scholarly journals APOE ε4 allele advances the age-dependent decline of amyloid β clearance in the human cortex

2021 ◽  
Author(s):  
Atsushi Saito ◽  
Yusuke Kageyama ◽  
Olga Pletnikova ◽  
Gay L Rudow ◽  
Yang An ◽  
...  
Keyword(s):  
Cerebral Cortex ◽  
Apoe Genotype ◽  
Amyloid Β ◽  
Clinical Intervention ◽  
Immunohistochemical Localization ◽  
Human Cortex ◽  
Apoe Ε4 ◽  
Age Related ◽  
Age Dependent ◽  
Ε4 Allele

Introduction: Our previous study indicated that the pericapillary clearance of amyloid β (Aβ) declines with age in APOE 3/3 subjects. Here, we examine whether the APOE ε4 allele has an impact on this age-related decline. Methods: We examined 69 autopsy brains of APOE ε3/ε4 or APOE ε3/ε3 individuals (30-65 years) for the immunohistochemical localization of intracellular, extracellular, and pericapillary Aβ in the cerebral cortex. Results: In APOE ε3/ε4 individuals, the percentage of Aβ positive pericapillary spaces began to decrease (p=0.030), and the number of extracellular Aβ particles increased in the early 30s (p=0.0008). Those average values were significantly lower (p<0.0001) and higher (p<0.0001), respectively, compared to APOE ε3/ε3 individuals. Discussion: Our observations indicate that APOE ε4 allele advances by one decade at the onset of age-related decline in Aβ glymphatic clearance. This finding supports early clinical intervention and stratification by APOE genotype to prevent Aβ deposition and AD progression.

scholarly journals Apolipoprotein ε4 allele is associated with frailty syndrome: results from the hellenic longitudinal investigation of ageing and diet study

2019 ◽  
Vol 48 (6) ◽  
pp. 917-921 ◽  
Author(s):  
Niki Mourtzi ◽  
Eva Ntanasi ◽  
Mary Yannakoulia ◽  
Mary Kosmidis ◽  
Costas Anastasiou ◽  
...  
Keyword(s):  
Apoe Genotype ◽  
Frailty Syndrome ◽  
Apoe Ε4 ◽  
Longitudinal Investigation ◽  
Age Related ◽  
Myocardial Infraction ◽  
History Of ◽  
Diet Study ◽  
Ε4 Allele ◽  
Adjusted Model

Abstract Apolipoprotein (APOE) ε4 allele has been associated with a number of age-related diseases but previous studies failed to identify any link with Frailty syndrome. The aim of the present study is to investigate the association between APOE ε4 allele and frailty syndrome. We operationalised Frailty according to the Fried definition, and we determined the APOE genotype in 1234 participants of the hellenic longitudinal investigation of ageing and diet study. Logistic regression analyses were performed to examine the association between APOE ε4 allele and frailty. Models were adjusted for age, education, sex, presence (or absence) of hypertension, diabetes, myocardial infraction, coronary disease, congestive heart failure, arrhythmia or other heart disease, family history of dementia and current smoking. The same models were performed after exclusion of patients with dementia and participants with APOE ε2/ε4 genotype. In the fully adjusted model, carriers of APOE ε4 allele had 2.753 higher odds of frailty relative to non-carriers. After trichotomization of APOE genotype, APOE ε4 heterozygotes had 2.675 higher risk of frailty compared to non-carriers while exclusion of patients with dementia or/and APOE ε2/ε4 genotype did not alter the association. The APOE ε4 allele may be a significant biomarker of frailty with diagnostic and prognostic capacity.

scholarly journals Disruption of Arterial Perivascular Drainage of Amyloid-β from the Brains of Mice Expressing the Human APOE ε4 Allele

