ASSOCIATION BETWEEN ODOR IDENTIFICATION AND REGIONAL GRAY MATTER IN EARLY PRECLINICAL ALZHEIMER'S DISEASE

Introduction Poor performance on odor identification tests has been associated with mild cognitive impairment (MCI) and dementia due to Alzheimer's disease (AD-dementia) in older individuals (Mesholam RI et al., 1998). In addition, longitudinal studies have indicated that the University of Pennsylvania Smell Identification Test (UPSIT) is a sensitive measure that predicts conversion from MCI to AD-dementia (Devanand DP et al., 2015) However, precise biological correlates between smell identification and neurodegeneration remain to be identified. Autopsy studies and PET imaging studies indicate amyloid bplaques and neurofibrillary tangle deposition in the olfactory network, suggesting the olfactory bulb as a possible contributor (Kovacs T et al., 1999). Regardless of the etiology, deficits in smell identification measured by the UPSIT may be a useful biomarker for early presymptomatic AD. In a recent study by Risacher et al., (2017), lower UPSIT scores were inversely associated with tau burden in the temporal lobe of cognitively normal (CN) older individuals (mean age 68.5). However, no association was found between UPSIT score and amyloid deposition or neuro-degeneration as measured by gray matter (GM) volume in CN individuals. In a previous study, we reported that in middle-aged preclinical participants with varying genetic risk for AD, amyloid burden correlated inversely with the GM fraction but not with UPSIT scores. In this study, we aim to investigate the correlations between smell identification scores and regional GM fraction among CN middle-aged individuals at varying genetic risk for AD. Methods Sample consisted of 45 cognitively normal participants aged 50-66 with a first-degree family history for AD divided among three groups: APOE genotype e4e4 (n=15), e3e4 (n=15), and e3e3 (n=15), who underwent [11C]PiB PET, MRI, and neuropsychological testing. The UPSIT was administered to all participants. To quantify GM within 9 regions (ROIs), we applied inverse transformations of the AAL from MNI to subject space and calculated GM fraction as the number of voxels segmenting as GM divided by the total number of voxels in a region. The ROIs were basal ganglia, posterior cingulate, frontal cortex, lateral parietal cortex, lateral temporal cortex, medial temporal lobe, occipital cortex, precuneus and composite cortex. GM fractions which account for intersubject variability in brain size were thus generated for each ROI using the AAL atlas after the structural MRI of each participant was normalized to the MNI template. Statistical analysis was performed using SPSS version 24.0 (IBM Corp). Pearson's r was calculated to assess bivariate correlations. p-values Results Mean age of the participants was 59.1 years (SD=4.71). The mean UPSIT score was 34.58 (SD=4.09). 22 subjects (out of 45) met quantitative criteria for a positive amyloid PET scan using the [11C]PiB BPNDcut-off of 0.08 in this cognitively normal sample (Villeneuve et al., 2015). No statistically significant correlations were found between the UPSIT and GM fraction in any ROI. (Table 1). Additional analyses were performed on groups stratified by genetic risk. After excluding individuals with lower genetic risk (APOE e3e3) from the sample, no statistically significant correlation was found between UPSIT scores and GM fraction (Table 2). Similarly, no correlation was found between UPSIT score and GM fraction in participants with APOE e4e4 genotype or APOE e3e3 genotype. Conclusions In middle aged preclinical AD participants, olfactory identification performance did not correlate with gray matter fraction. Our findings appear consistent with previously reported studies and indicate that olfactory identification may not be a sensitive biomarker for early preclinical disease. Further studies to assess associations between olfactory identification deficits and pathological tau accumulation in a similar early preclinical sample may be warranted. This research was funded by This research was supported by the Alzheimer's Association IIRG-07-60026 (CHvD) and National Institute on Aging (P50-AG047270). APM was supported in part by the NIH/NIA K23-AG057794. RSO was supported in part by the NIMH R25 IMPORT grant (R25MH071584).