scholarly journals Segmented Linear Mixed Model Analysis Reveals Association of the APOE ɛ4 Allele with Faster Rate of Alzheimer’s Disease Dementia Progression

2021 ◽  
pp. 1-17
Author(s):  
X. Richard Chen ◽  
Yongzhao Shao ◽  
Martin J. Sadowski ◽  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Mixed Model ◽  
Linear Mixed Model ◽  
Late Onset ◽  
Apoe Genotype ◽  
Middle Temporal Gyrus ◽  
Mixed Model Analysis ◽  
Increased Risk ◽  
E4 Allele

Background: APOE ɛ4 allele carriers present with increased risk for late-onset Alzheimer’s disease (AD), show cognitive symptoms at earlier age, and are more likely to transition from mild cognitive impairment (MCI) to dementia but despite this, it remains unclear whether or not the ɛ4 allele controls the rate of disease progression. Objective: To determine effects of the ɛ4 allele on rates of cognitive decline and brain atrophy during MCI and dementia stages of AD. Methods: A segmented linear mixed model was chosen for longitudinal modeling of cognitive and brain volumetric data of 73 ɛ3/ɛ3, 99 ɛ3/ɛ4, and 39 ɛ4/ɛ4 Alzheimer’s Disease Neuroimaging Initiative participants who transitioned during the study from MCI to AD dementia. Results: ɛ4 carriers showed faster decline on MMSE, ADAS-11, CDR-SB, and MoCA scales, with the last two measures showing significant ɛ4 allele-dose effects after dementia transition but not during MCI. The ɛ4 effect was more prevalent in younger participants and in females. ɛ4 carriers also demonstrated faster rates of atrophy of the whole brain, the hippocampus, the entorhinal cortex, the middle temporal gyrus, and expansion of the ventricles after transitioning to dementia but not during MCI. Conclusion: Possession of the ɛ4 allele is associated with a faster progression of dementia due to AD. Our observations support the notion that APOE genotype not only controls AD risk but also differentially regulates mechanisms of neurodegeneration underlying disease advancement. Furthermore, our findings carry significance for AD clinical trial design.

ACE I/D polymorphism in Alzheimer’s disease

2008 ◽  
Vol 3 (1) ◽  
pp. 49-54
Author(s):  
Marianna Trebunova ◽  
Eva Slaba ◽  
Viera Habalova ◽  
Zuzana Gdovinova
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Interaction Analysis ◽  
Neurological Diseases ◽  
Apoe Genotype ◽  
Gene Interaction ◽  
Genotype Distribution ◽  
Ace Gene ◽  
Increased Risk ◽  
E4 Allele

AbstractAngiotensin-converting enzyme (ACE) has been reported to show altered activity in patients with neurological diseases. The recent studies found that a 287 bp insertion/deletion (I/D) polymorphism of the ACE gene may be associated with susceptibility to Alzheimer’s disease (AD) but the results have been heterogenous between studies in Europe. In the present study we examined for the first time the association of ACE I/D polymorphism along with APOE genotype in 70 sporadic AD and 126 control subjects in Slovak Caucasians (Central Europe). An increased risk for AD was observed in subjects with at least one APOE*E4 allele (OR=3.99, 95% CI=1.97–8.08). No significant differences for the genotype distribution or the allele frequency were revealed comparing controls and patients for ACE gene. Gene-gene interaction analysis showed increase of the risk to develop AD in subjects carrying both the ACE DD genotype and the APOE*E4 allele (OR=10.32, 95% C.I. 2.67–39.81).

scholarly journals Steady-state cerebral autoregulation in older adults with amnestic mild cognitive impairment: linear mixed model analysis

2020 ◽  
Vol 129 (2) ◽  
pp. 377-385
Author(s):  
Li Zhang ◽  
Evan P. Pasha ◽  
Jie Liu ◽  
Chang-Yang Xing ◽  
Danilo Cardim ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cognitive Impairment ◽  
Mild Cognitive Impairment ◽  
Cerebral Autoregulation ◽  
Mixed Model ◽  
Linear Mixed Model ◽  
Amnestic Mild Cognitive Impairment ◽  
Pathophysiological Mechanism ◽  
Mixed Model Analysis

Cerebral autoregulation is a fundamental regulatory mechanism to protect brain perfusion against changes in blood pressure that, if impaired, may contribute to the development of Alzheimer’s disease. Using a linear mixed model, we demonstrated that the efficacy of cerebral autoregulation, assessed during stepwise changes in arterial pressure, was reduced in individuals with amnestic mild cognitive impairment, a prodromal stage of Alzheimer’s disease. These findings support the hypothesis that cerebrovascular dysfunction may be an important underlying pathophysiological mechanism for the development of clinical Alzheimer’s disease.

