Background:

The rare APOE3-Christchurch (APOE3Ch) variant is associated with reduced tau pathology, lower neuroinflammation, and delayed cognitive decline in autosomal-dominant Alzheimer's disease (ADAD). Heterozygous APOE3Ch carriers demonstrate delayed clinical onset yet, the plasma biomarker mechanisms underlying this resilience remain uncharacterized. Plasma GFAP, NfL and p-tau181 are early markers of AD progression and promising indicators of resilience. Defining the APOE3Ch plasma profile could inform APOE3Ch-mimetic therapies and biomarker-guided clinical trials.

Study aims:

1. Compare age-related biomarker trajectories between APOE3Ch carriers and non-carriers, stratified by PSEN1 E280A status.

2. Examine associations between plasma biomarkers and cognitive performance (MMSE, CERAD Word List Delayed Recall).

Methods:

Data collection: Blood samples were collected at the University of Antioquia (Medellín). Plasma was obtained without fasting and stored at −80°C. GFAP, p-tau181, Aβ42/40, and NfL were measured using SIMOA assays on a Quanterix HD-X platform. Cognition was assessed using the MMSE and Spanish CERAD Word List Delayed Recall. Data analysis: Biomarkers were log-transformed and standardized using APOE3Ch-negative, PSEN1 E280A non-carriers as the reference. Group differences were assessed using t-tests and Fisher's exact tests. Linear regression models, stratified by PSEN1 E280A status, examined associations of age, sex, APOE3Ch status, and the APOE3Ch × age interaction with biomarker levels. Effect sizes were quantified using Cohen's f². Biomarker–cognition associations were evaluated using linear regression adjusted for age and education.

Results:

Among PSEN1 E280A carriers, the APOE3Ch×age interaction showed medium-to-large effects on p-tau181(f²=0.133), GFAP ((f²=0.247, the largest), and NfL (f²=0.133), but a negligible effect on Aβ42/40. Among cognitively unimpaired PSEN1 E280A non-carriers, interaction effects were small to negligible, with no significant APOE3Ch×age interactions for any biomarker. In PSEN1 E280A carriers: Elevated GFAP and NfL were associated with worse delayed recall (β=−0.476, p=0.034; β=−0.668, p=0.012; respectively), and higher p-tau181 showed a marginal association with lower MMSE (β=−0.453, p=0.065). Aβ42/40 was not significantly associated with cognitive performance. In PSEN1 E280A non-carriers: Higher Aβ42/40 was associated with lower MMSE (β=−0.270, p=0.031). Higher p-tau181 and GFAP showed trends toward lower MMSE (β=−0.204, p=0.094 and β=−0.210, p=0.091, respectively); Higher NfL trended toward lower CERAD scores (β=−0.319, p=0.089). No other associations were significant.

Conclusion:

APOE3Ch heterozygosity attenuated age-related increases in plasma GFAP, p-tau181, and NfL in PSEN1 E280A carriers, particularly GFAP, implicating reduced neuroinflammation in APOE3Ch-mediated resilience. These biomarkers may serve as pharmacodynamic endpoints in APOE3Ch-mimetic trials, pending longitudinal validation.