Apolipoprotein E ϵ4 Allele Has No Effect on Age at Onset or Duration of Disease in Cases of Frontotemporal Dementia with Pick- or Microvacuolar-Type Histology

doi:10.1006/exnr.2000.7387

Experimental Neurology

Volume 163, Issue 2, June 2000, Pages 452-456

https://doi.org/10.1006/exnr.2000.7387 Get rights and content

Abstract

Frontotemporal dementia (FTD) is the second most common cause of presenile dementia. Here we have investigated the frequency of the ϵ4 allele of the Apolipoprotein (APOE) gene in FTD and in other non-Alzheimer forms of dementia related to FTD such as Motor Neurone disease dementia, semantic dementia, progressive aphasia, progressive supranuclear palsy, and corticobasal degeneration. In none of these diagnostic groups did we find a significant increase in the APOE ϵ4 allelic frequency, compared to population values. Neither did we observe any affects of the ϵ4 allele upon age at onset or duration of disease. We conclude therefore that polymorphic variations in the APOE gene do not modulate either the occurrence or progression of these non-Alzheimer forms of dementia.

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Citation Excerpt :
Recently, a study of 134 CBD cases found no significant associations of ε2 or ε4 with disease risk (Zhao et al., 2018). The role of APOE variants in risk of developing PSP has been controversial (Anouti et al., 1996; Baba et al., 2006; Morris et al., 2000; Morris et al., 2001; Pickering-Brown et al., 2000; Tabaton et al., 1995). A higher frequency of APOE ε2 allele, but not ε4 allele, in PSP was found in a Japanese cohort (Sawa et al., 1997).
Atypical parkinsonism syndromes are a heterogeneous group of neurodegenerative disorders that include corticobasal degeneration (CBD), Lewy body dementia (LBD), multiple system atrophy (MSA), and progressive supranuclear palsy (PSP). The APOE ε4 allele is a well-established risk factor for Alzheimer's disease; however, the role of APOE in atypical parkinsonism syndromes remains controversial. To examine the associations of APOE ε4 and ε2 alleles with risk of developing these syndromes, a total of 991 pathologically-confirmed atypical parkinsonism cases were genotyped using the Illumina NeuroChip array. We also performed genotyping and logistic regression analyses to examine APOE frequency and associated risk in patients with Alzheimer's disease (n = 571) and Parkinson's disease (n = 348). APOE genotypes were compared to those from neurologically healthy controls (n = 591). We demonstrate that APOE ε4 and ε2 carriers have a significantly increased and decreased risk, respectively, of developing Alzheimer's disease (ε4: OR: 4.13, 95% CI: 3.23–5.26, p = 3.67 × 10⁻³⁰; ε2: OR: 0.21, 95% CI: 0.13–0.34; p = 5.39 × 10⁻¹⁰) and LBD (ε4: OR: 2.94, 95% CI: 2.34–3.71, p = 6.60 × 10⁻²⁰; ε2: OR = OR: 0.39, 95% CI: 0.26–0.59; p = 6.88 × 10⁻⁶). No significant associations with risk for CBD, MSA, or PSP were observed. We also show that APOE ε4 decreases survival in a dose-dependent manner in Alzheimer's disease and LBD. Taken together, this study does not provide evidence to implicate a role of APOE in the neuropathogenesis of CBD, MSA, or PSP. However, we confirm association of the APOE ε4 allele with increased risk for LBD, and importantly demonstrate that APOE ε2 reduces risk of this disease.
TMEM106B and ApoE polymorphisms in CHMP2B-mediated frontotemporal dementia (FTD-3)
2017, Neurobiology of Aging
Citation Excerpt :
The apolipoprotein E (ApoE) ε4 allele is a risk factor in sporadic AD whereas the ApoE ε2 allele seems to be protective (Boccardi et al., 2004; Giau et al., 2015; Gustafson et al., 1997; Raber, 2008; Raichlen and Alexander, 2014); however, the role of ApoE in FTD is unclear. Several studies have investigated the correlation of ApoE genotypes and disease but the results are somewhat contradictive (Bernardi et al., 2006; Boccardi et al., 2004; Chiò et al., 2016; Engelborghs et al., 2006; Giau et al., 2015; Gustafson et al., 1997; Mehta et al., 2007; Minthon et al., 1997; Pickering-Brown et al., 2000; Riemenschneider et al., 2002; van Blitterswijk et al., 2014b; Verpillat et al., 2002). The presence of an ApoE ε2 allele significantly modulated the risk of FTD in ALS patients independent of C9orf72 expansion status, whereas ApoE ε4 was ineffectual (Chiò et al., 2016).
Single-nucleotide polymorphisms in the TMEM106B gene have been identified as a risk factor in frontotemporal dementia (FTD). The major allele of SNP rs3173615 is a risk factor in sporadic FTD, whereas the minor allele seems protective in GRN- and C9orf72-mediated FTD. The role of apolipoprotein E (ApoE) in FTD is uncertain, though an established risk factor in Alzheimer's disease. In a unique Danish family, inherited FTD is caused by a mutation in the CHMP2B gene located on chromosome 3 (FTD-3). In this family, both risk factors TMEM106B and ApoE were analyzed and correlated to age at onset (AAO) and progression in terms of age at institutionalization (AAI) and age at death (AAD). Although TMEM106B and CHMP2B share cellular function in that both localize to endolysosomes, TMEM106B genotypes appeared to have no influence on the clinical disease course. ApoE ε4 was found to be a protective factor with later AAO and AAI, whereas ε2 seemed to aggravate the disease with earlier AAO and AAD. These results indicate ApoE ε2 as a risk factor in FTD-3 and suggest a protective role of ε4.
Apolipoprotein e polymorphisms in frontotemporal lobar degeneration: A meta-analysis
2013, Alzheimer's and Dementia
Citation Excerpt :
Two additional studies compared PPA patients and control subjects. Data from 33 articles met the inclusion criteria [6,13–44]. Stevens and colleagues [44], Pickering-Brown and associates [43], Ingelson and coworkers [42], Boccardi and colleagues [41], and Acciarri and associates [40] were excluded because the cohorts of patients they analyzed were later included in papers by Rosso and coworkers [25], Srinivasan and colleagues [30], Fabre and associates [21], Boccardi and coworkers [27], and Seripa and colleagues [37], respectively.
Case–control studies have not been consistent in showing association between apolipoprotein E (APOE) polymorphisms and frontotemporal lobar degeneration (FTLD), producing contradictory findings. The study objective was to define and quantify further the disease risk associated with the carriage of different APOE alleles to determine whether APOE gene polymorphism is a risk factor for FTLD.
