scholarly journals [S2-01-04]: The role of statins in delaying Alzheimer's disease. Circulating cholesterol levels, ApoE genotype and initial dementia severity influence the level of benefit produced by atorvastatin in mild-to-moderate AD: Results of the ADCLT

2005 ◽  
Vol 1 ◽  
pp. S92-S92
Author(s):  
D. Larry Sparks ◽  
Donald J. Connor ◽  
Marwan N. Sabbagh ◽  
Jean Lopez ◽  
Patrick Browne ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Apoe Genotype ◽  
Dementia Severity ◽  
Cholesterol Levels

Total Cholesterol and APOE-Related Risk for Alzheimer’s Disease in the Alzheimer’s Disease Neuroimaging Initiative

2021 ◽  
pp. 1-10
Author(s):  
Michelle M. Dunk ◽  
Ira Driscoll ◽  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Total Cholesterol ◽  
Cholesterol Metabolism ◽  
Apoe Genotype ◽  
Control Group ◽  
Cholesterol Levels ◽  
Related Risk ◽  
E4 Allele

Background: APOE ɛ4 allele confers greatest genetic risk for Alzheimer’s disease (AD), yet mechanisms underlying this risk remain elusive. APOE is involved in lipid metabolism, and literature suggest relationships between high total cholesterol, APOE, and AD. Further investigation is needed to elucidate the potential role of total cholesterol in AD risk. Objective: To investigate the relationship between total cholesterol and APOE-related AD risk in the Alzheimer’s Disease Neuroimaging Initiative. Methods: Participants (N = 1,534) were classified as controls (cognitively normal; N = 404), early mild cognitive impairment (MCI; N = 294), late MCI (N = 539), or AD (N = 297). Total cholesterol levels were compared across APOE genotype and diagnosis. Mendelian randomization was performed to examine causality between total cholesterol and AD risk using APOE as a genetic instrument. Results: Total cholesterol was higher in APOE4+ compared to APOE3 and APOE2+ (ps < 0.04) carriers. Those with AD and late MCI (ps < 0.001) had higher total cholesterol than the control group. Comparing APOE4+ to APOE3 carriers, the predicted odds ratios per mg/dL greater total cholesterol were 1.11 for MCI (95% confidence interval, 1.04–7.32), 1.05 for early MCI (1.01–3.22), 1.13 for late MCI (1.05–11.70), 1.21 for AD (1.09–54.05), and 1.13 for composite dementia (MCI or AD; 1.06–11.59) (ps < 0.05, F-statistics>10). Conclusion: Higher total cholesterol may be a significant contributor to AD risk, particularly in APOE4 carriers who, based on existing literature, tend to have impaired cholesterol metabolism. Our findings highlight a possible mechanism by which APOE confers AD risk and indicate potential for AD risk modification through maintenance of healthy total cholesterol levels.

scholarly journals Abnormal brain cholesterol homeostasis in Alzheimer’s disease—a targeted metabolomic and transcriptomic study

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Vijay R. Varma ◽  
H. Büşra Lüleci ◽  
Anup M. Oommen ◽  
Sudhir Varma ◽  
Chad T. Blackshear ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Brain Tissue ◽  
Cholesterol Metabolism ◽  
Cholesterol Biosynthesis ◽  
Cholesterol Homeostasis ◽  
Transcriptomic Data ◽  
Brain Cholesterol ◽  
Cholesterol Levels

AbstractThe role of brain cholesterol metabolism in Alzheimer’s disease (AD) remains unclear. Peripheral and brain cholesterol levels are largely independent due to the impermeability of the blood brain barrier (BBB), highlighting the importance of studying the role of brain cholesterol homeostasis in AD. We first tested whether metabolite markers of brain cholesterol biosynthesis and catabolism were altered in AD and associated with AD pathology using linear mixed-effects models in two brain autopsy samples from the Baltimore Longitudinal Study of Aging (BLSA) and the Religious Orders Study (ROS). We next tested whether genetic regulators of brain cholesterol biosynthesis and catabolism were altered in AD using the ANOVA test in publicly available brain tissue transcriptomic datasets. Finally, using regional brain transcriptomic data, we performed genome-scale metabolic network modeling to assess alterations in cholesterol biosynthesis and catabolism reactions in AD. We show that AD is associated with pervasive abnormalities in cholesterol biosynthesis and catabolism. Using transcriptomic data from Parkinson’s disease (PD) brain tissue samples, we found that gene expression alterations identified in AD were not observed in PD, suggesting that these changes may be specific to AD. Our results suggest that reduced de novo cholesterol biosynthesis may occur in response to impaired enzymatic cholesterol catabolism and efflux to maintain brain cholesterol levels in AD. This is accompanied by the accumulation of nonenzymatically generated cytotoxic oxysterols. Our results set the stage for experimental studies to address whether abnormalities in cholesterol metabolism are plausible therapeutic targets in AD.

