The dual role of APOE ε4 allele in cerebral small vessel disease: independent genetic effects and effect modification of traditional risk factors.
APOE ε4 exhibits both an independent genetic effect—selectively associated with periventricular white matter injury—and a modifying effect on the associations of smoking and alcohol use with specific CSVD phenotypes.
Key Findings
Results
APOE ε4 was independently associated only with periventricular white matter hyperintensity (PWMH) burden, with no significant independent associations for other CSVD markers.
β = 0.411, 95% CI: 0.046–0.776, p = 0.027 for periventricular WMH burden
No significant independent associations were found for global CSVD burden, total WMH, deep WMH, cerebral microbleeds (CMBs), or enlarged perivascular spaces (EPVS)
Ordinal logistic regression was used to assess independent effects of APOE ε4 on CSVD markers in a fully adjusted model
Study included 728 patients with chronic lacunar infarcts; APOE ε4 carriers n = 139, non-carriers n = 589
Results
Significant multiplicative interactions were observed between APOE ε4 and smoking on global CSVD burden, CMBs, total WMH, and periventricular WMH.
Interaction terms (APOE ε4 × smoking) were significant for global CSVD burden, CMBs, total WMH, and PWMH (adjusted p < 0.05 after Holm-Bonferroni correction)
Multiplicative interaction terms were added to fully adjusted models
P-values were adjusted using the Holm-Bonferroni method to control for multiple comparisons
Findings remained robust after excluding APOE ε2 carriers in sensitivity analyses
Results
Significant multiplicative interactions were observed between APOE ε4 and alcohol use on global CSVD burden and cerebral microbleeds.
Interaction terms (APOE ε4 × alcohol use) were significant for global CSVD burden and CMBs (adjusted p < 0.05 after Holm-Bonferroni correction)
These interactions were assessed within fully adjusted models with Holm-Bonferroni-corrected p-values
Sensitivity analyses excluding APOE ε2 carriers confirmed the robustness of these findings
The cross-sectional design used 3 T brain MRI in 728 patients with chronic lacunar infarcts
Methods
CSVD burden was quantified using a study-specific composite score integrating white matter hyperintensities, cerebral microbleeds, and enlarged perivascular spaces.
The composite CSVD score ranged from 0 to 6
Score integrated white matter hyperintensities (WMH), cerebral microbleeds (CMBs), and enlarged perivascular spaces (EPVS)
All patients underwent 3 T brain MRI
Firth's penalized logistic regression was specifically used for EPVS analyses, presumably due to sparse data
The study was cross-sectional and included 728 patients with chronic lacunar infarcts
Results
The independent genetic effect of APOE ε4 on CSVD is phenotypically specific, limited to periventricular white matter injury rather than a global CSVD effect.
No significant associations were found between APOE ε4 and global CSVD burden, total WMH, deep WMH, CMBs, or EPVS in independent effect analyses
Only periventricular WMH showed a significant independent association (β = 0.411, 95% CI: 0.046–0.776, p = 0.027)
Authors describe APOE ε4 as having a 'dual role': an independent genetic effect and an effect modifier of traditional risk factors
Findings support integration of genetic background with modifiable risk factors for precision risk stratification
What This Means
This research suggests that a common genetic variant called APOE ε4—well known for its role in Alzheimer's disease—also plays a complex role in cerebral small vessel disease (CSVD), a condition involving damage to the brain's small blood vessels that can cause strokes and cognitive problems. The study examined 728 patients who had experienced small strokes (lacunar infarcts) and used high-resolution brain MRI to measure different types of small vessel damage. The key finding is that APOE ε4 appears to act in two distinct ways: it directly increases the risk of a specific type of white matter damage near the brain's fluid-filled chambers (periventricular white matter hyperintensities), but it does not independently raise the overall burden of other small vessel disease markers like microbleeds or enlarged perivascular spaces.
The second, perhaps more novel, finding is that APOE ε4 changes how lifestyle risk factors—specifically smoking and alcohol use—affect the brain. In people who carry the APOE ε4 gene variant, smoking and alcohol use appear to have a different (likely amplified or altered) relationship with brain small vessel damage compared to non-carriers. This 'interaction' effect was seen for overall CSVD burden and for specific markers like microbleeds and white matter changes, and the results held up even after rigorous statistical corrections and when certain other genetic variants were excluded.
This research suggests that having the APOE ε4 genetic variant may make the brain more susceptible to the harmful effects of smoking and alcohol on small blood vessels, beyond what these risk factors do in the general population. From a practical standpoint, this supports the idea that genetic information could one day be incorporated into personalized risk assessments for cerebrovascular disease, potentially identifying individuals for whom avoiding smoking and heavy alcohol use is especially important. However, because this was a cross-sectional study (a single snapshot in time) conducted in a specific patient population, further research is needed to confirm these findings and understand the underlying mechanisms.
Liu F, Gou Y. (2026). The dual role of APOE ε4 allele in cerebral small vessel disease: independent genetic effects and effect modification of traditional risk factors.. Frontiers in neurology. https://doi.org/10.3389/fneur.2026.1778289