Cumulative Incidence in Monogenic Alzheimer’s Disease and Frontotemporal Dementia: Gene–Gene Interaction Effect

Monogenic forms of Alzheimer’s Disease (AD) and Frontotemporal Dementia (FTD) represent the two principal neurodegenerative disorders leading to early-onset dementia, primarily linked to mutations in key AD- and FTD-associated genes. The marked heterogeneity in age at onset and penetrance among carriers of pathogenic mutations suggests that monogenic variants act within a broader polygenic background. The combined impact of AD- and FTD-related genetic variation on disease incidence in monogenic forms remains largely unexplored. Herein, we investigate gene–gene interaction patterns in monogenic AD and FTD, with a focus on genetic variability in key AD (APP, PSEN1, PSEN2) and FTD (MAPT, GRN, C9orf72)-associated genes and their association with cumulative disease incidence. Within the GARDENIA Consortium, we studied 426 individuals from Italian pedigrees, including patients (n = 319) and presymptomatic (n = 107) carriers of causative variants in APP (n = 39), PSEN1 (n = 71), PSEN2 (n = 13), MAPT (n = 29), GRN (n = 188), and C9orf72 (n = 86). Age at symptoms onset, age at last follow-up and sex were recorded. Whole exome sequencing was performed, focusing on non-causative variants (n = 64) in the key AD (APP, PSEN1, PSEN2) and FTD genes (MAPT, GRN, C9orf72). Weighted genetic burden scores were derived using Fine–Gray competing risk models to estimate variant-specific effects on cumulative AD and FTD incidence, accounting for mutually exclusive outcomes and family clustering. Model fit was evaluated using Akaike Information Criterion. Higher AD-risk-weighted burden scores in AD-related genes were associated with a significantly increased cumulative incidence of AD, while higher FTD-risk-weighted scores in FTD-related genes showed a trend toward association with increased cumulative incidence of FTD. A significant interaction between burden scores was observed. AD and FTD burden scores showed a negative interaction for AD (~79% attenuation) but a modest synergistic effect for FTD (~6% increase). These findings could imply context-dependent pleiotropy rather than simple additive genetic effects. Our study suggests that even in carriers oh highly penetrant AD or FTD causative variants, genetic background could substantially modulate cumulative disease incidence. Integrating polygenic information with monogenic status may improve prognostic stratification and inform precision approaches in dementia research and clinical trials.