Apathy and APOE in mild behavioral impairment, and risk for incident dementia

INTRODUCTION: Mild behavioral impairment (MBI) is a high‐risk state for incident dementia and comprises five core domains including affective dysregulation, impulse dyscontrol, social inappropriateness, psychotic symptoms, and apathy. Apathy is among the most common neuropsychiatric symptoms (NPS) in dementia but can also develop in persons with normal cognition (NC) or mild cognitive impairment (MCI). The later‐life emergence and persistence of apathy as part of the MBI syndrome may be a driving factor for dementia risk. Therefore, we investigated MBI‐apathy–associated progression to dementia, and effect modification by sex, race, cognitive diagnosis, and apolipoprotein E (APOE) genotype. METHODS: Dementia‐free National Alzheimer's Coordinating Center participants were stratified by persistent apathy status, based on Neuropsychiatric Inventory (NPI)–Questionnaire scores at two consecutive visits. Hazard ratios (HRs) for incident dementia for MBI‐apathy and NPI‐apathy relative to no NPS, and MBI‐apathy relative to no apathy, were determined using Cox proportional hazards regressions, adjusted for baseline age, sex, years of education, race, cognitive diagnosis, and APOE genotype. Interactions with relevant model covariates were explored. RESULTS: Of the 3932 participants (3247 with NC), 354 had MBI‐apathy. Of all analytic groups, MBI‐apathy had the greatest dementia incidence (HR = 2.69, 95% confidence interval [CI]: 2.15–3.36, P < 0.001). Interaction effects were observed between cognitive diagnosis and APOE genotype with the NPS group. The contribution of apathy to dementia risk was greater in NC (HR = 5.91, 95% CI: 3.91–8.93) than in MCI (HR = 2.16, 95% CI: 1.69–2.77, interaction P < 0.001) and in all APOE genotypes, was greatest in APOE ɛ3 (HR = 4.25, 95% CI: 3.1–5.82, interaction P < 0.001). DISCUSSION: Individuals with MBI‐apathy have a markedly elevated risk for future dementia, especially when symptoms emerge in those with NC. Both cognitive status and APOE genotype are important moderators in the relationship between MBI‐apathy and incident dementia. MBI‐apathy may represent a group in whom apathy is a preclinical or prodromal manifestation of dementia and identify a precision medicine target for preventative interventions.