<i>APOE</i> ε4 carrier status and sex differentiate rates of cognitive decline in early‐ and late‐onset Alzheimer's disease

Polsinelli, Angelina J.; Logan, Paige E.; Lane, Kathleen A.; Manchella, Mohit K.; Nemes, Sára; Sanjay, Apoorva Bharthur; Gao, Sujuan; Apostolova, Liana G.

doi:10.1002/alz.12831

Cited by 12 publications

(10 citation statements)

References 55 publications

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“…The LOAD group outperformed the EOAD group on Clinical Dementia Rating Scale–Sum of Boxes ( P = 0.0084) and Montreal Cognitive Assessment (MoCA; P = 0.0006) at their initial visit. Of note, some MoCA scores were Mini‐Mental State Examination scores converted using crosswalk analysis ( n = 2992; see Polsinelli et al 8 . for a description of crosswalk data used in these analyses and Powell et al 7 .…”

Section: Resultsmentioning

confidence: 99%

APOE ε4 is associated with earlier symptom onset in LOAD but later symptom onset in EOAD

Polsinelli

Lane

Manchella

et al. 2023

Alzheimer's & Dementia

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Background:We studied the effect of apolipoprotein E (APOE) ε4 status and sex on age of symptom onset (AO) in early-(EO) and late-(LO) onset Alzheimer's disease (AD).Method: A total of 998 EOAD and 2562 LOAD participants from the National Alzheimer's Coordinating Center (NACC) were included. We used analysis of variance to examine AO differences between sexes and APOE genotypes and the effect of APOE ε4, sex, and their interaction on AO in EOAD and LOAD, separately.Results: APOE ε4 carriers in LOAD had younger AO and in EOAD had older AO. Female EOAD APOE ε4 carriers had older AO compared to non-carriers (P < 0.0001). There was no difference for males. Both male and female LOAD APOE ε4 carriers had younger AO relative to non-carriers (P < 0.0001). Conclusion:The observed earlier AO in EOAD APOE ε4 non-carriers relative to carriers, particularly in females, suggests the presence of additional AD risk variants.

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Section: Resultsmentioning

confidence: 99%

APOE ε4 is associated with earlier symptom onset in LOAD but later symptom onset in EOAD

Polsinelli

Lane

Manchella

et al. 2023

Alzheimer's & Dementia

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“…It has been observed that women who are APOE4 carriers experience faster cognitive decline and amyloid-beta (Aβ) accumulation compared to men with the same genetic makeup (Corder et al 2004 ). This sex–APOE4 genotype interaction significantly influences a range of AD-related outcomes (Christensen et al 2010 ; Altmann et al 2014 ; Kanekiyo et al 2014 ; Tao et al 2018 ; Duarte-Guterman et al 2020 ; Farmer et al 2021 ; Polsinelli et al 2023 ). For instance, males with APOE4 tend to have more cerebral microbleeds, whereas females with the same allele predominantly develop plaques and tangles (Cacciottolo et al 2016 ).…”

Section: Discussionmentioning

confidence: 99%

Vivaria housing conditions expose sex differences in brain oxidation, microglial activation, and immune system states in aged hAPOE4 mice

Reyes-Reyes,

Brown,

Trial

et al. 2024

Exp Brain Res

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Apolipoprotein E ε4 allele (APOE4) is the predominant genetic risk factor for late-onset Alzheimer’s disease (AD). APOE4 mouse models have provided advances in the understanding of disease pathogenesis, but unaccounted variables like rodent housing status may hinder translational outcomes. Non-sterile aspects like food and bedding can be major sources of changes in rodent microflora. Alterations in intestinal microbial ecology can cause mucosal barrier impairment and increase pro-inflammatory signals. The present study examined the role of sterile and non-sterile food and housing on redox indicators and the immune status of humanized-APOE4 knock-in mice (hAPOe4). hAPOE4 mice were housed under sterile conditions until 22 months of age, followed by the transfer of a cohort of mice to non-sterile housing for 2 months. At 24 months of age, the redox/immunologic status was evaluated by flow cytometry/ELISA. hAPOE4 females housed under non-sterile conditions exhibited: (1) higher neuronal and microglial oxygen radical production and (2) lower CD68+ microglia (brain) and CD8+ T cells (periphery) compared to sterile-housed mice. In contrast, hAPOE4 males in non-sterile housing exhibited: (1) higher MHCII+ microglia and CD11b+CD4+ T cells (brain) and (2) higher CD11b+CD4+ T cells and levels of lipopolysaccharide-binding protein and inflammatory cytokines in the periphery relative to sterile-housed mice. This study demonstrated that sterile vs. non-sterile housing conditions are associated with the activation of redox and immune responses in the brain and periphery in a sex-dependent manner. Therefore, housing status may contribute to variable outcomes in both the brain and periphery.

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“…The early‐onset AD (EOAD; onset < 65 years) variant is an atypical, insidious, and aggressive form of AD with an accelerated trajectory of cognitive decline and greater pathology burden compared to late‐onset AD (LOAD) 2–5 . EOAD manifests with more extensive neurodegeneration and tau burden in regions classically correlated with AD.…”

Section: Introductionmentioning

confidence: 99%

Sex and APOE ε4 carrier effects on atrophy, amyloid PET, and tau PET burden in early‐onset Alzheimer's disease

Nemes,

Logan,

Manchella

et al. 2023

Alzheimer's & Dementia

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INTRODUCTIONWe used sex and apolipoprotein E ε4 (APOE ε4) carrier status as predictors of pathologic burden in early‐onset Alzheimer's disease (EOAD).METHODSWe included baseline data from 77 cognitively normal (CN), 230 EOAD, and 70 EO non‐Alzheimer's disease (EOnonAD) participants from the Longitudinal Early‐Onset Alzheimer's Disease Study (LEADS). We stratified each diagnostic group by males and females, then further subdivided each sex by APOE ε4 carrier status and compared imaging biomarkers in each stratification. Voxel‐wise multiple linear regressions yielded statistical brain maps of gray matter density, amyloid, and tau PET burden.RESULTSEOAD females had greater amyloid and tau PET burdens than males. EOAD female APOE ε4 non‐carriers had greater amyloid PET burdens and greater gray matter atrophy than female ε4 carriers. EOnonAD female ε4 non‐carriers also had greater gray matter atrophy than female ε4 carriers.DISCUSSIONThe effects of sex and APOE ε4 must be considered when studying these populations.HIGHLIGHTS Novel analysis examining the effects of biological sex and apolipoprotein E ε4 (APOE ε4) carrier status on neuroimaging biomarkers among early‐onset Alzheimer's disease (EOAD), early‐onset non‐AD (EOnonAD), and cognitively normal (CN) participants. Female sex is associated with greater pathology burden in the EOAD cohort compared to male sex. The effect of APOE ε4 carrier status on pathology burden was the most impactful in females across all cohorts.

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APOE ε4 carrier status and sex differentiate rates of cognitive decline in early‐ and late‐onset Alzheimer's disease

Cited by 12 publications

References 55 publications

APOE ε4 is associated with earlier symptom onset in LOAD but later symptom onset in EOAD

APOE ε4 is associated with earlier symptom onset in LOAD but later symptom onset in EOAD

Vivaria housing conditions expose sex differences in brain oxidation, microglial activation, and immune system states in aged hAPOE4 mice

Sex and APOE ε4 carrier effects on atrophy, amyloid PET, and tau PET burden in early‐onset Alzheimer's disease

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