A systematic review of all case–control studies investigating the association between the APOE gene and FTLD up to December 2011 was conducted. Case–control studies using clinical or pathological criteria for FTLD and reporting APOE allelic or genotypic data were included. Pooled odds ratios (ORs) were estimated using a random effects model, and 95% confidence intervals (CIs) were calculated.
Twenty-eight case–control studies met the inclusion criteria. Carriage of the ε2 allele had no effect on disease risk. On the contrary, carriage of the ε4 allele was associated with a significantly increased disease risk (ε4 carriers vs non-ε4 carriers: OR, 1.94; 95% CI, 1.43–2.64; ε4 vs ε3 allele: OR, 1.83; 95% CI, 1.34–2.52). Furthermore, a gene–dosage effect for the ε4 allele was found. There was no evidence of publication bias, but heterogeneity between the studies was high.
Our study provides evidence for an association between the APOE ε4 allele and frontotemporal lobar degeneration.
The genetics of frontotemporal dementia
2008, Handbook of Clinical Neurology
This chapter emphasizes that frontotemporal dementia (FTD) is the second most common form of primary degenerative dementia after Alzheimer's disease (AD). The onset of the disease is most commonly in middle age between 45 and 65 years. However, there is huge variation in the age at onset and FTD represents up to 20% of presenile dementia cases. The chapter describes that disease duration also varies significantly in different patients, ranging from 2 to 20 years, with men and women having approximately equal incidence. Significantly, a large proportion of FTD patients have a family history of dementia, consistent with a strong genetic component to the disease. Clinically, FTD is characterized by profound behavioral and personality change occurring in a context of relative preservation of perception and memory. A motor disorder, with akinesia and rigidity, often develops in patients as the disease progresses although this is normally absent at onset. The chapter concludes that considerable progress has been made over the past decade in unraveling the genetics of FTD. There are more genetic causes of FTD yet to be identified and hopefully when these genes are found, it will provide a greater understanding of the pathogenesis of this terrible disease.
Epidemiological aspects of frontotemporal dementia
2008, Handbook of Clinical Neurology
Citation Excerpt :
Regarding genetic risk factors for FTD, most emphasis has been placed on the apolipoprotein (Apo) E gene and the MAPT gene because of known associations with other types of dementia and tauopathies. Although the ApoE4 allele has consistently been associated with AD in many studies (Slooter et al., 1998), its association with FTD is controversial as several studies have shown conflicting results (Stevens et al., 1997; Geschwind et al., 1998; Pickering‐Brown et al., 1999). A number of clinical studies showed a significant association of sporadic FTD with the ApoE4 allele (Fabre et al., 2001; Rosso et al., 2002), while another study showed only an association with the age at onset (Minthon et al., 1997).
This chapter explains that frontotemporal dementia (FTD) is a neurodegenerative disorder, characterized by progressive behavioral change and a disturbance of language and frontal functions. Semantic dementia (SD) and primary progressive aphasia (PPA) are clinical subtypes of FTD that present with prominent language disturbance; both show the same neuropathological characteristics as in typical FTD cases, suggesting a common etiology. The chapter reviews the epidemiological studies on FTD, with emphasis on prevalence studies and patients characteristics. Number of clinical subtypes are described in the chapter―all of which are associated with similar neuropathological substrates; familiar FTD is discussed separately. It also summarizes a number of case-control studies regarding genetic and non-genetic risk factors for sporadic FTD.
Neuropathology of Pick body disease
2008, Handbook of Clinical Neurology
Citation Excerpt :
Although the number of autopsied cases of PiBD is limited, most of the reports claimed overrepresentation of the apolipoprotein ε4 genotype in pathologically verified tauopathies (Schneider et al., 1995), more specifically in sporadic PiBD (Kalman et al., 2000; Mott et al., 2005) and its association with an earlier onset (Farrer et al., 1995). However, conflicting results are available (Gomez‐Isla et al., 1996; Pickering‐Brown et al., 2000b). As opposed to the more frequent H1 haplotype of the tau gene in progressive supranuclear palsy (PSP), a non‐significant increase (Russ et al., 2001) or no increase (Morris et al., 2002) in the H2H2 haplotype was reported in autopsy‐verified PiBD.
This chapter describes pick body disease on the basis of the presence of specific microscopic lesions, argyrophilic intraneuronal Pick bodies (PiBs) and ballooned neurons. Failure to identify a specific cause of the disease led to a speculation that the cortical atrophy of Pick's disease is accentuated in “primary atrophic centers,” macroscopically evident as Pick's atrophy. The chapter describes that in the majority of cases, “primary atrophic centers” are roughly in parallel with phylogenetically new areas, where myelination of the white matter occurs relatively late after birth. The chapter emphasizes that recent advances clarified molecular events related to the nature or mechanism, probably closer to the ultimate cause of PiBD and related conditions. “Pick bodies” are not always homogeneous from both biochemical and morphological viewpoints and await a reasonable definition. Moreover, the reported molecular events around PiBs are not yet sufficient to explain the localization, the extent of lesions or regional differences in brainswith PiBs, which have an actual relevance to the diagnosis and care of the patients. Because these two different aspects are of the same origin, partly shared with other degenerative processes, multidisciplinary approaches to PiBD will strengthen the understanding of this disease.

