Associations of Olfaction With Longitudinal Trajectories of Brain Volumes and Neuropsychological Function in Older Adults

Background and objectives: Olfactory function declines with aging and olfactory deficits are one of the earliest features of neurodegenerative diseases, such as Parkinson’s disease and Alzheimer’s disease. Previous studies have shown that olfaction is associated with brain volumes and cognitive function, but data are exclusively cross-sectional. We aimed to examine longitudinal associations of olfaction with changes in brain volumes and neuropsychological function. Methods: In the Baltimore Longitudinal Study of Aging, we chose the first assessment of olfaction to examine the associations with retrospective and prospective changes in neuropsychological performance and brain volumes in participants aged 50 or older using linear mixed-effects models, adjusted for demographic variables and cardiovascular disease. Olfaction was measured as odor identification scores via the 16-item Sniffin’ sticks. Results: We analyzed data from 567 (58% women, 42% men, 27% Black, 66% White, 7% Others) participants who had data on odor identification scores and brain volumetric MRI (n=420 with retrospective repeats over a mean of 3.7 years, n=280 with prospective repeats over a mean of 1.2 years). We also analyzed data from 754 participants (56% women, 44% men, 29% Black, 65% White, 6% Others) with neuropsychological assessments (n=630 with retrospective repeats over a mean of 6.6 years, n=280 with prospective repeats over a mean of 1.5 years). After adjustment, higher odor identification scores were associated with prior and subsequent slower brain atrophy in entorhinal cortex (β±SE=0.0093±0.0031,p=0.0028 and β±SE=0.0176±0.0073,p=0.0169,respectively), hippocampus (β±SE=0.0070±0.0030,p=0.0192 and β±SE=0.0173±0.0066,p=0.0089,respectively), and additional frontal and temporal areas (all p<0.05). Higher odor identification scores were also associated with prior slower decline in memory, attention, processing speed, and manual dexterity, and subsequent slower decline in attention (all p<0.05). Some associations were attenuated after exclusion of data points at and after symptom onset of cognitive impairment or dementia. Discussion: In older adults, olfaction is related to brain atrophy of specific brain regions and neuropsychological changes in specific domains over time. The observed associations are driven, in part, by those who developed cognitive impairment or dementia. Future longitudinal studies with longer follow-ups are needed to understand whether olfactory decline precedes cognitive decline and whether it is mediated through regionally-specific brain atrophy.