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    • An issue related to research without

    2023-01-28

    An issue related to research without biomarkers is that many studies will ascertain some but not all biomarker groups in study participants. Because tau PET is relatively new, incomplete biomarker information will occur in studies that use imaging for amyloid and neurodegenerative biomarker characterization but lack tau PET. A missing biomarker group is denoted *; missing T would therefore be T* (Table 2). Participants in these studies may be categorized on the basis of information that is available, that is, A+T* places the participant in the “Alzheimer's continuum,” and A−T*(N)+ is suspected non-AD pathologic change (Table 2). Another common situation will be studies with MRI but without either PET or CSF molecular biomarkers for amyloid and tau. In this situation, while MRI cannot be used as a biomarker of the Alzheimer's continuum, it is useful as a measure of cerebrovascular disease and of nonspecific neurodegeneration, which in turn is a predictor of future clinical decline.
    Hypothesis testing using the research framework This framework is a flexible platform to generate and test hypotheses concerning the interactions among different pathologic processes (denoted by biomarkers) and cognitive symptoms. Abundant human and animal data implicate A and T in the primary pathogenesis of AD [9,100], including the observation that the age-related exponential increase in prevalence of A (by biomarkers and neuropathology) anticipates the age-related exponential increase in prevalence of clinically defined possible/probable “AD” by around 15 years [53,212]. However, we point out the potential distinction between possible cause(s) of AD and a biologically based definition of AD. This framework does not depend on A and T being causal in AD pathogenesis. The AT(N) biomarker system is an unbiased system for grouping biomarkers and classifying research participants on the basis of biomarker profiles. Thus, this framework can serve as a regadenoson mg testing platform for disease models where A and T are present as epiphenomena and models where they are causal. We emphasize though that A and T proteinopathies define AD as a unique disease among the many that can lead to dementia. As a consequence, disease models where A and T are not in the primary causal pathway must provide a mechanistic explanation for the development of both of these diagnostic proteinopathies, as well as neurodegeneration and clinical symptoms. Many in the field are convinced that amyloidosis induces or facilitates the spread of pathologic tau (perhaps by promoting pathologic tau strains [218,219]), pathologic tau is immediately proximate to neurodegeneration, and neurodegeneration is the proximate cause of cognitive decline (C). If this “modified amyloid cascade hypothesis” were correct, then the logical biomarker sequence of AD pathogenesis would be that denoted in Fig. 6A [153,220,221]. Indeed, Fig. 6A maps onto the definitions outlined in Table 2. However, other biomarker sequences are possible and can be investigated through this framework. T could induce A (Fig. 6B), although if this were true, individuals with primary tauopathies (particularly MAPT mutations that produce 3R/4R fibrillar pathological tau that is morphologically identical to tau deposits in AD) would be expected to develop Aβ plaques, which is not the case. Both A and T could arise spontaneously and independently with the combination of both required to induce (N) (Fig. 6C). A and T could arise simultaneously due to a common upstream pathologic process (W) (Fig. 6D). For example, Repetition frequency is possible that cell senescence [222] or age-related breakdown of systems involved in immune surveillance or clearance of proteinaceous debris could be the upstream etiology for both A and T accumulation. A and T could be promoted by different and independent upstream pathologic processes (X and Y) [223] (Fig. 6E). For example, an age-related decrease in the rate of Aβ turnover could represent mechanism X in Fig. 6E [224]. “X” could also be a complement component receptor-1 variant that may influence Aβ clearance [164]. A yet unknown or unproven upstream pathologic process (Z) could induce A, T, and (N), with A and T being epiphenomena that are not in the causal pathway of (N) and (C). “Z” could represent many different possible mechanisms, for example, immune function, over or under activation of inflammatory pathways [165], and network failure [225,226] (Fig. 6F). It is also possible that mechanisms exist that lead to A and T but never lead to (N) and (C). Ultimately, proof of causality requires that mechanistically targeted interventions alter the natural history of the disease. If interventions that prevent A and T do not prevent (N) and (C), then this would be evidence that neither A nor T is central to the pathogenesis of AD. The research framework provides a platform to test these hypotheses.