Basic Science and Pathogenesis

Alzheimers Dement. 2025 Dec;21 Suppl 1:e107130. doi: 10.1002/alz70855_107130.

ABSTRACT

BACKGROUND: Alzheimer's disease (AD) is known as a progressive neurodegenerative disorder. Evidence suggest that Apolipoprotein E (APOE) plays a significant role with AD, but only limited work has examined APOE relationships with vascular pathology lesions in the brain. The objective here is to investigate the association between APOE genotypes and vascular pathology lesions using the National Alzheimer's Coordinating Center (NACC) dataset and to further explore absent TDP-43 proteinopathy vs. any TDP-43 proteinopathy.

METHODS: We used NACC data to evaluate the relationship between APOE genotype and vascular pathology lesions: arteriolosclerosis, atherosclerosis, large arterial infarcts, lacunes, hippocampal sclerosis of aging, and hemorrhages and microbleeds. Participants were classified by APOE genotype into APOE ɛ4 carriers (ɛ24, ɛ34, ɛ44), APOE ɛ3 homozygotes (ɛ33), and APOE ɛ2 carriers (ɛ22, ɛ23). Logistic regression models adjusting for age, sex, self-reported ancestry, and education were used. We also assessed effect modification by TDP-43 proteinopathy in the association between APOE genotype and each of the vascular lesions. Statistical significance was set at α=0.05.

RESULTS: This study consisted of 7117 participants (mean age 79.1 ± 11.6 years, 47.6% female). Compared to participants with ε3 homozygotes, those carrying at least one APOE ε4 allele have higher odds of Arteriolosclerosis (OR [95% CI], p: 1.19[1.09,1.31],<0.001) and hippocampal sclerosis of aging (1.28[1.07,1.53],0.006) while participants with APOE ɛ2 carriers had an increased odds of large arterial infarcts (1.71[1.15, 2.55],0.009). We observed significant effect modification by TDP-43 proteinopathy in the association between APOE genotype and arteriolosclerosis (p = 0.037) and hippocampal sclerosis (p = 0.044). Among those with absent TDP-43 proteinopathy, APOE ɛ4 carriers showed increased odds of arteriolosclerosis (1.37[1.12,1.68],0.002) as compared to ε3 homozygotes, but not among those with any TDP-43 proteinopathy present, and none of the other associations were statistically significant.

CONCLUSIONS: Our findings suggest that carrying at least one APOE ɛ4 allele increases the risk of arteriolosclerosis and hippocampal sclerosis, while the presence of at least one APOE ɛ2 increased the risk of large arterial infarcts. TDP-43 proteinopathy modifies these effects, with APOE ε4 showing stronger vascular and neurodegenerative associations in those with absent TDP-43 proteinopathy but not in those with TDP-43 proteinopathy.

PMID:41445422 | DOI:10.1002/alz70855_107130