Olfactory Function in Preclinical Alzheimer’s Disease: A Multi-Cohort Study

  1. Benoît Jobin
  2. Yasmine Salman
  3. Kamar Bouchoucha
  4. Lara Huyghe
  5. Lisa Quenon
  6. Lise Colmant
  7. Thomas Gérard
  8. Vincent Malotaux
  9. Laurence Dricot
  10. Paul Dulieu
  11. Adrian Ivanoiu
  12. Renaud Lhommel
  13. Anabelle Decottignies
  14. Bernard Hanseeuw
  15. Caroline Huart
  16. The PREVENT-AD Research Group
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Abstract

Introduction

Olfactory impairment is an early feature of Alzheimer’s disease (AD). However, it is unclear if olfactory performance reflects early pathological changes during preclinical AD and/or predicts subsequent clinical progression among characterized cognitively normal (CN) individuals. We aimed to determine whether odor identification differs by amyloid status, relates to medial temporal lobe (MTL) tau burden and morphometry, and predicts longitudinal conversion to mild cognitive impairment (MCI).

Methods

We analyzed data from 257 cognitively normal (CN) older adults enrolled in PREVENT-AD (n = 217) and UCLouvain (n = 40), including 76 amyloid-positive (CN A+) and 181 amyloid-negative participants (CN A–). Participants completed olfactory testing, underwent tau-PET imaging, and structural MRI.

Results

CN A+ participants had significantly lower odor identification performance than CN A− participants, with no evidence of cohort heterogeneity. Tau-PET associations with odor identification differed by cohort. After whole-brain FDR correction and exclusion of extreme values, parahippocampal tau burden was negatively associated with odor identification score in UCLouvain ([18F]MK-6240), an association that was not found in PREVENT-AD ([ 18 F]flortaucipir). No morphometric association survived multiple comparison correction. In 250 participants with longitudinal follow-up, each 10-percentage-point higher odor identification score was associated with a 16% lower hazard of incident MCI, independent of baseline global cognition and APOE ε4-carrier status.

Discussion

Odor identification was lower in preclinical AD and associated with incident MCI independently of baseline global cognition and APOE ε4-carrier status. Its association with parahippocampal tau burden differed between cohorts, supporting further investigation using harmonized imaging methods.

Clinical trial registration

Not applicable; this was an observational cohort study.

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  1. Mentioned by @prepub-neurodegen.bsky.social on Bluesky

    Olfactory Function in Preclinical Alzheimer's Disease: A Multi-Cohort Study #NeuroDegeneration 🧪🧠 https://www.medrxiv.org/content/10.64898/2026.11.03.26367202v1

  2. Version published to 10.64898/2026.11.03.26367202v1 on medRxiv