PLoS ONE ◽  
2012 ◽  
Vol 7 (7) ◽  
pp. e41636 ◽  
Author(s):  
Cheryl A. Hawkes ◽  
Patrick M. Sullivan ◽  
Sarah Hands ◽  
Roy O. Weller ◽  
James A. R. Nicoll ◽  
...  
Keyword(s):  
Amyloid Β ◽  
Human Apoe ◽  
Apoe Ε4 ◽  
Ε4 Allele ◽  
Perivascular Drainage

scholarly journals Decline in verbal memory during preclinical Alzheimer's disease: Examination of the effect of APOE genotype

2002 ◽  
Vol 8 (7) ◽  
pp. 943-955 ◽  
Author(s):  
KELLY L. LANGE ◽  
MARK W. BONDI ◽  
DAVID P. SALMON ◽  
DOUGLAS GALASKO ◽  
DEAN C. DELIS ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Older Adults ◽  
Alzheimer's Disease ◽  
Episodic Memory ◽  
Verbal Memory ◽  
Verbal Learning ◽  
Apoe Genotype ◽  
Apoe Ε4 ◽  
Dementia Syndrome ◽  
Ε4 Allele

A subtle decline in episodic memory often occurs prior to the emergence of the full dementia syndrome in nondemented older adults who develop Alzheimer's disease (AD). The APOE-ε4 genotype may engender a more virulent form of AD that hastens this decline. To examine this possibility, we compared the rate of decline in episodic memory during the preclinical phase of AD in individuals with or without at least one APOE ε4 allele. Nondemented normal control (NC; n = 84) participants, nondemented older adults who subsequently developed dementia within 1 or 2 years (i.e., preclinical AD; n = 20), and patients with mild AD (n = 53) were examined with 2 commonly employed tests of episodic memory, the Logical Memory subtest of the Wechsler Memory Scale–Revised and the California Verbal Learning Test. Results revealed a precipitous decline in verbal memory abilities 1 to 2 years prior to the onset of the dementia syndrome, but there was little effect of APOE genotype on the rate of this memory decline. The presence of an APOE-ε4 allele, however, did have a differential effect on the sensitivity of the 2 types of memory tests for tracking progression and made an independent contribution to the prediction of conversion to AD. (JINS, 2002, 8, 943–955.)

Interplay between the APOE Genotype and Possible Plasma Biomarkers in Alzheimer’s Disease

2018 ◽  
Vol 15 (10) ◽  
pp. 938-950 ◽  
Author(s):  
Martina Zverova ◽  
Eva Kitzlerova ◽  
Zdenek Fisar ◽  
Roman Jirak ◽  
Jana Hroudova ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Molecular Mechanisms ◽  
Neurodegenerative Disorder ◽  
Apoe Genotype ◽  
Plasma Biomarkers ◽  
Plasma Melatonin ◽  
Apoe Ε4 ◽  
Ε4 Allele ◽  
Severity Of Dementia

Background: Alzheimer’s disease (AD) is a progressive neurodegenerative disorder with a complex pathogenesis and a common occurrence of comorbid diseases such as depression. It is accepted that the presence of the ε4 allele of the gene that encodes apolipoprotein E (APOE) is the strongest genetic risk factor for the development of sporadic AD. Melatonin, cortisol, homocysteine, and prolactin are presumed to be risk factors or biomarkers for stress- and age-related disorders. Objective: The interplay between the APOE genotype and plasma biomarkers was examined in patients with AD presenting with or without depression to contribute to understanding the interdependence of various molecular mechanisms in the pathophysiology of AD. Method: The APOE genotype and morning plasma melatonin, cortisol, homocysteine, and prolactin concentrations were measured in 85 patients with AD and 44 elderly controls. Results: A significant association between AD and the allele (ε4) or genotype (ε3/ε4 or ε4/ε4) frequencies of APOE was confirmed. Plasma homocysteine and cortisol levels were significantly increased in patients with AD compared to those in controls, independent of the presence of comorbid depressive symptoms or the severity of dementia. Significantly lower plasma melatonin concentration was found in patients with AD but not in controls, who were noncarriers of the APOE ε4 allele, regardless of the presence of depression or the severity of dementia in AD. Conclusion: Our findings indicate the existence of a little-known specific APOE-mediated mechanism that increases the plasma melatonin level in a subgroup of patients with AD who are carriers of the APOE ε4 allele.

