Benoît Jobin

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.

Background: Olfactory identification is impaired early in the clinical continuum of Alzheimer's disease (AD) and is already observable in mild cognitive impairment (MCI). A recent meta‐analysis showed significant associations between olfactory identification and episodic memory scores in older adults without cognitive impairment. Thus, olfactory identification could potentially serve as a marker for episodic memory decline in individuals at risk of AD. This study aimed to (1) evaluate the predictive value of olfactory identification on episodic memory functioning in individuals with MCI and subjective cognitive decline (SCD) and (2) explore the role of olfactory identification in discriminating between the two groups. Method: Using the University of Pennsylvania Smell Identification Test (UPSIT), we assessed the olfactory identification function of 93 participants: 48 with SCD (mean age: 75.82, SD: 5.64) and 45 with MCI (mean age: 80.08, SD: 5.86) from the Consortium for the Early Identification of Alzheimer's Disease (CIMA‐Q) cohort. Episodic memory was evaluated using immediate and delayed recall scores from the Rey Auditory Verbal Learning Test (RAVLT). LASSO regression models were applied, with 80% of the data used for training and 20% for testing. Linear Discriminant Analysis (LDA) was applied to assess group classification accuracy using the UPSIT score. Result: The UPSIT score demonstrates significant associations with both immediate ( ß = 0.56, p < .001) and delayed recall scores ( ß = 0.19, p < .001). Incorporating the UPSIT score in predictive models ‐ along with age, sex, and education ‐ improved the explained variance for RAVLT immediate recall from 9% to 19% and for delayed recall from 8% to 20%. The MCI group exhibited significantly lower UPSIT scores compared to the SCD group ( p = .01); LDA achieved moderate accuracy (69%) for distinguishing groups, with higher specificity to rule out MCI (79%) than sensitivity to detect it (58%). Conclusion: Olfactory identification enhanced the prediction of episodic memory in individuals with SCD or MCI; highlighting its potential utility as a screening tool for cognitive decline associated with AD. However, because olfactory impairment is not specific to AD, further research is necessary to elucidate the underlying mechanisms driving this impairment.

Background: Olfactory identification decline is a known early marker of Alzheimer's disease and is already present at the mild cognitive impairment (MCI) stage. While being linked with episodic memory, its predictive value for cognitive performance and distinguishing between clinical stages remains unclear. Objective: This study examined (1) the predictive value of olfactory identification for episodic memory performance and (2) its utility for discriminating individuals with MCI from those with subjective cognitive decline (SCD). Methods: Participants included 45 individuals with MCI (mean age = 80.08, SD = 5.86) and 48 with SCD (mean age = 75.82, SD = 5.64) from the Consortium for the Early Identification of Alzheimer's Disease–Quebec cohort. We evaluated olfactory identification with the University of Pennsylvania Smell Identification Test (UPSIT), and episodic memory with the Rey Auditory Verbal Learning Test (RAVLT). LASSO regression models were used to predict RAVLT total and delayed recall scores, using 80% of data for training and 20% for testing. Results: UPSIT significantly predicted both RAVLT total (β = 0.45, p = 0.03) and delayed recall (β = 0.18, p = 0.02), independent of diagnostic group. Including UPSIT in the models increased explained variance from 9% to 19% for total recall, and from 8% to 20% for delayed recall. The MCI group had significantly lower UPSIT performance than the SCD group ( p = 0.01). Linear discriminant analysis yielded 69% classification accuracy, with higher specificity (79%) than sensitivity (58%). Conclusions: Olfactory identification enhances prediction of episodic memory performance and may be used as a cost-effective, non-invasive early screening tool for MCI.

INTRODUCTION: Odor identification correlates with Alzheimer's disease (AD) biomarkers, and its decline may emerge before measurable cognitive deficits – as early as the subjective cognitive decline (SCD) stage. We aimed to compare odor identification between SCD and cognitively normal (CN) stages.METHODS: A systematic search of four databases identified studies assessing olfactory identification and cognitive screening in individuals aged 50+. A random‐effects meta‐analysis was performed on 11 studies (660 SCD, 574 CN).RESULTS: Individuals with SCD exhibited lower olfactory identification scores compared to CN participants (SMD = −0.67, 95% CI [−1.31, −0.03], p = 0.04). Meta‐regression revealed a negative association (β = −1.79, p = 0.02) between cognitive and olfactory differences; lower olfactory identification scores in SCD occurred despite minimal cognitive differences across groups.DISCUSSION: Odor identification is lower in pre‐mild cognitive impairment individuals reporting SCD. Olfactory decline may emerge prior to measurable general cognitive decline, supporting its role as a screen for AD.Highlights: Individuals with SCD exhibit lower odor identification scores. Olfactory identification may serve as an early marker of neurodegeneration in preclinical AD. Heterogeneity highlights the need for multimodal biomarker approaches.

