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Article ; Online: Expression of ABCA7 in Alzheimer's disease.

Sleegers, Kristel

2020 Volume 139, Issue 5, Page(s) 941–942

MeSH term(s)	ATP-Binding Cassette Transporters/genetics ; Alleles ; Alzheimer Disease/genetics ; Gene Expression ; Genetic Association Studies ; Genetic Predisposition to Disease ; Humans
Chemical Substances	ABCA7 protein, human ; ATP-Binding Cassette Transporters
Language	English
Publishing date	2020-02-28
Publishing country	Germany
Document type	Journal Article ; Comment
ZDB-ID	1079-0
ISSN	1432-0533 ; 0001-6322
ISSN (online)	1432-0533
ISSN	0001-6322
DOI	10.1007/s00401-020-02136-8
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Article ; Online: The ABC's of Alzheimer risk gene ABCA7.

Duchateau, Lena / Wawrzyniak, Nicole / Sleegers, Kristel

Alzheimer's & dementia : the journal of the Alzheimer's Association

2024

Abstract: Alzheimer's disease (AD) is a growing problem worldwide. Since ABCA7's identification as a risk gene, it has been extensively researched for its role in the disease. We review its recently characterized structure and what the mechanistic insights teach ... ...

Abstract	Alzheimer's disease (AD) is a growing problem worldwide. Since ABCA7's identification as a risk gene, it has been extensively researched for its role in the disease. We review its recently characterized structure and what the mechanistic insights teach us about its function. We furthermore provide an overview of identified ABCA7 mutations, their presence in different ancestries and protein domains and how they might cause AD. For ABCA7 PTC variants and a VNTR expansion, haploinsufficiency is proposed as the most likely mode-of-action, although splice events could further influence disease risk. Overall, the need to better understand expression of canonical ABCA7 and its isoforms in disease is indicated. Finally, ABCA7's potential functions in lipid metabolism, phagocytosis, amyloid deposition, and the interplay between these three, is described. To conclude, in this review, we provide a comprehensive overview and discussion about the current knowledge on ABCA7 in AD, and what research questions remain. HIGHLIGHTS: Alzheimer's risk-increasing variants in ABCA7 can be found in up to 7% of AD patients. We review the recently characterized protein structure of ABCA7. We present latest insights in genetics, expression patterns, and functions of ABCA7.
Language	English
Publishing date	2024-03-31
Publishing country	United States
Document type	Journal Article ; Review
ZDB-ID	2211627-8
ISSN	1552-5279 ; 1552-5260
ISSN (online)	1552-5279
ISSN	1552-5260
DOI	10.1002/alz.13805
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Article ; Online: Definition of a Threshold for the Plasma Aβ42/Aβ40 Ratio Measured by Single-Molecule Array to Predict the Amyloid Status of Individuals without Dementia.

Colmant, Lise / Boyer, Emilien / Gerard, Thomas / Sleegers, Kristel / Lhommel, Renaud / Ivanoiu, Adrian / Lefèvre, Philippe / Kienlen-Campard, Pascal / Hanseeuw, Bernard

International journal of molecular sciences

2024 Volume 25, Issue 2

Abstract: Alzheimer's disease (AD) is characterized by amyloid beta (Aβ) plaques and hyperphosphorylated tau in the brain. Aβ plaques precede cognitive impairments and can be detected through amyloid-positron emission tomography (PET) or in cerebrospinal fluid ( ... ...

Abstract	Alzheimer's disease (AD) is characterized by amyloid beta (Aβ) plaques and hyperphosphorylated tau in the brain. Aβ plaques precede cognitive impairments and can be detected through amyloid-positron emission tomography (PET) or in cerebrospinal fluid (CSF). Assessing the plasma Aβ42/Aβ40 ratio seems promising for non-invasive and cost-effective detection of brain Aβ accumulation. This approach involves some challenges, including the accuracy of blood-based biomarker measurements and the establishment of clear, standardized thresholds to categorize the risk of developing brain amyloid pathology. Plasma Aβ42/Aβ40 ratio was measured in 277 volunteers without dementia, 70 AD patients and 18 non-AD patients using single-molecule array. Patients (
MeSH term(s)	Humans ; Amyloid beta-Peptides ; Amyloidogenic Proteins ; Positron-Emission Tomography ; Alzheimer Disease/diagnosis ; Brain ; Plaque, Amyloid
Chemical Substances	Amyloid beta-Peptides ; Amyloidogenic Proteins
Language	English
Publishing date	2024-01-18
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2019364-6
ISSN	1422-0067 ; 1422-0067 ; 1661-6596
ISSN (online)	1422-0067
ISSN	1422-0067 ; 1661-6596
DOI	10.3390/ijms25021173
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Article ; Online: Novel Alzheimer's disease risk genes: exhaustive investigation is paramount.

