## 3 Positron Emission Tomography & Tracers for the Detection of AD
### Tau-Binding Tracers  
The accumulation of neurofibrillary tangles of hyperphosphorylated tau proteins is a well-known pathological characteristic of AD alongside the accrual of amyloid plaques [57]. The amyloid cascade hypothesis states that downstream from the accumulation of insoluble amyloid, misfolded and hyperphosphorylated tau proteins weaken tau's binding affinity to microtubules within neuronal bodies, resulting in the generalized breakdown of cytoskeletal architecture and leading to neurodegeneration [58]. Tau deposition in vivo correlates very well with hypometabolism revealed by FDG-PET and also with Braak staging in post-mortem studies. Tau retention tends to first occur in the hippocampus and entorhinal cortex during Braak stages I-II, adjacent neocortices in Braak stages III-IV, and throughout the whole brain in Braak stages V-VI [20; 59; 60]. The accumulation of tau tangles in the temporal lobe is inversely correlated with memory performance, while accumulation in the frontal lobe is inversely correlated with general cognition, and with FDG-PET and amyloid-PET [61; 62]. Individuals with the _APOE-e4_ allele showed a substantially increased tau protein burden [63; 64].  
The development of tracers for tau-PET has been marked by significant challenges regarding off-target binding, specifically to amyloid proteins and monoamine oxidase [65]. Even highly tau-specific tracers must deal with the complication of tau proteins having many unique isoforms with significantly different structures at the secondary and tertiary levels of protein organization, making isoform selectivity an important challenge to overcome [66]. Tau tracer design is further complicated by the fact that neurofibrillary tau tangles occur within neuronal bodies, which would require that the tracer not only be capable of crossing the BBB but also be capable of crossing neuronal cell membranes. Currently, there is only one tracer that is approved for clinical use by the FDA (tradename: flortaucipir); however, extensive effort is underway to design validation procedures for the design of next-generation tau tracers [67; 68; 69; 70].  
One important advantage of tau-PET over amyloid-PET is that tau neurofibrillary tangles follow a well-defined sequential spread defined by Braak stages, which is markedly different from the plateau typically seen in amyloid accumulation. The spread of these tau tangles may, in fact, be indicative of disease progression in vivo [57; 59]. Tau-PET has been shown to outperform amyloid-PET and volumetric MR studies for the prognostication of cognitive decline [71]. As with the accumulation of amyloid plaques, the presence of tau tangles does not necessarily prescribe a diagnosis of AD dementia nor any other DSD. For instance, tau deposition also occurs in elderly healthy control patients in a process known as primary age-related tauopathy (PART) and is believed to be an insufficient condition for the progression of cognitive decline in the absence of amyloid positivity [72]. Tau-PET may also be very useful in the differential diagnosis of non-tauopathic DSDs (e.g., Parkinson's disease dementia and multiple system atrophy).