Cumulative Incidence in Monogenic Alzheimer's Disease and Frontotemporal Dementia: Gene-Gene Interaction Effect.
Level 3 - non-randomized controlled study
Non-randomized pedigree cohort study evaluating cumulative disease incidence using competing-risk regression
PubMed 42123659 · doi:10.3390/ijms27094081
What was done
Researchers investigated whether non-causative genetic background variants modify cumulative disease incidence in carriers of causative Alzheimer's Disease (AD) or Frontotemporal Dementia (FTD) mutations. Within the Italian GARDENIA Consortium, 426 individuals (319 symptomatic patients and 107 presymptomatic carriers) carrying causative mutations in APP (n = 39), PSEN1 (n = 71), PSEN2 (n = 13), MAPT (n = 29), GRN (n = 188), or C9orf72 (n = 86) were analyzed. Whole exome sequencing identified 64 non-causative variants across these six genes. Fine-Gray competing risk models accounting for family clustering were used to calculate weighted genetic burden scores and estimate cumulative incidence.
What was found
Higher AD-risk-weighted scores in AD genes were significantly associated with increased cumulative incidence of AD, while higher FTD-risk-weighted scores in FTD genes showed a trend toward increased FTD cumulative incidence. A significant interaction between burden scores was identified: AD and FTD burden scores demonstrated a negative interaction for AD (~79% attenuation) and a modest synergistic effect for FTD (~6% increase).
Why it matters
The study indicates that non-causative background variants across related dementia genes interact to modify penetrance and disease incidence in carriers of monogenic mutations. Integrating polygenic background data with monogenic testing could refine prognostic timelines and clinical trial stratification.
Limits
The cohort was restricted to Italian pedigrees, limiting ancestral generalizability. Subgroup sizes for certain genes were very small (e.g., PSEN2 n = 13, MAPT n = 29). The analysis evaluated only 64 non-causative variants in six candidate genes rather than a comprehensive genome-wide polygenic score.
Cited by
- supports Monogenic dominant mutations in PSEN1, PSEN2, or APP account for less than 5%, and possibly as little as 1%, of Alzheimer's disease cases.