Sex differences in associations between <i>APOE ε2</i> and longitudinal cognitive decline

Wood, Madeline; Xiong, Lisa Y.; Wong, YW; Buckley, Rachel F.; Swardfager, Walter; Masellis, Mario; Lim, Andrew; Nichols, Emma; Joie, Renaud La; Casaletto, Kaitlin B.; Kumar, Raj G.; Dams-O’Connor, Kristen; Palta, Priya; George, Kristen M; Barnes, Lisa L.; Schneider, Julie A.; Binet, Alexa Pichette; Villeneuve, Sylvia; Pa, Judy; Brickman, Adam M.; Black, Sandra E.; Rabin, Jennifer S.

doi:10.1002/alz.13036

Cited by 4 publications

(6 citation statements)

References 62 publications

(134 reference statements)

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Section: Discussionsupporting

confidence: 69%

“… 14 Additionally, a recent study found that the APOE ε2 association with cognitive decline in cognitively normal White men was stronger than in White women. 56 In the present analysis, which included some of the same cohorts, we saw similar evidence of a stronger association between APOE ε2 and longitudinal decline in cognitively normal White men compared with cognitively normal White women, but the APOE ε2 × sex interaction did not reach statistical significance ( Table 3 ). Continued reporting by sex and race will allow for larger studies to confirm whether the intersectional effects and the previous mixed findings in APOE ε2 carriers persist.…”

Section: Discussionsupporting

confidence: 64%

“…Studies are also mixed regarding differential APOE ε2 effects among the sexes, with one study demonstrating stronger effects among cognitively normal males, but another highlighting stronger effects among females . Additionally, a recent study found that the APOE ε2 association with cognitive decline in cognitively normal White men was stronger than in White women . In the present analysis, which included some of the same cohorts, we saw similar evidence of a stronger association between APOE ε2 and longitudinal decline in cognitively normal White men compared with cognitively normal White women, but the APOE ε2 × sex interaction did not reach statistical significance (Table 3).…”

Section: Discussionsupporting

confidence: 62%

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Associations of Sex, Race, and Apolipoprotein E Alleles With Multiple Domains of Cognition Among Older Adults

et al. 2023

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ImportanceSex differences are established in associations between apolipoprotein E (APOE) ε4 and cognitive impairment in Alzheimer disease (AD). However, it is unclear whether sex-specific cognitive consequences of APOE are consistent across races and extend to the APOE ε2 allele.ObjectiveTo investigate whether sex and race modify APOE ε4 and ε2 associations with cognition.Design, Setting, and ParticipantsThis genetic association study included longitudinal cognitive data from 4 AD and cognitive aging cohorts. Participants were older than 60 years and self-identified as non-Hispanic White or non-Hispanic Black (hereafter, White and Black). Data were previously collected across multiple US locations from 1994 to 2018. Secondary analyses began December 2021 and ended September 2022.Main Outcomes and MeasuresHarmonized composite scores for memory, executive function, and language were generated using psychometric approaches. Linear regression assessed interactions between APOE ε4 or APOE ε2 and sex on baseline cognitive scores, while linear mixed-effect models assessed interactions on cognitive trajectories. The intersectional effect of race was modeled using an APOE × sex × race interaction term, assessing whether APOE × sex interactions differed by race. Models were adjusted for age at baseline and corrected for multiple comparisons.ResultsOf 32 427 participants who met inclusion criteria, there were 19 007 females (59%), 4453 Black individuals (14%), and 27 974 White individuals (86%); the mean (SD) age at baseline was 74 years (7.9). At baseline, 6048 individuals (19%) had AD, 4398 (14%) were APOE ε2 carriers, and 12 538 (38%) were APOE ε4 carriers. Participants missing APOE status were excluded (n = 9266). For APOE ε4, a robust sex interaction was observed on baseline memory (β = −0.071, SE = 0.014; P = 9.6 × 10−7), whereby the APOE ε4 negative effect was stronger in females compared with males and did not significantly differ among races. Contrastingly, despite the large sample size, no APOE ε2 × sex interactions on cognition were observed among all participants. When testing for intersectional effects of sex, APOE ε2, and race, an interaction was revealed on baseline executive function among individuals who were cognitively unimpaired (β = −0.165, SE = 0.066; P = .01), whereby the APOE ε2 protective effect was female-specific among White individuals but male-specific among Black individuals.Conclusions and RelevanceIn this study, while race did not modify sex differences in APOE ε4, the APOE ε2 protective effect could vary by race and sex. Although female sex enhanced ε4-associated risk, there was no comparable sex difference in ε2, suggesting biological pathways underlying ε4-associated risk are distinct from ε2 and likely intersect with age-related changes in sex biology.