Apolipoprotein E Genotype and its Effect on Duration and Severity of Early and Late Onset Alzheimer's Disease

1995 ◽  
Vol 167 (4) ◽  
pp. 533-536 ◽  
Author(s):  
Jennie Norrman ◽  
Anthony J. Brookes ◽  
Celia Yates ◽  
David St Clair
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Apolipoprotein E ◽  
Late Onset ◽  
Apoe Genotype ◽  
Increased Risk ◽  
Apolipoprotein E Genotype

BackgroundThe apolipoprotein E (ApoE) ∊4 allele is associated with an increased risk of senile and probably presenile Alzheimer's disease. It is not yet clear whether the ∊4 allele also influences the duration/rate of progress of illness and the severity of the dementia.MethodWe have retrospectively examined a series of ApoE genotyped presenile and senile autopsy cases of Alzheimer's disease (AD) for length of illness and severity of pathology.ResultsWe find no evidence that ApoE genotype affects the rate of progress of AD, but the degree of pathology at death may be increased.ConclusionIt appears that the rate of progress of AD as a whole is independent of the ApoE genotype.

The Association of Essential Metals with APOE Genotype in Alzheimer’s Disease

2021 ◽  
pp. 1-12
Author(s):  
Mirjana Babić Leko ◽  
Jasna Jurasović ◽  
Matea Nikolac Perković ◽  
Ena Španić ◽  
Ankica Sekovanić ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Plasma Levels ◽  
Late Onset ◽  
Apoe Genotype ◽  
Plasma Sodium ◽  
Essential Metals ◽  
E4 Allele

Background: The major confirmed genetic risk factor for late-onset, sporadic Alzheimer’s disease (AD) is variant ɛ4 of apolipoprotein E gene (APOE). It is proposed that ApoE, a protein involved in transport of cholesterol to neurons can cause neurodegeneration in AD through interaction with metals. Previous studies mostly associated copper, iron, zinc, and calcium with ApoE4-mediated toxicity. Objective: To test the association of essential metals with APOE genotype. Methods: We compared plasma and cerebrospinal fluid (CSF) levels of copper, zinc, iron, sodium, magnesium, calcium, cobalt, molybdenum, manganese, boron, and chromium, and CSF ferritin levels among AD, mild cognitive impairment (MCI) patients, and healthy controls (HC) with different APOE genotype. Results: Sodium, copper, and magnesium levels were increased in carriers of ɛ4 allele. Additionally, the increase in sodium, calcium and cobalt plasma levels was observed in carriers of ɛ4/ɛx genotype. The decrease in boron plasma levels was observed in carriers of ɛ4 allele and ɛ4/ɛ4 genotype. Additionally, CSF zinc levels as well as plasma sodium levels were increased in AD patients compared to HC. Conclusion: These results indicate that the molecular underpinnings of association of essential metals and metalloids with APOE should be further tested and clarified in vivo and in vitro.

Associations of APOE e2 genotype with cerebrovascular pathology: a postmortem study of 1275 brains

2020 ◽  
Vol 92 (1) ◽  
pp. 7-11 ◽  
Author(s):  
Terry E Goldberg ◽  
Edward D Huey ◽  
Davangere P Devanand
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Genetic Variant ◽  
Apoe Genotype ◽  
Amyloid Plaques ◽  
Amyloid Angiopathy ◽  
Protective Effects ◽  
Comprehensive Investigation ◽  
Increased Risk ◽  
E4 Allele

ObjectiveWe assessed the association of apolipoprotein E (APOE) genotype with cerebrovascular disease (CVD) in a large neuropathological database maintained by the National Alzheimer’s Coordinating Center (NACC). Such a comprehensive investigation of APOE and CVD pathology has not heretofore been conducted. We focused on APOE e2, an established neuroprotective genetic variant against Alzheimer’s disease.MethodsTo implement these objectives APOE associations in the NACC database of 1275 brains with 11 CVD pathologies, including old and recent infarcts, haemorrhages, cerebral amyloid angiopathy (CAA) and arteriosclerosis, were examined. These pathologies were uniformly and semiquantitatively measured across 39 Alzheimer’s Disease Center sites. We used χ2 statistics and ordinal regression to assess the significance of associations and Bonferroni corrected for multiple comparisons.ResultsOf the cases, 98 were e2/e3 or e2/e2 genotypes (‘e2’ carriers), 621 were e3 homozygotes (‘e3’ group), and 556 were e4/e3 (442) or e4/e4 (114) genotypes (‘e4’ group). Results indicated that the APOE e4 allele significantly increased risk for CAA. After stratification by CAA presence/absence, we found that in those cases in which CAA was present, APOE e2 significantly increased risk for gross haemorrhage. All other associations were negative.ConclusionsIn this, the largest study of APOE e2 effects on pathologically verified CVD, e2 was not protective against any CVD pathology compared with e3 homozygotes, including CAA. Regarding the latter pathology, e4 was associated with increases in its severity. Furthermore, and perhaps unexpectedly, e2 significantly increased risk of acute/subacute gross haemorrhage in the presence of CAA. Thus, there were limits to e2 neuroprotection against amyloidosis, despite its known and large protective effects against diffuse and neuritic amyloid plaques compared with e3/e3 and e4 carriers in this very collection.

