Basic Science and Pathogenesis

Alzheimers Dement. 2025 Dec;21 Suppl 1:e106320. doi: 10.1002/alz70855_106320.

ABSTRACT

BACKGROUND: The APOE genotype, particularly APOE-ε4, increases AD risk and influences neuropathology. However, its role in disease progression remains complex, varying with individual factors like age and sex, requiring further investigation. Our objective is to assess the relationship between APOE genotype and neuropathological outcomes and explore modifying effect of TDP-43 proteinopathy.

METHODS: This study used the NACC dataset with 7,117 participants (mean age 79 ± 11.6 years), 47.6% female, 94.6% White, and 30.7% post-master educated. Participants were classified by APOE-ε2 carriers (ε22 or ε32), ε3 homozygotes (ε33), and APOE-ε4 carriers (ε24, ε43 or ε44). Neuropathological outcomes including Thal Phase, Braak Stage, neuritic plaques, diffuse plaques, and cerebral amyloid angiopathy, were examined. Logistic regression models adjusted for age, sex, self-reported ancestry, and education were used. Additionally, to assess the modifying effect of TDP-43 proteinopathy interaction analyses were performed. Statistical significance was set at α=0.05.

RESULTS: Compared to ε3 homozygotes, APOE-ε4 carriers had significantly higher odds of Thal Phase (OR[95%CI], p: 4.70[4.09,5.41],<0.001), Braak Stage (3.78[3.42,4.18],<0.001), neuritic plaques (3.48[3.17,3.83],<0.001), diffuse plaques (3.46[3.12,3.85],<0.001) and Cerebral amyloid angiopathy (3.49[3.18,3.84],<0.001). APOE-ɛ2 carriers showed reduced odds of Thal Phase (0.51[0.42,0.63], <0.001), Braak Stage (0.56 [0.48, 0.66], <0.001), neuritic plaques (0.48 [0.41, 0.56], <0.001), diffuse plaques (0.49 [0.42, 0.57], <0.001). We did not observe any other statistically significant associations. We observed a statistically significant interaction by TDP-43 proteinopathy in the association between APOE and neuritic plaques (p = 0.028) but not with other pathologies. The effect of APOE-ε4 was reduced in individuals with any TDP-43 presence (3.68[2.89, 4.69], <0.001) compared to those with absence of TDP-43 (4.17[3.36, 5.17], <0.001). Interestingly, the protective effect of APOE-ε2 was enhanced in individuals with any TDP-43 presence (0.28[0.18, 0.45], <0.001) compared to those with absence of TDP-43 (0.63[0.45, 0.87], 0.006).

CONCLUSIONS: These findings suggest that TDP-43 proteinopathy modifies the genetic risk associated with APOE, attenuating the impact of APOE-ε4 while amplifying the protective role of APOE-ε2. APOE-ɛ2 carriers appear to have a protective effect. The presence of TDP-43 proteinopathy may further modify these associations. Future studies should explore the impact of additional genetic and environmental factors on AD neuropathology burden.

PMID:41443243 | DOI:10.1002/alz70855_106320