Introduction: Odor identification correlates with Alzheimer’s disease (AD) biomarkers, and its decline may emerge before measurable cognitive deficits—as early as the subjective cognitive decline (SCD) stage. We aimed to compare odor identification between SCD and cognitively normal (CN) stages and investigate whether cognitive differences moderate olfactory deficits. Methods: A systematic search of four databases identified studies assessing olfactory identification and cognitive screening in individuals aged 50+. A random-effects meta-analysis was performed on 11 studies (660 SCD, 574 CN). Results: Individuals with SCD exhibited lower olfactory identification scores compared to CN participants (SMD = −0.67, 95%CI [−1.31, −0.03], p = .04). Meta-regression revealed a negative association (β = −1.79, p = .02) between cognitive and olfactory differences, indicating that greater cognitive decline was not consistently associated with greater olfactory deficits, lower odor identification scores in SCD occurred despite minimal cognitive differences across groups. Discussion: Odor identification is lower in pre-MCI individuals reporting SCD. Olfactory decline may emerge independently prior to measurable cognitive decline, supporting the role of odor identification as a screen for AD.

Background: Olfactory identification is impaired in the early stages of Alzheimer’s disease (AD), including mild cognitive impairment (MCI). This early sensory impairment could result from several factors such as early cognitive or structural cerebral damages caused by the disease. It is however not clear which factors are contributing the most to the olfactory impairment in older people at risk of developing AD. The aim of this study was to explore and determine the cerebral and cognitive correlates of olfactory identification functioning in a cohort of older adults at risk of developing AD.Method: Here we report preliminary data on 16 participants with subjective cognitive decline (SCD) (mean age: 76.58, SD: 5.53) and 17 patients with MCI (mean age: 79.94, SD: 7.06) from the Consortium for the Early Identification of Alzheimer’s Disease‐Quebec (CIMA‐Q). Olfactory assessment was completed using the University of Pennsylvania Smell Identification Test (UPSIT), while episodic memory was assessed using the Logical Memory subtests of the Wechsler Memory Scale. All participants underwent a clinical examination and neuropsychological assessment. Further, grey matter volume (GMV) of olfactory‐related structures was extracted using CAT12 in a subgroup of 16 participants for whom MRI data were available.Result: The UPSIT score was significantly correlated with the Logical Memory immediate recall score in the MCI group (r = .53, p = .03) but not in the SCD group (r = ‐.26, p = .33). No significant differences were found regarding olfactory identification between both groups (p = .75). Bilateral middle cingulate cortex (r = .51, p = .04) and caudate (r = .51, p = .04) GMV were correlated to the UPSIT score, while no significant correlation was found for other structures (p > .05).Conclusion: These preliminary data suggest that short‐term episodic memory, as well as GMV of middle cingulate cortex and caudate are related to olfactory identification in older adults at risk of AD. Future studies to validate these findings will incorporate more participants from the CIMA‐Q cohort.

Background: Olfactory identification is impaired in the early stages of Alzheimer’s disease (AD), including mild cognitive impairment (MCI). This early sensory impairment could result from several factors such as early cognitive or structural cerebral damages caused by the disease. It is however not clear which factors are contributing the most to the olfactory impairment in older people at risk of developing AD. The aim of this study was to explore and determine the cerebral and cognitive correlates of olfactory identification functioning in a cohort of older adults at risk of developing AD.Method: Here we report preliminary data on 16 participants with subjective cognitive decline (SCD) (mean age: 76.58, SD: 5.53) and 17 patients with MCI (mean age: 79.94, SD: 7.06) from the Consortium for the Early Identification of Alzheimer’s Disease‐Quebec (CIMA‐Q). Olfactory assessment was completed using the University of Pennsylvania Smell Identification Test (UPSIT), while episodic memory was assessed using the Logical Memory subtests of the Wechsler Memory Scale. All participants underwent a clinical examination and neuropsychological assessment. Further, grey matter volume (GMV) of olfactory‐related structures was extracted using CAT12 in a subgroup of 16 participants for whom MRI data were available.Result: The UPSIT score was significantly correlated with the Logical Memory immediate recall score in the MCI group (r = .53, p = .03) but not in the SCD group (r = ‐.26, p = .33). No significant differences were found regarding olfactory identification between both groups (p = .75). Bilateral middle cingulate cortex (r = .51, p = .04) and caudate (r = .51, p = .04) GMV were correlated to the UPSIT score, while no significant correlation was found for other structures (p > .05).Conclusion: These preliminary data suggest that short‐term episodic memory, as well as GMV of middle cingulate cortex and caudate are related to olfactory identification in older adults at risk of AD. Future studies to validate these findings will incorporate more participants from the CIMA‐Q cohort.