scholarly journals APOE missense variant R145C is associated with increased Alzheimer's disease risk in African ancestry individuals with the APOE ϵ3/ϵ4 genotype

2021 ◽  
Author(s):  
Yann Le Guen ◽  
Michael E Belloy ◽  
Sarah J Eger ◽  
Annabel Chen ◽  
Gabriel Kennedy ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Mixed Model ◽  
Linear Mixed Model ◽  
African Ancestry ◽  
Age At Onset ◽  
Missense Variant ◽  
Competing Risk ◽  
Next Generation Sequencing Data ◽  
Increased Risk

BACKGROUND The APOE gene has two common missense variants that greatly impact the risk of late-onset Alzheimer's disease (AD). Here we examined the risk of a third APOE missense variant, R145C, that is rare in European-Americans but present in 4% of African-Americans and always in phase with APOE ϵ3. METHODS In this study, we included 11,790 individuals of African and Admixed-African ancestry (4,089 cases and 7,701 controls). The discovery sample was composed of next generation sequencing data (2,888 cases and 4,957 controls), and the replication was composed of microarray data imputed on the TOPMed reference panel (1,201 cases and 2,744 contols). To assess the effect of R145C independently of the ϵ2 and ϵ4 alleles, we performed stratified analyses in ϵ2/ϵ3, ϵ3/ϵ3, and ϵ3/ϵ4 subjects. In primary analyses, the AD risk associated with R145C was estimated using a linear mixed model regression on case-control diagnosis. In secondary analyses, we estimated the influence of R145C on age-at-onset using linear-mixed-model regression, and risk of conversion to AD using competing risk regression. RESULTS In ϵ3/ϵ4-stratified meta-analyses, R145C carriers had an almost three-fold increased risk compared to non-carriers (odds ratio, 2.75; 95% confidence interval [CI], 1.84 to 4.11; P = 8.3x10-7) and had a reported AD age-at-onset almost 6 years younger (β, -5.72; 95% CI, 7.87 to -3.56; P = 2.0x10-7). Competing risk regression showed that the cumulative incidence of AD grows faster with age in R145C carriers compared to non-carriers (hazard ratio, 2.42, 95% CI, 1.81 to 3.25; P = 3.7x10-9). CONCLUSION The R145C variant is a potent risk factor for AD among African ancestry individuals with the ϵ3/ϵ4 genotype. Our findings should enhance AD risk prediction in African ancestry individuals and help elucidate the mechanisms linking the apoE protein to AD pathogenesis. The findings also add to the growing body of evidence demonstrating the importance of including ancestrally-diverse populations in genetic studies.

Race-Related Association between APOE Genotype and Alzheimer’s Disease: A Systematic Review and Meta-Analysis

2021 ◽  
pp. 1-10
Author(s):  
Wei Qin ◽  
Wenwen Li ◽  
Qi Wang ◽  
Min Gong ◽  
Tingting Li ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Black People ◽  
Late Onset ◽  
Meta Analysis ◽  
Group Analysis ◽  
Apoe Genotype ◽  
Cochrane Library ◽  
Data Sets ◽  
Apoe Genotypes

