Transcriptomic analysis from 3D cultures of Presilinin‐1 G206A carriers reveals genetic expression differences associated with age‐of‐onset variability

Topic: Brain proteins, microglia and lab models

We sequenced a total of 38,577 nuclei and detected an average of 2,700 genes per cell. We identified eight cell type clusters. The oligodendrocyte cluster showed the highest expression of PSEN1. No significant difference was observed for of PSEN1 or its substrates in any cluster between early and late AOO groups. However, we found significantly decreased expression of genes involved in presynaptic differentiation (LRFN5), ER stress response and apoptosis (RNF13), neuroinflammation (FUT8) and lipid metabolism (SOX9-AS1) in early vs late AOO in multiple cell type clusters. Additionally, we found significantly higher expression of genes involved in vascular (CAV1, COL4A1), neurodevelopment and lipid metabolism (PSAP) in early vs late AOO carriers. Our analysis identified transcriptomic changes between spheroid 3D cultures of early and late AOO G206A carriers in genes previously implicated in multiple studies of AD pathogenesis and neurodevelopmental disorders. Our results suggest that pathways involved in vascular morphogenesis, lipid processing, protein aggregation and neuronal regulation may be contributing to the variability in AD AOO observed in G206A carriers.

Key findings

• We sequenced a total of 38,577 nuclei and detected an average of 2,700 genes per cell.
• The oligodendrocyte cluster showed the highest expression of PSEN1.
• No significant difference was observed for of PSEN1 or its substrates in any cluster between early and late AOO groups.
• However, we found significantly decreased expression of genes involved in presynaptic differentiation (LRFN5), ER stress response and apoptosis (RNF13), neuroinflammation (FUT8) and lipid metabolism (SOX9-AS1) in early vs late AOO in multiple cell type clusters.
• Additionally, we found significantly higher expression of genes involved in vascular (CAV1, COL4A1), neurodevelopment and lipid metabolism (PSAP) in early vs late AOO carriers.

Why it matters

In 3D cultures from PSEN1 G206A carriers, no significant difference was found in PSEN1 or its substrates between early and late age-of-onset groups, but genes involved in presynaptic differentiation, ER stress, neuroinflammation and lipid metabolism differed. This is a cell-culture transcriptomic study exploring why age of onset varies, not a treatment.

New to this subject? Start with our plain-English guide: Genetics →

Study details

• Participants38,577
• Evidence strengthLow

Read the original

• DOI: 10.1002/alz70855_104923
• PubMed: 41443185
• Original source →
• Free full text: Alzheimer s & Dementia →

Full text: free to read — OpenAlex lists this copy as free to read: the link above (checked 6 Feb 1020).

@article{celis2025-41443185,
  author  = {Celis, Katrina and Griswold, Anthony J. and Rajabli, Farid and Ramírez, Aura María and Nam, Younji and Adams, Larry Deon and Whitehead, Patrice G. and Mena, Pedro Ramon and others},
  title   = {{Transcriptomic analysis from 3D cultures of Presilinin‐1 G206A carriers reveals genetic expression differences associated with age‐of‐onset variability}},
  journal = {Alzheimer s \& Dementia},
  year    = {2025},
  doi     = {10.1002/alz70855_104923},
  pmid    = {41443185},
  url     = {https://doi.org/10.1002/alz70855_104923}
}

Related studies in Risk genes beyond APOE

• Too early for LATE? Age at onset is associated with the clinical and neuroimaging expression of limbic-predominant age- related TDP-43 pathology in Alzheimer’s disease medRxiv · 2026-10-20 · usefulness score 16/100
• Retinal Imaging Findings in Carriers With PSEN1-Associated Early-Onset Familial Alzheimer Disease Before Onset of Cognitive Symptoms JAMA ophthalmology · 2021-01-01 · usefulness score 46/100
• MicroRNA-339-5p down-regulates protein expression of β-site amyloid precursor protein-cleaving enzyme 1 (BACE1) in human primary brain cultures and is reduced in brain tissue specimens of Alzheimer disease subjects The Journal of biological chemistry · 2013-12-18 · usefulness score 44/100
• Analysis of the 5' sequence, genomic structure, and alternative splicing of the presenilin-1 gene (PSEN1) associated with early onset Alzheimer disease Genomics · 1997-03-01 · usefulness score 43/100
• R47H Variant of TREM2 Associated With Alzheimer Disease in a Large Late-Onset Family: Clinical, Genetic, and Neuropathological Study JAMA neurology · 2015-08-01 · usefulness score 55/100
• Screening for Genetic Mutations Associated with Early-Onset Alzheimer's Disease in Han Chinese Current Alzheimer research · 2022 · usefulness score 52/100

Also tagged “amyloid-beta”

1,339 studies in the library carry the topic tag “amyloid-beta”; these are this study's neighbours in a fixed, alphabetical-by-hash tour of them, not the closest in content. All 1,339 tagged studies.

• β-amyloid PET Signal Reduction in Regions with ARIA-E Following Anti-amyloid Therapy for Alzheimer Disease (P1-12.010) Neurology · 2026-06-09 · usefulness score 32/100 · Biomarkers
• Regional amyloid accumulation and cognitive decline in initially amyloid-negative adults Neurology · 2018-10-10 · usefulness score 51/100 · Genetics
• In vivo demonstration of Congo Red labeled amyloid plaques via perfusion in the Alzheimer disease rat model Journal of neuroscience methods · 2021-01-25 · usefulness score 37/100 · Biomarkers

Similar studies

• Estimation of the genetic contribution of presenilin-1 and -2 mutations in a population-based study of presenile Alzheimer disease 1998 · Risk genes beyond APOE
• Genetic association between intronic polymorphism in presenilin-1 gene and late-onset Alzheimer's disease. Alzheimer's Disease Collaborative Group 1996 · Genetics
• Genome-wide expression analysis of cultured trophoblast with trisomy 21 karyotype 2007 · Down syndrome and Alzheimer's
• The substrate repertoire of γ-secretase/presenilin 2020 · TREM2 and immune genetics
• Two transmembrane aspartates in presenilin-1 required for presenilin endoproteolysis and γ-secretase activity 1999 · Risk genes beyond APOE
• Presenilin mutations in familial Alzheimer disease and transgenic mouse models accelerate neuronal lysosomal pathology 2004 · Risk genes beyond APOE

More on Risk genes beyond APOE

• A review that covers this ground SORL1 genetic variants and Alzheimer disease risk: a literature review and meta-analysis of sequencing data Acta neuropathologica · 2019-03-25 · usefulness score 64/100
• Newest in this subject Pregnancy History and Loss of Normal PSEN2 Function Impact Female Late-Life Cognitive Processing, Inhibitory Signaling, and Gliosis bioRxiv · 2026-10-30 · Preprint — not yet peer-reviewed · usefulness score 16/100
• Newest in this subject Temporal Proteomics Links the APP London Mutation to Early Cholesterol Remodeling Cell Programs in Human Neurons bioRxiv · 2026-10-24 · Preprint — not yet peer-reviewed · usefulness score 16/100

See all studies in Risk genes beyond APOE →