3 Olfactory Dysfunction as a Preclinical Biomarker of AD: Psychophysical Olfactory Performance Reflects Hippocampal Integrity in Non-Demented Older Adults
Authors: Albertazzi Abigail S , Frank Conner , Murphy Claire 
Published: December 2023

Objective:One of the greatest challenges of the Alzheimer’s disease (AD) epidemic is identifying the disease prior to substantial neurological compromise. The established biomarkers of AD, such as measures of cognitive impairment, hippocampal atrophy, and CSF measures of beta amyloid and tau, used in research and drug trials are less indicative of AD pathology in preclinical, non-demented, populations. Olfactory dysfunction, a well-established sensory impairment of AD found to correlate strongly with tau burden and hippocampal volume measures, has shown to be a promising preclinical biomarker for AD progression. Several studies have found either impaired odor identification or odor memory at baseline to predict 5-year follow-up cognitive decline and conversion from MCI to AD, but less is known about how olfactory performance reflects the integrity of associated brain regions such as the hippocampus. The present analysis aims to explore the value of psychophysical olfactory assessment as biomarker measure in preclinical AD studies and drug trials by investigating its relationships with structural measures of the hippocampus.Participants and Methods:A sample consisted of non-demented older adults (age >75), recruited from the UCSD Alzheimer’s Disease Research Center as part of a ongoing olfactory biomarker study. Participants completed the AD Assessment Scale-Cognitive Subscale-13 (ADAS-Cog-13), San Diego Odor Identification Test (SDOIT), tests of odor recognition memory (ORMem) and odor associative memory (OAM), and MRI derived hippocampal volumes and average hippocampal occupancy (Avg HOC). Left and right hippocampal volumes were adjusted for each participant’s estimated intracranial volume. Bivariate correlations were calculated for ADAS-Cog-13 and SDOIT total scores, performance scores for odor recognition and odor associative memory tests, and the three hippocampal measures (bilateral volumes and average occupancy).Results:ADAS-Cog-13 score did not show significant correlations with either hippocampal measure at the .05 level. SDOIT scores were significantly correlated with the measure of Avg HOC (p<.05). ORMem false positive responses were significantly correlated with Avg HOC (p<.01) and right hippocampal volume (p<.05). ORMem miss responses and OAM errors were both correlated with left (p<.05) and right (p<.01) hippocampal volumes.Conclusions:These results demonstrate that psychophysical assessments of odor identification and odor memory can better reflect the integrity of the hippocampus in nondemented older adults, compared to the neuropsychological ADAS-Cog-13. This is congruent with olfactory dysfunction preceding cognitive-memory decline in AD cases and provides support for the utility of psychophysical olfactory assessment along with other established AD biomarkers in research and drug trials in preclinical populations.Acknowledgements:Supported by NIH grant # R01AG062006-04 from the National Institute on Aging to CM. Special thank you to the staff and participants of the UCSD ADRC, especially Christina Gigliotti, and Aaron Jacobson at the UCSD Center for fMRI.