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Genetic validation of ABI3 p.Ser209Phe variant and its effects on early brain pathology in asymptomatic elderly individuals
Koivumäki Mikko, Martiskainen Henna, Takalo Mari, Lehtisalo Jenni, Ngandu Tiia, Snellman Anniina, Hiltunen Mikko, Rinne Juha O. Alzheimer's research & therapy, 2026-02-19
Topic: Brain proteins, microglia and lab models
Alzheimer's disease (AD) has a strong genetic component, with APOE ε4 being the most established risk factor through its effects on beta-amyloid (Aβ) metabolism and microglial function. Recent genetic studies have also implicated microglial genes, such as the ABI3S209F variant, to increased AD risk. As APOE ε4 and ABI3S209F influence microglial pathways through distinct mechanisms, their combined analysis may provide novel insights into AD pathophysiology. Therefore, we investigated ABI3S209F in the Finnish FinnGen cohort and in an imaging study of cognitively healthy older adults. We used FinnGen R12 data (> 500,000 individuals), including 8,490 ABI3S209F carriers and 511,670 non-carriers, with survival analyses matched by sex and birth year. Disease endpoints (AD, dementia, neurodegenerative disorder) were defined from national health registries using harmonized ICD codes, medication, and reimbursement records. For the imaging study, 58 participants aged ≥ 50 years were recruited into three genotype-based groups (ABI3S209F/APOE ε4, ABI3S209F/APOE ε3, non-carriers). All imaging participants underwent structural MRI, [11C]PiB PET for amyloid beta, [11C]PK11195 PET for microglial activity, and a comprehensive neuropsychological battery. ABI3S209F was significantly associated with increased risk of AD (OR = 1.22, p = 0.0012) and neurodegenerative disorders (OR = 1.21, p = 0.00023), but not with dementia (OR = 1.10, p = 0.06). Survival analyses indicated that ABI3S209F carriers developed AD at an earlier age than non-carriers with the same APOE genotype. The carriers of ABI3S209F and APOE ε4 had higher brain Aβ burden when compared to the ABI3S209F carriers without APOE ε4 (SUVR 2.0 (0.7) vs. 1.67 (0.5); mean (sd), p = 0.017), but there was no difference in Aβ between the ABI3S209F carriers and controls (1.67 (0.5) vs 1.75 (0.6), p = 0.75 (HST)). ABI3S209F was not associated with global neuroinflammation, although subtle regional increases in [11C]PK11195 binding were observed in ABI3S209F ε4 carriers. No differences were found in brain volumes or cognition. ABI3S209F increases AD risk and is associated with earlier disease onset. The variant alone does not significantly influence cortical Aβ deposition, neuroinflammation, or brain structure. Its effect may be pronounced in combination with APOEε4.
Cite this study APA, Vancouver, BibTeX · download .bib or .ris
APA 7th
Mikko, K., Henna, M., Mari, T., Jenni, L., Tiia, N., Anniina, S., et al. (2026). Genetic validation of ABI3 p.Ser209Phe variant and its effects on early brain pathology in asymptomatic elderly individuals. Alzheimer's research & therapy. https://doi.org/10.1186/s13195-026-01984-y
Vancouver
Mikko K, Henna M, Mari T, Jenni L, Tiia N, Anniina S, et al. Genetic validation of ABI3 p.Ser209Phe variant and its effects on early brain pathology in asymptomatic elderly individuals. Alzheimer's research & therapy. 2026. doi:10.1186/s13195-026-01984-y. PMID: 41709289.
BibTeX
@article{mikko2026-41709289,
author = {Mikko, Koivumäki and Henna, Martiskainen and Mari, Takalo and Jenni, Lehtisalo and Tiia, Ngandu and Anniina, Snellman and Mikko, Hiltunen and Rinne Juha, O.},
title = {{Genetic validation of ABI3 p.Ser209Phe variant and its effects on early brain pathology in asymptomatic elderly individuals}},
journal = {Alzheimer's research \& therapy},
year = {2026},
doi = {10.1186/s13195-026-01984-y},
pmid = {41709289},
url = {https://doi.org/10.1186/s13195-026-01984-y}
}
Built from the record alzhub holds for this paper, not looked up. Volume, issue and page numbers are not held in the record. The record names 8 authors; APA and Vancouver show the first six, BibTeX and the downloads carry all of them. Check the citation against the original before you use it.
