<i>APOE</i> ε4-specific associations between agitation, cerebrospinal fluid biomarkers, and cognitive decline in cognitively impaired patients

Background The associations between agitation, cerebrospinal fluid (CSF) biomarkers, and cognitive decline, and whether these relationships vary by APOE genotype, remain unclear in Alzheimer's disease (AD) and mild cognitive impairment (MCI). Objective To investigate the association between CSF biomarkers and agitation in cognitively impaired individuals, with a focus on the potential moderating role of APOE ε4 status. Methods We analyzed 491 cognitively impaired individuals (359 MCI and 132 AD) from the Alzheimer's Disease Neuroimaging Initiative (ADNI) with available CSF biomarker data. Neuropsychiatric symptoms were assessed using the Neuropsychiatric Inventory (NPI), focusing on agitation. Results Among APOE ε4 carriers, agitation was significantly associated with higher CSF GAP-43 (OR = 1.584, 95% CI: 1.159–2.195, p = 0.005) and p-tau levels (OR = 1.49, 95% CI: 1.073–2.101, p = 0.02). These associations were not observed in non-carriers. In addition, APOE ε4 carriers with agitation showed a higher risk of progression to dementia compared with other groups (HR = 4.422, 95% CI: 2.542–7.692, p &lt; 0.001). Conclusions CSF GAP-43 and p-tau levels are associated with agitation in APOE ε4 carriers. Agitation in this subgroup is also associated with an increased risk of progression to dementia, suggesting that it may reflect underlying disease-related processes.