Apolipoprotein E is a relevant susceptibility gene that affects the rate of expression of Alzheimer's disease

AbstractBackground and objectiveAlzheimer’s disease (AD) is a neurodegenerative condition where the underlying aetiology is still unclear. Investigating the potential influence of apolipoprotein e (APOE), a major genetic risk factor, on common blood biomarkers could provide a greater understanding of the mechanisms of AD and dementia risk. Our objective was to conduct the largest (to date) single-protocol investigation of blood biomarkers in the context of APOE genotype, in UK Biobank.MethodsAfter quality control and exclusions, data on 395,769 participants of White European ancestry were available for analysis. Linear regressions were used to test potential associations between APOE genotypes and biomarkers.ResultsSeveral biomarkers significantly associated with APOE e4 ‘risk’ and e2 ‘protective’ genotypes (vs. neutral e3/e3). Most associations supported previous data: for example, e4 genotype was associated with elevated low-density lipoprotein cholesterol (LDL) (standardized beta [b] = 0.150 standard deviations [SDs] per allele, p<0.001) and e2 with lower LDL (b = −0.456 SDs, p<0.001). There were however instances of associations found in unexpected directions: e.g. e4 and increased insulin-like growth factor (IGF-1) (standardized beta = 0.017, p<0.001) where lower levels have been previously suggested as an AD risk factor.ConclusionsThese findings highlight biomarker differences in non-demented people at genetic risk for dementia. The evidence here in supports previous hypotheses of involvement from cardiometabolic and neuroinflammatory pathways.

Download Full-text

Rapamycin rescues vascular, metabolic and learning deficits in apolipoprotein E4 transgenic mice with pre-symptomatic Alzheimer’s disease

Journal of Cerebral Blood Flow & Metabolism ◽

10.1177/0271678x15621575 ◽

2016 ◽

Vol 37 (1) ◽

pp. 217-226 ◽

Cited By ~ 61

Author(s):

Ai-Ling Lin ◽

Jordan B Jahrling ◽

Wei Zhang ◽

Nicholas DeRosa ◽

Vikas Bakshi ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Transgenic Mice ◽

Apolipoprotein E ◽

Late Onset ◽

Human Subjects ◽

Susceptibility Gene ◽

Learning Deficits ◽

Cerebrovascular Function

Apolipoprotein E ɛ4 allele is a common susceptibility gene for late-onset Alzheimer's disease. Brain vascular and metabolic deficits can occur in cognitively normal apolipoprotein E ɛ4 carriers decades before the onset of Alzheimer's disease. The goal of this study was to determine whether early intervention using rapamycin could restore neurovascular and neurometabolic functions, and thus impede pathological progression of Alzheimer's disease-like symptoms in pre-symptomatic Apolipoprotein E ɛ4 transgenic mice. Using in vivo, multimodal neuroimaging, we found that apolipoprotein E ɛ4 mice treated with rapamycin had restored cerebral blood flow, blood–brain barrier integrity and glucose metabolism, compared to age- and gender-matched wild-type controls. The preserved vasculature and metabolism were associated with amelioration of incipient learning deficits. We also found that rapamycin restored the levels of the proinflammatory cyclophilin A in vasculature, which may contribute to the preservation of cerebrovascular function in the apolipoprotein E ɛ4 transgenics. Our results show that rapamycin improves functional outcomes in this mouse model and may have potential as an effective intervention to block progression of vascular, metabolic and early cognitive deficits in human Apolipoprotein E ɛ4 carriers. As rapamycin is FDA-approved and neuroimaging is readily used in humans, the results of the present study may provide the basis for future Alzheimer's disease intervention studies in human subjects.

Download Full-text

Relationship between apolipoprotein E and the amyloid deposits and dystrophic neurites of Alzheimer's disease

Neuropathology and Applied Neurobiology ◽

10.1046/j.1365-2990.1997.00072.x ◽

1997 ◽

Vol 23 (6) ◽

pp. 483-491 ◽

Cited By ~ 1

Author(s):

T. C. Dickson ◽

H. L. Saunders ◽

J. C. Vickers

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Apolipoprotein E ◽

Dystrophic Neurites ◽

Amyloid Deposits

Download Full-text

Age Modifies the Association Between Apolipoprotein E Genotype and Alzheimer's Disease: A CSF Biomarker-Based Multicentric Case-Control Study

SSRN Electronic Journal ◽

10.2139/ssrn.3417885 ◽

2019 ◽

Author(s):

Hana Sadikki ◽

Aurore Fayosse ◽

Emmanuel Cognat ◽

Séverine Sabia ◽

Sebastiaan Engelborghs ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Apolipoprotein E ◽

Case Control Study ◽

Case Control ◽

Csf Biomarker ◽

Control Study ◽

Apolipoprotein E Genotype

Download Full-text

P4-068: CLINICAL RELEVANCE OF APOE GENOTYPING AND APOLIPOPROTEIN E-ɛ4 IMMUNOASSAYS IN ALZHEIMER'S DISEASE

Alzheimer s & Dementia ◽

10.1016/j.jalz.2014.05.1583 ◽

2014 ◽

Vol 10 ◽

pp. P808-P808

Author(s):

Femke Soetewey ◽

Hanne Struyfs ◽

Erik Stoops ◽

Christine Van Broeckhoven ◽

Hugo Vanderstichele ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Apolipoprotein E ◽

Clinical Relevance

Download Full-text

Association between methylation of BIN1 promoter in peripheral blood and preclinical Alzheimer’s disease

Translational Psychiatry ◽

10.1038/s41398-021-01218-9 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Hao Hu ◽

Lan Tan ◽

Yan-Lin Bi ◽

Wei Xu ◽

Lin Tan ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Peripheral Blood ◽

Late Onset ◽

Early Stage ◽

Susceptibility Gene ◽

Subjective Cognitive Decline ◽

Preclinical Ad ◽

T Tau ◽

New Evidence

AbstractThe bridging integrator 1 (BIN1) gene is the second most important susceptibility gene for late-onset Alzheimer’s disease (LOAD) after apolipoprotein E (APOE) gene. To explore whether the BIN1 methylation in peripheral blood changed in the early stage of LOAD, we included 814 participants (484 cognitively normal participants [CN] and 330 participants with subjective cognitive decline [SCD]) from the Chinese Alzheimer’s Biomarker and LifestylE (CABLE) database. Then we tested associations of methylation of BIN1 promoter in peripheral blood with the susceptibility for preclinical AD or early changes of cerebrospinal fluid (CSF) AD-related biomarkers. Results showed that SCD participants with significant AD biological characteristics had lower methylation levels of BIN1 promoter, even after correcting for covariates. Hypomethylation of BIN1 promoter were associated with decreased CSF Aβ42 (p = 0.0008), as well as increased p-tau/Aβ42 (p = 0.0001) and t-tau/Aβ42 (p < 0.0001) in total participants. Subgroup analysis showed that the above associations only remained in the SCD subgroup. In addition, hypomethylation of BIN1 promoter was also accompanied by increased CSF p-tau (p = 0.0028) and t-tau (p = 0.0130) in the SCD subgroup, which was independent of CSF Aβ42. Finally, above associations were still significant after correcting single nucleotide polymorphic sites (SNPs) and interaction of APOE ɛ4 status. Our study is the first to find a robust association between hypomethylation of BIN1 promoter in peripheral blood and preclinical AD. This provides new evidence for the involvement of BIN1 in AD, and may contribute to the discovery of new therapeutic targets for AD.

Download Full-text