This thesis has other potential implications in the preclinical AD research field, the first of which refers to the conceptualization of preclinical AD. In the Introduction of this thesis we exposed the controversy in the field, with two international sets of criteria:
the IWG-2 (Dubois et al., 2016) and the NIA-AA (Sperling et al., 2011). The IWG-2 criteria required the demonstration of both amyloid and tau to define preclinical AD, whereas in the NIA-AA the demonstration of amyloid is sufficient to be in stage 1 of
5.8. Other implications for research in preclinical AD 133 preclinical AD (labeled as amyloid asymptomatic-at-risk in the IWG-2). Application of one model over the other would drastically change the percentage of the elderly population defined as having preclinical AD. The results of this thesis provide evidence that amyloid deposition in the absence of p-tau induce the first structural changes. This would support the idea that these subjects, or at least a great proportion of them, defined as being in the asymptomatic-at-risk state “only” in the IWG-2 framework, would effectively be in the course of the disease already. Moreover, the fact that tau requires the presence of amyloid to exert its deleterious effects also favors the preclinical AD conceptualization by Sperling et al in 2011. The tau asymptomatic-at-risk state of the IWG-2 does not have such clear biological consequences. Our results therefore favor the sequence of events proposed in the NIA-AA criteria with a stage of amyloidosis followed by a stage of amyloidosis and tau pathology synergistically exerting toxic effects on the cortex.
This temporal ordering of events in the theoretical AD cascade supports the amyloid cas-cade hypothesis (Hardy and Selkoe, 2002). This theory has been recently challenged by the failures of anti-amyloid therapies in clinical trials and from a conceptual point of view by the definition of a SNAP state in which subjects would show neuronal injury biomark-ers independent of Aβ (Jack et al., 2012; Knopman et al., 2013). This group would be partially coincident (only when defined with tau biomarkers, not with neurodegeneration biomarkers) with the tau asymptomatic-at-risk state of the IWG-2. As mention before our data suggests that amyloid only subjects would be in the course of the disease but that tau only subjects would not. Our results are supported with recent evidence that shows the critical difference of defining the SNAP construct with tau biomarkers or with both tau and neurodegeneration biomarkers (Vos et al., 2016). When SNAP is defined with CSF measures of tau the risk of this group for progression into MCI has been shown to be dramatically diminished in several works (Roe et al., 2013; Vos et al., 2013). Moreover, recent results in the literature present that the SNAP group show very similar longitudinal trajectories of change in Aβaccumulation and hippocampal atrophy than stage 0 subjects (Gordon et al., 2016). However the group of SNAP is highly heterogeneous (Mormino et al., 2016), and the potential role of this group in the AD pathogenesis is still to be elucidated (Dani et al., 2017; Clifford R. Jack et al., 2016; Villeneuve, 2016). Tau accu-mulation in the medial temporal lobe has been clearly established. Whether this finding is related to AD or to the aging process (Crary et al., 2014) requires further research.
We hypothesize that tau and amyloid could be independent pathologies, and that the deleterious effect of tau is potentiated when amyloid is present. Indeed, recent Tau-PET studies have suggested that Aβis a necessary factor for tau to spread from the temporal lobe to cortical areas (Johnson et al., 2016; Schöll et al., 2016; Villemagne et al., 2017).
On the contrary, in the absence of Aβ, tau would be confined to hippocampal and medial temporal structures (Wang et al., 2016).
Our thesis also has clinical implications, especially in the individual risk attributed to the biomarker status. We have shown that subjects with both amyloid and tau alterations would be more advanced on the road of AD pathology than amyloid only (stage 1) or the SNAP group. These results are in agreement with both the NIA-AA and IWG-2 models and also in line with recent literature that supports the notion that the synergy of amyloid and tau leads to greater neuronal dysfunction (T A Pascoal et al., 2016), atrophy (Desikan et al., 2011) and, importantly, greater clinical progression (Dani et al., 2017; Desikan et al., 2012; Illán-Gala et al., 2017; Tharick A. Pascoal et al., 2016).
Our results highlight the importance of the inflammation in the pathogenesis of AD.
Inflammation has been considered an important factor in AD (Blennow et al., 2010;
Heneka et al., 2015; Jagust, 2016; Maphis et al., 2015; Pimplikar et al., 2010; Tejera and Heneka, 2015), and recently a study reported that the implication of inflammation in the disease could be earlier than we previously thought (Rodriguez-Vieitez et al., 2016).
This fact opens a window of opportunity for therapeutic interventions that could tackle inflammation-related physiopathological processes. Indeed, it was suggested in observa-tional studies that a long-term use of non-steroidal anti-inflammatory drugs was associated with a 28% decreased risk of AD. As pointed out by Jack in 2013, the development of new biomarkers that could capture other aspects of the pathophysiology of AD, such as inflammation, is crucial over the next decade. In this sense, we hypothesize that the de-creased MD detected in stage 1 in areas that showed cortical thickening is an indirect sign of neuroinflammation.
Finally, our results directly impact the design of AD clinical trials and would help to understand some unexpected findings in previous anti-amyloid immunotherapy trials. In both the active (AN1792 trial) (Fox et al., 2005) and passive (Solanezumab (Doody et al., 2014) and Bapineuzumab (Salloway et al., 2014)) immunization trials, the active arm showed shrinkage or no changes without clinical deterioration (http://www.alzforum.
org/new/detail.asp?id53312). As discussed in these studies, the brain shrinkage is unlikely due to neuronal death because the levels of CSF tau were reduced after the treatment.
We believe that these findings are better explained if we consider the pathological cortical thickening related to brain amyloidosis (Fortea et al., 2014; Pegueroles et al., 2017). There-fore, our findings affect the use of MRI as a surrogate marker in preclinical AD trials. Is a biomarker that behaves non-linearly an adequate marker for clinical trials? At the very least the use is much more problematic and would require appropriate modeling. Second, our results suggest that MD could be a potential biomarker for clinical trials, although further research is required to clarify whether it is an earlier marker than macrostructural changes. Finally, the results presented in this thesis predict different trajectories for each preclinical AD stage. Nevertheless, recent clinical trials in preclinical AD selected patients
5.9. Limitations and future work 135