Longitudinal modeling of frontal cognition in
            <i>APOE</i>
            ε4 homozygotes, heterozygotes, and noncarriers

Caselli, Richard J.; Dueck, Amylou C.; Locke, Dona E.C.; Hoffman-Snyder, Charlene; Woodruff, Bryan K.; Rapcsak, Steven Z.; Reiman, Eric M.

doi:10.1212/wnl.0b013e3182167147

Cited by 86 publications

(83 citation statements)

References 36 publications

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“…Trends of PI/PIP 2 changes were seen in ApoE4/4 mouse brains at as early as 3 mo of age (whole-brain lipid analysis; Fig. S3B), suggesting the intrinsic effects of ApoE4 on PI metabolism, particularly PIP 2 levels, which become more prominent with the ApoE4-induced accelerated aging processes (14)(15)(16)(17)(18)(19). Therefore, we speculate that ApoE4-induced PIP 2 changes may contribute to ApoE4-induced exacerbation of neurodegenerative processes.…”

Section: Significancementioning

confidence: 92%

Phospholipid dysregulation contributes to ApoE4-associated cognitive deficits in Alzheimer’s disease pathogenesis

Zhu

Zhong

Elder

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

115

100

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The apolipoprotein E4 (ApoE4) allele is the strongest genetic risk factor for developing sporadic Alzheimer's disease (AD). However, the mechanisms underlying the pathogenic nature of ApoE4 are not well understood. In this study, we have found that ApoE proteins are critical determinants of brain phospholipid homeostasis and that the ApoE4 isoform is dysfunctional in this process. We have found that the levels of phosphoinositol biphosphate (PIP 2 ) are reduced in postmortem human brain tissues of ApoE4 carriers, in the brains of ApoE4 knock-in (KI) mice, and in primary neurons expressing ApoE4 alleles compared with those levels in ApoE3 counterparts. These changes are secondary to increased expression of a PIP 2 -degrading enzyme, the phosphoinositol phosphatase synaptojanin 1 (synj1), in ApoE4 carriers. Genetic reduction of synj1 in ApoE4 KI mouse models restores PIP 2 levels and, more important, rescues AD-related cognitive deficits in these mice. Further studies indicate that ApoE4 behaves similar to ApoE null conditions, which fails to degrade synj1 mRNA efficiently, unlike ApoE3 does. These data suggest a loss of function of ApoE4 genotype. Together, our data uncover a previously unidentified mechanism that links ApoE4-induced phospholipid changes to the pathogenic nature of ApoE4 in AD.Alzheimer's disease | apolipoprotein E4 | phospholipid | dysregulation | cognitive deficits

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Section: Significancementioning

confidence: 92%

Phospholipid dysregulation contributes to ApoE4-associated cognitive deficits in Alzheimer’s disease pathogenesis

Zhu

Zhong

Elder

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

115

100

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“…10 The e4e4 children with smaller hippocampal volumes and thinner temporal pole had poorer WM and attention; these findings resemble the thinnest frontal cortices 29 in middle-aged e4e4 individuals without dementia, who showed the most rapid decline on mental arithmetic tasks requiring WM. 26 Hence, e4 homozygosity might slow maturation of the hippocampus and cortical thickness, which in turn might negatively affect WM and attention. Mirroring these findings, older individuals with e4 homozygosity had the highest prevalence for AD (50%-91%) 4,15 and the greatest hippocampal and temporal lobe atrophy 30 among genotypes.…”

