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

Stephen, Terri‐Leigh; Breningstall, Bayla; Suresh, Sharanya; McGill, Cassandra; Pike, Christian J.

doi:10.1186/s12974-022-02650-4

Cited by 10 publications

(17 citation statements)

References 45 publications

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“…Each CTRP member showed correlations with a majority of these representative biomarkers in the AD group. It should be pointed out that both female sex and APOE4 represent the strongest risk factors for AD in addition to aging, even though there is currently no consensus on which one is stronger [25][26][27] ; thus, the similar correlations in the subgroups based on sex or ApoE4 status were further investigated following previous studies. 19,28 All correlation analysis results indicate that CTRPs are associated with the symptomatic severity and neurodegeneration degree of AD.…”

Section: Discussionmentioning

confidence: 99%

Association between plasma CTRPs with cognitive impairment and neurodegeneration of Alzheimer's disease

Huang,

Zhao,

Wang

et al. 2024

CNS Neurosci Ther

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AimsRecent evidence indicated the biological basis of complement 1q (C1q)/tumor necrosis factor (TNF)‐related protein (CTRP) 3, 4, and 14 for affecting brain structure and cognitive function. Thus, we aimed to investigate the association between plasma CTRPs with Alzheimer's disease (AD).MethodsA multicenter, cross‐sectional study recruited patients with AD (n = 137) and cognitively normal (CN) controls (n = 140). After the data collection of demographic characteristics, lifestyle risk factors, and medical history, plasma levels of tau phosphorylated at threonine 217 (pT217), pT181, neurofilament light (NfL), CTRP3, 4, and 14 were examined and compared. Multivariate logistic regression analysis was applied to determine associations of plasma CTPRs with the presence of AD. The correlation analysis was used to explore correlations between plasma CTPRs with scores of Mini‐Mental State Examination (MMSE), Montreal Cognitive Assessment (MoCA), Activities of Daily Living (ADL) scale, and Clinical Dementia Rating Sum of Boxes (CDR‐SB), and levels of plasma pT217, pT181, and NfL. Receiver‐operating characteristic (ROC) analysis and Delong's test were used to determine the diagnostic power of plasma CTPRs.ResultsPlasma levels of CTRP3, 4, and 14 were higher in AD group than those in CN group. After adjusting for conventional risk factors, CTRP3, CTRP4, and CTRP14 were associated with the presence of AD. In AD patients, CTRP3 was negatively correlated with scores of MMSE and MoCA, while positively correlated with ADL score, CDR‐SB score, pT217, and pT181; CTRP4 was positively correlated with CDR‐SB score, pT181, and NfL; CTRP14 was negatively correlated with MMSE score, while positively correlated with CDR‐SB score, pT217, and NfL. An independent addition of CTRP3 and 4 to the basic model combining age, sex, years of education, APOE4 status, BMI, TG, and HDL‐C led to a significant improvement in diagnostic power for AD, respectively.ConclusionsAll the findings preliminarily uncovered associations between plasma CTRPs and AD and suggested the potential of CTRPs as a blood‐derived biomarker for AD.

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Section: Discussionmentioning

confidence: 99%

Association between plasma CTRPs with cognitive impairment and neurodegeneration of Alzheimer's disease

Huang,

Zhao,

Wang

et al. 2024

CNS Neurosci Ther

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“…Mouse models indicate that ApoE controls glial activation, but ApoE4 locks microglia in a homeostatic state, decreasing in phagocytic capacity, and resulting in a failure to clear pathological debris [ 7 , 66 , 72 ]. Therefore, microglial and astrocyte coverage of plaques is likely protective for surrounding neurons, and ApoE4 is associated with decreased coverage and more neuronal dystrophy [ 73 – 75 ].…”

Section: Discussionmentioning

confidence: 99%

Onset of Alzheimer disease in apolipoprotein ɛ4 carriers is earlier in butyrylcholinesterase K variant carriers

