A Clinicogenomic Examination of the Relationship Between Symptoms of Apathy and Depression in Late-life and Dementia

Apathy is a common syndrome across various neurodegenerative diseases that severely affects quality of life and is linked to faster cognitive decline, and higher risk of dementia in older adults. In people with dementia, apathy leads to faster disease progression, reduced treatment response, higher caregiver burden, and mortality. Apathy has been overlooked and possibly under reported, due to the complexity of overlapping and co-occurring with depression as well as a lack of a consistent definition of apathy. The current work focuses on exploring apathy as a syndrome, by analysing apathy course and frequency, with a particular focus on the overlap with depression. Using a data-driven approach apathy and depression symptom in dementia were analysed, with exploration of symptom clusters, sub-groups and the genetic underpinnings of apathy using polygenic risk scores. The same data driven approach was employed within the cognitively normal (CN) older adults’ cohort. A large database analysis provided supporting evidence on the prevalence and persistence of apathy, with four distinct classes identified: No Symptoms; Depression; Apathy and Combined Apathy/Depression. Replicated in two independent cohorts, findings provide evidence to support a novel stratification approach for apathy and depression. Analysis in CN older adults found the same four distinct classes in the MBI group. Genetic analysis showed that genetic liability for major depression was not linked to apathy, underscoring its distinction from depression, and emphasising the importance of recognising apathy as a unique syndrome. Revealing a novel combined apathy/depression syndrome that warrants further investigation.