A case of amyloid-β-related cerebral angiitis with ApoE ε4/ε2 genotype

Abstract Background: To assess effects of apolipoprotein E (ApoE) ε4 genotype on Aβ and tau burden and their longitudinal changes in Alzheimer’s disease (AD) spectrum.Methods: Among 272 individuals who underwent PET scans (18F-florbetaben for Aβ and 18F-flortaucipir for tau) and ApoE genotyping, 187 individuals completed 2-year follow-up PET scans. After correcting for partial-volume effect, we compared the standardized uptake value ratio (SUVR) for Aβ and tau burden between the ε4+ and ε4- groups. By using a linear mixed-effect model, we measured changes in SUVR in the ApoE ε4+ and ε4- groups.Results: The ε4+ group showed greater baseline Aβ burden in the diffuse cortical regions and greater tau burden in the lateral, and medial temporal, cingulate, and insula cortices. Tau accumulation rate was higher in the parietal, occipital, lateral, and medial temporal cortices in the ε4+ group. In Aβ+ individuals, baseline tau burden was greater in the medial temporal cortex, while Aβ burden was conversely greater in the ε4- group. Tau accumulation rate was higher in the ε4+ group in a small region in the lateral temporal cortex. The effect of ApoE ε4 on enhanced tau accumulation persisted even after adjusting for the global cortical Aβ burden.Conclusions: Progressive tau accumulation may be more prominent in ε4 carriers, particularly in the medial and lateral temporal cortices. ApoE ε4 allele has differential effects on Aβ burden depending on the existing amyloidosis and enhances vulnerability to progressive tau accumulation in the AD spectrum independent of Aβ.

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

Brain Research ◽

10.1016/j.brainres.2016.09.022 ◽

2016 ◽

Vol 1651 ◽

pp. 11-16 ◽

Cited By ~ 12

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

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

10.1101/2021.04.07.438832 ◽

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.

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Smaller hippocampal volume in APOE ε4 carriers independent of amyloid-β (Aβ) burden

Psychiatry Research Neuroimaging ◽

10.1016/j.pscychresns.2021.111381 ◽

2021 ◽

Vol 317 ◽

pp. 111381

Author(s):

Hwagyu Suh ◽

Young-Min Lee ◽

Je-Min Park ◽

Byung-Dae Lee ◽

Eunsoo Moon ◽

...

Keyword(s):

Amyloid Β ◽

Hippocampal Volume ◽

Apoe Ε4

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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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Differential associations of APOE-ε2 and APOE-ε4 alleles with PET-measured amyloid-β and tau deposition in older individuals without dementia

European Journal of Nuclear Medicine and Molecular Imaging ◽

10.1007/s00259-021-05192-8 ◽

2021 ◽

Author(s):

Gemma Salvadó ◽

◽

Michel J. Grothe ◽

Colin Groot ◽

Alexis Moscoso ◽

...

Keyword(s):

Reference Group ◽

Temporal Cortex ◽

Amyloid Β ◽

Cognitive Testing ◽

Inferior Temporal Cortex ◽

Independent Effect ◽

Older Individuals ◽

Apoe Ε4 ◽

Tau Pet ◽

Over Time

Abstract Purpose To examine associations between the APOE-ε2 and APOE-ε4 alleles and core Alzheimer’s disease (AD) pathological hallmarks as measured by amyloid-β (Aβ) and tau PET in older individuals without dementia. Methods We analyzed data from 462 ADNI participants without dementia who underwent Aβ ([18F]florbetapir or [18F]florbetaben) and tau ([18F]flortaucipir) PET, structural MRI, and cognitive testing. Employing APOE-ε3 homozygotes as the reference group, associations between APOE-ε2 and APOE-ε4 carriership with global Aβ PET and regional tau PET measures (entorhinal cortex (ERC), inferior temporal cortex, and Braak-V/VI neocortical composite regions) were investigated using linear regression models. In a subset of 156 participants, we also investigated associations between APOE genotype and regional tau accumulation over time using linear mixed models. Finally, we assessed whether Aβ mediated the cross-sectional and longitudinal associations between APOE genotype and tau. Results Compared to APOE-ε3 homozygotes, APOE-ε2 carriers had lower global Aβ burden (βstd [95% confidence interval (CI)]: − 0.31 [− 0.45, − 0.16], p = 0.034) but did not differ on regional tau burden or tau accumulation over time. APOE-ε4 participants showed higher Aβ (βstd [95%CI]: 0.64 [0.42, 0.82], p < 0.001) and tau burden (βstd range: 0.27-0.51, all p < 0.006). In mediation analyses, APOE-ε4 only retained an Aβ-independent effect on tau in the ERC. APOE-ε4 showed a trend towards increased tau accumulation over time in Braak-V/VI compared to APOE-ε3 homozygotes (βstd [95%CI]: 0.10 [− 0.02, 0.18], p = 0.11), and this association was fully mediated by baseline Aβ. Conclusion Our data suggest that the established protective effect of the APOE-ε2 allele against developing clinical AD is primarily linked to resistance against Aβ deposition rather than tau pathology.

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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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A Non-APOE Polygenic Risk Score for Alzheimer’s Disease Is Associated With Cerebrospinal Fluid Neurofilament Light in a Representative Sample of Cognitively Unimpaired 70-Year Olds

The Journals of Gerontology Series A ◽

10.1093/gerona/glab030 ◽

2021 ◽

Author(s):

Ingmar Skoog ◽

Silke Kern ◽

Jenna Najar ◽

Rita Guerreiro ◽

Jose Bras ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Cerebrospinal Fluid ◽

Amyloid Β ◽

Enzyme Linked Immunosorbent Assay ◽

Polygenic Risk Score ◽

Neurofilament Light ◽

Polygenic Risk ◽

Apoe Ε4 ◽

T Tau

Abstract The effect of Alzheimer’s disease (AD) polygenic risk scores (PRS) on amyloid and tau pathophysiology and neurodegeneration in cognitively unimpaired older adults is not known in detail. This study aims to investigate non-APOE AD-PRS and APOE ε4 in relation to AD pathophysiology evaluated by cerebrospinal fluid (CSF) biomarkers in a population-based sample of 70-year olds. A total of 303 dementia-free individuals from the Gothenburg H70 Birth Cohort Studies were included. Genotyping was performed using the NeuroChip, and AD-PRS were calculated. CSF levels of amyloid-β (Aβ42), total tau (t-tau), phosphorylated tau (p-tau), neurogranin (Ng), and neurofilament light (NfL) were measured with enzyme-linked immunosorbent assay. Associations were found between non-APOE PRS and both NfL (p = .001) and Aβ42 (p = .02), and between APOE ε4 and Aβ42 (p = 1e−10), t-tau (p = 5e−4), and p-tau (p = .002). Similar results were observed when only including individuals with CDR = 0, except for no evidence of an association between non-APOE PRS and Aβ42. There was an interaction between non-APOE PRS and Aβ42 pathology status in relation to NfL (p = .005); association was only present in individuals without Aβ42 pathology (p = 3e-4). In relation to Aβ42, there was a borderline interaction (p = .06) between non-APOE PRS and APOE ε4; association was present in ε4 carriers only (p = .03). Similar results were observed in individuals with CDR = 0 (n = 246). In conclusion, among cognitively healthy 70-year olds from the general population, genetic risk of AD beyond the APOE locus was associated with NfL in individuals without Aβ42 pathology, and with Aβ42 in APOE ε4 carriers, suggesting these associations are driven by different mechanisms.

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