AbstractBackgroundApathy is among the earliest and most clinically distressing neuropsychiatric symptoms (NPS) in Alzheimer’s Disease (AD). Examining the relationships between apathy and AD pathology is needed to better understand neurobiological mechanisms for therapeutic intervention that could delay disease progression. Research has shown that tau may correlate more closely with cognitive and behavioral manifestations in AD than amyloid. In the current study, we examined the relationship between regional tau burden and longitudinal change in apathy in older adults with mild cognitive impairment (MCI) and AD dementia from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database.MethodA total of 319 ADNI participants (233 with MCI; 86 with AD dementia; age: 75.5 ±8.2; 56% female) underwent flortaucipir (FTP) tau positron emission tomography (PET) and clinical assessment with the Neuropsychiatric Inventory (NPI) every 6‐12 months (average follow up= 39.1 months). The NPI Apathy (NPI‐A) score was examined in relation to tau PET signal in four FreeSurfer defined regions of interest implicated in AD and mood regulation: entorhinal cortex (EC), precuneus, inferior temporal cortex and rostral anterior cingulate cortex (rACC). Separate linear mixed models examined the association between NPI‐A (for each study visit) and FTP SUVR in the above regions and their interactions with time as predictors of interest. Age and sex were included as covariates.ResultHigher precuneus, EC and inferior temporal cortex tau were each significantly associated with greater NPI‐A over time (precuneus: ß=0.0273; t=5.01; 95 % CI (0.016, 0.04); p<0.001; EC: ß=0.023; t=5.05; 95 % CI (0.014, 0.032); p<0.001; inferior temporal: ß=.018; t=4.92; 95 % CI (0.011, 0.026); p<0.001. rACC tau was marginally associated with higher NPI‐A over time: ß=.013; t=1.93; 95 % CI (‐0.00, 0.027) p=0.05.ConclusionThese findings suggest that tau burden in brain regions associated with AD, and less so with mood regulation, is associated with increasing apathy over time in individuals with MCI and AD dementia. Further study of emergent apathy in relation to core AD pathology and other neurobiological mechanisms will provide insight into opportunities for interventions that could slow clinical progression and alleviate patient and caregiver burden.