Faculty Opinions recommendation of Integrative genomics identifies APOE ε4 effectors in Alzheimer's disease.

: Alzheimer’s disease (AD) is the most common form of dementia in the elderly and this complex disorder is associated with environmental as well as genetic components. Early-onset AD (EOAD) and late-onset AD (LOAD, more common) are major identified types of AD. The genetics of EOAD is extensively understood with three genes variants such as APP, PSEN1, and PSEN2 leading to disease. On the other hand, some common alleles including APOE are effectively associated with LOAD identified but the genetics of LOAD is not clear to date. It has been accounted that about 5% to 10% of EOAD patients can be explained through mutations in the three familiar genes of EOAD. The APOE ε4 allele augmented the severity of EOAD risk in carriers, and APOE ε4 allele was considered as a hallmark of EOAD. A great number of EOAD patients, who are not genetically explained, indicate that it is not possible to identify disease- triggering genes yet. Although several genes have been identified through using the technology of next-generation sequencing in EOAD families including SORL1, TYROBP, and NOTCH3. A number of TYROBP variants were identified through exome sequencing in EOAD patients and these TYROBP variants may increase the pathogenesis of EOAD. The existence of ε4 allele is responsible for increasing the severity of EOAD. However, several ε4 allele carriers live into their 90s that propose the presence of other LOAD genetic as well as environmental risk factors that are not identified yet. It is urgent to find out missing genetics of EOAD and LOAD etiology to discover new potential genetics facets which will assist to understand the pathological mechanism of AD. These investigations should contribute to developing a new therapeutic candidate for alleviating, reversing and preventing AD. This article based on current knowledge represents the overview of the susceptible genes of EOAD, and LOAD. Next, we represent the probable molecular mechanism which might elucidate the genetic etiology of AD and highlight the role of massively parallel sequencing technologies for novel gene discoveries.

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Disease progression modelling from preclinical Alzheimer’s disease (AD) to AD dementia

Scientific Reports ◽

10.1038/s41598-021-83585-3 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Soo Hyun Cho ◽

Sookyoung Woo ◽

Changsoo Kim ◽

Hee Jin Kim ◽

Hyemin Jang ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Disease Progression ◽

Disease Assessment ◽

Time Interval ◽

Disease Course ◽

Preclinical Alzheimer’S Disease ◽

Apoe Ε4 ◽

Preclinical Ad ◽

Cognitive Subscale

AbstractTo characterize the course of Alzheimer’s disease (AD) over a longer time interval, we aimed to construct a disease course model for the entire span of the disease using two separate cohorts ranging from preclinical AD to AD dementia. We modelled the progression course of 436 patients with AD continuum and investigated the effects of apolipoprotein E ε4 (APOE ε4) and sex on disease progression. To develop a model of progression from preclinical AD to AD dementia, we estimated Alzheimer’s Disease Assessment Scale-Cognitive Subscale 13 (ADAS-cog 13) scores. When calculated as the median of ADAS-cog 13 scores for each cohort, the estimated time from preclinical AD to MCI due to AD was 7.8 years and preclinical AD to AD dementia was 15.2 years. ADAS-cog 13 scores deteriorated most rapidly in women APOE ε4 carriers and most slowly in men APOE ε4 non-carriers (p < 0.001). Our results suggest that disease progression modelling from preclinical AD to AD dementia may help clinicians to estimate where patients are in the disease course and provide information on variation in the disease course by sex and APOE ε4 status.

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Changes in retinal microvasculature and retinal layer thickness in association with apolipoprotein E genotype in Alzheimer’s disease

Scientific Reports ◽

10.1038/s41598-020-80892-z ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Joo Youn Shin ◽

