We sought to determine if upstream amyloid accumulation and downstream cognitive impairment have independent relationships with microglial activation and tau pathology. Fifty-eight older adults were stratified by amyloid and cognitive status based on 18 F-florbetaben PET, history, and neuropsychological testing. Of these, 57 had 11 C-PBR28 PET to measure microglial activation and 43 had 18 F-MK-6240 PET to measure tau pathology. Amyloid and cognitive status were associated with increased overall binding for both 11 C-PBR28 and 18 F-MK-6240 (p's < 0.01). While there was no interaction between amyloid and cognitive status in their association with 11 C-PBR28 binding (p ¼ 0.6722), there was an interaction in their association with 18 F-MK-6240 binding (p ¼ 0.0115). Binding of both radioligands was greater in amyloid-positive controls than in amyloid-negative controls; however, this difference was seen in neocortical regions for 11 C-PBR28 and only in medial temporal cortex for 18 F-MK-6240. We conclude that, in the absence of cognitive symptoms, amyloid deposition has a greater association with microglial activation than with tau pathology.

Introduction Positron emission tomography (PET) imaging for neurofibrillary tau allows investigation of the in vivo spatiotemporal progression of Alzheimer's disease (AD) pathology. We evaluated the suitability of 18F‐MK‐6240 in a clinical sample and determined the relationships among 18F‐MK‐6240 binding, age, cognition, and cerebrospinal fluid (CSF)‐based AD biomarkers. Methods Participants (n = 101, 72 ± 9 years, 52% women) underwent amyloid PET, tau PET, structural T1‐weighted magnetic resonance imaging, and neuropsychological evaluation. Twenty‐one participants had lumbar puncture for CSF measurement of amyloid beta (Aβ)42, tau, and phosphorylated tau (p‐tau). Results 18F‐MK‐6240 recapitulated Braak staging and correlated with CSF tau and p‐tau, normalized to Aβ42. 18F‐MK‐6240 negatively correlated with age across Braak regions in amyloid‐positive participants, consistent with greater tau pathology in earlier onset AD. Domain‐specific, regional patterns of 18F‐MK‐6240 binding were associated with reduced memory, executive, and language performance, but only in amyloid‐positive participants. Discussion 18F‐MK‐6240 can approximate Braak staging across the AD continuum and provide region‐dependent insights into biomarker‐based AD models.

Background: Olfactory impairment is evident in Alzheimer’s disease (AD); however, its precise relationships with clinical biomarker measures of tau pathology and neuroinflammation are not well understood. Objective: To determine if odor identification performance measured with the University of Pennsylvania Smell Identification Test (UPSIT) is related to in vivo measures of tau pathology and neuroinflammation. Methods: Cognitively normal and cognitively impaired participants were selected from an established research cohort of adults aged 50 and older who underwent neuropsychological testing, brain MRI, and amyloid PET. Fifty-four participants were administered the UPSIT. Forty-one underwent 18F-MK-6240 PET (measuring tau pathology) and fifty-three underwent 11C-PBR28 PET (measuring TSPO, present in activated microglia). Twenty-three participants had lumbar puncture to measure CSF concentrations of total tau (t-tau), phosphorylated tau (p-tau), and amyloid-β (Aβ 42). Results: Low UPSIT performance was associated with greater18F-MK-6240 binding in medial temporal cortex, hippocampus, middle/inferior temporal gyri, inferior parietal cortex, and posterior cingulate cortex (p <  0.05). Similar relationships were seen for 11C-PBR28. These relationships were primarily driven by amyloid-positive participants. Lower UPSIT performance was associated with greater CSF concentrations of t-tau and p-tau (p <  0.05). Amyloid status and cognitive status exhibited independent effects on UPSIT performance (p <  0.01). Conclusion: Olfactory identification deficits are related to extent of tau pathology and neuroinflammation, particularly in those with amyloid pathophysiology. The independent association of amyloid-positivity and cognitive impairment with odor identification suggests that low UPSIT performance may be a marker for AD pathophysiology in cognitive normal individuals, although impaired odor identification is associated with both AD and non-AD related neurodegeneration. NCT Registration Numbers: NCT03373604; NCT02831283

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