Early functional changes and plasma GFAP in Swedish families with Autosomal Dominant Alzheimer's disease mutations.
Level 3 - non-randomized controlled study
Prospective longitudinal observational cohort study tracking biomarker trajectories over time.
PubMed 41593046 · doi:10.1038/s41398-026-03829-6
What was done
Forty-five individuals from Swedish families with Autosomal Dominant Alzheimer's Disease (ADAD)—including 19 mutation carriers (11 APP, 8 PSEN1; baseline estimated years to symptom onset [EYO] = -7.9 ± 11.7 years) and non-carriers—were followed longitudinally over 7.4 ± 6.4 years (1 to 5 visits, EYO range -25.8 to +10.3 years). Participants underwent cognitive testing and 18F-Flurodeoxyglucose (FDG) PET imaging (106 total scans), and a subset of 26 participants had plasma glial fibrillary acidic protein (GFAP) measured. Mixed-effects models were applied to evaluate longitudinal biomarker associations.
What was found
APP and PSEN1 mutation carriers showed distinct FDG-PET uptake profiles between EYO = -20 to -10 years, with PSEN1 carriers displaying hypermetabolism before hypometabolism. Early increases in plasma GFAP were primarily associated with subcortical FDG reductions and cognitive changes in APP mutation carriers compared to non-carriers. Specific numerical effect sizes, variance estimates, and p-values were not provided in the abstract.
Why it matters
This study indicates that biomarker trajectories in preclinical autosomal dominant Alzheimer's disease differ by specific causative gene mutation, suggesting clinical trials and natural history models should account for gene-specific timelines.
Limits
The sample size is small overall (n = 45) and further restricted for subgroups (11 APP, 8 PSEN1, and 26 with GFAP data). The abstract reports no statistical effect sizes or confidence intervals, and findings from rare familial ADAD mutations may not generalize to sporadic Alzheimer's disease.
Cited by
- supports In the early stages of Alzheimer's disease, affected brain regions show an increase in energy demand and hypermetabolism before progressing to hypometabolism as symptoms emerge.