Effect of apolipoprotein E ε4 allele on the progression of cognitive decline in the early stage of Alzheimer's disease

Background: Apolipoprotein E (APOE) ε4 is highly associated with mild cognitive impairment (MCI). However, the specific influence of APOE ε4 status on tau pathology and cognitive decline in early MCI (EMCI) and late MCI (LMCI) is poorly understood. Our goal was to evaluate the association of APOE ε4 with cerebrospinal fluid (CSF) tau levels and cognition in EMCI and LMCI patients in the Alzheimer’s Disease Neuroimaging Initiative database, and whether this association was mediated by amyloid-β (Aβ). Methods: Participants were 269 cognitively normal (CN), 262 EMCI, and 344 LMCI patients. They underwent CSF Aβ42 and tau detection, APOE ε4 genotyping, Mini-Mental State Examination, (MMSE), and Alzheimer’s disease assessment scale (ADAS)-cog assessments. Linear regressions were used to examine the relation of APOE ε4 and CSF tau levels and cognitive scores in persons with and without Aβ deposition (Aβ+ and Aβ−). Results: The prevalence of APOE ε4 is higher in EMCI and LMCI than in CN (p < 0.001 for both), and in LMCI than in EMCI (p = 0.001). APOE ε4 allele was significantly higher in Aβ+ subjects than in Aβ− subjects (p < 0.001). Subjects who had a lower CSF Aβ42 level and were APOE ε4-positive experienced higher levels of CSF tau and cognitive scores in EMCI and/or LMCI. Conclusions: An APOE ε4 allele is associated with increased CSF tau and worse cognition in both EMCI and LMCI, and this association may be mediated by Aβ. We conclude that APOE ε4 may be an important mediator of tau pathology and cognition in the early stages of AD.

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Apolipoprotein E and cognitive decline in Alzheimer's disease

Neurology ◽

10.1212/wnl.47.2.317 ◽

1996 ◽

Vol 47 (2) ◽

pp. 317-320 ◽

Cited By ~ 20

Author(s):

B. L. Plassman ◽

J. C.S. Breitner

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Cognitive Decline ◽

Apolipoprotein E

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Association of Subjective Hearing Loss and Apolipoprotein E ε4 Allele on Alzheimer's Disease Neurodegeneration

Otology & Neurotology ◽

10.1097/mao.0000000000002855 ◽

2020 ◽

Vol Publish Ahead of Print ◽

Author(s):

Ryan M. Neff ◽

Gregory Jicha ◽

Gregory S. Hawk ◽

Matthew L. Bush ◽

Beth McNulty

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Hearing Loss ◽

Apolipoprotein E ◽

Ε4 Allele

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Reduced Hippocampal Insulin-Degrading Enzyme in Late-Onset Alzheimer's Disease Is Associated with the Apolipoprotein E-ε4 Allele

American Journal Of Pathology ◽

10.1016/s0002-9440(10)63822-9 ◽

2003 ◽

Vol 162 (1) ◽

pp. 313-319 ◽

Cited By ~ 213

Author(s):

David G. Cook ◽

James B. Leverenz ◽

Pamela J. McMillan ◽

J. Jacob Kulstad ◽

Sasha Ericksen ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Apolipoprotein E ◽

Late Onset ◽

Insulin Degrading Enzyme ◽

Degrading Enzyme ◽

Ε4 Allele

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Genetic Effects on Longitudinal Cognitive Decline During the Early Stages of Alzheimer's Disease

10.21203/rs.3.rs-149163/v1 ◽

2021 ◽

Author(s):

Atul Kumar ◽

Maryam Shoai ◽

Sebastian Palmqvist ◽

Erik Stomrud ◽

John Hardy ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Cognitive Decline ◽

Genome Wide Association Study ◽

Early Stage ◽

Cognitive Change ◽

Preclinical Ad ◽

Genome Wide ◽

A Genome ◽

Polygenic Scores

Abstract Background Cognitive decline in early-stage Alzheimer’s disease (AD) may depend on genetic variability. Methods In the Swedish BioFINDER study, we used polygenic scores (PGS) (for AD, intelligence and educational attainment), and genetic variants (in a genome-wide association study [GWAS]) to predict longitudinal cognitive change (measured by MMSE) over a mean of 4.2 years. We included 555 β-amyloid (Aβ) negative cognitively unimpaired (CU) individuals, 206 Aβ-positive CU (preclinical AD), 110 Aβ-negative mild cognitive impairment (MCI) patients, and 146 Aβ-positive MCI patients (prodromal AD). Results Polygenic scores for AD (in Aβ-positive individuals) and intelligence (independent of Aβ-status) were associated with cognitive decline. Eight genes were associated with cognitive decline in GWAS (3 independent of Aβ-status). Conclusions AD risk genes may influence cognitive decline in early AD, while genes related to intelligence may modulate cognitive decline irrespective of disease. Therapies targeting the implicated biological pathways may modulate the clinical course of AD.

