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Alzheimer's Association International Conference 2026

July 12-15, 2026 | London, United Kingdom, and Online

5011

Associations Of Plasma Biomarkers With Age In The Presenilin-1 E280A Autosomal Dominant Alzheimer's Disease Kindred

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Poster Presenter

Vincent Malotaux

Authors

Vincent Malotaux, Vivian Ku, Paula Ospina Lopera, Yi Su, Yinghua Chen, Alpana Singh, Jonathan Ruiz-Triviño, María José Hidalgo, Laura Osorio, Laura Serna, Daniela Giraldo, Diana Alzate, Bing He, Catarina Tristão-Pereira, Liliana Ramirez Gomez, Sonia Do Carmo, A Claudio Cuello, Nicholas J Ashton, Eric M Reiman, David Aguillón, Yakeel T Quiroz

Affiliations

Banner Alzheimer's Institute, Phoenix, AZ, USA, Department of Psychological & Brain Sciences, Boston University, Boston, MA, USA, Grupo de Neurociencias de Antioquia, Universidad de Antioquia, Medellín, Colombia, Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA, Department of Pharmacology & Therapeutics, McGill University, Montreal, Quebec, Canada, Department of Pharmacology & Therapeutics, McGill University, Montreal, Quebec, Canada; Integrated Program in Neuroscience, McGill University, Montreal, Quebec, Canada; Department of Neurology & Neurosurgery, McGill University, Montreal, Quebec, Canada; Department of Anatomy & Cell Biology, McGill University, Montreal, Quebec, Canada; Department of Pharmacology, Oxford University, Oxford, United Kingdom; Affiliated member, Karolinska Institutet, Stockholm, Sweden, Department of Psychological & Brain Sciences, Boston University, Boston, MA, USA; Grupo de Neurociencias de Antioquia, Universidad de Antioquia, Medellín, Colombia; Department of Psychiatry, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA

Part of Topic

Background:

Autosomal-dominant Alzheimer's disease (ADAD) caused by PSEN1 mutations offers a model for studying the earliest biological changes in AD, given its highly predictable age at symptom onset. The Colombian PSEN1 E280A kindred (Antioquia) includes ~6,000 relatives and ~1,400 confirmed mutation carriers, with median onset of 44 years for MCI and 49 years for dementia. Ultrasensitive plasma assays are now available and could reduce reliance on CSF and PET biomarkers, but their relationships with age in ADAD remain incompletely characterized. Plasma p-tau217 has shown the strongest diagnostic accuracy for AD pathology to date; Aβ42/Aβ40, GFAP, BD-tau, and NfL are other key candidate markers, each reflecting a distinct pathological process (amyloid accumulation, astrogliosis, brain-specific tau, and neuroaxonal injury, respectively).

Study aims:

1) Characterize age-related changes in plasma biomarkers among PSEN1 E280A carriers and non-carriers.

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

3) Estimate the age at which each biomarker diverges between carriers and non-carriers.

4) Compare each biomarker's ability to classify mutation carriers versus non-carriers.

Methods:

Participants (ages 18–64) were recruited from the Colombian Alzheimer Prevention Initiative registry near the University of Antioquia (Medellín). Neuropsychological assessment included MMSE, Spanish CERAD Word List Delayed Recall, and FAST staging (≤2 indicating unimpaired status). Plasma p-tau217, Aβ42, and Aβ40 were measured using Lumipulse G1200 RUO (Fujirebio), and NfL, GFAP, and BD-tau using Simoa HDx (Neuro-4-plex D, Quanterix). Age-related biomarker trajectories were modeled using sex-adjusted linear regression and Bayesian restricted cubic splines to estimate divergence ages. Carrier discrimination was assessed using age- and sex-adjusted ROC analyses with DeLong’s tests. Cognitive associations were tested using multiple regression adjusted for age, sex, and education, with backward AIC selection.

Plasma Biomarkers vs Age and Cognition:

In PSEN1 E280A carriers, age was associated with lower Aβ42/Aβ40 and higher p-tau217, BD-tau, GFAP, and NfL, whereas in non-carriers only Aβ42/Aβ40 and p-tau217 showed age-related changes. Plasma p-tau217 was the strongest predictor of both MMSE and delayed recall, with only modest gains in explained variance from adding additional biomarkers (ΔR² ≤ 0.076). In individual models, GFAP showed the second strongest associations with cognition after p-tau217. See Figures for detailed biomarker divergence-age estimates and ROC curves.

Conclusion:

Plasma biomarkers exhibit a clear temporal cascade in PSEN1 E280A ADAD: Aβ42/Aβ40 changes emerge earliest (childhood), followed sequentially by p-tau217, GFAP, BD-tau, and NfL. Plasma p-tau217, and to a lesser extent GFAP, show the strongest cross-sectional links to cognitive decline, supporting their use as sensitive markers for tracking disease progression and treatment response in PSEN1 E280A carriers.

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