Association of Early-Onset Alzheimer Disease With Elevated Low-Density Lipoprotein Cholesterol Levels and Rare Genetic Coding Variants of <i>APOB</i>

Wingo, Thomas S.; Cutler, David J.; Le, Ngoc‐Anh; Rabinovici, Gil D.; Miller, Bruce L.; Lah, James J.; Levey, Aĺlan I.

doi:10.1001/jamaneurol.2019.0648

Cited by 103 publications

(88 citation statements)

References 47 publications

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“…However, whether elevated LDL-c level is related to the risk of AD remains unconfirmed. Several studies reported that patients with AD exhibited higher level of LDL-c when compared with normal controls (Lesser et al, 2009;Wingo et al, 2019). In contrast, some of the studies detected no significant difference in LDL-c level between AD patients and healthy controls (Davidson et al, 2012;Li et al, 2017).…”

Section: Introductionmentioning

confidence: 99%

Low-Density Lipoprotein Cholesterol and Alzheimer's Disease: A Systematic Review and Meta-Analysis

Zhou

Liang

Zhang

et al. 2020

Front. Aging Neurosci.

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Objective: To assess the association between low-density lipoprotein cholesterol (LDL-c) and risk of Alzheimer's disease (AD).Methods: Embase, Pubmed, and Web of Science were searched until June 2019. Standard mean difference (SMD) with 95% confidence intervals (CI) was estimated using random-effects models.Results: Our meta-analysis of 26 studies revealed higher levels of LDL-c in AD than that of non-dementia controls (SMD = 0.35, 95% CI 0.12-0.58, p < 0.01). The meta-regression analysis on confounders showed that age (p < 0.01, Adj R-squared = 92.41%) and cardiovascular disease (p = 0.01, Adj R-squared = 85.21%), but not the body mass index, education, smoking, hypertension and diabetes mellitus, exerted an impact on the relationship between LDL-c and risk of ICH. Further subgroup analysis of age showed LDL-c levels in AD patients aged 60-70 were higher than that of non-dementia (60 ≤ age < 70: SMD = 0.80, 95% CI 0.23-1.37, p < 0.01); but no association between the SMD of AD in LDL-c and age over 70 was noted across the studies (70 ≤ age < 77: SMD = −0.02, 95% CI −0.39∼0.34, p = 9.0; 77 ≤ age < 80: SMD = 0.15, 95% CI −0.17∼0.47, p = 0.35; ≥80: SMD = 0.53, 95% CI −0.04∼1.11, p = 0.07). The concentrations of LDL-c during the quintile interval of 3∼4 were positively associated with AD (121 ≤ concentration < 137: SMD = 0.98, 95% CI 0.13∼1.82, p = 0.02; ≥137: SMD = 0.62, 95% CI 0.18∼1.06, p < 0.01); whereas there was no correlation between AD and LDL-c within the quintile interval of 1∼2 (103.9 ≤ concentration < 112: SMD = 0.08, 95% CI −0.20∼0.35, p = 0.59; 112 ≤ concentration < 121: SMD = −0.26, 95% CI −0.58∼0.06, p = 0.11). Conclusions: Elevated concentration of LDL-c (>121 mg/dl) may be a potential risk factor for AD. This association is strong in patients aged 60-70 years, but vanishes with advancing age.

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Section: Introductionmentioning

confidence: 99%

Low-Density Lipoprotein Cholesterol and Alzheimer's Disease: A Systematic Review and Meta-Analysis

Zhou

Liang

Zhang

et al. 2020

Front. Aging Neurosci.

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“…Collectively, these data provided evidences that ApoB and APOEε4 status may contribute to the changes of CSF AD core biomarkers, independently of each other. However, a recent study found that rare genetic coding variants of APOB gene were strongly associated with familial AD, which indicated that APOB gene might also harbor protective and deleterious variants in sporadic AD similar to the APOEε2 and APOEε4 alleles (35). Identifying such a protective coding variant of APOB gene would greatly strengthen the link between ApoB and AD pathogenesis.…”

Section: Discussionmentioning

confidence: 99%

Association of serum apolipoprotein B with cerebrospinal fluid biomarkers of Alzheimer’s disease pathology in elderly adults with subjective cognitive decline