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A Strategy for Identifying the Risk of Developing Alzheimer's Disease From Healthy Controls: Distance to Novelty Detection Boundary

10.21203/rs.3.rs-129454/v1 ◽

2020 ◽

Author(s):

Jiangbing Mao ◽

Qinyong Ye ◽

Hongqing Yang ◽

Magda Bucholc ◽

Shuo Liu ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Cognitive Impairment ◽

Cognitive Decline ◽

Early Stage ◽

Novelty Detection ◽

Imaging Biomarkers ◽

Support Vector ◽

Support Vector Data Description ◽

Healthy Controls

Abstract Background:Machine learning (ML) techniques are expected to tackle the problem of the high prevalence of Alzheimer’s disease (AD) we are facing worldwide. However, few studies of novelty detection (ND), a typical ML technique for safety-critical systems especially in healthcare, were engaged for identifying the risk of developing cognitive impairment from healthy controls (HC) population.Materials and Methods: Two independent datasets were used for this study, including the Australian Imaging Biomarkers and Lifestyle Study of Ageing (AIBL) and the Fujian Medical University Union Hospital (FMUUH), China datasets. Multiple feature selection methods were applied to identify the most relevant features for predicting the severity of AD. Four easily interpretable ND algorithms, including k nearest neighbor, Mixture of Gaussian (MoG), KMEANS, and support vector data description were used to construct predictive models. The models were visualized by drawing their decision boundaries tightly surrounding the HC data. A distance to boundary (DtB) strategy was proposed to differentiate individuals with mild cognitive impairment (MCI) and AD from HC. Results: The best overall MCI&AD detection performance in both AIBL and FMUUH was obtained on the cognitive and functional assessments (CFA) modality only using MoG-based ND with AUC of 0.8757 and 0.9443, respectively. The highest sensitivity of MCI was presented by using a combination of CFA and brain imaging modality. The DTB value reflects the risk of developing cognitive impairment for HC and the dementia severity of MCI/AD.Conclusions: Our findings suggest that applying some non-invasive and cost-effective features can significantly detect cognitive decline in an early stage. The visualized decision boundary and the proposed DtB strategy illustrated the severity of cognitive decline of potential MCI&AD patients in an early stage. The results would help inform future guidelines for developing a clinical decision-making support system aiming at an early diagnosis and prognosis of MCI&AD.

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A-5 Examining the Interactive Effects of Traumatic Brain Injury and Apolipoprotein E on Cognitive Decline in Alzheimer’s Disease

Archives of Clinical Neuropsychology ◽

10.1093/arclin/acab062.23 ◽

2021 ◽

Vol 36 (6) ◽

pp. 1044-1044

Author(s):

Claire Alexander ◽

Julie Suhr

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Cognitive Decline ◽

Apolipoprotein E ◽

Negative Impact ◽

Interactive Effects ◽

Decline Rate ◽

History Of ◽

Positive Effect

Abstract Objective Little research has focused on possible effects of TBI on cognitive decline rate after Alzheimer’s disease (ad) diagnosis. We examined whether Apolipoprotein E (APOE) status and TBI history interact to predict cognitive decline. Method We used data from the National Alzheimer’s Coordinating Centers (N = 463; 42.3% APOE e4 carriers, 7.8% with TBI history, mean baseline age 79.3). Inclusion criteria included normal cognition at baseline with diagnosis of ad at a follow-up visit; baseline age 50 or older; and at least 3 years of follow-up data. Mixed models (random intercept, random slope) were used, with TBI history, APOE status, and their interaction as predictors of interest. Education, race, and history of TIA, stroke, or hypertension were included as covariates. Cognitive measures included mental status exam scores and immediate/delayed story memory. Results After accounting for covariates, TBI history had a positive effect on cognitive decline rate on the screener and immediate memory measures. APOE status did not affect rate of cognitive decline on the screener, but presence of e4 predicted faster decline on immediate and delayed memory. TBI history and APOE status interacted to predict delayed memory decline, such that history of TBI was associated with a reduced rate of decline for e4 non-carriers but there was no effect of TBI for e4 carriers. Conclusion When examining cognitive decline trajectory, TBI history predicted slower decline (a positive effect) while APOE had either a negative impact or no effect, depending on the measure. Future study should examine cognitive decline in the context of demographic and genetic factors.

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Apolipoprotein E ε4/4 genotype limits response to dietary induction of hyperhomocysteinemia and resulting inflammatory signaling

Journal of Cerebral Blood Flow & Metabolism ◽

10.1177/0271678x211069006 ◽

2022 ◽

pp. 0271678X2110690

Author(s):

Charles E Seaks ◽

Erica M Weekman ◽

Tiffany L Sudduth ◽

Kevin Xie ◽

Brandi Wasek ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Risk Factor ◽

Apolipoprotein E ◽

Late Onset ◽

Apoe Ε4 ◽

Perivascular Inflammation ◽

Ε4 Allele ◽

Barrier Breakdown ◽

The Impact

Vascular contributions to cognitive impairment and dementia (VCID) are the second leading cause of dementia behind Alzheimer’s disease. Apolipoprotein E (ApoE) is a lipid transporting lipoprotein found within the brain and periphery. The APOE ε4 allele is the strongest genetic risk factor for late onset Alzheimer’s disease and is a risk factor for VCID. Our lab has previously utilized a dietary model of hyperhomocysteinemia (HHcy) to induce VCID pathology and cognitive deficits in mice. This diet induces perivascular inflammation through cumulative oxidative damage leading to glial mediated inflammation and blood brain barrier breakdown. Here, we examine the impact of ApoE ε4 compared to ε3 alleles on the progression of VCID pathology and inflammation in our dietary model of HHcy. We report a significant resistance to HHcy induction in ε4 mice, accompanied by a number of related differences related to homocysteine (Hcy) metabolism and methylation cycle, or 1-C, metabolites. There were also significant differences in inflammatory profiles between ε3 and ε4 mice, as well as significant reduction in Serpina3n, a serine protease inhibitor associated with ApoE ε4, expression in ε4 HHcy mice relative to ε4 controls. Finally, we find evidence of pervasive sex differences within both genotypes in response to HHcy induction.

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