Pattern and Progression of Cognitive Decline in Alzheimer’s Disease: Role of Premorbid Intelligence and ApoE Genotype

2007 ◽  
Vol 24 (6) ◽  
pp. 483-491 ◽  
Author(s):  
Laura Bracco ◽  
Carolina Piccini ◽  
Michela Baccini ◽  
Valentina Bessi ◽  
Federica Biancucci ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cognitive Decline ◽  
Apoe Genotype ◽  
Premorbid Intelligence

P2-126: THE ROLE OF APOE GENOTYPE, SEX, AND 17β-ESTRADIOL IN MEMORY CONSOLIDATION IN A MOUSE MODEL OF ALZHEIMER'S DISEASE

2006 ◽  
Vol 14 (7S_Part_13) ◽  
pp. P717-P717
Author(s):  
Lisa R. Taxier ◽  
Sarah M. Philippi ◽  
Jason York ◽  
Mary Jo LaDu ◽  
Karyn M. Frick
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Mouse Model ◽  
Memory Consolidation ◽  
Apoe Genotype ◽  
Model Of Alzheimer’S Disease ◽  
17Β Estradiol

Antipsychotic Use and Mortality Risk in Community-Dwelling Alzheimer’s Disease Patients: Evidence for a Role of Dementia Severity

2012 ◽  
Vol 9 (9) ◽  
pp. 1106-1116 ◽  
Author(s):  
Virginie Gardette ◽  
Maryse Lapeyre-Mestre ◽  
Nicola Coley ◽  
Christelle Cantet ◽  
Jean-Louis Montastruc ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Mortality Risk ◽  
Community Dwelling ◽  
Dementia Severity

scholarly journals Interplay Between Microglia and Alzheimer’s Disease—Focus on the Most Relevant Risks: APOE Genotype, Sex and Age

2021 ◽  
Vol 13 ◽  
Author(s):  
Yanting Chen ◽  
Tingting Hong ◽  
Feng Chen ◽  
Yuanhong Sun ◽  
Yan Wang ◽  
...  
Keyword(s):  
Risk Factors ◽  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Synergistic Effects ◽  
Apoe Genotype ◽  
Amyloid Β ◽  
Early Event ◽  
Normal Female ◽  
Brain Physiology

As the main immune cells of the central nervous system (CNS), microglia regulates normal development, homeostasis and general brain physiology. These functions put microglia at the forefront of CNS repair and recovery. Uncontrolled activation of microglia is related to the course of neurodegenerative diseases such as Alzheimer’s disease. It is clear that the classic pathologies of amyloid β (Aβ) and Tau are usually accompanied by the activation of microglia, and the activation of microglia also serves as an early event in the pathogenesis of AD. Therefore, during the occurrence and development of AD, the key susceptibility factors for AD—apolipoprotein E (APOE) genotype, sex and age—may further interact with microglia to exacerbate neurodegeneration. In this review, we discuss the role of microglia in the progression of AD related to the three risk factors for AD: APOE genotype, sex and aging. APOE-expressing microglia accumulates around Aβ plaques, and the presence of APOE4 may disrupt the phagocytosis of Aβ aggregates and aggravate neurodegeneration in Tau disease models. In addition, females have a high incidence of AD, and normal female microglia and estrogen have protective effects under normal conditions. However, under the influence of AD, female microglia seem to lose their protective effect and instead accelerate the course of AD. Aging, another major risk factor, may increase the sensitivity of microglia, leading to the exacerbation of microglial dysfunction in elderly AD. Obviously, in the role of microglia in AD, the three main risk factors of APOE, sex, and aging are not independent and have synergistic effects that contribute to the risk of AD. Moreover, new microglia can replace dysfunctional microglia after microglial depletion, which is a new promising strategy for AD treatment.

scholarly journals Increasing Membrane Cholesterol Level Increases the Amyloidogenic Peptide by Enhancing the Expression of Phospholipase C

2013 ◽  
Vol 2013 ◽  
pp. 1-12 ◽  
Author(s):  
Yoon Sun Chun ◽  
Hyun Geun Oh ◽  
Myoung Kyu Park ◽  
Tae-Wan Kim ◽  
Sungkwon Chung
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Phospholipase C ◽  
Cholesterol Level ◽  
Cholesterol Metabolism ◽  
Membrane Cholesterol ◽  
Neuronal Dysfunction ◽  
Carrier System ◽  
Cholesterol Levels

Cerebral elevation of 42-residue amyloid β-peptide (Aβ42) triggers neuronal dysfunction in Alzheimer's disease (AD). Even though a number of cholesterol modulating agents have been shown to affect Aβ generation, the role of cholesterol in the pathogenesis of AD is not clear yet. Recently, we have shown that increased membrane cholesterol levels downregulates phosphatidylinositol 4,5-bisphosphate (PIP2) via activation of phospholipase C (PLC). In this study, we tested whether membrane cholesterol levels may affect the Aβ42 production via changing PIP2 levels. Increasing membrane cholesterol levels decreased PIP2 and increased secreted Aβ42. Supplying PIP2, by using a PIP2-carrier system, blocked the effect of cholesterol on Aβ42. We also found that cholesterol increased the expressions of β1 and β3 PLC isoforms (PLCβ1, PLCβ3). Silencing the expression of PLCβ1 prevented the effects of cholesterol on PIP2 levels as well as on Aβ42 production, suggesting that increased membrane cholesterol levels increased secreted Aβ42 by downregulating PIP2 via enhancing the expression of PLCβ1. Thus, cholesterol metabolism may be linked to Aβ42 levels via PLCβ1 expression and subsequent changes in PIP2 metabolism.

Sign in / Sign up

Export Citation Format

Share Document