Association of Circulating Vitamin D in Midlife With Increased Tau-PET Burden in Dementia-Free Adults

Background and Objectives: Low circulating vitamin D in later-life has been associated with increased risk of cognitive impairment and clinical dementia. However, whether serum vitamin D in early mid-life is associated with neuroimaging markers of preclinical dementia is unknown. We aimed to determine the association between early mid-life serum vitamin D and subsequent tau- and amyloid- burden on brain-PET, in a cohort of dementia-free adults. Methods: This was a prospective cohort study of Framingham Heart Study Generation 3 cohort participants who were dementia-free at time of PET, had serum 25-hydroxyvitamin D [25(OH)D] measured at examination cycle 1 (2002-2005) and had available 11C-Pittsburgh Compound-B (PiB)- and/or 18F-Flortaucipir (FTP)-PET completed between 2016 and 2019. Outcomes included global tau-PET deposition (across all 34 FreeSurfer defined cortical regions), composite tau (those regions most susceptible to early tau involvement in AD dementia, namely entorhinal cortex, parahippocampal gyrus, fusiform gyrus, amygdala and inferior and middle temporal cortices) and amyloid-PET deposition (composite region including the frontal, lateral temporal, parietal and retrosplenial cortices [FLR]). Data were analyzed using multivariable linear regression models adjusted for age, sex, time from blood sampling to PET, PET camera type, depression, season, current smoking, systolic blood pressure, use of antihypertensive medication, diabetes mellitus, cardiovascular disease, and body mass index. Results: In our sample (n= 793, 53% women, mean age 39±8years) with available serum 25(OH)D and amyloid (n=424) and/or tau-PET (n=369), the mean time between blood sampling and PET was 16±2 years. On multivariable linear regression analysis, higher serum 25(OH)D was associated with lower global (β= -0.022; 95% CI: -0.040 to -0.004; p = 0.010]) and composite tau-PET deposition (β= -0.023; 95% CI: -0.043 to -0.003; p = 0.016]),but was not associated with amyloid-PET burden. Discussion: In a group of dementia-free individuals, higher serum 25(OH)D at early mid-life was associated with lower tau deposition on brain PET a mean of 16 years later. Low vitamin D in mid-life may represent a potentially modifiable target to mitigate the risk of neuroimaging signs of preclinical dementia.