# Genetic validation of ABI3 p.Ser209Phe variant and its effects on early brain pathology in asymptomatic elderly individuals

## TL;DR

This study validates the ABI3 p.Ser209Phe variant as a genetic risk factor for Alzheimer's disease, showing it increases AD risk and earlier onset, especially when combined with APOE ε4.

## Contribution

The study provides genetic validation of ABI3 p.Ser209Phe and its interaction with APOE ε4 in influencing Alzheimer's disease risk and early brain pathology.

## Key findings

- ABI3S209F carriers have a higher risk of AD and earlier onset compared to non-carriers with the same APOE genotype.
- ABI3S209F carriers with APOE ε4 show higher brain amyloid-beta burden than those without APOE ε4.
- ABI3S209F alone does not significantly affect Aβ deposition, neuroinflammation, or brain structure.

## Abstract

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.

The online version contains supplementary material available at 10.1186/s13195-026-01984-y.