Background: One of the major challenges in the diagnosis of Alzheimer’s disease (AD) is to increase the specificity of the early diagnosis. While episodic memory impairment is a sensitive marker of AD, other markers are needed to improve diagnostic specificity. A promising biomarker might be a cerebral atrophy of the central olfactory processing areas in the early stages of the disease since an impairment of olfactory identification is present at early clinical stages of AD. Our goal was to evaluate whether reduced grey matter volume (GMV) in the central olfactory processing regions could be observed in early and preclinical stages of AD. We also aimed to verify if GMV of central olfactory processing regions is associated with episodic memory performance.Method: 166 participants from the Consortium for the Early Identification of Alzheimer’s Disease‐Quebec (CIMA‐Q) (92 with subjective cognitive decline ‐ SCD, 40 with mild cognitive impairment ‐ MCI and 34 cognitively healthy controls) were included. We performed regions of interest (ROI) analysis using a mask of the regions that are activated during olfactory stimulation. We also extracted GMV outside ROIs, representing non‐olfactory areas of these regions, i.e., regions which do not respond to olfactory stimulation. Verbal episodic memory was assessed using a free word recall task from Memoria Word Recall test.Result: Compared to controls (p = .019) and participants with SCD (p = .003), participants with MCI exhibited a smaller total GMV of central olfactory processing regions, with a significant interaction effect between region and group (p = .004). Specifically, the piriform cortex, amygdala, entorhinal cortex, and left hippocampus were significantly smaller in individuals with MCI (p≤.05, corrected). In contrast, when comparing GMV outside ROIs between the three groups, there was no such interaction between region and group (p = .428). Additionally, GMV in the olfactory areas of the piriform cortex, amygdala, and left hippocampal gyrus was correlated with episodic memory performance, while GMV in the non‐olfactory areas of the left hippocampus and left parahippocampal gyrus was correlated with episodic memory performance (p≤.05, corrected).Conclusion: There is a specific neurodegeneration of limbic and medial‐temporal olfactory‐structures in MCI, GMV of these regions being related to cognitive performance.

Background: One of the major challenges in the diagnosis of Alzheimer’s disease (AD) is to increase the specificity of the early diagnosis. While episodic memory impairment is a sensitive marker of AD, other markers are needed to improve diagnostic specificity. A promising biomarker might be a cerebral atrophy of the central olfactory processing areas in the early stages of the disease since an impairment of olfactory identification is present at early clinical stages of AD. Our goal was to evaluate whether reduced grey matter volume (GMV) in the central olfactory processing regions could be observed in early and preclinical stages of AD. We also aimed to verify if GMV of central olfactory processing regions is associated with episodic memory performance.Method: 166 participants from the Consortium for the Early Identification of Alzheimer’s Disease‐Quebec (CIMA‐Q) (92 with subjective cognitive decline ‐ SCD, 40 with mild cognitive impairment ‐ MCI and 34 cognitively healthy controls) were included. We performed regions of interest (ROI) analysis using a mask of the regions that are activated during olfactory stimulation. We also extracted GMV outside ROIs, representing non‐olfactory areas of these regions, i.e., regions which do not respond to olfactory stimulation. Verbal episodic memory was assessed using a free word recall task from Memoria Word Recall test.Result: Compared to controls (p = .019) and participants with SCD (p = .003), participants with MCI exhibited a smaller total GMV of central olfactory processing regions, with a significant interaction effect between region and group (p = .004). Specifically, the piriform cortex, amygdala, entorhinal cortex, and left hippocampus were significantly smaller in individuals with MCI (p = .05, corrected). In contrast, when comparing GMV outside ROIs between the three groups, there was no such interaction between region and group (p = .428). Additionally, GMV in the olfactory areas of the piriform cortex, amygdala, and left hippocampal gyrus was correlated with episodic memory performance, while GMV in the non‐olfactory areas of the left hippocampus and left parahippocampal gyrus was correlated with episodic memory performance (p = .05, corrected).Conclusion: There is a specific neurodegeneration of limbic and medial‐temporal olfactory‐structures in MCI, GMV of these regions being related to cognitive performance.