Diagnosing Alzheimer's disease is challenging, partly due to the closely related pathological features shared with other neurodegenerative diseases. Presently, a definite diagnosis of Alzheimer's disease can only be established by post mortem pathological examination focusing on two main pathological hallmarks: (i) amyloid plaques consisting of aggregated amyloid beta (Aβ) peptides, and (ii) neurofibrillary tangles made of abnormally phosphorylated tau protein.In living individuals, Alzheimer's disease diagnosis relies on two main approaches: (i) imaging of the accumulation of tau tangles and Aβ plaques in the brain using positron emission tomography (PET), and (ii) measuring brain-specific biochemical changes in CSF reflecting tau and Aβ pathophysiology. However, tau PET is expensive and only available in specialised medical centres. In 1995, our group developed two immunoassays for quantifying tau in CSF, one for measuring pathological tau phosphorylated at threonine-181 (p-tau181) and the other for the neuronal injury marker "total tau." These assays, targeting mid-region tau species, were subsequently developed into commercial kit assays, and have recently been approved by the United States Food and Drugs Administration to support diagnosis and candidate drug testing.The assays have been used in hundreds of published independent clinical studies. In reviewing

SUMMARY Tau pathology is a hallmark of Alzheimer’s disease (AD) but also occurs in normal cognitive aging. Using the tau PET agent 18F-AV-1451, we examined retention patterns in cognitively normal older people in relation to young controls and AD patients. Age and β-amyloid (measured using PiB PET) were differentially associated with tau tracer retention in healthy aging. Older age was related to increased tracer retention in regions of the medial temporal lobe, which predicted worse episodic memory performance. PET detection of tau in other isocortical regions required the presence of cortical β-amyloid, and was associated with decline in global cognition. Furthermore, patterns of tracer retention corresponded well with Braak staging of neurofibrillary tau pathology. The present study defined patterns of tau tracer retention in normal aging in relation to age, cognition, and β-amyloid deposition.

The advent of the positron emission tomography tracer 18 F-AV1451 provides the unique opportunity to visualize the regional distribution of tau pathology in the living human brain. In this study, we tested the hypothesis that tau pathology is closely linked to symptomatology and patterns of glucose hypometabolism in Alzheimer's disease, in contrast to the more diffuse distribution of amyloid-b pathology. We included 20 patients meeting criteria for probable Alzheimer's disease dementia or mild cognitive impairment due to Alzheimer's disease, presenting with a variety of clinical phenotypes, and 15 amyloid-b-negative cognitively normal individuals, who underwent 18 F-AV1451 (tau), 11 C-PiB (amyloid-b) and 18 F-FDG (glucose metabolism) positron emission tomography, apolipoprotein E (APOE) genotyping and neuropsychological testing. Voxel-wise contrasts against controls (at P 5 0.05 family-wise error corrected) showed that 18 F-AV1451 and thresholded at P 5 0.05 (uncorrected) showed that, across all patients, younger age was associated with greater 18 F-AV1451 uptake in wide regions of the neocortex, while older age was associated with increased 18 F-AV1451 in the medial temporal lobe. APOE e4 carriers showed greater temporal and parietal 18 F-AV1451 uptake than non-carriers. Finally, worse performance on domain-specific neuropsychological tests was associated with greater 18 F-AV1451 uptake in key regions implicated in memory (medial temporal lobes), visuospatial function (occipital, right temporoparietal cortex) and language (left 4 right temporoparietal cortex). In conclusion, tau imaging-contrary to amyloid-b imaging-shows a strong regional association with clinical and anatomical heterogeneity in Alzheimer's disease. Although preliminary, these results are consistent with and expand upon findings from post-mortem, animal and cerebrospinal fluid studies, and suggest that the pathological aggregation of tau is closely linked to patterns of neurodegeneration and clinical manifestations of Alzheimer's disease. Keywords: Alzheimer's disease; tau; AV1451 PET; cognition; APOE Abbreviations: AI = asymmetry index; DVR = distribution volume ratio; MMSE = Mini-Mental State Examination; PCA = posterior cortical atrophy; PiB = Pittsburgh compound B; PPA = primary progressive aphasia; SUVR = standardized uptake value ratio