Olfactory Impairment Is Related to Tau Pathology and Neuroinflammation in Alzheimer’s Disease

Abstract

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

Patterns of tau pathology identified with 18F‐MK‐6240 PET imaging

“…Visual reads rather than quantitative thresholds were used to determine amyloid positivity, as participants were selected from feeder studies that used different amyloid radioligands and imaging windows; we were prevented from quantitation using a harmonization method such as Centiloid conversion, as Centiloid methodology has not been developed for FBB imaging from 50 to 70 minutes post‐injection. However, our visual reads are unlikely to have biased group assignment considering the high concordance with SUVR thresholds 22,43 . Partial volume effect correction was not reported, but would likely increase the difference in tau between diagnostic groups; however, it may have the benefit of reducing the potential contribution of off‐target, neuromelanin‐related binding to neocortical regions.…”

“…These reads were performed by an experienced neurologist (WCK) or nuclear medicine physician (AM) blinded to diagnosis and trained in interpretation of amyloid imaging for each radioligand. We previously validated visual determination of amyloid status using FBB against an SUVR threshold 22 …”

Neuroimmune contributions to Alzheimer’s disease: a focus on human data

“…However, their properties need better definition in large-scale studies. They will be very important in helping to validate possible causal relationships that emerge from autopsy studies; in one example, the relation of amyloid proteinopathy, tau proteinopathy, microglial activation, and other factors such as olfactory loss were assessed together to map the interconnections of these factors in cognitive decline [ 253 , 254 ]. Similarly, as reduced glucose transport constitutes a feature of AD that might even precede neurodegeneration and brain atrophy in AD, F-2-fluoro-2-deoxy-d-glucose-PET for functional imaging could be another important tool to deploy [ 89 ].…”

Olfactory Measures as Predictors of Conversion to Mild Cognitive Impairment and Alzheimer’s Disease

“…[ 14 , 15 , 16 , 17 , 18 ]. Importantly, the areas targeted early in AD tau pathology are also areas that are very important for processing olfactory information [ 19 , 20 , 21 , 22 ], and poorer odor identification has been associated with tau pathology [ 23 ].…”