Eileen Ruth Samson Torres ¹ G William Rebeck ² Tal Nuriel ^3*

• ¹ Brain Mind Research Institute, Weill Cornell Medicine, Cornell University, New York, New York, United States
• ² Department of Neuroscience, Georgetown University Medical Center, Washington, DC,, District of Columbia, United States
• ³ Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University Irving Medical Center, New York, New York, United States

descent over 12 years. They found that APOE4 carriers possessed greater associations between numerous baseline dietary factors/blood biomarkers and 12-year medial temporal lobe white matter integrity. On the other hand, while cardiovascular disease and body mass index were also associated with white matter integrity, this association was not affected by APOE4 carrier status.Another important aspect of APOE4-associated AD risk is the varying disease penetrance that exists between male and female APOE4 carriers and between APOE4 carriers with differing races/ethnicities [2; 3]. For example, it has been reported that female APOE4 carriers (regardless of racial/ethnic background) possess an increased risk of AD compared to their male counterparts [2]. While the reason for this increased AD risk in women has not been fully elucidated, previous studies have uncovered specific metabolic changes that occur in the female brain during menopause as a potential mediating factor [4; 5], with several studies reporting that early intervention with hormone replacement therapy can reduce this APOE4-associated AD risk [6; 7]. On this topic, Wugalter et al. measured serum estrone (E1) and estradiol (E2) levels in postmenopausal women from the MsBrain cohort to assess the separate and interactive associations of estrogen, plasma AD biomarkers, and APOE4 carrier status on regional brain volumes. The authors reported that higher endogenous estrogen levels were associated with increased regional brain volumes only in women with more severe AD biomarker profiles. However, this effect was driven by APOE4 non-carriers, suggesting that APOE4 carriers do not benefit similarly from higher estrogen levels on regional brain volumes.Balu et al. also investigated the interaction of APOE4 carrier status and sex, this time in a mouse model of APOE genotype and AD. Utilizing the EFAD mouse model of AD, the authors reported that the combination of APOE4 and female sex led to earlier cognitive impairment in the mice, as well as increased Aβ pathology and higher levels of neuroinflammation. Interestingly, female APOE3 EFAD mice possessed similar pathology to male APOE4 EFAD mice, indicating that female sex alone can lead to greater AD pathology in these mice. Meanwhile, Christensen et al. utilized only female APOE mice to explore the relationship between obesity (a modifiable AD risk factor), estrogen therapy, and cognitive deficits. When female APOE3/3, APOE3/4, and APOE4/4 mice were fed a high fat diet (HFD), the APOE4/4 mice were overall more impaired cognitively and had worse metabolic function; however, the APOE3/3 mice were more affected by the HFD compared to their regular chow-fed counterparts. Interestingly, estradiol treatment improved metabolic function and cognitive performance in all the HFD-treated mice, but the APOE4/4 mice benefitted the most.Lastly, it's important to note that APOE4 associated heterogeneity is already contributing to real-world AD treatment decisions, since APOE4 carriers are known to be at greater risk of developing Amyloid-Related Imaging Abnormalities (ARIA) while being treated with the newly approved amyloid immunotherapies Leqembi and Kisunla [8; 9]. In a review article by Foley and Wilcock, the authors highlighted three hypothesized mechanisms by which APOE4 may be influencing ARIA risk: (1) reduced cerebrovascular integrity, (2) increased neuroinflammation and immune dysregulation, and (3) elevated levels of cerebral amyloid angiopathy (CAA). Importantly, they detail how these three potential mechanisms could be pursued in clinical and preclinical studies, emphasizing that the usefulness of AD therapies, now and in the future, requires that the AD research community understand the pathological heterogeneity mediated by possession of the APOE4 allele.