Heterogeneous trajectories of executive function in clinical Alzheimer’s disease: Results from the 3C study

Hélène Amieva, Maris Dussartre, Viviane Philipps, Anaïs Rouanet, Carole Dufouil, Hélène Jacqmin‐Gadda, Jean‐François Dartigues, Karine Pérès, Cécilia Samieri, Gwenaëlle Catheline, Catherine Helmer, Cécile Proust‐Lima
Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring. 2026-04-01; 18(2):
DOI: 10.1002/dad2.70385

Abstract

BACKGROUND
Alzheimer’s disease (AD) shows considerable heterogeneity in cognitive decline. Executive function (EF), a core cognitive domain, may contribute to this heterogeneity and modulate AD progression.

METHODS
We analyzed the trajectories of four EF‐related tests in 649 incident cases of AD from the Three‐City cohort, using multivariate latent class mixed modeling. We linked latent EF patterns with lifestyle at study entry, brain magnetic resonance imaging, clinical markers, and prognosis.

RESULTS
The three identified EF patterns, Steep EF Decline, Low EF, and High EF, showed differences in lifestyle‐related factors at baseline, white matter hyperintensity burden, hippocampal volume, and clinical progression. Steep EF Decline predicted worse outcomes and higher mortality. High EF indicated slower decline and better prognosis.

DISCUSSION
EF trajectories diverge substantially before AD diagnosis, with implications for prognosis. Preserved EF appears protective, while early or steep EF decline correlates with worse evolution. Lifestyle and vascular factors contribute significantly, highlighting potential intervention targets for cognitive resilience in AD.