Association between long‐term donepezil treatment and brain regional amyloid and tau burden among individuals with mild cognitive impairment assessed using 18 F‐AV‐45 and 18 F‐AV‐1451 PET

Abstract This study aims to investigate the association between long‐term donepezil treatment and brain neuropathological burden and cognitive function in mild cognitive impairment (MCI) patients. Preprocessed 18 F‐AV‐45 amyloid and 18 F‐AV‐1451 tau positron emission tomography (PET) images, magnetic resonance imaging images (MRIs), demographic information, and donepezil use status were downloaded from 255 MCI participants enrolled in the Alzheimer's Disease Neuroimaging Initiative database. Partial volume correction was applied to all PET images. Structural MRIs were used for PET spatial normalization. Regions of interest (ROIs) were defined in standard space, and standardized uptake value ratio (SUVR) images relative to the cerebellum were computed. Multiple linear regression with the least absolute shrinkage selector operator was performed to analyze the effect of long‐term donepezil treatment on (a) the SUVR of each 18 F‐AV‐45 or 18 F‐AV‐1451 brain PET ROI after adjusting for age, sex, education, ApoE ε4 status, and AD‐associated disease risk factors; and (b) cognitive performance after adjusting for age, sex education, ApoE ε4 status, AD‐associated disease risk factors, and regional amyloid or tau burden. In adjusted models, long‐term donepezil treatment was associated with greater amyloid load in the orbital frontal, superior frontal, parietal, posterior precuneus, posterior cingulate, lateral temporal, inferior temporal and fusiform regions, and tau burden in the posterior cingulate, entorhinal and parahippocampal gyrus. Long‐term donepezil treatment was also associated with worse performance on the 13‐item Alzheimer's Disease Assessment Scale‐Cognitive subscale after adjusting for AD‐related risk factors and regional brain amyloid or tau load. These results indicate that long‐term donepezil treatment is associated with increased regional amyloid and tau burden and worse cognitive performance among individuals with MCI. Our study highlights the importance of using noninvasive and quantitative 18 F‐AV‐45 and 18 F‐AV‐1451 PET to elucidate the consequences of drug administration in AD studies.