Background: The global race-dependent association of Alzheimer’s disease (AD) and apolipoprotein E (APOE) genotype is not well understood. Transethnic analysis of APOE could clarify the role of genetics in AD risk across populations. Objective: This study aims to determine how race and APOE genotype affect the risks for AD. Methods: We performed a systematic search of PubMed, Embase, Web of Science, and the Cochrane Library since 1993 to Aug 25, 2020. A total of 10,395 reports were identified, and 133 were eligible for analysis with data on 77,402 participants. Studies contained AD clinical diagnostic and APOE genotype data. Homogeneous data sets were pooled in case-control analyses. Odds ratios and 95% confidence intervals for developing AD were calculated for populations of different races and APOE genotypes. Results: The proportion of APOE genotypes and alleles differed between populations of different races. Results showed that APOE ɛ4 was a risk factor for AD, whereas APOE ɛ2 protected against it. The effects of APOE ɛ4 and ɛ2 on AD risk were distinct in various races, they were substantially attenuated among Black people. Sub-group analysis found a higher frequency of APOE ɛ4/ɛ4 and lower frequency of APOE ɛ3/ɛ3 among early-onset AD than late-onset AD in a combined group and different races. Conclusion: Our meta-analysis suggests that the association of APOE genotypes and AD differ between races. These results enhance our understanding of APOE-related risk for AD across race backgrounds and provide new insights into precision medicine for AD.

scholarly journals Could Altered Evoked Pain Responsiveness Be a Phenotypic Biomarker for Alzheimer’s Disease Risk? A Cross-Sectional Analysis of Cognitively Healthy Individuals

2020 ◽  
pp. 1-7
Author(s):  
Raymond R. Romano ◽  
Michael A. Carter ◽  
Mary S. Dietrich ◽  
Ronald L. Cowan ◽  
Stephen P. Bruehl ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Healthy Subjects ◽  
Pain Sensitivity ◽  
Late Onset ◽  
Thermal Pain ◽  
Apoe4 Allele ◽  
Increased Risk ◽  
Pain Stimuli ◽  
Experimentally Induced

Background: This study evaluated whether the apolipoprotein ɛ4 (APOE4) allele, a genetic marker associated with increased risk of developing late-onset Alzheimer’s disease (AD), was associated with differences in evoked pain responsiveness in cognitively healthy subjects. Objective: The aim was to determine whether individuals at increased risk of late-onset AD based on APOE allele genotype differ phenotypically in their response to experimentally-induced painful stimuli compared to those who do not have at least one copy of the ɛ4 allele. Methods: Forty-nine cognitively healthy subjects aged 30–89 years old with the APOE4 allele (n = 12) and without (n = 37) were assessed for group differences in pain thresholds and affective (unpleasantness) responses to experimentally-induced thermal pain stimuli. Results: Statistically significant main effects of APOE4 status were observed for both the temperature at which three different pain intensity percepts were reached (p = 0.040) and the level of unpleasantness associated with each (p = 0.014). APOE4 positive participants displayed lower overall pain sensitivity than those who were APOE4 negative and also greater overall levels of pain unpleasantness regardless of intensity level. Conclusion: Cognitively healthy APOE4 carriers at increased risk of late-onset AD demonstrated reduced thermal pain sensitivity but greater unpleasantness to thermal pain stimuli relative to individuals at lower risk of late-onset AD. These results suggest that altered evoked pain perception could potentially be used as a phenotypic biomarker of late-onset AD risk prior to disease onset. Additional studies of this issue may be warranted.

scholarly journals Late Onset Alzheimer Dementia in Patients with Genotype E3/E4: A Case Report

2021 ◽  
Vol 9 (C) ◽  
pp. 5-9
Author(s):  
Anak Agung Ayu Putri Laksmidewi ◽  
Chiquita Putri Vania Rau
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Case Report ◽  
Mini Mental State Examination ◽  
Late Onset ◽  
Apoe Genotype ◽  
Time Orientation ◽  
Alzheimer Dementia ◽  
The Family ◽  
State Examination

BACKGROUND: Dementia is one of the leading causes of disability and dependence in elderly worldwide. Epidemiological statistics indicate that data show that at about 60–80%, Alzheimer’s is the most common type of dementia. Alzheimer’s is also the third-most prominent cause of death in elderly. CASE REPORT: A 72-years-old male patient, complained by the family often forgets about things that have just been done for 3 years ago. According to the family, patient also often discussing the same things repeatedly. Patients tend not to have the initiative to start his daily activities. The family admitted that patient also became often angry and felt suspicious for the last 2 years. From the mini mental state examination showed disturbances in time orientation and recall; from Montreal Cognitive Assessment Ina found disturbances in visuospatial, fluency, abstraction, delayed memory, and time orientation; accompanied by activities of daily living (ADL) and instrumental ADL disorders. Patient also performed a molecular examination of the apolipoprotein E (APOE) genotype and the genotype E3/E4 was detected. CONCLUSION: The function of the APOE gene, in particular APOE4, is the most emphasized genetic relationship in late onset Alzheimer’s disease. It is proposed that blocking the action of APOE4 can delay or stop Alzheimer’s disease progression.

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