Neuropsychiatric symptoms as predictors of progression to Alzheimer's disease in mild cognitive impairment: A comparative meta-analysis of apathy, depression, and anxiety.

Abstract

Background: Identifying mild cognitive impairment (MCI) patients at high risk for Alzheimer's disease (AD) is a priority. The independent prognostic utility of neuropsychiatric symptoms (NPS) remains debated.

Methods: We systematically searched longitudinal cohort studies that evaluated the predictive role of baseline apathy, depression, and anxiety for progression from MCI to clinical AD dementia. Pooled hazard ratios (HRs) with 95% confidence intervals (CIs) were calculated using random-effects models with Hartung-Knapp adjustment.

Results: Twenty-two studies (346,185 MCI patients) were included. Apathy demonstrated a statistically significant predictive association with progression (HR = 2.57, 95% CI: 1.58-4.17, p = 0.003). Depression was not significantly associated with progression overall (HR = 1.32, 95% CI: 0.69-2.50). In pre-specified subgroup analyses, a significant association was observed only among studies with follow-up ≥ 3 years (HR = 2.20, 95% CI: 1.08-4.46), although the test for subgroup differences did not reach conventional significance. Anxiety was not significantly associated with progression risk (HR = 1.27).

Conclusion: Apathy is a robust and consistent behavioral predictor of progression from MCI to clinical AD dementia. Depression may represent a potential long-term risk pattern, whereas anxiety requires further validation. Domain-specific neuropsychiatric assessment may improve future risk stratification.