Abstract
BACKGROUND AND OBJECTIVES: To examine associations between olfactory dysfunction, Alzheimer disease (AD) pathology, and motoric cognitive risk syndrome (MCR), a predementia syndrome characterized by cognitive complaints and slow gait that is associated with risk for AD and other dementias. METHODS: We conducted a retrospective analysis of a prospective cohort study to examine whether baseline olfactory function was associated with the risk of incident MCR in 1,119 adults aged 60 years and older (75.1% female). The association between performance on the Brief Smell Identification Test (BSIT) and incident MCR risk was computed using Cox models and reported as the hazard ratio (HR) with 95% CIs adjusted for demographic, comorbidity, and cognitive factors. Furthermore, we assessed the relationship between postmortem AD pathology and non-AD pathology and olfactory function at the time of MCR diagnosis using linear regression models adjusted for sex, education, age at death, and time from diagnosis to death. RESULTS: There were 544 (48.6%) incident cases of MCR over a median follow-up of 3.94 years. Lower BSIT scores (poor olfaction) at baseline were associated with an increased risk of incident MCR (HR for a 1-point increase in BSIT score 0.92; 95% CI 0.88-0.96) in fully adjusted models. Those with hyposmia (scores of ≤8 on the BSIT) at baseline (26.6%) were at an increased risk of MCR (HR 1.44; 95% CI 1.19-1.74) compared with those with normal olfactory function. Higher levels of the composite measure of global AD pathology and presence of Lewy body pathology were associated with lower BSIT scores at the time of incident MCR diagnosis (n = 118). τ tangle density, a specific component of AD pathology, was inversely associated with olfactory function, and the correlation remained after controlling for mild cognitive impairment syndrome and the presence of Lewy body pathology. DISCUSSION: The results provide evidence that olfactory dysfunction precedes MCR incidence and is related to Alzheimer pathology, providing a clinical approach to risk stratify and subtype MCR.