Age-Dependent Changes in the Plasma and Brain Pharmacokinetics of Amyloid-β Peptides and Insulin

2021 ◽  
pp. 1-14
Author(s):  
Andrew L. Zhou ◽  
Nidhi Sharda ◽  
Vidur V. Sarma ◽  
Kristen M. Ahlschwede ◽  
Geoffry L. Curran ◽  
...  
Keyword(s):  
Neurodegenerative Disorder ◽  
Single Photon ◽  
Photon Emission ◽  
Amyloid Β ◽  
Emission Computed Tomography ◽  
Systemic Injection ◽  
Age Related ◽  
Age Dependent ◽  
Plasma Pharmacokinetics ◽  
The Brain

Background: Age is the most common risk factor for Alzheimer’s disease (AD), a neurodegenerative disorder characterized by the hallmarks of toxic amyloid-β (Aβ) plaques and hyperphosphorylated tau tangles. Moreover, sub-physiological brain insulin levels have emerged as a pathological manifestation of AD. Objective: Identify age-related changes in the plasma disposition and blood-brain barrier (BBB) trafficking of Aβ peptides and insulin in mice. Methods: Upon systemic injection of 125I-Aβ 40, 125I-Aβ 42, or 125I-insulin, the plasma pharmacokinetics and brain influx were assessed in wild-type (WT) or AD transgenic (APP/PS1) mice at various ages. Additionally, publicly available single-cell RNA-Seq data [GSE129788] was employed to investigate pathways regulating BBB transport in WT mice at different ages. Results: The brain influx of 125I-Aβ 40, estimated as the permeability-surface area product, decreased with age, accompanied by an increase in plasma AUC. In contrast, the brain influx of 125I-Aβ 42 increased with age, accompanied by a decrease in plasma AUC. The age-dependent changes observed in WT mice were accelerated in APP/PS1 mice. As seen with 125I-Aβ 40, the brain influx of 125I-insulin decreased with age in WT mice, accompanied by an increase in plasma AUC. This finding was further supported by dynamic single-photon emission computed tomography (SPECT/CT) imaging studies. RAGE and PI3K/AKT signaling pathways at the BBB, which are implicated in Aβ and insulin transcytosis, respectively, were upregulated with age in WT mice, indicating BBB insulin resistance. Conclusion: Aging differentially affects the plasma pharmacokinetics and brain influx of Aβ isoforms and insulin in a manner that could potentially augment AD risk.

scholarly journals Metabolic syndrome is associated with poor cognition: a population-based study of 70-year-olds without dementia

2021 ◽  
Author(s):  
Anna Marseglia ◽  
Alexander Darin-Mattsson ◽  
Johan Skoog ◽  
Lina Rydén ◽  
Timothy Hadarsson-Bodin ◽  
...  
Keyword(s):  
Metabolic Syndrome ◽  
Heart Disease ◽  
Executive Function ◽  
Cognitive Performance ◽  
Birth Cohort ◽  
Verbal Fluency ◽  
Apoe Genotype ◽  
Perceptual Speed ◽  
Apoe Ε4 ◽  
Ε4 Allele

