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38/100

✓ Peer-reviewed alzhub usefulness score 38 out of 100. Genetics

Topic: Amyloid, tau and blood-test diagnosis

Abstract Background Alzheimer Disease (AD) is a highly polygenic dementia that presents with relatively earlier onset (≤65yo; EOAD) in about 5% of cases. Around 90% of these EOAD cases remain unexplained by pathogenic mutations. Method We used data from EOAD cases ≤ 70 and controls > 70 to ensure they would not develop AD. genome‐wide association study (GWAS) and trans‐ancestry meta‐analysis were performed for non‐Hispanic European (EUR, N Case =6,282, N Control =13,386), African (AFR N Case =782, N Control =3,663) and East Asian (ASN: N Case =375, N Control =838 CO) ancestries. We performed QTL mapping and in‐silico annotation to identify the functional gene for each genome‐wide loci, and PRS and LDSC to compare the genetic architecture of EOAD vs LOAD Result We identified a total of 15 genome‐wide significant loci, 7 already reported to be associated with LOAD and 8 novel loci. Of the novel loci: six were found in the ancestry‐specific analyses and two in the trans‐ancestry analysis. By integrating gene‐based analysis, eQTL, pQTL and functional annotations, we nominate four novel functional genes ( CDH12, FOLH1, ALG10B and LRRC25 ) for four loci that are involved in microglia activation, glutamate production, and signaling pathways. LOAD‐derived PRS showed a strong association with EOAD (R 2 =0.170, p <10 ‐300 , and R 2 =0.048, p = 1.20×10 ‐143 : for PRS with and without APOE ). LDSC found strong overall genetic covariance between EOAD and LOAD (rg=0.791, p = 6.80×10 ‐12 ) Conclusion These results indicate that EOAD, although sharing many genes with LOAD, harbors unique genes and pathways that could be used to create better prediction models or target identification for this type of AD.

Key findings

We performed QTL mapping and in‐silico annotation to identify the functional gene for each genome‐wide loci, and PRS and LDSC to compare the genetic architecture of EOAD vs LOAD Result We identified a total of 15 genome‐wide significant loci, 7 already reported to be associated with LOAD and 8 novel loci.
LDSC found strong overall genetic covariance between EOAD and LOAD (rg=0.791, p = 6.80×10 ‐12 ) Conclusion These results indicate that EOAD, although sharing many genes with LOAD, harbors unique genes and pathways that could be used to create better prediction models or target identification for this type of AD.

Why it matters

Eight novel genome-wide significant loci for early-onset Alzheimer's disease were identified, with four functional genes involved in microglia activation, glutamate production, and signaling pathways. Early-onset Alzheimer's shares many genes with late-onset but harbors unique genetic contributors.

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Study details

Participants15
Evidence strengthLow

How this study scored 38/100

Published in a peer-reviewed journal. Scored zero for study design, effect reported and randomised / blinded because the record does not state it. We have no data on senior author's track record, so that was left out: it earned 36 of the 96 points we could judge it on, which is 38 out of 100.

Component	Points	Why
Journal tier	7 / 10	Tier 3 — peer-reviewed journal (Alzheimer s & Dementia)
Journal's citation record	2 / 4	Alzheimer s & Dementia: journal h-index 228 (OpenAlex, 2026-10-29)
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	10 / 10	Peer-reviewed. Published as an article in a named peer-reviewed journal.
How recent	4 / 5	2025 — within 3 year(s) of the newest study here
Sample size	1 / 4	15 participants
Effect reported	0 / 3	No effect size reported — scores zero (not stated in the record — scored 0)
Studied in people	3 / 3	Studied in people (participant count stated)
Randomised / blinded	0 / 2	No randomisation or blinding stated — scores zero (not stated in the record — scored 0)
Times cited	0 / 7	Cited 0 times (OpenAlex, 2026-10-10)
Citations per year	0 / 5	0.0 citations a year over 3 year(s) since 2025
Impact for its field and year	0 / 6	Cited 0.0× the average for papers of its field and year (OpenAlex FWCI)
Cited by studies here	0 / 6	No other study in this library cites it
Still being cited	0 / 4	Cited 0 times in 2024–2026 (2026 still in progress; OpenAlex)
Senior author's track record	— / 4	OpenAlex's profile for last-listed author Gary W Beecham holds only 5 work(s), too few to judge a track record — left out of this score
Institution's track record	2 / 3	Washington University in St. Louis: institution h-index 1,962 (OpenAlex)
Multi-centre collaboration	2 / 3	OpenAlex lists 9 institution(s) in 2 countries
Indexed in PubMed	2 / 2	Indexed in PubMed (PMID 41444475)
Free to read	2 / 2	Free to read
Points	36 / 96	Scored on 19 of 20 parts. We have no data for the rest, so they are left out: 36 of the 96 points we could judge it on is 38 out of 100.
Total	38 / 100	—

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Read the original

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

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APA 7th

Bradley, J. L., Western, D., Wang, C., da Fonseca, E. L., Neupane, A., Kurup, J. T., et al. (2025). Novel early‐onset Alzheimer‐associated genes influence risk through dysregulation of glutamate, immune activation, and intracell signaling pathways. Alzheimer s & Dementia. https://doi.org/10.1002/alz70855_107379

Vancouver

Bradley JL, Western D, Wang C, da Fonseca EL, Neupane A, Kurup JT, et al. Novel early‐onset Alzheimer‐associated genes influence risk through dysregulation of glutamate, immune activation, and intracell signaling pathways. Alzheimer s & Dementia. 2025. doi:10.1002/alz70855_107379. PMID: 41444475.

BibTeX

@article{bradley2025-41444475,
  author  = {Bradley, Joseph L. and Western, Daniel and Wang, Ciyang and da Fonseca, Eder Lúcio and Neupane, Asmita and Kurup, Jiji Thulaseedhara and Ray, Nicholas R. and Jean‐Francois, Melissa N. and others},
  title   = {{Novel early‐onset Alzheimer‐associated genes influence risk through dysregulation of glutamate, immune activation, and intracell signaling pathways}},
  journal = {Alzheimer s \& Dementia},
  year    = {2025},
  doi     = {10.1002/alz70855_107379},
  pmid    = {41444475},
  url     = {https://doi.org/10.1002/alz70855_107379}
}

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