Eun Young Choi ◽

Min Kim ◽

Hyung Keun Lee ◽

Suk Ho Byeon

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Layer Thickness ◽

Structural Changes ◽

Foveal Avascular Zone ◽

Retinal Layer ◽

Inner Plexiform Layer ◽

Apoe Ε4 ◽

Retinal Microvasculature ◽

Capillary Plexus

AbstractBiomarker tests of Alzheimer’s disease (AD) are invasive and expensive. Recent developments in optical coherence tomography (OCT) and OCT angiography (OCTA) have enabled noninvasive, cost-effective characterization of retinal layer vasculature and thickness. Using OCTA and OCT, we characterized retinal microvascular changes in the mild cognitive impairment (MCI) stage of AD and assessed their correlation with structural changes in each retinal neuronal layer. We also evaluated the effect of the APOE-ε4 genotype on retinal microvasculature and layer thickness. Retinal layer thickness did not differ between MCI patients (40 eyes) and controls (37 eyes, all p > 0.05). MCI patients had lower vessel density (VD) (p = 0.003) of the superficial capillary plexus (SCP) and larger foveal avascular zone area (p = 0.01) of the deep capillary plexus (DCP) than those of controls. VD of the SCP correlated with the ganglion cell layer (r = 0.358, p = 0.03) and inner plexiform layer thickness (r = 0.437, p = 0.007) in MCI patients. APOE-ε4-carrying MCI patients had a lower VD of the DCP than non-carriers (p = 0.03). In conclusion, retinal microvasculature was reduced in patients with AD-associated MCI, but retinal thickness was not changed; these changes might be affected by the APOE genotype. OCTA of the retinal microvasculature may be useful to detect vascular changes in AD.

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The clinical utility of gene testing for Alzheimer’s disease

Neurology International ◽

10.4081/ni.2011.e1 ◽

2011 ◽

Vol 3 (1) ◽

pp. 1 ◽

Cited By ~ 8

Author(s):

Emily R. Atkins ◽

Peter K. Panegyres

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Early Onset ◽

Late Onset ◽

Association Studies ◽

Susceptibility Gene ◽

Genome Wide Association Studies ◽

Apoe Ε4 ◽

Gene Testing ◽

A Genome

Alzheimer’s disease (AD) is the largest cause of dementia, affecting 35.6 million people in 2010. Amyloid precursor protein, presenilin 1 and presenilin 2 mutations are known to cause familial early-onset AD, whereas apolipoprotein E (APOE) ε4 is a susceptibility gene for late-onset AD. The genes for phosphatidylinositol- binding clathrin assembly protein, clusterin and complement receptor 1 have recently been described by genome-wide association studies as potential risk factors for lateonset AD. Also, a genome association study using single neucleotide polymorphisms has identified an association of neuronal sortilin related receptor and late-onset AD. Gene testing, and also predictive gene testing, may be of benefit in suspected familial early-onset AD however it adds little to the diagnosis of lateonset AD and does not alter the treatment. We do not recommend APOE ε4 genotyping.

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

Journal of the International Neuropsychological Society ◽

10.1017/s1355617702870096 ◽

2002 ◽

Vol 8 (7) ◽

pp. 943-955 ◽

Cited By ~ 65

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.)

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Lower cerebral oxygen utilization is associated with Alzheimer’s disease-related neurodegeneration and poorer cognitive performance among apolipoprotein E ε4 carriers

Journal of Cerebral Blood Flow & Metabolism ◽

10.1177/0271678x211056393 ◽

2021 ◽

pp. 0271678X2110563

Author(s):

W Hudson Robb ◽

Omair A Khan ◽

Humza A Ahmed ◽

Judy Li ◽

Elizabeth E Moore ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Episodic Memory ◽

Apolipoprotein E ◽

Cognitive Performance ◽

Lateral Ventricle ◽

Oxygen Metabolism ◽

Cerebral Oxygen ◽

P Values ◽

Apoe Ε4

Oxygen extraction fraction (OEF) and cerebral metabolic rate of oxygen (CMRO2) are markers of cerebral oxygen homeostasis and metabolism that may offer insights into abnormal changes in brain aging. The present study cross-sectionally related OEF and CMRO2 to cognitive performance and structural neuroimaging variables among older adults (n = 246, 74 ± 7 years, 37% female) and tested whether apolipoprotein E ( APOE)-ε4 status modified these associations. Main effects of OEF and CMRO2 were null (p-values >0.06), and OEF interactions with APOE-ε4 status on cognitive and structural imaging outcomes were null (p-values >0.06). However, CMRO2 interacted with APOE-ε4 status on language (p = 0.002), executive function (p = 0.03), visuospatial (p = 0.005), and episodic memory performances (p = 0.03), and on hippocampal (p = 0.006) and inferior lateral ventricle volumes (p = 0.02). In stratified analyses, lower oxygen metabolism related to worse language (p = 0.02) and episodic memory performance (p = 0.03) among APOE-ε4 carriers only. Associations between CMRO2 and cognitive performance were primarily driven by APOE-ε4 carriers with existing cognitive impairment. Congruence across language and episodic memory results as well as hippocampal and inferior lateral ventricle volume findings suggest that APOE-ε4 may interact with cerebral oxygen metabolism in the pathogenesis of Alzheimer’s disease and related neurodegeneration.

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

Current Alzheimer Research ◽

10.2174/1567205015666180601090533 ◽

2018 ◽

Vol 15 (10) ◽

pp. 938-950 ◽

Cited By ~ 4

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.

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