P4-033 Dose dependent effect of APOE ε4 on behavioral symptoms in frontal lobe dementia patients

Engelborghs, Sebastiaan; Dermaut, Bart; Mariën, Peter; Symons, A.; Vloeberghs, Ellen; Maertens, Karen; Somers, Nore; Goeman, J.; Rademakers, R; Broeck, Marleen Van den; Pickut, Barbara A.; Cruts, Marc; Broeckhoven, Christine Van; Deyn, Peter Paul De

doi:10.1016/s0197-4580(04)81591-4

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“…Increased levels of tau and phospho-tau were detected in the cerebrospinal fluid of individuals with AD and at least 1 copy of APOE-ε4. 18,19 Several reports have also indicated that APOE-ε4 carriers diagnosed with frontotemporal dementia display significantly higher brain atrophy and exacerbated behavioral deficits, [20][21][22] in addition to a lower age of disease onset. 23 Additionally, we recently documented more severe regional brain degeneration in APOE-ε4 individuals diagnosed with Pick's disease, corticobasal degeneration, and progressive supranuclear palsy.…”

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confidence: 99%

Apolipoprotein E4 Reduction with Antisense Oligonucleotides Decreases Neurodegeneration in a Tauopathy Model

Litvinchuk

Huynh

Shi

et al. 2021

Annals of Neurology

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Objective: Apolipoprotein E (ApoE) genotype is the strongest genetic risk factor for late-onset Alzheimer's disease, with the ε4 allele increasing risk in a dose-dependent fashion. In addition to ApoE4 playing a crucial role in amyloid-β deposition, recent evidence suggests that it also plays an important role in tau pathology and tau-mediated neurodegeneration. It is not known, however, whether therapeutic reduction of ApoE4 would exert protective effects on tau-mediated neurodegeneration. Methods: Herein, we used antisense oligonucleotides (ASOs) against human APOE to reduce ApoE4 levels in the P301S/ApoE4 mouse model of tauopathy. We treated P301S/ApoE4 mice with ApoE or control ASOs via intracerebroventricular injection at 6 and 7.5 months of age and performed brain pathological assessments at 9 months of age. Results: Our results indicate that treatment with ApoE ASOs reduced ApoE4 protein levels by~50%, significantly protected against tau pathology and associated neurodegeneration, decreased neuroinflammation, and preserved synaptic density. These data were also corroborated by a significant reduction in levels of neurofilament light chain (NfL) protein in plasma of ASO-treated mice. Interpretation: We conclude that reducing ApoE4 levels should be explored further as a therapeutic approach for APOE4 carriers with tauopathy including Alzheimer's disease.

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confidence: 99%

Apolipoprotein E4 Reduction with Antisense Oligonucleotides Decreases Neurodegeneration in a Tauopathy Model

Litvinchuk

Huynh

Shi

et al. 2021

Annals of Neurology

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“…The study cohort comprised 37 subjects with probable (n=18) or definite (n=19) dementia due to AD, and 32 probable (n=21) or definite (n=11) FTLD patients (Table 1). Patients were selected from the Memory Clinic of Hospital Network Antwerp (Engelborghs et al, 2006(Engelborghs et al, , 2003. To ensure a high certainty level of dementia subtypes for patients without definite diagnosis, only patients with extensive clinical follow-up were included.…”

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confidence: 99%

Improved Alzheimer’s disease versus frontotemporal lobar degeneration differential diagnosis combining EEG and neurochemical biomarkers

Laton

Goossens

Wiels

et al. 2019

Preprint

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Introduction: Distinguishing between two of the most common causes of dementia, Alzheimer disease (AD) and frontotemporal lobar degeneration (FTLD), on clinical diagnostic criteria alone has poor diagnostic accuracy. Promising tools to increase the diagnostic accuracy of AD are the use of cerebrospinal fluid (CSF) biomarkers and electroencephalography (EEG), which is being investigated as a diagnostic tool for neurodegenerative brain disorders. In this study, we investigated the utility of EEG-based biomarkers in comparison and in addition to established neurochemical biomarkers in the AD versus FTLD differential diagnosis. Methods: Our study cohort comprised 37 AD and 32 FTLD patients, of which 19 AD and 11 FTLD had definite diagnoses. All these participants had CSF biomarker analyses resulting in four neurochemical (NCM) biomarkers (Aβ1-42, T-tau, P-tau181 and Nf-L) and underwent 19-channel resting-state EEG. From the EEG spectra, dominant frequency peaks (DFP) were extracted in four regions resulting in four dominant frequencies (in left-temporal, frontal, right-temporal and parieto-occipital regions). This yielded a total of eight features (4 NCM + 4 EEG), which we used to train and test a classifier and assess the diagnostic value of the markers separately (using only the NCM or EEG subset) and combined. Results: The classification accuracies were much higher when training and testing on the definite subgroup than on the whole group. Furthermore, we found that the NCM feature subset allowed a better accuracy than the EEG feature subset, both when training and testing on the whole group (NCM 82% vs EEG 72%), as on the definite group only (92% vs 86%). Using both feature subsets together increased the accuracy to 86% in the whole group and 94% in the definite subgroups. Another interesting finding was the presence of two spectral peaks in a considerable number of patients in both groups. Conclusion: Combining EEG with neurochemical biomarkers resulted in differential diagnostic accuracies of 86% in clinically diagnosed AD and FTD patients and of 94% in patients having a definite diagnosis. Furthermore, we found evidence that the slowing down of the dominant EEG rhythm might be a gradual appearance of a slow rhythm and fading out of the normal ground rhythm, rather than a gradual slowing down of the ground rhythm. Finally, we have discovered two differences in the occurrence of the dominant EEG frequency: people lacking a clear dominant peak almost all had definite AD, while people with two peaks more often had FTLD. These unexpected but interesting findings need to be explored further.

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P4-033 Dose dependent effect of APOE ε4 on behavioral symptoms in frontal lobe dementia patients

Cited by 2 publications

References 0 publications

Apolipoprotein E4 Reduction with Antisense Oligonucleotides Decreases Neurodegeneration in a Tauopathy Model

Apolipoprotein E4 Reduction with Antisense Oligonucleotides Decreases Neurodegeneration in a Tauopathy Model

Improved Alzheimer’s disease versus frontotemporal lobar degeneration differential diagnosis combining EEG and neurochemical biomarkers

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