Purpose: [¹⁸F]MK-6240, a second-generation tau PET tracer, is increasingly used for the detection and the quantification of in vivo cerebral tauopathy in Alzheimer’s disease (AD). Given that neurological symptoms are better explained by the topography rather than by the nature of brain lesions, our study aimed to evaluate whether cognitive impairment would be more closely associated with the spatial extent than with the intensity of tau-PET signal, as measured by the standard uptake value ratio (SUVr). Methods: [¹⁸F]MK6240 tau-PET data from 82 participants in the AD spectrum were quantified in three different brain regions (Braak ≤ 2, Braak ≤ 4, and Braak ≤ 6) using SUVr and the extent of tauopathy (EOT, percentage of voxels with SUVr ≥ 1.3). PET data were first compared between diagnostic categories, and ROC curves were computed to evaluate sensitivity and specificity. PET data were then correlated to cognitive performances and cerebrospinal fluid (CSF) tau values. Results: The EOT in the Braak ≤ 2 region provided the highest diagnostic accuracies, distinguishing between amyloid-negative and positive clinically unimpaired individuals (threshold = 9%, sensitivity = 79%, specificity = 82%) as well as between prodromal AD and preclinical AD (threshold = 38%, sensitivity = 81%, specificity = 93%). The EOT better correlated with cognition than SUVr (∆R² + 0.08–0.09) with the best correlation observed for EOT in the Braak ≤ 4 region (R² = 0.64). Cognitive performances were more closely associated with PET metrics than with CSF values. Conclusions: Quantifying [¹⁸F]MK-6240 tau PET in terms of EOT rather than SUVr significantly increases the correlation with cognitive performances. Quantification in the mesiotemporal lobe is the most useful to diagnose preclinical AD or prodromal AD.

INTRODUCTION: Magnetic resonance imaging (MRI) segmentation algorithms make it possible to study detailed medial temporal lobe (MTL) substructures as hippocampal subfields and amygdala subnuclei, offering opportunities to develop biomarkers for preclinical Alzheimer's disease (AD).METHODS: We identified the MTL substructures significantly associated with tau‐positron emission tomography (PET) signal in 581 non‐demented individuals from the Alzheimer's Disease Neuroimaging Initiative (ADNI‐3). We confirmed our results in our UCLouvain cohort including 110 non‐demented individuals by comparing volumes between individuals with different visual Braak's stages and clinical diagnosis.RESULTS: Four amygdala subnuclei (cortical, central, medial, and accessory basal) were associated with tau in amyloid beta‐positive (Aβ+) clinically normal (CN) individuals, while the global amygdala and hippocampal volumes were not. Using UCLouvain data, we observed that both Braak I‐II and Aβ+ CN individuals had smaller volumes in these subnuclei, while no significant difference was observed in the global structure volumes or other subfields.CONCLUSION: Measuring specific amygdala subnuclei, early atrophy may serve as a marker of temporal tauopathy in preclinical AD, identifying individuals at risk of progression.Highlights: Amygdala atrophy is not homogeneous in preclinical Alzheimer's disease (AD). Tau pathology is associated with atrophy of specific amygdala subnuclei, specifically, the central, medial, cortical, and accessory basal subnuclei. Hippocampal and amygdala volume is not associated with tau in preclinical AD. Hippocampus and CA1‐3 volume is reduced in preclinical AD, regardless of tau.

Alzheimer’s disease (AD) is characterized by amyloid beta (Aβ) plaques and hyperphosphorylated tau in the brain. Aβ plaques precede cognitive impairments and can be detected through amyloid-positron emission tomography (PET) or in cerebrospinal fluid (CSF). Assessing the plasma Aβ42/Aβ40 ratio seems promising for non-invasive and cost-effective detection of brain Aβ accumulation. This approach involves some challenges, including the accuracy of blood-based biomarker measurements and the establishment of clear, standardized thresholds to categorize the risk of developing brain amyloid pathology. Plasma Aβ42/Aβ40 ratio was measured in 277 volunteers without dementia, 70 AD patients and 18 non-AD patients using single-molecule array. Patients (n = 88) and some volunteers (n = 66) were subject to evaluation of amyloid status by CSF Aβ quantification or PET analysis. Thresholds of plasma Aβ42/Aβ40 ratio were determined based on a Gaussian mixture model, a decision tree, and the Youden’s index. The 0.0472 threshold, the one with the highest sensitivity, was retained for general population without dementia screening, and the 0.0450 threshold was retained for research and clinical trials recruitment, aiming to minimize the need for CSF or PET analyses to identify amyloid-positive individuals. These findings offer a promising step towards a cost-effective method for identifying individuals at risk of developing AD.

