Disruption of Arterial Perivascular Drainage of Amyloid-β from the Brains of Mice Expressing the Human APOE 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.

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Senile dementia associated with amyloid β protein angiopathy and tau perivascular pathology but not neuritic plaques in patients homozygous for the APOE-ε4 allele

Acta Neuropathologica ◽

10.1007/s004010051186 ◽

2000 ◽

Vol 100 (1) ◽

pp. 1-12 ◽

Cited By ~ 52

Author(s):

Rubén Vidal ◽

Miguel Calero ◽

Pedro Piccardo ◽

Martin R. Farlow ◽

Frederick W. Unverzagt ◽

...

Keyword(s):

Senile Dementia ◽

Amyloid Β ◽

Amyloid Β Protein ◽

Neuritic Plaques ◽

Apoe Ε4 ◽

Β Protein ◽

Ε4 Allele

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Looking at Alzheimer’s Disease Pathogenesis from the Nuclear Side

Biomolecules ◽

10.3390/biom11091261 ◽

2021 ◽

Vol 11 (9) ◽

pp. 1261

Author(s):

Laura D’Andrea ◽

Ramona Stringhi ◽

Monica Di Luca ◽

Elena Marcello

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Tau Protein ◽

Neurodegenerative Disorder ◽

Senile Plaques ◽

Amyloid Β ◽

Apoe Ε4 ◽

Hyperphosphorylated Tau Protein ◽

Ε4 Allele ◽

Therapeutic Tools

Alzheimer’s disease (AD) is a neurodegenerative disorder representing the most common form of dementia. It is biologically characterized by the deposition of extracellular amyloid-β (Aβ) senile plaques and intracellular neurofibrillary tangles, constituted by hyperphosphorylated tau protein. The key protein in AD pathogenesis is the amyloid precursor protein (APP), which is cleaved by secretases to produce several metabolites, including Aβ and APP intracellular domain (AICD). The greatest genetic risk factor associated with AD is represented by the Apolipoprotein E ε4 (APOE ε4) allele. Importantly, all of the above-mentioned molecules that are strictly related to AD pathogenesis have also been described as playing roles in the cell nucleus. Accordingly, evidence suggests that nuclear functions are compromised in AD. Furthermore, modulation of transcription maintains cellular homeostasis, and alterations in transcriptomic profiles have been found in neurodegenerative diseases. This report reviews recent advancements in the AD players-mediated gene expression. Aβ, tau, AICD, and APOE ε4 localize in the nucleus and regulate the transcription of several genes, part of which is involved in AD pathogenesis, thus suggesting that targeting nuclear functions might provide new therapeutic tools for the disease.

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Brain imaging measurements of fibrillar amyloid‐β burden, paired helical filament tau burden, and atrophy in cognitively unimpaired persons with two, one, and no copies of the APOE ε4 allele

Alzheimer s & Dementia ◽

10.1016/j.jalz.2019.08.195 ◽

2020 ◽

Vol 16 (4) ◽

pp. 598-609 ◽

Cited By ~ 1

Author(s):

Valentina Ghisays ◽

Dhruman D. Goradia ◽

Hillary Protas ◽

Robert J. Bauer ◽

Vivek Devadas ◽

...

Keyword(s):

Brain Imaging ◽

Amyloid Β ◽

Paired Helical Filament ◽

Apoe Ε4 ◽

Ε4 Allele

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Molecular Genetics of Early- and Late-Onset Alzheimer’s Disease

Current Gene Therapy ◽

10.2174/1566523220666201123112822 ◽

2020 ◽

Vol 20 ◽

Author(s):

Md. Sahab Uddin ◽

Sharifa Hasana ◽

Md. Farhad Hossain ◽

Md. Siddiqul Islam ◽

Tapan Behl ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Massively Parallel Sequencing ◽

Late Onset ◽

Current Knowledge ◽

The Elderly ◽

Apoe Ε4 ◽

Sequencing Technologies ◽

Genetic Components ◽

Ε4 Allele

: 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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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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Apolipoprotein E ε4 allele is associated with deposition of amyloid β-protein following head injury

Nature Medicine ◽

10.1038/nm0295-135 ◽

1995 ◽

Vol 1 (2) ◽

pp. 135-137 ◽

Cited By ~ 335

Author(s):

James A.R. Nicoll ◽

Gareth W. Roberts ◽

David I. Graham

Keyword(s):

Head Injury ◽

Apolipoprotein E ◽

Amyloid Β ◽

Amyloid Β Protein ◽

Β Protein ◽

Ε4 Allele

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P4-189: Effect of the APOE-ε4 allele on longitudinal changes in cortical thickness in normal aging

Alzheimer s & Dementia ◽

10.1016/j.jalz.2012.05.1893 ◽

2012 ◽

Vol 8 (4S_Part_19) ◽

pp. P702-P703

Author(s):

Tara Madhyastha ◽

Paul Borghesani ◽

Elizabeth Aylward ◽

Monique Cherrier ◽

Katie Askren ◽

...

Keyword(s):

Cortical Thickness ◽

Normal Aging ◽

Longitudinal Changes ◽

Apoe Ε4 ◽

Ε4 Allele

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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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