scholarly journals Alzheimer’s disease susceptibility gene apolipoprotein e (APOE) and blood biomarkers in UK Biobank (N=395,769)

2020 ◽  
Author(s):  
Amy C. Ferguson ◽  
Rachana Tank ◽  
Laura M. Lyall ◽  
Joey Ward ◽  
Carlos Celis-Morales ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Risk Factor ◽  
Apolipoprotein E ◽  
Genetic Risk ◽  
Susceptibility Gene ◽  
Density Lipoprotein ◽  
European Ancestry ◽  
Uk Biobank ◽  
Blood Biomarkers

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.

scholarly journals ApoE4 attenuates cortical neuronal activity and impairs memory in young apoE4 rats

2021 ◽  
Author(s):  
Ilona Har-Paz ◽  
Elor Arieli ◽  
Anan Moran
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Risk Factor ◽  
Neuronal Activity ◽  
Genetic Risk ◽  
Cortical Neurons ◽  
Late Onset ◽  
Genetic Risk Factor ◽  
Normal Brain ◽  
Brain Functions

AbstractThe E4 allele of apolipoprotein E (apoE4) is the strongest genetic risk factor for late-onset Alzheimer’s disease (AD). However, apoE4 may cause innate brain abnormalities before the appearance of AD related neuropathology. Understanding these primary dysfunctions is vital for early detection of AD and the development of therapeutic strategies for it. Recently we have shown impaired extra-hippocampal memory in young apoE4 mice – a deficit that was correlated with attenuated structural pre-synaptic plasticity in cortical and subcortical regions. Here we test the hypothesis that these early structural deficits impact learning via changes in basal and stimuli evoked neuronal activity. We recorded extracellular neuronal activity from the gustatory cortex (GC) of three-month-old humanized apoE4 and wildtype rats, before and after conditioned taste aversion (CTA) training. Despite normal sucrose drinking behavior before CTA, young apoE4 rats showed impaired CTA learning, consistent with our previous results in apoE4 mice. This behavioral deficit was correlated with decreased basal and taste-evoked firing rates in both putative excitatory and inhibitory GC neurons. Single neuron and ensemble analyses of taste coding demonstrated that apoE4 neurons could be used to correctly classify tastes, but were unable to undergo plasticity to support learning. Our results suggest that apoE4 impacts brain excitability and plasticity early in life and may act as an initiator for later AD pathologies.Significant statementThe ApoE4 allele is the strongest genetic risk-factor for late-onset Alzheimer’s disease (AD), yet the link between apoE4 and AD is still unclear. Recent molecular and in-vitro studies suggest that apoE4 interferes with normal brain functions decades before the development of its related AD neuropathology. Here we recorded the activity of cortical neurons from young apoE4 rats during extra-hippocampal learning to study early apoE4 neuronal activity abnormalities, and their effects over coding capacities. We show that apoE4 drastically reduces basal and stimuli-evoked cortical activity in both excitatory and inhibitory neurons. The apoE4-induced activity attenuation did not prevent coding of stimuli identity and valence, but impaired capacity to undergo activity changes to support learning. Our findings support the hypothesis that apoE4 interfere with normal neuronal plasticity early in life; a deficit that may lead to late-onset AD development.

scholarly journals 1152 Genetic Risk Of Alzheimer’S Disease Is Linked To Short Sleep Duration

SLEEP ◽  
2020 ◽  
Vol 43 (Supplement_1) ◽  
pp. A439-A439
Author(s):  
Y Leng ◽  
K Yaffe ◽  
S Ackley ◽  
M Glymour ◽  
W Brenowitz
Keyword(s):  
Alzheimer’S Disease ◽  
Older Adults ◽  
Alzheimer's Disease ◽  
Sleep Duration ◽  
Genetic Risk ◽  
Genetic Risk Score ◽  
Genetic Ancestry ◽  
European Ancestry ◽  
Short Sleep Duration ◽  
Short Sleep

Abstract Introduction Sleep disturbances including short sleep duration are common in older adults, especially in those with Alzheimer’s disease (AD). However, it is unclear to what extent sleep duration is a manifestation of AD disease process. We examined whether genetic variants related to AD influence sleep duration in middle-aged and older adults and estimated the causal effects of AD on sleep duration using a mendelian randomization (MR) analysis. Methods We examined 406,687 UK Biobank participants with Caucasian genetic ancestry who self-reported sleep duration at baseline (2006-2010). Sleep duration was assessed by asking: “About how many hours sleep do you get in every 24 hours? (please include naps).” A genetic risk score for AD (AD-GRS) was calculated as a weighted sum of 23 previously identified AD-related single nucleotide polymorphisms in individuals of European ancestry. We evaluated whether AD-GRS predicted sleep duration using linear regression, adjusting for age, sex and principle components for genetic ancestry. We also stratified the analysis by age at baseline (≤55y or &gt;55y) and conducted a MR analysis to estimate the effect of AD (ICD-9/10 codes for AD/dementia diagnosis) on sleep duration. Results The participants (aged 56.91±8.00y) had an average sleep duration of 7.2 (Standard deviation [SD]=1.1) hours and AD-GRS of 0.11 (SD=0.40) (range: -1.15~1.85). Higher AD-GRS score predicted shorter sleep duration (b= -0.013, 95%CI:-0.022,-0.005), mainly among those aged over 55y (b= -0.023, 95%CI:-0.034,-0.012) and not in those 55y or younger (b= 0.006, 95%CI:-0.012,0.013); p for interaction by age=0.02. MR analysis using AD-GRS as an instrumental variable suggested that AD was associated with 1.76 hrs (b=-1.76, -2.62~ -0.90) shorter sleep duration in those aged &gt;55y. Conclusion Using a novel analytical approach, we found that higher genetic risk for AD predicted shorter sleep duration among older adults. This suggests shared genetic pathways; the biologic processes that lead to AD may also affect sleep duration. Support Dr. Leng received support from the National Institute on Aging (NIA) 1K99AG056598, and from GBHI, Alzheimer’s Association, and Alzheimer’s Society (GBHI ALZ UK-19-591141).

Confirmation of the  4 allele of the apolipoprotein E gene as a risk factor for late-onset Alzheimer's disease

Neurology ◽  
1994 ◽  
Vol 44 (2) ◽  
pp. 342-342 ◽  
Author(s):  
T. Brousseau ◽  
S. Legrain ◽  
C. Berr ◽  
V. Gourlet ◽  
O. Vidal ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Risk Factor ◽  
Apolipoprotein E ◽  
Late Onset ◽  
E Gene ◽  
Apolipoprotein E Gene

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

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.

ABCA2 is a strong genetic risk factor for early-onset Alzheimer's disease

2005 ◽  
Vol 18 (1) ◽  
pp. 119-125 ◽  
Author(s):  
Sandrine Macé ◽  
Emmanuelle Cousin ◽  
Sylvain Ricard ◽  
Emmanuelle Génin ◽  
Emmanuel Spanakis ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Risk Factor ◽  
Genetic Risk ◽  
Early Onset ◽  
Genetic Risk Factor ◽  
Early Onset Alzheimer’S Disease
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