Section: Figurementioning

confidence: 99%

Gray matter maturation and cognition in children with different APOE ε genotypes

et al. 2016

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Objective: The aims of the current study were to determine whether children with the 6 different APOE e genotypes show differences in gray matter maturation, particularly for those with e4 and e2 alleles, which are associated with poorer outcomes in many neurologic disorders.Methods: A total of 1,187 healthy children (aged 3-20 years, 52.1% boys, 47.9% girls) with acceptable data from the cross-sectional Pediatric Imaging Neurocognition and Genetics Study were evaluated for the effects of 6 APOE e genotypes on macroscopic and microscopic cortical and subcortical gray matter structures (measured with 3-tesla MRI and FreeSurfer for automated morphometry) and on cognition (NIH Toolbox).Results: Among APOE e4 carriers, age-related changes in brain structures and cognition varied depending on genotype, with the smallest hippocampi in e2e4 children, the lowest hippocampal fractional anisotropy in younger e4e4 children, the largest medial orbitofrontal cortical areas in e3e4 children, and age-dependent thinning of the entorhinal cortex in e4e4 children. Younger e4e4 children had the lowest scores on executive function and working memory, while younger e2e4 children performed worse on attention tasks. Larger parietal gyri in the younger e2e4 children, and thinner temporal and cingulate isthmus cortices or smaller hippocampi in the younger e4e4 children, predicted poorer performance on attention or working memory.Conclusions: Our findings validated and extended prior smaller studies that showed altered brain development in APOE e4-carrier children. The e4e4 and e2e4 genotypes may negatively influence brain development and brain aging at the extremes of age. Studying APOE e polymorphisms in young children may provide the earliest indicators for individuals who might benefit from early interventions or preventive measures for future brain injuries and dementia. Neurology ® 2016;87:585-594 GLOSSARY AD 5 Alzheimer disease; FA 5 fractional anisotropy; GAF 5 genetic ancestry factor; GAM 5 general additive model; PING 5 Pediatric Imaging, Neurocognition, and Genetics; ROI 5 region of interest; SES 5 socioeconomic status; WM 5 working memory.

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“…The ε4 allele is also correlated with decreased brain metabolism in distinct brain areas even in young cognitively normal adults and children [12,13] and has a direct pathological effect on the cerebrovascular system [14]. It is also related to changes in the level of CSF biomarkers (i.e., Tau-protein and Αβ-42) [8] and it contributes to cognitive deterioration [8,15].…”

Section: Introductionmentioning

confidence: 99%

Prevalence of Apolipoprotein E Polymorphisms in Alzheimer’s Disease, Mild Cognitive Impairment, and Healthy Elderly: A Northern Greece Study

et al. 2018

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Background: Apolipoprotein E ε4 allele (APOEε4) is a major genetic risk factor for Alzheimer’s disease (AD). APOEε4 carriers have a higher risk of cognitive impairment and AD in a gene dose-dependent manner. The above notion is investigated in the Greek population. Methods: A sample of 1,703 subjects (967 AD patients, 576 mild cognitive impairment [MCI] and 160 Healthy Elderly), was genotyped for APOE from 2008 to 2017. DNA was extracted from peripheral blood using the QIAamp Blood DNA purification kit (Qiagen Inc., USA). Descriptive statistics, one-way analysis of variance with Bonferroni post hoc tests, Pearson chi-square test, and binary logistic regression models were used for the statistical analysis. Results: The APOE genotype and allele frequencies in AD group were significantly different from those in the Control and MCI groups. The frequencies of ε4/4 homozygotes were 1.9, 1.6, and 5.7%, while the ε4/– carriers’ distribution was 22.5, 24.1, and 37.4% in the Control, MCI, and AD groups respectively. The estimated odds of ε4/4 for AD was 5.731-fold higher compared to the estimated odds of ε3/3. The interaction between gender and APOE did not have a significant effect on the odds for MCI (p = 0.942) and AD (p = 0.984). Conclusion: In Greece, APOE ε4 presence is related to an increased risk for AD in a dose-related manner. Contrary to long-standing views, men and women with the APOE ε4 genotype have nearly the same odds of developing MCI and AD.

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Longitudinal modeling of frontal cognition in APOE ε4 homozygotes, heterozygotes, and noncarriers

Abstract: Background: Fibrillar amyloid deposition preferentially affects the frontal lobes, temporal pole/

Cited by 86 publications

References 36 publications

Phospholipid dysregulation contributes to ApoE4-associated cognitive deficits in Alzheimer’s disease pathogenesis

Phospholipid dysregulation contributes to ApoE4-associated cognitive deficits in Alzheimer’s disease pathogenesis

Gray matter maturation and cognition in children with different APOE ε genotypes

Prevalence of Apolipoprotein E Polymorphisms in Alzheimer’s Disease, Mild Cognitive Impairment, and Healthy Elderly: A Northern Greece Study

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