Scientists identify genetic variant that accelerates brain aging in healthy elderly
Researchers have validated a gene variant called ABI3 S209F that increases Alzheimer's disease risk through a distinct biological pathway from the well-known APOE ε4 variant. The finding could enable companies developing diagnostics and therapeutics to better stratify patients and design targeted treatments, while helping healthcare systems identify high-risk individuals before symptoms emerge.
Originaltitel: Genetic validation of ABI3 p.Ser209Phe variant and its effects on early brain pathology in asymptomatic elderly individuals
Abstract 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 (SUVR 2.0 (0.7) vs. 1.67 (0.5); mean (sd), p = 0.017), but there was no difference in Aβ between the ABI3 S209F carriers and controls (1.67 (0.5) vs 1.75 (0.6), p = 0.75 (HST)). ABI3 S209F was not associated with global neuroinflammation, although subtle regional increases in [ 11 C]PK11195 binding were observed in ABI3 S209F ε4 carriers. No differences were found in 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.