scholarly journals APOE4 exacerbates α-synuclein pathology and related toxicity independent of amyloid

2020 ◽  
Vol 12 (529) ◽  
pp. eaay1809 ◽  
Author(s):  
Na Zhao ◽  
Olivia N. Attrebi ◽  
Yingxue Ren ◽  
Wenhui Qiao ◽  
Berkiye Sonustun ◽  
...  
Keyword(s):  
Risk Factor ◽  
Genetic Risk ◽  
Late Onset ◽  
Lewy Bodies ◽  
Amyloid Β ◽  
Lewy Body Dementia ◽  
Genetic Risk Factor ◽  
Adeno Associated Virus ◽  
Postmortem Brains ◽  
Ε4 Allele

The apolipoprotein E (APOE) ε4 allele is the strongest genetic risk factor for late-onset Alzheimer’s disease mainly by driving amyloid-β pathology. Recently, APOE4 has also been found to be a genetic risk factor for Lewy body dementia (LBD), which includes dementia with Lewy bodies and Parkinson’s disease dementia. How APOE4 drives risk of LBD and whether it has a direct effect on α-synuclein pathology are not clear. Here, we generated a mouse model of synucleinopathy using an adeno-associated virus gene delivery of α-synuclein in human APOE-targeted replacement mice expressing APOE2, APOE3, or APOE4. We found that APOE4, but not APOE2 or APOE3, increased α-synuclein pathology, impaired behavioral performances, worsened neuronal and synaptic loss, and increased astrogliosis at 9 months of age. Transcriptomic profiling in APOE4-expressing α-synuclein mice highlighted altered lipid and energy metabolism and synapse-related pathways. We also observed an effect of APOE4 on α-synuclein pathology in human postmortem brains with LBD and minimal amyloid pathology. Our data demonstrate a pathogenic role of APOE4 in exacerbating α-synuclein pathology independent of amyloid, providing mechanistic insights into how APOE4 increases the risk of LBD.

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.

Apolipoprotein E (APOE) ε4 Status Moderates the Relationship Between Close-Range Blast Exposure and Cognitive Functioning

2020 ◽  
pp. 1-14
Author(s):  
Thomas Wooten ◽  
Danielle R. Sullivan ◽  
Mark W. Logue ◽  
Jennifer R. Fonda ◽  
Catherine B. Fortier ◽  
...  
Keyword(s):  
Risk Factor ◽  
Genetic Risk ◽  
Cognitive Outcomes ◽  
Genetic Risk Factor ◽  
Carrier Status ◽  
Blast Exposure ◽  
Close Range ◽  
Ε4 Allele ◽  
The Impact

Abstract Objectives: Recent studies suggest that close-range blast exposure (CBE), regardless of acute concussive symptoms, may have negative long-term effects on brain health and cognition; however, these effects are highly variable across individuals. One potential genetic risk factor that may impact recovery and explain the heterogeneity of blast injury’s long-term cognitive outcomes is the inheritance of an apolipoprotein (APOE) ε4 allele, a well-known genetic risk factor for Alzheimer’s disease. We hypothesized that APOE ε4 carrier status would moderate the impact of CBE on long-term cognitive outcomes. Methods: To test this hypothesis, we examined 488 post-9/11 veterans who completed assessments of neuropsychological functioning, psychiatric diagnoses, history of blast exposure, military and non-military mild traumatic brain injuries (mTBIs), and available APOE genotypes. We separately examined the effects of CBE on attention, memory, and executive functioning in individuals with and without the APOE ε4 allele. Results: As predicted, we observed a differential impact of CBE status on cognition as a function of APOE ε4 status, in which CBE ε4 carriers displayed significantly worse neuropsychological performance, specifically in the domain of memory. These results persisted after adjusting for clinical, demographic, and genetic factors and were not observed when examining other neurotrauma variables (i.e., lifetime or military mTBI, distant blast exposure), though these variables displayed similar trends. Conclusions: These results suggest APOE ε4 carriers are more vulnerable to the impact of CBE on cognition and highlight the importance of considering genetic risk when studying cognitive effects of neurotrauma.

scholarly journals Association between the APOE ε4 Allele and Late-Onset Alzheimer’s Disease in an Ecuadorian Mestizo Population

2017 ◽  
Vol 2017 ◽  
pp. 1-9 ◽  
Author(s):  
Stefany Montufar ◽  
Cristian Calero ◽  
Rodrigo Vinueza ◽  
Patricio Correa ◽  
Andrea Carrera-Gonzalez ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Risk Factor ◽  
Genetic Risk ◽  
Disease Risk ◽  
Late Onset ◽  
Genetic Risk Factor ◽  
Genotype Frequencies ◽  
Healthy Control ◽  
Genetic Contributions

