Associations of Sensory and Motor Functions in Midlife with Longitudinal Blood‐Based Biomarker Levels of Alzheimer’s Disease and Neurodegeneration

Background Dementia has a long preclinical phase and pathological fluid biomarker levels change decades before clinical symptoms. Thus, early detection of people at risk for neurodegenerative and pathological changes, especially in midlife, might improve future treatments and preventions. Sensory and motor changes are common in aging adults and may be early markers of neurodegeneration since they are associated with cognition and risk factors of neurodegeneration. However, their associations with blood‐based neurodegenerative and AD biomarkers are not yet known. We aimed to determine if midlife sensory and motor functions are associated with long‐term changes in blood‐based biomarkers of neurodegeneration and AD (neurofilament light chain(NfL), total tau(TT), and amyloid beta(Aβ)). Method This longitudinal study is based on n=1529 (54% women, mean age 49years) Beaver Dam Offspring Study (BOSS) participants. The BOSS started in 2005 and had 5‐year and 10‐year follow‐up exams. We assessed sensory (pure‐tone audiometry, contrast sensitivity, olfactory identification) and motor (Grooved Pegboard) function, plus multiple potential confounding risk factors at baseline. NfL, TT, Aβ42, and Aβ40 levels were analyzed in serum samples from all three waves (SIMOA, Quanterix). We used linear mixed‐effects models with baseline hearing, vision, olfaction, and motor function as determinant and repeated biomarker levels as outcome and adjusted for age, sex, education, random intercept, random slope (if model fit was improved), and other confounders. NfL and TT were log‐transformed. Due to sex interactions, Aβ42/Aβ40 models were sex‐stratified. Results Overall, NfL increased 3% and TT 1% per year. Aβ42/Aβ40 decreased 0.5/year in women and 0.24/year in men. Individuals with hearing and vision impairment showed faster NfL level increase over time (0.8%/year; CI 0.3,1.4;p=.004; 0.5%/year; CI ‐0.1,1;p=.09; respectively). Worse motor function was associated with faster NfL increase (0.4%/year per 20s test time; CI 0.2,0.7;p<.001). These effects compared to effects of 2‐3 months of aging. There were no significant associations with Aβ42/Aβ40 or TT. Conclusion We found associations between midlife sensory and motor functions and long‐term changes in NfL levels, a non‐specific marker of neurodegeneration, while there were no associations with AD‐specific biomarkers. Future studies with longer follow‐up should determine if sensory and motor changes are more reflective of general neurodegenerative than AD‐specific pathology.