Lane,

Darreh-Shori,

Junge

et al. 2024

BMC Neurol

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Background The authors sought to examine the impact of the K-variant of butyrylcholinesterase (BCHE-K) carrier status on age-at-diagnosis of Alzheimer disease (AD) in APOE4 carriers. Methods Patients aged 50–74 years with cerebrospinal fluid (CSF) biomarker-confirmed AD, were recruited to clinical trial (NCT03186989 since June 14, 2017). Baseline demographics, disease characteristics, and biomarkers were evaluated in 45 patients according to BCHE-K and APOE4 allelic status in this post-hoc study. Results In APOE4 carriers (N = 33), the mean age-at-diagnosis of AD in BCHE-K carriers (n = 11) was 6.4 years earlier than in BCHE-K noncarriers (n = 22, P < .001, ANOVA). In APOE4 noncarriers (N = 12) there was no observed influence of BCHE-K. APOE4 carriers with BCHE-K also exhibited slightly higher amyloid and tau accumulations compared to BCHE-K noncarriers. A predominantly amyloid, limited tau, and limbic-amnestic phenotype was exemplified by APOE4 homozygotes with BCHE-K. In the overall population, multiple regression analyses demonstrated an association of amyloid accumulation with APOE4 carrier status (P < .029), larger total brain ventricle volume (P < .021), less synaptic injury (Ng, P < .001), and less tau pathophysiology (p-tau181, P < .005). In contrast, tau pathophysiology was associated with more neuroaxonal damage (NfL, P = .002), more synaptic injury (Ng, P < .001), and higher levels of glial activation (YKL-40, P = .01). Conclusion These findings have implications for the genetic architecture of prognosis in early AD, not the genetics of susceptibility to AD. In patients with early AD aged less than 75 years, the mean age-at-diagnosis of AD in APOE4 carriers was reduced by over 6 years in BCHE-K carriers versus noncarriers. The functional status of glia may explain many of the effects of APOE4 and BCHE-K on the early AD phenotype. Trial registration NCT03186989 since June 14, 2017

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“…Glia in APOE4 mice demonstrate a significant decrease in phagocytic capacity (64). Microglial and astrocyte coverage of plaques is likely protective for surrounding neurons, and ApoE4 is associated with decreased coverage and more neuronal dystrophy (65)(66)(67).…”

Section: Both Aβ and Apoe Modulate The Cholinergic Systemmentioning

confidence: 99%

Onset of Alzheimer disease in apolipoprotein ɛ4 carriers is earlier in butyrylcholinesterase K variant carriers

Lane,

Darreh-Shori,

Junge

et al. 2024

Preprint

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BackgroundWe wished to examine the impact of the K-variant ofbutyrylcholinesterase(BCHE-K) carrier status on age-at-diagnosis of Alzheimer disease (AD) inAPOE4carriers.MethodsIn 45 patients, aged 50-74 years, with cerebrospinal fluid (CSF) biomarker confirmed mild AD, recruited into a clinical trial (NCT03186989), baseline demographics, disease characteristics, and biomarkers were evaluated byBCHE-KandAPOE4allelic status.ResultsInAPOE4carriers (N = 33), mean age-at-diagnosis of AD inBCHE-Kcarriers (n = 11) was 6.4 years earlier than inBCHE-Knoncarriers (n = 22,P <.001, ANOVA). InAPOE4noncarriers (N = 12) there was no similar influence ofBCHE-K. InAPOE4carriers with versus those withoutBCHE-K, mean age-at-baseline was over 6 years earlier and accompanied by slightly higher amyloid and tau accumulations. A predominant amyloid, limited tau pathophysiology, and limbic-amnestic phenotype was exemplified byAPOE4homozygotes withBCHE-K. Multiple regression analyses demonstrated association of amyloid accumulation withAPOE4carrier status (P <.029), larger total brain ventricle volume (P <.021), less synaptic injury (Ng,P <.001), and less tau (p-tau181,P <.005). In contrast, tau pathophysiology was associated with more neuroaxonal damage (NfL,P= .002), more synaptic injury (Ng,P <.001), and higher levels of glial activation (YKL-40,P= .01).ConclusionFindings concern the genetic architecture of prognosis in early AD, that is fundamental for patients and the design of clinical trials, and that is less well established than the genetics of susceptibility. In mild AD patients aged less than 75 years, the mean age-at-diagnosis of AD inAPOE4carriers was reduced by over 6 years inBCHE-Kcarriers versus noncarriers. Functional activation of glia may explain much of the effects ofAPOE4andBCHE-Kon the phenotype of early AD.

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

Cited by 10 publications

References 45 publications

Association between plasma CTRPs with cognitive impairment and neurodegeneration of Alzheimer's disease

Association between plasma CTRPs with cognitive impairment and neurodegeneration of Alzheimer's disease

Onset of Alzheimer disease in apolipoprotein ɛ4 carriers is earlier in butyrylcholinesterase K variant carriers

Onset of Alzheimer disease in apolipoprotein ɛ4 carriers is earlier in butyrylcholinesterase K variant carriers

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