Key findings
- ABI3S209F was significantly associated with increased risk of AD (OR = 1.22, p = 0.0012) and neurodegenerative disorders (OR = 1.21, p = 0.00023), but not with dementia (OR = 1.10, p = 0.06).
- Survival analyses indicated that ABI3S209F carriers developed AD at an earlier age than non-carriers with the same APOE genotype.
- The carriers of ABI3S209F and APOE ε4 had higher brain Aβ burden when compared to the ABI3S209F carriers without APOE ε4 (SUVR 2.0 (0.7) vs. 1.67 (0.5); mean (sd), p = 0.017), but there was no difference in Aβ between the ABI3S209F carriers and controls (1.67 (0.5) vs 1.75 (0.6), p = 0.75 (HST)).
- ABI3S209F was not associated with global neuroinflammation, although subtle regional increases in [11C]PK11195 binding were observed in ABI3S209F ε4 carriers.
- ABI3S209F increases AD risk and is associated with earlier disease onset.
Why it matters
This study found that the ABI3S209F variant was associated with increased risk of Alzheimer's disease and neurodegenerative disorders, and that carriers with APOE ε4 had higher brain amyloid burden. It is a genetic and imaging study in asymptomatic older adults and does not test any treatment, cure, or prevention.
Study details
- Participants500,000
- Effect sizeOR = 1.22; OR = 1.21; OR = 1.10
- Evidence strengthModerate
How this study scored 61/100
Published in a peer-reviewed journal. Scored zero for study design 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 and still being cited, so those were left out: it earned 44 of the 72 points we could judge it on, which is 61 out of 100.
| Component | Points | Why |
|---|---|---|
| Journal tier | 7 / 10 | Tier 3 — peer-reviewed journal (Alzheimer's research & therapy) |
| Journal's citation record | 1 / 4 | Alzheimer s Research & Therapy: journal h-index 146 (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 | 3 / 5 | Rated “moderate” in our summary |
| Peer-review validation | 10 / 10 | Peer-reviewed. Published as an article in a named peer-reviewed journal. |
| How recent | 5 / 5 | 2026 — within 1 year(s) of the newest study here |
| Sample size | 4 / 4 | 500,000 participants |
| Effect reported | 3 / 3 | Effect reported with a statistic (interval, p-value, ratio or similar) |
| 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 | — / 7 | Citation count not trusted: 7 of 8 library studies citing it were published more than a year before it - a sign OpenAlex merged several works under this DOI — left out of this score |
| Citations per year | — / 5 | Citation count not trusted (see above) — left out of this score |
| Impact for its field and year | — / 6 | Citation count not trusted (see above) — left out of this score |
| Cited by studies here | — / 6 | Library citations not trusted (see above) — left out of this score |
| Still being cited | — / 4 | Citation count not trusted (see above) — left out of this score |
| Senior author's track record | 3 / 4 | Last-listed author Juha O. Rinne: h-index 99 (OpenAlex, whole career) |
| Institution's track record | 1 / 3 | Karolinska Institutet: institution h-index 1,474 (OpenAlex) |
| Multi-centre collaboration | 2 / 3 | OpenAlex lists 6 institution(s) in 2 countries |
| Indexed in PubMed | 2 / 2 | Indexed in PubMed (PMID 41709289) |
| Free to read | 0 / 2 | Behind a paywall — scores zero |
| Points | 44 / 72 | Scored on 15 of 20 parts. We have no data for the rest, so they are left out: 44 of the 72 points we could judge it on is 61 out of 100. |
| Total | 61 / 100 | — |
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