Genetic Validation of ABI3 p.S209F Variant and Its effects On Early Brain Pathology in Asymptomatic Elderly Individuals
Open accessAbstract
Background: 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 ABI3 S209F variant, to increased AD risk. As APOE ε4 and ABI3 S209F influence microglial pathways through distinct mechanisms, their combined analysis may provide novel insights into AD pathophysiology. Therefore, we investigated ABI3 S209F in the Finnish FinnGen cohort and in an imaging study of cognitively healthy older adults Methods : We used FinnGen R12 data (>500,000 individuals), including 8,490 ABI3 S209F 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 (ABI3 S209F / APOE ε4, ABI3 S209F / APOE ε3, non-carriers). All imaging participants underwent structural MRI, [ 11 C]PiB PET for amyloid beta, [ 11 C]PK11195 PET for microglial activity, and a comprehensive neuropsychological battery. Results: ABI3 S209F 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 ABI3 S209F carriers developed AD at an earlier age than non-carriers with the same APOE genotype. The carriers of ABI3 S209F and APOE ε4 had higher brain Aβ burden when compared to the ABI3 S209F carriers without APOE ε4 (1.7 [1.5-2.6] vs. 1.5 [1.4-1.6]; median [IQR], p = 0.017). ABI3 S209F did not affect neuroinflammation, brain volumes or cognition. Conclusions: ABI3 S209F 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.
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The extremely low allele frequency of ABI3 S209F (MAF ≈0.008) makes obtaining endogenous human samples challenging.
“Given the extremely low allele frequency of ABI3 S209F (minor allele frequency [MAF] ≈0.008), 15 , 20 obtaining endogenous human samples is challenging.”
From Aberrant phase separation from a rare <i>ABI3</i> mutation drives microglial dysfunction and Alzheimer's risk (2026) · cites this paper as [20]
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- Authors
- Koivumäki, M., Martiskainen, H., Takalo, M., Lehtisalo, J., Ngandu, T., Snellman, A., Hiltunen, M., & Rinne, J. O.
- Affiliations
- University of Turku (FI)
- University of Eastern Finland (FI)
- Finnish Institute for Health and Welfare (FI)
- ORCID
- Venue
- Research Square
- Published
- 2025-10-13
- OpenAlex
- W4415115553
- Cited by
- 0
- References
- 13
- Type
- posted content
- Language
- en
- Open access
- green
- doi.org
- Locations
- Research Square (acceptedVersion, cc-by)
- Funders
- Yrjö Jahnssonin Säätiö
- Jane ja Aatos Erkon Säätiö
- Deutsches Zentrum für Neurodegenerative Erkrankungen
- Sigrid Juséliuksen Säätiö (338182, 355604)
- Business Finland
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- F#, Alzheimer's disease, APOE ε4, amyloid burden, neurodegeneration, early-onset Alzheimer's disease, brain atrophy, microglial activation, genetic risk, Finnish population, 11C-PiB PET, [11C]PK11195 PET, structural MRI, cognitive decline, age of onset
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