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Section: Discussionsupporting

confidence: 69%

Section: Discussionsupporting

confidence: 64%

Section: Discussionsupporting

confidence: 62%

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Associations of Sex, Race, and Apolipoprotein E Alleles With Multiple Domains of Cognition Among Older Adults

et al. 2023

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“…Female APOE3/4 heterozygotes have an odds ratio of 4 (compared with 1 in men) of developing AD, and the risk of AD in homozygous APOE 4/4 is also higher in females compared to males [ 51 ]. APOE2 is neuroprotective, but only in women, and may be mediated by a differential lipid expression and biomarkers [ 52 , 53 ]. Lastly, differences in comorbid disease incidence and prevalence may also lead to increased disparity in neurocognitive decline based on sex.…”

Section: Sexual Dimorphism and The Brainmentioning

confidence: 99%

Sex, sepsis and the brain: defining the role of sexual dimorphism on neurocognitive outcomes after infection

et al. 2023

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Sexual dimorphisms exist in multiple domains, from learning and memory to neurocognitive disease, and even in the immune system. Male sex has been associated with increased susceptibility to infection, as well as increased risk of adverse outcomes. Sepsis remains a major source of morbidity and mortality globally, and over half of septic patients admitted to intensive care are believed to suffer some degree of sepsis-associated encephalopathy (SAE). In the short term, SAE is associated with an increased risk of in-hospital mortality, and in the long term, has the potential for significant impairment of cognition, memory, and acceleration of neurocognitive disease. Despite increasing information regarding sexual dimorphism in neurologic and immunologic systems, research into these dimorphisms in sepsis-associated encephalopathy remains critically understudied. In this narrative review, we discuss how sex has been associated with brain morphology, chemistry, and disease, sexual dimorphism in immunity, and existing research into the effects of sex on SAE.

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“…Among APOE e4 carriers with moderate to severe AD, disinhibition has been shown to be more common and more severe in women compared to men [ 110 ]. Sex also affected the association between cognitive decline and the APOE e2 allele in non-Hispanic White participants in a recent study, with men displaying slower decline compared to women [ 111 ]. APOE e4 homozygosity among participants with MCI was also related to a greater NPS burden in women compared to men [ 112 ].…”

Section: Future Perspectivesmentioning

confidence: 99%

Exploring the Genetic Landscape of Mild Behavioral Impairment as an Early Marker of Cognitive Decline: An Updated Review Focusing on Alzheimer’s Disease

Angelopoulou,

Koros,

Hatzimanolis

et al. 2024

IJMS

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The clinical features and pathophysiology of neuropsychiatric symptoms (NPSs) in dementia have been extensively studied. However, the genetic architecture and underlying neurobiological mechanisms of NPSs at preclinical stages of cognitive decline and Alzheimer’s disease (AD) remain largely unknown. Mild behavioral impairment (MBI) represents an at-risk state for incident cognitive impairment and is defined by the emergence of persistent NPSs among non-demented individuals in later life. These NPSs include affective dysregulation, decreased motivation, impulse dyscontrol, abnormal perception and thought content, and social inappropriateness. Accumulating evidence has recently begun to shed more light on the genetic background of MBI, focusing on its potential association with genetic factors related to AD. The Apolipoprotein E (APOE) genotype and the MS4A locus have been associated with affective dysregulation, ZCWPW1 with social inappropriateness and psychosis, BIN1 and EPHA1 with psychosis, and NME8 with apathy. The association between MBI and polygenic risk scores (PRSs) in terms of AD dementia has been also explored. Potential implicated mechanisms include neuroinflammation, synaptic dysfunction, epigenetic modifications, oxidative stress responses, proteosomal impairment, and abnormal immune responses. In this review, we summarize and critically discuss the available evidence on the genetic background of MBI with an emphasis on AD, aiming to gain insights into the potential underlying neurobiological mechanisms, which till now remain largely unexplored. In addition, we propose future areas of research in this emerging field, with the aim to better understand the molecular pathophysiology of MBI and its genetic links with cognitive decline.

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Sex differences in associations between APOE ε2 and longitudinal cognitive decline

Cited by 4 publications

References 62 publications

Associations of Sex, Race, and Apolipoprotein E Alleles With Multiple Domains of Cognition Among Older Adults

Associations of Sex, Race, and Apolipoprotein E Alleles With Multiple Domains of Cognition Among Older Adults

Sex, sepsis and the brain: defining the role of sexual dimorphism on neurocognitive outcomes after infection

Exploring the Genetic Landscape of Mild Behavioral Impairment as an Early Marker of Cognitive Decline: An Updated Review Focusing on Alzheimer’s Disease

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