Olfactory impairment in Huntington's disease: A systematic review and meta-analysis

Huntington's disease (HD) is an autosomal-dominant neurodegenerative disorder characterised by progressive impairment in cognitive, behavioural, and motor functions. Odour identification deficits have long been recognised as a non-motor impairment associated with HD and may thus represent a plausible biomarker candidate for use in the context of clinical trials evaluating novel disease-modifying therapies. This systematic review and meta-analysis aim to evaluate whether odour identification is reduced in persons with Huntington's disease (PwHD) compared to healthy controls (HC). The protocol was registered on PROSPERO (CRD420251019430) on April 5th, 2025. Comprehensive searches were conducted across PubMed, Embase, Web of Science, Google Scholar, BASE, and WorldCat, including grey literature, up to April 15, 2025. Included studies used case-control and cross-sectional designs involving human participants, comparing PwHD to HC, explicitly reporting sample sizes, documenting the use of psychophysical methods for odour identification, and providing sufficient data to calculate group differences. Eligible publications were peer-reviewed and available in English and non-English. Risk of bias was assessed independently by two reviewers using the Joanna Briggs Institute (JBI) checklists. Two reviewers independently screened and extracted data. The meta-analysis employed a random-effects model using restricted maximum likelihood estimation. Heterogeneity was evaluated via subgroup analyses and meta-regression, and sensitivity analyses examined the robustness of results. Results from all studies identified according to the specified criteria were merged into a single dataset and treated as a whole sample for review. Of the 43 eligible studies, 19 (44.2%) were included, comprising 1745 PwHD and 814 HC. Mean (SD) age at enrolment was 46.1 (5.3) years for PwHD and 44.1 (5.9) years for HC. Meta-analysis revealed a large negative overall difference (θ = -1.294; 95% CI: -1.626 to -0.962; 95% prediction interval: -2.704 to 0.116), confirming significantly lower odour identification accuracy in the PwHD group. Substantial heterogeneity (I² = 88%) was observed. The systematic review of the clinical evidence indicates that odour identification is impaired in HD. It also supports measures of odour identification as a plausible biomarker candidate for HD. Of note, the effect sizes are not fully consistent across studies. As the reported range of likely effects includes the possibility of no difference in some settings or clinical sub-groups, this limits the extent to which the findings of this systematic review can be applied. Further research is needed to define odour identification deficits and to improve assessment methodologies. Validating new odour identification measures as biomarkers within HD therapeutic trials represents a promising direction for future work.