BACKGROUND: Potentially modifiable lifestyle and psychological factors may influence Alzheimer’s disease (AD)-related brain pathology and cognitive function, thereby influencing cognitive resilience in late life.

OBJECTIVE: This cross-sectional study investigated associations and pathways between lifestyle and psychological factors related to cognitive reserve and psychological debt, AD-related biomarkers, and cognitive function, as well as potential differences in these associations between AD risk groups.

METHODS: In total, 298 non-demented older adults (mean age = 69.5 years, 44% women) of the DELCODE study were included. Structural equation modeling was used to assess the associations between the constructs of cognitive reserve (education, occupational complexity, leisure activity participation) and psychological debt (depression and anxiety symptoms, neuroticism, sleep quality), manifest AD-related biomarkers (cerebrospinal fluid [CSF] amyloid-beta [Aβ] 42, splenial white matter hyperintensities [WMH], hippocampal volume), and latent cognitive function of increased AD risk (Preclinical Alzheimer’s Cognitive Composite [PACC]). In the structural equation model, biomarkers were transformed such that higher values indicated greater AD-related brain pathology and age was included as a covariate. Multigroup analyses assessed moderations by established AD risk modifiers, namely sex and apolipoprotein ε4 (APOE ε4) genotype.

RESULTS: In the total sample, higher cognitive reserve was associated with better cognitive function (p = .005), independent of AD-related biomarkers. Higher cognitive reserve was associated with lower psychological debt (p = .035); however, neither construct showed a significant association with the AD-related biomarkers (p ≥ .177). AD-related biomarkers of CSF Aβ42 (p = .021), splenial WMH (p = .044), and hippocampal neurodegeneration (p = .007) were each independently associated with lower cognitive function. Most associations were comparable between AD risk groups stratified by sex and APOE ε4 genotype. The relationships between cognitive reserve and psychological debt, and between CSF Aβ42 and splenial WMH were stronger in APOE ε4 non-carriers than in carriers (all p ≤ .020).

CONCLUSIONS: Cognitive reserve emerges as a key resilience pathway, supporting late-life cognition independently of AD-related pathology, with largely consistent effects across AD risk groups. The role of psychological debt warrants longitudinal investigation, particularly in vulnerable older populations.

TRIAL REGISTRATION: German Clinical Trials Register: DRKS00007966, Registered: 4 May 2015.

SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13195-026-02054-z.