzheimer observed a progressive dementing illness in a 55-year-old woman 1. Using a new Bielschowsky silver stain, he observed the co-occurrence of amyloid plaques, previously described by Blocq and Marinescu, alongside a distinctive new lesion, termed the neurofibrillary tangle (NFT). The moniker Alzheimer's disease (AD), promulgated by Emil Kraepelin, was originally applied strictly to early-onset (i.e., pre-senile) dementia patients. But later, the term was broadened to encompass all dementia patients where plaques and tangles could be observed. A series of findings provided the foundation for the amyloid cascade hypothesis, which maintains that increased Aβ is the root cause of both rare familial and the more common sporadic forms of AD 2. All other features (e.g., synaptic dysfunction, neurodegeneration, and cognitive impairment) were considered secondary, including NFT. Mutations in genes that influence Aβ production (i.e., presenilin 1, presenilin 2 and the amyloid precursor protein) cause familial early-onset AD 3-6. Patients with trisomy 21 (Down syndrome) have triplication of the APP gene and essentially all develop AD 7. Further, APOE ε4, the strongest risk allele for late-onset AD, is strongly associated with Aβ deposition 8. Together with the argument that all patients with AD have Aβ deposition, though tautological because