Inflammation in Alzheimer’s Disease: Do Sex and APOE Matter?

Duarte‐Guterman, Paula; Albert, Arianne; Inkster, Amy M.; Barha, Cindy K.; Galea, Liisa A.M.

doi:10.3233/jad-200982

Cited by 19 publications

(8 citation statements)

References 85 publications

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“…Furthermore, on investigating the cultures from both genotypes in a sex-specific manner, we found that both APOE3 and APOE4 females had a more pronounced inflammatory profile. Importantly, this is consistent with clinical data from healthy individuals carrying the APOE3 or APOE4 gene; APOE4 females show a greater increase in both pro-inflammatory cytokine release and gene expression [ 82 , 85 , 86 ].…”

Section: Discussionsupporting

confidence: 85%

Sex and APOE Genotype Alter the Basal and Induced Inflammatory States of Primary Microglia from APOE Targeted Replacement Mice

Mhatre-Winters

Eid

Han

et al. 2022

IJMS

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The sex and APOE4 genotype are significant risk factors for Alzheimer’s disease (AD); however, the mechanism(s) responsible for this interaction are still a matter of debate. Here, we assess the responses of mixed-sex and sex-specific APOE3 and APOE4 primary microglia (PMG) to lipopolysaccharide and interferon-gamma. In our investigation, inflammatory cytokine profiles were assessed by qPCR and multiplex ELISA assays. Mixed-sex APOE4 PMG exhibited higher basal mRNA expression and secreted levels of TNFa and IL1b. In sex-specific cultures, basal expression and secreted levels of IL1b, TNFa, IL6, and NOS2 were 2–3 fold higher in APOE4 female PMG compared to APOE4 males, with both higher than APOE3 cells. Following an inflammatory stimulus, the expression of pro-inflammatory cytokines and the secreted cytokine level were upregulated in the order E4 female > E4 male > E3 female > E3 male in sex-specific cultures. These data indicate that the APOE4 genotype and female sex together contribute to a greater inflammatory response in PMG isolated from targeted replacement humanized APOE mice. These data are consistent with clinical data and indicate that sex-specific PMG may provide a platform for exploring mechanisms of genotype and sex differences in AD related to neuroinflammation and neurodegeneration.

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Section: Discussionsupporting

confidence: 85%

Sex and APOE Genotype Alter the Basal and Induced Inflammatory States of Primary Microglia from APOE Targeted Replacement Mice

Mhatre-Winters

Eid

Han

et al. 2022

IJMS

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“…Our group and others have shown that males tend to have poorer cognitive outcomes following certain neurologic conditions, especially those involving X chromosome effects ( Kesler et al, 2009a , b ; Green et al, 2019 ). However, females also have increased susceptibility to certain brain-based disorders including depression and Alzheimer’s disease, for example ( Kuehner, 2017 ; Duarte-Guterman et al, 2020 ). Our sample was largely female so other potential sex effects in cognitive and psychosocial outcomes may not have been detected.…”

