APOE is a potential modifier gene in an autosomal dominant form of frontotemporal dementia (IBMPFD)

Mehta, Sarju G.; Watts, G.F.; Adamson, Jennifer; Hutton, Mike; Umberger, Geanie; Xiong, Shuling; Ramdeen, Sheena; Lovell, Mark A.; Kimonis, Virginia; Smith, Charles D.

doi:10.1097/gim.0b013e31802d830d

Cited by 49 publications

(38 citation statements)

References 34 publications

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“…It has been suggested that there may be an interaction between different apoE genotypes and tau pathology (1, 9, 22, 28, 48). To determine whether the onset or distribution profile of the tau pathology was altered by replacing the mouse apoE gene with the human apoE4 alleles, we immunostained sections from 3xTg-AD, 3xTg-AD/ε4h and 3xTg-AD/ε4H mice with a human-specific anti-tau antibody.…”

Section: Resultsmentioning

confidence: 99%

Genetically Altering Aβ Distribution from the Brain to the Vasculature Ameliorates Tau Pathology

et al. 2009

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The inheritance of the ε4 allele of the apolipoprotein E (apoE) gene is the major genetic risk factor for developing late-onset Alzheimer disease. In transgenic mice overexpressing amyloid precursor protein (APP), replacing the endogenous mouse apoE gene with the human apolipoprotein E4 (apoE4) gene alters the distribution of amyloid-β (Aβ) deposits from the brain parenchyma to the vasculature. However, the effects of this distribution on the onset and progression of tau pathology remain to be established. To address this issue, we used a genetic approach to replace the endogenous apoE gene with the human apoE4 allele in the 3xTg-AD mice. We showed that changing Aβ distribution from the parenchyma to the vasculature drastically reduces the tau pathology. The 3xTg-AD mice expressing the human apoE4 gene were virtually depleted of any somatodendritic tau deposits. These data strongly suggest that the somatodendritic tau accumulation is dependent on the parenchyma Aβ deposits.

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Section: Resultsmentioning

confidence: 99%

Genetically Altering Aβ Distribution from the Brain to the Vasculature Ameliorates Tau Pathology

et al. 2009

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“…Loss-of-function mutations in VCP are expected to cause ER stress, oxidative stress, and mitochondria-dependent apoptosis [95*]. Interestingly, patients with VCP mutations who also carry an apolipoprotein E4 (ApoE4) allele are more likely to develop FTD [96], suggesting that apoE4 is a genetic modifier for the clinical presentation of FTLD; thus apoE4 targeted therapy, which is under investigation [97] may benefit patients with FTLD. CHMP2B is involved in endosomal trafficking through the ESCRT (endosomal secretory complex required for trafficking) III complex, which may be involved in degradation of growth factors.…”

Section: Future Directionsmentioning

confidence: 99%

New approaches to the treatment of frontotemporal lobar degeneration

Vossel

Miller

2008

Current Opinion in Neurology

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Purpose of review-Treatment approaches for frontotemporal lobar degeneration (FTLD) are rapidly evolving with improved understanding of the disease. This brief review highlights recent advances.Recent findings-Early-onset dementia has a devastating impact on families and rids its victims of their most productive and rewarding years. Over the past ten years, FTLD has emerged as the commonest cause of dementia under the age of 60 years, outstripping even Alzheimer's disease in prevalence. Remarkable progress has occurred in our understanding of FTLD both as a set of distinctive clinical syndromes and as a set of disorders with unique genetic and pathological profiles. While there are no Food and Drug Administration approved medications for FTLD, new evidence of specific genetic and neurochemical defects are beginning to provide a strong rationale for pharmacological treatment.Summary-Behavioral changes, which are common in behavioral variant FTD and semantic dementia, often respond to treatment with selective serotonin inhibitors. Memantine also holds promise to treat neuropsychiatric symptoms, but more prospective trials are needed. With better understanding of pathogenic molecular pathways involving microtubule associated protein tau, progranulin and TDP-43, potential disease-modifying therapies are being studied in animal models and approaching human trials.

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“…There is a considerable intra and inter familial phenotypic variability in a kindred with VCP disease. The R155C mutation is associated with an earlier onset of disease when compared to the R155H mutation (Mehta et al, 2007). Interestingly, mutations in VCP gene have also been associated with non-syndromic familial FTD (Rohrer et al, 2011) and 1–2% of familial ALS (Johnson et al, 2010).…”

Section: Introductionmentioning

confidence: 99%

Psychological Impact of Predictive Genetic Testing in VCP Inclusion Body Myopathy, Paget Disease of Bone and Frontotemporal Dementia

Surampalli

Khare

Kubrussi

et al. 2015

Journal of Genetic Counseling

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Inclusion Body Myopathy associated with Paget’s disease of Bone and Fronto-temporal Dementia, also known as multisystem proteinopathy is an autosomal dominant, late onset neurodegenerative disorder caused by mutations in Valosin containing protein (VCP) gene. This study aimed to assess uptake and decision making for predictive genetic testing and the impact on psychological well-being. Individuals who had participated in the gene discovery study with a 50% a priori risk of inheriting VCP disease were sent a letter of invitation offering genetic counseling and testing and were also invited to participate in this psychosocial study. A total of 102 individuals received an invitation and 33 individuals participated in genetic counseling and testing (32.3%) with 29 completing baseline questionnaires. Twenty completed the follow-up post-test Hospital Anxiety and Depression Scale questionnaire including 13 who had tested positive. Mean risk perception at baseline was 50.1%. Reasons for testing included planning for the future, relieving uncertainty, informing children and satisfying curiosity. At baseline, one quarter of the participants had high levels of anxiety. However, scores were normal one year following testing. In this small cohort, one third of individuals at 50% risk chose pre-symptomatic testing. Although one quarter of those choosing testing had high anxiety at baseline, this was not evident at follow-up.

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APOE is a potential modifier gene in an autosomal dominant form of frontotemporal dementia (IBMPFD)

Cited by 49 publications

References 34 publications

Genetically Altering Aβ Distribution from the Brain to the Vasculature Ameliorates Tau Pathology

Genetically Altering Aβ Distribution from the Brain to the Vasculature Ameliorates Tau Pathology

New approaches to the treatment of frontotemporal lobar degeneration

Psychological Impact of Predictive Genetic Testing in VCP Inclusion Body Myopathy, Paget Disease of Bone and Frontotemporal Dementia

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