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 (Aβ42).

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.

Keywords: Alzheimer’s disease; anosmia; microglia; olfaction; tau proteins.

Conflict of interest statement

CONFLICTS OF INTEREST

Julia Klein- Reports no disclosures

Xinyu Yan- Reports no disclosures

Aubrey Johnson- Reports no disclosures

Zeljko Tomljanovic- Reports no disclosures

James Zou- Reports no disclosures

Krista Polly- Reports no disclosures

Lawrence Honig- Consultant: Cortexyme, Eisai, Medscape, Prevail; Research Grants: Abbvie, Alector, Biogen, Genentech, Eli Lilly, Roche

Adam M. Brickman- Consultant: Regeneron Pharmaceuticals, Cognition Therapeutics; Equity: Mars Holding Limited

Yaakov Stern- Reports no disclosures

D.P Devanand- Consultant: Acadia, BXcel, Corium, Genentech, Grifols

Seonjoo Lee- Reports no disclosures

William C. Kreisl- Consultant for Cerveau Technologies. However, Cerveau was not involved in the design or execution of this study or in the interpretation of the results.

Figures

Figure 1.. UPSIT performance across study groups

UPSIT scores across all four study groups. UPSIT scores were lower in amyloid-positive patients than amyloid-negative controls.

Figure 2.. Relationship between UPSIT score and 18F-MK-620 PET

Lower UPSIT scores were associated with greater 18F-MK-6240 binding when all participants included in medial temporal cortex (r = −0.59, p < 0.01) and hippocampus (r = −0.60, p < 0.01). Correlations remained when only amyloid-positive participants were included (medial temporal cortex: r = −0.52, p = 0.02; hippocampus: r = −0.53, p = 0.02) but not when only amyloid-negative participants were included. Data corrected for age and sex.

Figure 3.. Relationship between UPSIT score and 11C-PBR28 PET

Lower UPSIT scores were associated with greater 11C-PBR28 binding when all participants were included in medial temporal cortex (r = −0.58, p < 0.01) and combined middle and inferior temporal gyri (r = −0.47, p < 0.01). Correlations remained when only amyloid-positive participants were included (medial temporal cortex: r = −0.74, p < 0.01; combined middle and inferior temporal gyri: r = −0.47, p = .02) but not when only amyloid-negative participants were included. Data corrected for age, sex, and TSPO genotype.

Figure 4.. Relationship between UPSIT score and CSF concentrations of total tau and phosphorylated tau

Lower UPSIT scores were associated with greater CSF concentrations of phosphorylated tau (p-tau, r = −0.53, p = .02) and total tau (t-tau, r = −0.52, p = .02), after controlling for age and sex.

Figure 5.. Relationship among UPSIT score and hippocampal volume, Mini Mental State Exam (MMSE) score and Selective Reminding Test – Delayed Recall (SRT-DR) score

Positive correlations were observed between UPSIT performance and (A) hippocampal volume (r = 0.53, p< 0.001), (B) MMSE (r = 0.42, p< 0.001) and (C) SRT-DR performance (r = 0.65, p< 0.001) when all participants were included. Positive correlations between UPSIT performance and hippocampal volume (r= 0.69, p< 0.001) and UPSIT and SRT-DR performance (r = 0.68, p< 0.001) remained when only amyloid-positive participants were included.