Introduction: Second‐generation tau‐PET tracers like [¹⁸F]MK‐6240 are increasingly used both for diagnosing and quantifying Alzheimer's Disease (AD) tauopathy. However, while [¹⁸F]MK‐6240 tau‐PET has demonstrated excellent sensitivity for AD tauopathy, data assessing its specificity and binding in non‐AD tauopathies are still scarce.Methods: Participants were assigned to exclusive categorical diagnoses based on their amyloid (Aβ) and cognitive status. We quantified mesiotemporal (MTL) and neocortical [¹⁸F]MK‐6240 tau‐PET signal in 28 Aβ− cognitively impaired (CI) patients presenting various non‐AD neurodegenerative disorders. Tau‐PET quantifications were compared with Aβ− cognitively unimpaired (CU) subjects (n = 51) and Aβ+ CI patients (n = 77).Results: Among the 28 Aβ− impaired subjects, only five presented significant and isolated mesiotemporal signal, most of them being suspected of primary age‐related tauopathy (PART). Only two Aβ− impaired patients (7%) presented positive neocortical signal, both being diagnosed with fronto‐temporal degeneration (FTD). The Tau‐PET results of all the remaining Aβ− patients were comparable to the CU population, including eight other FTD patients. Importantly, 4R‐only tauopathies (CBD and PSP) and sv‐PPA were negative.Conclusion: [¹⁸F]MK‐6240 tau‐PET has a special affinity for tauopathies involving 3R/4R paired helical filaments: AD, PART (Aβ− subjects with MTL‐restricted tau‐PET signal) and some forms of FTD while most primary tauopathies do not exhibit significant cortical signal. Positive neocortical scans are therefore highly specific for AD tauopathy. Based on those and previous results, we propose a diagnostic flowchart for MCI subjects suspected of AD or another tauopathy which may significantly reduce the need for amyloid PET or CSF measurement.

Early Alzheimer’s disease diagnosis is crucial for preventive therapy development. Standard neuropsychological evaluation does not identify clinically normal individuals with brain amyloidosis, the first stage of the pathology, defined as preclinical Alzheimer’s disease. Spatial navigation assessment, in particular path integration, appears promising to detect preclinical symptoms, as the medial temporal lobe plays a key role in navigation and is the first cortical region affected by tau pathology. We have conducted a cross-sectional study. We related the path integration performance of 102 individuals without dementia, aged over 50, to amyloid and tau pathologies, measured using positron emission tomography. We included 75 clinically normal individuals (19 with brain amyloidosis, 56 without) and 27 individuals with mild cognitive impairment (18 with brain amyloidosis, 9 without). We fitted linear mixed models to predict the path integration performances according to amyloid status or tau pathology in the medial temporal lobal, adjusting for age, gender, cognitive status, education, and video game experience. We decomposed the error into rotation and distance errors. We observed that clinically normal adults with brain amyloidosis (preclinical Alzheimer’s disease) had spatial navigation deficits when relying only on self-motion cues. However, they were able to use a landmark to reduce their errors. Individuals with mild cognitive impairment had deficits in path integration that did not improve when a landmark was added in the environment. The amyloid status did not influence performance among individuals with mild cognitive impairment. Among all individuals, rotation, but not distance, errors increased with the level of tau pathology in the medial temporal lobe. Our results suggest that path integration performance in an environment without external cues allows identifying individuals with preclinical Alzheimer’s disease, before overt episodic memory impairment is noticeable. Specifically, we demonstrated that poor angular estimation is an early cognitive marker of tau pathology, whereas distance estimation relates to older ages, not to Alzheimer’s disease. Eudra-CT 2018–003473-94.