Section: Discussionmentioning

confidence: 99%

Cognitive Impairment in Non-critical, Mild-to-Moderate COVID-19 Survivors

et al. 2022

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ImportancePrevious studies of post-acute COVID-19 syndrome have focused on critical cases with severe disease. However, most cases are mild to moderate in disease severity.ObjectiveWe aimed to examine cognitive outcomes in cases of non-critical, mild-to-moderate COVID-19. Design, Setting, and Participants: In this cross-sectional study, we enrolled 72 adults aged 22 to 65 years in Central Texas who had non-critical, mild-to-moderate COVID-19 infection between 13 January 2021 and 20 April 2021.Main Outcomes and MeasuresWe remotely administered cognitive-behavioral testing to determine the frequency of cognitive impairment and examine demographic, clinical, and psychosocial contributors to impairment.ResultsThe frequency of objective cognitive impairment was 40%. The largest number of participants (24%) showed impairment on a measure of executive functioning. Attention and processing speed was more impaired in males (OR = 1.5, 95%CI = 0.23–2.9). Males endorsed lower adherence to social distancing guidelines (U = 590, p = 0.01), which was in turn associated with cognitive impairment across participants (r = −0.30, p = 0.01). Younger age was correlated with impairment (r = −0.26, p = 0.03) but was also associated with racial/ethnic minority status (r = −0.31, p = 0.01) and increased psychological symptoms (p < 0.04). Greater number of COVID-19 symptoms was correlated with lower subjective cognitive function (r = −0.38, p = 0.001) as well as psychosocial function (r > 0.24, p < 0.05). Moderate COVID-19 severity was associated with attention/processing speed impairment (r = 0.27, p = 0.03), increased pain (r = 0.31, p = 0.01), and higher number of COVID-19 symptoms (r = 0.32, p = 0.01).Conclusion and RelevanceMild or moderate COVID-19 infection may be associated with cognitive impairments, especially in the domain of executive functioning. A subgroup of younger individuals may be more vulnerable to cognitive and psychosocial effects of COVID-19.HighlightsQuestion: How frequent is cognitive impairment among non-critical, mild-to-moderate COVID-19 survivors?FindingsIn this cross-sectional study of 72 adults, 40% demonstrated cognitive impairment, particularly in executive function.MeaningNeurologic sequelae, such as cognitive impairment, may be common following COVID-19 infection.

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“…As such, ApoE ε4 carrier status may provide a very specific and distinct approach to the development of AD prevention strategies, as lifestyle, genomics, AD comorbidities, and other biological and behavioral factors may be affected by the presence of the ε4 allele [ 33 ]. Another study provided evidence that sex and the presence of ApoE ε4 allele were associated with CSF levels of inflammatory biomarkers [ 34 ]. Consequently, it may be a marker of the neurodegenerative process in the course of AD [ 35 ].…”

Section: Discussionmentioning

confidence: 99%

Assessment of Screening Approach in Early and Differential Alzheimer’s Disease Diagnosis

et al. 2021

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Background: Alzheimer’s disease (AD) is the leading cause of dementia in the elderly population. Currently, diagnosis is based on invasive and expensive techniques, so there is a growing need to look for other possible tests, as well as carry out clinical validation. Studies from the literature showed potential diagnosis models, including some AD risk factors (age, gender, ApoE-ε4 genotype) and other variables (biomarkers levels, neuroimaging). Specifically, a recent model was performed from lipid peroxidation compounds in plasma samples to identify patients with early AD. However, there is a lack of studies about clinical validation of these preliminary diagnosis models. Methods: Plasma samples from participants classified into AD (n = 61), non-AD (n = 17), and healthy (n = 44) were analyzed. In fact, lipid peroxidation compounds were determined by liquid chromatography and mass spectrometry. Then, a previously developed diagnosis model was clinically validated, evaluating some diagnosis indexes. Results: The validation of the preliminary diagnosis model showed satisfactory diagnosis indexes (accuracy 77%, sensitivity 89%, specificity 61%, diagnostic odds ratio 12.5, positive predictive value 76%). Next, a useful screening tool, including the ApoE genotype, was developed, identifying patients with a higher risk of developing AD and improving the corresponding diagnosis indexes (accuracy 82%, sensitivity 81%, specificity 85%, diagnostic odds ratio 23.2, positive predictive value 90.5%). Conclusion: A new screening approach could improve the early, minimally invasive, and differential AD diagnosis in the general population.

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Inflammation in Alzheimer’s Disease: Do Sex and APOE Matter?

Cited by 19 publications

References 85 publications

Sex and APOE Genotype Alter the Basal and Induced Inflammatory States of Primary Microglia from APOE Targeted Replacement Mice

Sex and APOE Genotype Alter the Basal and Induced Inflammatory States of Primary Microglia from APOE Targeted Replacement Mice

Cognitive Impairment in Non-critical, Mild-to-Moderate COVID-19 Survivors

Assessment of Screening Approach in Early and Differential Alzheimer’s Disease Diagnosis

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