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16/100

⚠ Preprint — not yet peer-reviewed alzhub usefulness score 16 out of 100. Down syndrome and Alzheimer's

Topic: Disease mechanisms in lab and animal studies

The amyloid precursor protein (APP) is heavily studied as the source of amyloid beta in Alzheimer’s disease (AD), however, the complex functions of APP remain poorly understood, as does the impact of APP dosage on neurodevelopment. Here we study APP specifically in the context of Trisomy 21. In an effort to reduce APP dosage in trisomy 21 iPSCs, we generated trisomic isogenic lines which vary in APP dosage, including a full APP knock-out line, as well as lines carrying mutations of the APP extracellular domain. We used a panel of these lines to study potential impacts of APP dosage or structure on two distinct steps of neurogenesis in trisomic cells: 1) terminal differentiation of human neuro-progenitor cells (NPC) to post-mitotic neurons and 2) neuron structure as reflected in neurite outgrowth. Complete loss of APP causes marked defects in each of these two distinct steps, reducing both the terminal differentiation of NPCs to neurons, and proper neurite development for extended neuron structure. Hence, APP is necessary for both aspects of normal neurogenesis. Further analyses of the null and other mutant lines indicate that APP likely impacts these two distinct steps by two different mechanisms. Collective results suggest that the reduced terminal differentiation of NPCs reflects an effect of APP dosage, whereas the defects in neurite extension are due to structural mutation of the APP extracellular domain. Absence of APP or reduced (monosomic) APP dosage prolonged the cycling of trisomic NPCs, which is known to be regulated by Notch signaling. APP and Notch are the main targets of gamma-secretase cleavage, hence we hypothesized that APP dosage may impact neurogenesis indirectly, potentially via effects on Notch signaling. To test this, we treated NPCs with Compound E which inhibits gamma-secretase (and Notch signaling); results show this restored levels of neurogenesis in APP depleted lines, supporting an indirect effect of APP dosage . In contrast, results indicate that disruption of APP extracellular domain integrity impacts neurite extension via a more direct role of APP in neuron structural maturation. This study describes a resource of well-characterized APP mutant isogenic DS iPSC lines, implicates a dynamic interplay between APP dosage and Notch signaling, and raises new questions about the impact of APP dosage in orchestrating neural progenitor fate decisions during human brain development, specifically in the context of trisomy 21.

Key findings

Further analyses of the null and other mutant lines indicate that APP likely impacts these two distinct steps by two different mechanisms.
Collective results suggest that the reduced terminal differentiation of NPCs reflects an effect of APP dosage, whereas the defects in neurite extension are due to structural mutation of the APP extracellular domain.
To test this, we treated NPCs with Compound E which inhibits gamma-secretase (and Notch signaling); results show this restored levels of neurogenesis in APP depleted lines, supporting an indirect effect of APP dosage .
In contrast, results indicate that disruption of APP extracellular domain integrity impacts neurite extension via a more direct role of APP in neuron structural maturation.

Study details

Evidence strengthLow

How this study scored 16/100

Preprint — not yet peer-reviewed. It scored 21 on the same rubric, but non-peer-reviewed sources are capped at 16, so it shows as 16. Scored zero for study design, sample size, effect reported, studied in people and randomised / blinded because the record does not state it. We have no data on times cited, citations per year, impact for its field and year, cited by studies here, still being cited, senior author's track record, institution's track record and multi-centre collaboration, so those were left out: it earned 13 of the 62 points we could judge it on, which is 21 out of 100.

Component	Points	Why
Journal tier	2 / 10	Tier 4 — not a peer-reviewed journal (bioRxiv)
Journal's citation record	0 / 4	Not a journal article, so the journal's record does not count
Study design	0 / 12	No study design recorded — scores zero, not guessed (not stated in the record — scored 0)
Strength of evidence	1 / 5	Rated “low” in our summary
Peer-review validation	4 / 10	Preprint — not yet peer-reviewed. Hosted on a preprint server.
How recent	5 / 5	2026 — within 1 year(s) of the newest study here
Sample size	0 / 4	Participant count not stated — scores zero (not stated in the record — scored 0)
Effect reported	0 / 3	No effect size reported — scores zero (not stated in the record — scored 0)
Studied in people	0 / 3	Not stated whether this was studied in people — scores zero (not stated in the record — scored 0)
Randomised / blinded	0 / 2	No randomisation or blinding stated — scores zero (not stated in the record — scored 0)
Times cited	— / 7	No citation count (not found in OpenAlex) — left out of this score
Citations per year	— / 5	No citation count or no year — left out of this score
Impact for its field and year	— / 6	No field-weighted citation impact (OpenAlex has none yet) — left out of this score
Cited by studies here	— / 6	Not yet checked against this library's citation graph — left out of this score
Still being cited	— / 4	No yearly citation counts — left out of this score
Senior author's track record	— / 4	Senior author's record not available — left out of this score
Institution's track record	— / 3	No institution listed in OpenAlex — left out of this score
Multi-centre collaboration	— / 3	Institutions not listed — left out of this score
Indexed in PubMed	1 / 2	Not in PubMed, but has a DOI
Free to read	0 / 2	Behind a paywall — scores zero
Points	13 / 62	Scored on 12 of 20 parts. We have no data for the rest, so they are left out: 13 of the 62 points we could judge it on is 21 out of 100.
Total	21 / 100	Capped to 16 because this is not a peer-reviewed article.

What each of these 20 components measures, and what this score is not →

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Cite this study APA, Vancouver, BibTeX · download .bib or .ris

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APA 7th

Valledor, M., Smith, K., Lawrence, J. B., & Sosa, L. J. (2026). APP Dosage and Extracellular Domain Variants Drive Distinct Defects in Neurogenesis modeled in Down Syndrome iPS cells. bioRxiv. https://doi.org/10.64898/2026.08.05.742240

Vancouver

Valledor M, Smith K, Lawrence JB, Sosa LJ. APP Dosage and Extracellular Domain Variants Drive Distinct Defects in Neurogenesis modeled in Down Syndrome iPS cells. bioRxiv. 2026. doi:10.64898/2026.08.05.742240.

BibTeX

@article{valledor2026-f87dce03,
  author  = {Valledor, M. and Smith, K. and Lawrence, J. B. and Sosa, L. J.},
  title   = {{APP Dosage and Extracellular Domain Variants Drive Distinct Defects in Neurogenesis modeled in Down Syndrome iPS cells}},
  journal = {bioRxiv},
  year    = {2026},
  doi     = {10.64898/2026.08.05.742240},
  url     = {https://doi.org/10.64898/2026.08.05.742240}
}

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