Tan

et al. 2020

Preprint

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Background: The preclinical stage of Alzheimer's disease (AD) has become a key target stage for future AD prevention trials. Serum apolipoprotein, an important lipid-related factor, has been found to be involved in the pathogenesis of AD. This study was to examine whether apolipoprotein B (ApoB), apolipoprotein A-1 (ApoA1) or the ratio of ApoB and ApoA1 (ApoB/A1) were associated with early changes of cerebrospinal fluid (CSF) AD biomarkers in elderly adults with subjective cognitive decline.Methods: This study included 201 cognitive normal (CN) elderly adults and 101 participants with subjective cognitive decline (SCD) from the Chinese Alzheimer’s Biomarker and LifestylE (CABLE) database. The Kruskall-Wallis test and Chisquare test were applied in the intergroup comparisons. Multiple linear regression models were used to examine the cross-sectional associations of serum ApoB, ApoA1 and ApoB/A1 levels with CSF AD-related biomarkers.Results: Compared with the control group, SCD participants with significant AD biological characteristics had lower ApoB levels. In the total participants, higher level of serum ApoB was associated with increases in CSF Aβ42 (p = 0.0009) and Aβ42/40 (p = 0.0038) as well as decreases in CSF t-tau/Aβ42 (p < 0.0001) and p-tau/Aβ42 (p < 0.0001), independent of APOEɛ4 status. In the further subgroup analysis, these associations were much more significant in the SCD participants. In addition, higher levels of serum ApoB were also found associated with decreases in CSF t-tau (p = 0.0224), p-tau (p = 0.0086) and Aβ40 (p = 0.0297) in the SCD subgroup. Furthermore, we found that these protective associations between serum ApoB and CSF AD core biomarkers were much more significant in the overweight participants. Results showed no association between ApoA1 and all CSF biomarkers in either total participants or subgroups. Conclusions: This study is the first to find protective associations of serum ApoB, but not ApoA1, with CSF AD core biomarkers in elderly adults, and these associations were more significant in SCD individuals. This finding indicated that ApoB may play a protective role in the preclinical stage of AD. Identifying the underlying mechanisms may contribute to the discovery of new pathogenic mechanisms and therapeutic targets.

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“…High total and low-density-lipoprotein cholesterol (LDL-C) levels during midlife were most consistently associated with chances of future dementia [ 96 ]. A recent study reported that early-onset AD patients have high LDL-C levels and 3% of them harbor rare variants in the APOB gene [ 97 ], providing both epidemiological and biological links between aberrant cholesterol metabolism and AD. Furthermore, hypercholesterolemia associated with a heavier burden of AD pathology and cerebral amyloid angiopathy in autoptic cases [ 98 ], while animal models of AD showed worsening of Aβ accumulation and cognitive deficits upon diet-induced hypercholesterolemia [ 99 ].…”

Section: Roles Of Diet and Microbiota In Neurodegenerative Diseasementioning

confidence: 99%

Diet, Microbiota and Brain Health: Unraveling the Network Intersecting Metabolism and Neurodegeneration

Gentile

Doneddu

Riva

et al. 2020

IJMS

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Increasing evidence gives support for the idea that extra-neuronal factors may affect brain physiology and its predisposition to neurodegenerative diseases. Epidemiological and experimental studies show that nutrition and metabolic disorders such as obesity and type 2 diabetes increase the risk of Alzheimer’s and Parkinson’s diseases after midlife, while the relationship with amyotrophic lateral sclerosis is uncertain, but suggests a protective effect of features of metabolic syndrome. The microbiota has recently emerged as a novel factor engaging strong interactions with neurons and glia, deeply affecting their function and behavior in these diseases. In particular, recent evidence suggested that gut microbes are involved in the seeding of prion-like proteins and their spreading to the central nervous system. Here, we present a comprehensive review of the impact of metabolism, diet and microbiota in neurodegeneration, by affecting simultaneously several aspects of health regarding energy metabolism, immune system and neuronal function. Advancing technologies may allow researchers in the future to improve investigations in these fields, allowing the buildup of population-based preventive interventions and development of targeted therapeutics to halt progressive neurologic disability.

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Association of Early-Onset Alzheimer Disease With Elevated Low-Density Lipoprotein Cholesterol Levels and Rare Genetic Coding Variants of APOB

Cited by 103 publications

References 47 publications

Low-Density Lipoprotein Cholesterol and Alzheimer's Disease: A Systematic Review and Meta-Analysis

Low-Density Lipoprotein Cholesterol and Alzheimer's Disease: A Systematic Review and Meta-Analysis

Association of serum apolipoprotein B with cerebrospinal fluid biomarkers of Alzheimer’s disease pathology in elderly adults with subjective cognitive decline

Diet, Microbiota and Brain Health: Unraveling the Network Intersecting Metabolism and Neurodegeneration

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