Are cases with tau pathology occurring in the absence of Aβ deposits part of the AD-related pathological process?

Abstract

and only at the same predilection sites as the tau lesions that are present in individuals with Aβ and in fully developed AD can represent possible preclinical (early) stages of the AD-related pathological process. In other words, an interim or transient absence of a minimum of Aβ deposits is not an adequate or compelling rationale for excluding tau-only cases from the developmental spectrum of the ADrelated process, nor is the existence of such cases in nonaged individuals (compare Table 3 here with Table 1 in [8]) consistent with the term ‘primary age-related tauopathy.’ The authors claim that PART, in contrast to AD, is probably not APOE e4 allele-driven. However, an earlier study showing that non-demented individuals with NFT stage I pathology displayed a significantly higher APOE e4 allele frequency than controls [11] reached the opposite conclusion. That study was retrospective (cross sectional), but so were the studies in the supporting literature (13, 67, 70, 122, 150, 151) cited by Crary et al. [8], who have not incorporated into their thinking the implications of recent original findings showing that neuronal injury develops independently of Aβ in APOE e4 allele carriers [7, 13]. The fundamental question whether 3R + 4R tau-only cases and cases with 3R + 4R tau plus Aβ deposits belong to essentially different pathological processes cannot be resolved without identifying potentially unique mechanisms for cases with tau-only pathology, e.g., by means of experimental models of tau seeding and neuron-to-neuron transmission [12], in which tau extracts are isolated not from AD brains but from brains of individuals with autopsy-confirmed 3R + 4R tau-only lesions. Biomarkerbased research and positron emission tomography (PET) imaging of brain Aβ and of tau that can quantify abnormalities in AD-associated neurodegeneration [19] have the developmental potential to reach the point at which the presence and progression of both pathological proteins can The current neuropathological diagnosis of clinically suspected Alzheimer’s disease (AD) requires the presence of advanced neurofibrillary tangle (NFT) stages and of Aβ deposits in the brain [15]. Both abnormal proteins (intraneuronal forms of aggregated and hyperphosphorylated tau and extracellular Aβ) develop at different times at different predilection sites and progress gradually but inexorably during the pathological process by sequential spreading into previously uninvolved regions. Tau pathology develops prior to Aβ deposits [1, 5, 6]. In their position paper, Crary et al. [8] present arguments for distinguishing two processes: an ‘AD-related process’ and a non-AD-related ‘primary age-related tauopathy’ (PART). Both are characterized by the presence of 3R and 4R tau isoforms as well as paired helical filaments but they differ in that the first displays the combined presence of tau and Aβ pathologies, whereas the second is marked by the presence of tau pathology alone. Nevertheless, application of the criteria required to confirm neuropathologically that the diagnosis of clinically manifest AD [15] does not warrant the disqualification of tau-only cases because the statement that “a diagnosis of AD neuropathologic changes requires at least a minimum threshold level of Aβ deposition” [8] is correct only in cases with clinically diagnosed AD but is inaccurate when applied to non-demented individuals. In the absence of Aβ deposits, tau pathology consisting of 3R and 4R isoforms that occurs in the same neuronal cell types as those known to be vulnerable to the pathological process underlying AD