Alzheimer’s disease (AD) is the most common neurodegenerative disease. It has two main pathological hallmarks: amyloid plaques and neurofibrillary tangles. The APOE ε4 allele has been recognized as the strongest genetic risk factor for late-onset Alzheimer’s disease (LOAD) in several populations worldwide, yet the risk varies by region and ethnicity. The aims of this study were to describe APOE allele and genotype frequencies and examine the relationship between the APOE ε4 allele and LOAD risk in an Ecuadorian Mestizo population. We carried out a case-control study comprising 56 individuals clinically diagnosed with probable AD (≥65 years of age) and 58 unrelated healthy control subjects (≥65 years of age). Genotyping was performed using the real-time PCR method. Our data showed that allelic and genotypic frequencies follow the trends observed in most worldwide populations. We also found a high-risk association between APOE ε4 allele carriers and LOAD (OR = 7.286; 95% CI = 2.824–18.799; p<0.001). Therefore, we concluded that APOE ε4 must be considered an important genetic risk factor for LOAD in the Ecuadorian Mestizo population. Additionally, we suggest that in mixed populations the effects of admixture and ethnic identity should be differentiated when evaluating genetic contributions to Alzheimer’s disease risk.

scholarly journals Genetic risk factor APOEε4 associates with plasma amyloid beta in amnestic mild cognitive impairment and alzheimer’s disease

2016 ◽  
Vol 25 (1) ◽  
pp. 44-50
Author(s):  
Rocksy F.V. Situmeang ◽  
Eka J. Wahjoepramono ◽  
Cahyono Kaelan ◽  
Jan S. Purba ◽  
Budhianto Suhadi ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Risk Factor ◽  
Cognitive Impairment ◽  
Mild Cognitive Impairment ◽  
Genetic Risk ◽  
Normal Aging ◽  
Amnestic Mild Cognitive Impairment ◽  
Genetic Risk Factor ◽  
Ε4 Allele

Background: APOEε4 is a strong genetic risk factor for Alzheimer’s disease (AD). AD itself has been associated with reduced Aβ clearance from the brain and plasma. Understanding the potential pathogenic link between APOEε4 and plasma Aβ might allow for earlier identification of people at risk of developing AD. The aim of this study is to find out the correlation between APOEε4 and plasma Aβ in amnestic mild cognitive impairment (aMCI) and AD patients.Methods: This is a comparative cross-sectional study of patients attending a memory clinic in Siloam Hospital Lippo Karawaci, Tangerang, during the period of 2013-2014. Subjects were categorized into three categories: normal aging, aMCI, and AD. We performed blood test to examine APOEε4, plasma Aβ4o level, and plasma Aβ42 level. All data analyses were performed using correlation test and logistic regression.Results: Sixty subjects (normal aging = 23, aMCI = 17, AD = 20) were included. There were 19 (31.7%) subjects with APOEε4 positive. Subjects carrying ε4 allele were more likely to have AD by 3.9-fold than subjects with APOE ε4 allele negative. There is a significant difference between the mean of plasma Aβ40 in aMCI group and AD group. We also found correlation between APOEε4 (+) and higher plasma Aβ42 (p<0.05).Conclusion: There is a correlation between APOEε4 and plasma Aβ42 level, which supports the hypothesis that this genetic isoform accelerates the rate and progression of AD through Aβ-dependent pathways.

scholarly journals Molecular Insight into the Therapeutic Promise of Targeting APOE4 for Alzheimer’s Disease

2020 ◽  
Vol 2020 ◽  
pp. 1-16 ◽  
Author(s):  
Abdullah Al Mamun ◽  
Md. Sahab Uddin ◽  
Md. Fahim Bin Bashar ◽  
Sonia Zaman ◽  
Yesmin Begum ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Risk Factor ◽  
Genetic Risk ◽  
Late Onset ◽  
Neurofibrillary Tangle ◽  
Cerebrovascular Diseases ◽  
Genetic Risk Factor ◽  
Synaptic Loss ◽  
Novel Drugs

Alzheimer’s disease (AD) is a progressive neurodegenerative disease that causes chronic cognitive dysfunction. Most of the AD cases are late onset, and the apolipoprotein E (APOE) isoform is a key genetic risk factor. The APOE gene has 3 key alleles in humans including APOE2, APOE3, and APOE4. Among them, APOE4 is the most potent genetic risk factor for late-onset AD (LOAD), while APOE2 has a defensive effect. Research data suggest that APOE4 leads to the pathogenesis of AD through various processes such as accelerated beta-amyloid aggregations that raised neurofibrillary tangle formation, cerebrovascular diseases, aggravated neuroinflammation, and synaptic loss. However, the precise mode of actions regarding in what way APOE4 leads to AD pathology remains unclear. Since APOE contributes to several pathological pathways of AD, targeting APOE4 might serve as a promising strategy for the development of novel drugs to combat AD. In this review, we focus on the recent studies about APOE4-targeted therapeutic strategies that have been advanced in animal models and are being prepared for use in humans for the management of AD.

The cystatin C gene as a novel genetic risk factor for late onset Alzheimer's disease

2000 ◽  
Vol 21 ◽  
pp. 204 ◽  
Author(s):  
Fiona Crawford ◽  
Melissa J. Freeman ◽  
John Schinka ◽  
Laila Abdullah ◽  
Mike Gold ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Risk Factor ◽  
Cystatin C ◽  
Genetic Risk ◽  
Late Onset ◽  
Genetic Risk Factor
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