Abstract Background Individual conditions of metabolic syndrome (MetS) have been related to dementia, however, their combined impact on the preclinical stage is unknown. We investigated the associations between MetS and domain-specific cognitive function as well as the role of sociodemographic, cardiovascular, and genetic factors. Methods Within the Gothenburg H70 Birth Cohort Study-Birth cohort 1944, 1131 dementia-free participants (aged 70 years) were examined during 2014-2016. MetS (central obesity plus at least two factors [reduced HDL-cholesterol, elevated triglycerides, blood pressure, or blood glucose]) was identified according to the International Diabetes Federation criteria. Five cognitive domains (memory, attention/perceptual speed, executive function, verbal fluency, visuospatial abilities) were generated after z-standardizing raw scores from ten neuropsychological tests. Education, heart disease, claudication (indicating peripheral atherosclerosis), and apolipoprotein (APOE) genotype were ascertained by trained staff. Data were analyzed with linear regression models. Results Overall, 618 participants (55%) had MetS. In multi-adjusted linear regressions, MetS was related to poorer performance in attention/perceptual speed (β -0.14 [95% CI -0.25, -0.02]), executive function (β -0.12 [95% CI -0.23, -0.01]), and verbal fluency (β -0.19 [95% CI -0.30, -0.08]). These associations were present only among individuals who did not carry any APOE-ε4 allele or were highly educated. However, among those with MetS, high education was related to better cognitive performance. MetS together with comorbid heart disease or claudication was associated with even worse cognitive performance than each alone. Conclusions MetS is associated with poor attention/perceptual speed, executive function, and verbal fluency performance. Education, APOE-ε4 allele, and comorbid cardiovascular disease influenced the observed associations.

scholarly journals Cerebrospinal fluid-induced retardation of amyloid β aggregation correlates with Alzheimer's disease and the APOE ε4 allele

2016 ◽  
Vol 1651 ◽  
pp. 11-16 ◽  
Author(s):  
E.R. Padayachee ◽  
H. Zetterberg ◽  
E. Portelius ◽  
J. Borén ◽  
J.L. Molinuevo ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cerebrospinal Fluid ◽  
Amyloid Β ◽  
Apoe Ε4 ◽  
Ε4 Allele

scholarly journals The Association between Polygenic Hazard and Markers of Alzheimer’s Disease Following Stratification for APOE Genotype

2020 ◽  
Vol 17 (7) ◽  
pp. 667-679
Author(s):  
Matteo De Marco ◽  
Riccardo Manca ◽  
Janine Kirby ◽  
Guillaume M. Hautbergue ◽  
Daniel J. Blackburn ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Executive Functioning ◽  
Grey Matter ◽  
Linear Models ◽  
Apoe Genotype ◽  
Apoe Ε4 ◽  
Allele Status ◽  
Ε4 Allele ◽  
Clinical Profiles

Background: Research indicates that polygenic indices of risk of Alzheimer’s disease are linked to clinical profiles. Objective: Given the “genetic centrality” of the APOE gene, we tested whether this held true for both APOE-ε4 carriers and non-carriers. Methods: A polygenic hazard score (PHS) was extracted from 784 non-demented participants recruited in the Alzheimer’s Disease Neuroimaging Initiative and stratified by APOE ε4 status. Datasets were split into sub-cohorts defined by clinical (unimpaired/MCI) and amyloid status (Aβ+/Aβ-). Linear models were devised in each sub-cohort and for each APOE-ε4 status to test the association between PHS and memory, executive functioning and grey-matter volumetric maps. Results: PHS predicted memory and executive functioning in ε4ε3 MCI patients, memory in ε3ε3 MCI patients, and memory in ε4ε3 Aβ+ participants. PHS also predicted volume in sensorimotor regions in ε3ε3 Aβ+ participants. Conclusion: The link between polygenic hazard and neurocognitive variables varies depending on APOE-ε4 allele status. This suggests that clinical phenotypes might be influenced by complex genetic interactions.

scholarly journals APOE ε4 allele modified the correlation between deep grey matter volume and cognitive performance in non-demented elders

2020 ◽  
Vol 3 (3) ◽  
pp. 152-161
Author(s):  
Weiping Li ◽  
Yu Xie ◽  
Tingting Yu ◽  
Wenbo Wu ◽  
Kun Wang ◽  
...  
Keyword(s):  
Cognitive Impairment ◽  
Grey Matter ◽  
Early Stage ◽  
Apoe Genotype ◽  
Grey Matter Volume ◽  
Matter Volume ◽  
Apoe Ε4 ◽  
Deep Grey Matter ◽  
Ε4 Allele ◽  
The Right

