Prefrontal Aβ pathology influencing the pathway from apathy to cognitive decline in non-dementia elderly

The purpose of this study is to investigate the complex connection between apathy and cognitive decline that remains unclear. A total of 1057 non-dementia elderly from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database received up to 13 years of follow-up and were divided into an apathy negative (−) group of 943 participants and an apathy positive (+) group of 114 participants through the Neuropsychiatric Inventory (NPI)-apathy subitem. Cerebrospinal fluid (CSF) AD biomarkers and amyloid β (Aβ) PET were measured, and their longitudinal changes were assessed using linear mixed-effects models. Risk factors for cognitive decline and apathy conversion were explored through the Cox proportional hazards model. Mediation effects of Aβ pathology on cognition were investigated using the causal mediation analysis. Apathy syndrome was associated with faster impairment of cognition and elevation of the Aβ burden. The effects of apathy on cognitive function and life quality were mediated by Aβ pathology, including CSF Aβ(42)/total tau ratio, and Aβ deposition in the prefrontal regions. Apathy syndrome was the risk factor for cognitive deterioration; meanwhile, frontal Aβ burden was the risk factor for apathy conversion. Apathy syndrome is an early manifestation of cognitive decline and there are bidirectional roles between apathy syndrome and Aβ pathology. Prefrontal Aβ pathology influenced the pathway from apathy to cognitive decline.