Neuropathological Correlates of Apathy Progression in Alzheimer Disease and Related Dementias

OBJECTIVE: Apathy is disabling in Alzheimer disease (AD) and related dementias, but its progression across neuropathologies remains unclear. This cohort study examined longitudinal apathy-neuropathology associations. METHODS: We analyzed 1488 participants from the National Alzheimer's Coordinating Center with autopsy-confirmed neuropathology and at least 2 caregiver-reported Neuropsychiatric Inventory Questionnaire assessments. Generalized linear mixed models tested associations between apathy and AD, Lewy body disease, frontotemporal lobar degeneration (FTLD), hippocampal sclerosis (HS), cerebrovascular disease, and cerebral amyloid angiopathy. Time was modeled as years to death, including pathology-by-time interactions. Models were adjusted for age at death, sex, and Neuropsychiatric Inventory Questionnaire total score excluding apathy. Sex-stratified analyses were conducted. RESULTS: Apathy prevalence increased over time across all pathology groups. FTLD [odds ratio (OR) = 2.11, 95% CI: 1.32-3.39] and HS (OR = 2.23, 95% CI: 1.38-3.60) were consistently associated with higher odds of apathy. No pathology-by-time interaction was significant. Among males, FTLD (OR = 2.58, 95% CI 1.40-4.77), HS (OR = 2.48, 95% CI 1.29-4.77), and Lewy body disease (OR = 1.64, 95% CI 1.03-2.61) were significantly associated with apathy, while only HS (OR = 2.18, 95% CI 1.06-4.47) remained significant in females. CONCLUSION: Apathy severity varied by neuropathologies but progressed similarly over time. The elevated burden in FTLD and HS, particularly among males, underscores the importance of stratified approaches to early detection and intervention targeting apathy in AD and related dementias.