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Basic Science and Pathogenesis
Lauren Bailey1, Leila Letica1, Takeshi Murai1
1University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
Alzheimer'S & Dementia : the Journal of the Alzheimer'S Association
|December 24, 2025
Summary
Early Alzheimer's disease (AD) models show increased amyloid beta in young PSEN1 mutation carriers, but this amyloid progression does not correlate with cognitive changes. This suggests amyloid accumulation alone may not drive early cognitive decline in AD.
Area of Science:
- Neuroscience
- Genetics
- Primate Models
Background:
- Alzheimer's disease (AD) pathogenesis and cognitive decline mechanisms remain unclear.
- Current AD therapies targeting amyloid plaques show limited success in preventing cognitive impairment.
- Understanding the early molecular drivers of AD is crucial for developing effective treatments.
Purpose of the Study:
- To investigate the relationship between amyloid burden and cognitive function in a non-human primate model of early-onset Alzheimer's disease (AD).
- To study the association of cognitive function with amyloid progression using fluid and neuroimaging biomarkers in PSEN1 mutation-carrying marmosets.
- To explore early primate-specific mechanisms contributing to cognitive decline in AD.
Main Methods:
- Longitudinal study of marmosets with PSEN1 mutations and age-matched controls from birth.
- Analysis of plasma biomarkers (amyloid-beta, tau, NfL, GFAP) at 6-month intervals.
- Annual cognitive testing battery assessing spatial working memory, recognition memory, attention, and motivation.
- Measurement of cortical amyloid burden using 11C-PiB-PET imaging.
Main Results:
- PSEN1 marmosets exhibited increased plasma amyloid-beta (Aβ) 42:40 ratio starting at 12 months of age.
- No significant cognitive impairments were observed in PSEN1 marmosets compared to controls up to 2 years of age.
- Cortical amyloid burden, measured by 11C-PiB-PET, showed no significant difference between PSEN1 carriers and controls.
Conclusions:
- Elevated amyloid-beta in plasma and brain does not correlate with cognitive changes in young PSEN1 carrier marmosets.
- These findings indicate a lack of direct association between early amyloid progression and cognitive decline in this model.
- This longitudinal primate study offers insights into the earliest molecular and cellular mechanisms underlying AD-related cognitive impairment.
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