Abstract APOE ε4 allele is the strongest predictor of Alzheimer’s disease (AD) risk, but its role in the association between the deep grey matter volume and cognitive impairment is still unclear. This study investigated the effects of APOE ε4 allele on this association in non-demented elders. We enrolled 24 patients with mild cognitive impairment (MCI) and 28 normal controls (NC), who underwent the whole brain 3DTIW MRI scanning, an APOE genotype test, and neuropsychological tests. The right thalamus (p = 0.026), the left pallidum (p = 0.026), and the bilateral amygdala (left p = 0.042, right p = 0.048) atrophied in MCI, and their volume were positively correlated with the cognitive scores (MoCA) (p < 0.05). Furthermore, the general liner regression model suggested that the correlation between the right thalamus and the putamen volume with MoCA scores was different in the APOE ε4 carriers and non- carriers. Compared with the non APOEε4 carriers, the right thalamus atrophied more rapidly when the cognition decline in APOE ε4 carriers, while the right putamen compensatory expansion to slow the rate of cognitive decline although failed. This suggested that the right putamen showed stronger compensation by increasing the volume at the early stage of cognitive impairments in the APOE ε4 carriers, while this compensatory change had been disappeared in the right thalamus. In conclusion, APOE ε4 allele modifies the correlation between the right thalamus, the right putamen, and MoCA scores, and it has a potential selective effect on the relationship between cognition and brain structures to some extent in non-demented elders.

scholarly journals Association Between Psychosis Phenotype and APOE Genotype on the Clinical Profiles of Alzheimer's Disease

2018 ◽  
Vol 15 (2) ◽  
pp. 187-194 ◽  
Author(s):  
Winnie Qian ◽  
Corinne E. Fischer ◽  
Tom A. Schweizer ◽  
David G. Munoz
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Apoe Genotype ◽  
Lewy Bodies ◽  
Functional Impairments ◽  
Significant Interaction Effect ◽  
Functional Activities ◽  
Apoe Ε4 ◽  
Lewy Body Pathology ◽  
Ε4 Allele

Background: Psychosis is a common phenomenon in Alzheimer's disease (AD). The APOE ε4 allele is the strongest genetic risk factor for the development of AD, but its association with psychosis remains unclear. Objective: We investigated the associations between psychosis, subdivided into delusions and hallucinations, as well as APOE ε4 allele on cognitive and functional outcomes. Secondarily, we investigated the associations between APOE ε4, Lewy bodies, and psychosis. Methods: Data from the National Alzheimer's Coordinating Center (NACC) were used. Nine hundred patients with a confirmed diagnosis of AD based on the NIA-AA Reagan were included in the analysis. Global cognition was assessed using the Mini-Mental State Exam (MMSE) and functional status was assessed using the Functional Activities Questionnaire (FAQ). Psychosis status was determined using the Neuropsychiatric Inventory Questionnaire (NPI-Q). Factorial design was used to assess the effects of psychosis and APOE ε4, as well as their interaction. Results: Psychosis and the presence of APOE ε4 were both associated with lower MMSE scores, while only psychosis was associated with higher FAQ scores. Furthermore, patients with hallucinations had lower MMSE and higher FAQ scores than patients with only delusions. There was a significant interaction effect between psychosis and APOE ε4 on MMSE scores, with APOE ε4 negatively affecting patients with hallucinations-only psychosis. APOE ε4 was positively associated with the presence of Lewy body pathology, and both were found to be more prevalent in psychotic patients, with a stronger association with hallucinations. Conclusion: Psychosis in AD was associated with greater cognitive and functional impairments. Patients with hallucinations-with or without delusions-conferred even greater deficits compared to patients with only delusions. The APOE ε4 allele was associated with worse cognition, especially for patients with hallucination-only psychosis. APOE ε4 may mediate cognitive impairment in the hallucinations phenotype through the development of Lewy bodies. Our findings support that subtypes of psychosis should be evaluated separately.

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