<i>APOE</i> ε4 and exercise interact in a sex‐specific manner to modulate dementia risk factors

Foley, Kate E.; Diemler, Cory; Hewes, Amanda E.; Garceau, Dylan; Sasner, Michael; Howell, Gareth R.

doi:10.1002/trc2.12308

Cited by 2 publications

(2 citation statements)

References 74 publications

(148 reference statements)

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“…Therefore, the two optimal exposures may jointly interact with dementia related genetic risk. Emerging evidence confirmed that a higher frequency of participation in physical activity can improve handgrip strength and increase vitamin D level, and the interaction between physical and APOE genotype have been reported [ 44 , 45 ]. Brain structural alteration may be another potential mechanism.…”

Section: Discussionmentioning

confidence: 93%

Ideal vitamin D and handgrip strength counteracts the risk effect of APOE genotype on dementia: a population-based longitudinal study

2023

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Background Higher vitamin D concentrations and grip strength contribute to lower individual-level risk of dementia, while apolipoprotein 4 (APOE e4) genotype carries increases dementia risk, but whether combination of ideal vitamin D and grip strength counteracts the risk effect of dementia related to APOE e4 genotype remains unclear. We aimed to investigate the interactions between vitamin D/grip strength and APOE e4 genotype and their association with dementia. Methods The UK Biobank cohort comprised 165,688 dementia-free participants (aged at least 60 years) for the dementia analysis. Dementia was ascertained using hospital inpatient, mortality, and self-reported data until 2021. Vitamin D and grip strength were collected at baseline and divided into tertiles. APOE genotype was coded as APOE e4 non-carries and APOE e4 carries. Data were analyzed using Cox proportional hazard models and restricted cubic regression splines, with adjusted for known confounders. Results Over the follow-up (median: 12.0 years), 3917 participants developed dementia. In women and men, respectively, compared with to the lowest tertile of vitamin D, the HRs (95% CIs) of dementia were lower in the middle [0.86 (0.76–0.97)/0.80 (0.72–0.90)] and the highest tertile [0.81 (0.72–0.90)/0.73 (0.66–0.81)]. Tertiles of grip strength showed similar patterns. In women and men, respectively, participants who had both highest tertile of vitamin D and grip strength was associated with a lower risk of dementia compared to those with both lowest tertile of these two exposures among APOE e4 genotype carries (HR = 0.56, 95% CI 0.42–0.76, and HR = 0.48, 95% CI 0.36–0.64) and APOE e4 genotype non-carries (HR = 0.56, 95% CI 0.38–0.81, and HR = 0.34, 95% CI 0.24–0.47). There were significant additive interactions between lower vitamin D/grip strength and APOE e4 genotype on dementia among women and men. Conclusions Higher vitamin D and grip strength were associated with a lower risk of dementia, and seemed to halve the adverse effects of APOE e4 genotype on dementia. Our findings suggested that vitamin D and grip strength may be imperative for estimating the risks of dementia, especially among APOE e4 genotype carries.

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Section: Discussionmentioning

confidence: 93%

Ideal vitamin D and handgrip strength counteracts the risk effect of APOE genotype on dementia: a population-based longitudinal study

2023

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“…The lack of concordance between astroglial-plaque interactions and measures of AD-related pathology suggest the possibility of inherent sex and APOE genotype effects. Indeed, there are numerous observations of sex × APOE interactions across multiple domains in the absence of significant Ab pathology in rodents and humans [32][33][34][35][36].…”

Section: Discussionmentioning

confidence: 99%

APOE genotype and biological sex regulate astroglial interactions with amyloid plaques in Alzheimer’s disease mice

Stephen

Breningstall

Suresh

et al. 2022

J Neuroinflammation

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The most significant genetic risk factor for developing late-onset Alzheimer’s disease (AD) is the ε4 allele of apolipoprotein E (APOE4). APOE genotype and biological sex are key modulators of microglial and astroglial function, which exert multiple effects on AD pathogenesis. Here, we show astroglial interactions with amyloid plaques in the EFAD transgenic mouse model of AD. Using confocal microscopy, we observed significantly lower levels of astrocytic plaque coverage and plaque compaction (beneficial effects of glial barrier formation) with APOE4 genotype and female sex. Conversely, neurite damage and astrocyte activation in the plaque environment were significantly higher in APOE4 carriers and female mice. Astrocyte coverage of plaques was highest in APOE3 males and poorest in APOE4 females. Collectively, our findings provide new insights into the roles of astroglia and highlight the importance of addressing independent and interactive effects of APOE genotype and biological sex in understanding processes contributing to AD pathogenesis.

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APOE ε4 and exercise interact in a sex‐specific manner to modulate dementia risk factors

Cited by 2 publications

References 74 publications

Ideal vitamin D and handgrip strength counteracts the risk effect of APOE genotype on dementia: a population-based longitudinal study

Ideal vitamin D and handgrip strength counteracts the risk effect of APOE genotype on dementia: a population-based longitudinal study

APOE genotype and biological sex regulate astroglial interactions with amyloid plaques in Alzheimer’s disease mice

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