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¹: To whom correspondence and reprint requests should be addressed at Department of Medicine, University of Manchester, Oxford Road, Manchester M13 9PT, Great Britain. Fax: 44 161 275 5423; E-mail: [email protected].

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Regular ArticleApolipoprotein E ϵ4 Allele Has No Effect on Age at Onset or Duration of Disease in Cases of Frontotemporal Dementia with Pick- or Microvacuolar-Type Histology

Abstract

Exp. Neurol.

Neurosci. Lett.

Neurodegeneration

Neurosci. Lett.

Am. J. Hum. Genet.

Neurosci. Lett.

Am. J. Hum. Genet.

Lancet

Localization of frontotemporal dementia with Parkinsonism in an Australian kindred to chromosome 17q21–22

Ann. Neurol.

Chromosome 17 and hereditary dementia: Linkage studies in three non-Alzheimer families and kindreds with late onset FAD

Neurology

Familial non-specific dementia maps to chromosome 3

Hum. Mol. Genet.

Clinical, neuropsychological and neuropathological criteria for fronto-temporal dementia

J. Neurol. Neurosurg. Psychiatr.

Pathogenic implications of mutations in the tau gene in pallido-ponto-nigral degeneration and related neurodegenerative disorders linked to chromosome 17

Proc. Natl. Acad. Sci. USA

Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer's disease in late onset families

Science

ApoE4 in clinically diagnosed Alzheimer's disease, frontal lobe degeneration and non-demented controls

Neurobiol. Aging

Neurodegenerative disorders with extensive tau pathology: A comparative study and review

Ann. Neurol.

Clinical and pathological correlates of Apolipoprotein E ϵ4 in Alzheimer's disease

Ann. Neurol.

Apolipoprotein E E4 allele frequency in non-Alzheimer dementias

Neurobiol. Aging

Apolipoprotein E genotype and Alzheimer's disease

Lancet

Hereditary frontotemporal dementia is linked to chromosome 17q21–q22, A genetic and clinicopathological study of three Dutch families

Ann. Neurol.

Association of missense and 5-splice-site mutations in tau with the inherited dementia FTDP-17

Nature

Regular Article
Apolipoprotein E ϵ4 Allele Has No Effect on Age at Onset or Duration of Disease in Cases of Frontotemporal Dementia with Pick- or Microvacuolar-Type Histology