Sleegers, Kristel / Van Broeckhoven, Christine

Acta neuropathologica

2019 Volume 138, Issue 2, Page(s) 171–172

MeSH term(s)	ATP-Binding Cassette Transporters/genetics ; Alzheimer Disease/genetics ; Apolipoprotein E4/genetics ; Genetic Predisposition to Disease ; Genome-Wide Association Study ; Humans ; LDL-Receptor Related Proteins/genetics ; Membrane Transport Proteins/genetics ; Risk ; Sialic Acid Binding Ig-like Lectin 3/genetics
Chemical Substances	ABCA7 protein, human ; ATP-Binding Cassette Transporters ; Apolipoprotein E4 ; CD33 protein, human ; LDL-Receptor Related Proteins ; Membrane Transport Proteins ; SORL1 protein, human ; Sialic Acid Binding Ig-like Lectin 3
Language	English
Publishing date	2019-07-12
Publishing country	Germany
Document type	Editorial ; Introductory Journal Article
ZDB-ID	1079-0
ISSN	1432-0533 ; 0001-6322
ISSN (online)	1432-0533
ISSN	0001-6322
DOI	10.1007/s00401-019-02041-9
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Article: Understanding Alzheimer Disease at the Interface between Genetics and Transcriptomics.

Verheijen, Jan / Sleegers, Kristel

Trends in genetics : TIG

2018 Volume 34, Issue 6, Page(s) 434–447

Abstract: Over 25 genes are known to affect the risk of developing Alzheimer disease (AD), the most common neurodegenerative dementia. However, mechanistic insights and improved disease management remains limited, due to difficulties in determining the functional ... ...

Abstract	Over 25 genes are known to affect the risk of developing Alzheimer disease (AD), the most common neurodegenerative dementia. However, mechanistic insights and improved disease management remains limited, due to difficulties in determining the functional consequences of genetic associations. Transcriptomics is increasingly being used to corroborate or enhance interpretation of genetic discoveries. These approaches, which include second and third generation sequencing, single-cell sequencing, and bioinformatics, reveal allele-specific events connecting AD risk genes to expression profiles, and provide converging evidence of pathophysiological pathways underlying AD. Simultaneously, they highlight brain region- and cell-type-specific expression patterns, and alternative splicing events that affect the straightforward relation between a genetic variant and AD, re-emphasizing the need for an integrated approach of genetics and transcriptomics in understanding AD.
MeSH term(s)	Alzheimer Disease/genetics ; Alzheimer Disease/pathology ; Brain/metabolism ; Brain/pathology ; Brain Mapping/methods ; Computational Biology ; Gene Expression/genetics ; Genetic Predisposition to Disease ; Humans ; Metabolic Networks and Pathways/genetics ; Sequence Analysis, DNA/methods ; Single-Cell Analysis/methods ; Transcriptome/genetics
Language	English
Publishing date	2018-03-21
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	619240-3
ISSN	1362-4555 ; 0168-9525 ; 0168-9479
ISSN (online)	1362-4555
ISSN	0168-9525 ; 0168-9479
DOI	10.1016/j.tig.2018.02.007
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Article ; Online: Dissociating effects of aging and genetic risk of sporadic Alzheimer's disease on path integration.

Colmant, Lise / Bierbrauer, Anne / Bellaali, Youssef / Kunz, Lukas / Van Dongen, Jasper / Sleegers, Kristel / Axmacher, Nikolai / Lefèvre, Philippe / Hanseeuw, Bernard

Neurobiology of aging

2023 Volume 131, Page(s) 170–181

Abstract: Path integration is a spatial navigation ability that requires the integration of information derived from self-motion cues and stable landmarks, when available, to return to a previous location. Path integration declines with age and Alzheimer's disease ...

Abstract	Path integration is a spatial navigation ability that requires the integration of information derived from self-motion cues and stable landmarks, when available, to return to a previous location. Path integration declines with age and Alzheimer's disease (AD). Here, we sought to separate the effects of age and AD risk on path integration, with and without a landmark. Overall, 279 people participated, aged between 18 and 80 years old. Advanced age impaired the appropriate use of a landmark. Older participants furthermore remembered the location of the goal relative to their starting location and reproduced this initial view without considering that they had moved in the environment. This lack of adaptative behavior was not associated with AD risk. In contrast, participants at genetic risk of AD (apolipoprotein E ε4 carriers) exhibited a pure path integration deficit, corresponding to difficulty in performing path integration in the absence of a landmark. Our results show that advanced-age impacts landmark-supported path integration, and that this age effect is dissociable from the effects of AD risk impacting pure path integration.
MeSH term(s)	Humans ; Aged ; Aged, 80 and over ; Alzheimer Disease/genetics ; Aging/genetics ; Adaptation, Psychological ; Apolipoprotein E4/genetics ; Cues
Chemical Substances	Apolipoprotein E4
Language	English
Publishing date	2023-07-29
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	604505-4
ISSN	1558-1497 ; 0197-4580
ISSN (online)	1558-1497
ISSN	0197-4580
DOI	10.1016/j.neurobiolaging.2023.07.025
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Article ; Online: The role of ABCA7 in Alzheimer's disease: evidence from genomics, transcriptomics and methylomics.

De Roeck, Arne / Van Broeckhoven, Christine / Sleegers, Kristel

Acta neuropathologica

2019 Volume 138, Issue 2, Page(s) 201–220

Abstract: Genome-wide association studies (GWAS) originally identified ATP-binding cassette, sub-family A, member 7 (ABCA7), as a novel risk gene of Alzheimer's disease (AD). Since then, accumulating evidence from in vitro, in vivo, and human-based studies has ... ...

Abstract	Genome-wide association studies (GWAS) originally identified ATP-binding cassette, sub-family A, member 7 (ABCA7), as a novel risk gene of Alzheimer's disease (AD). Since then, accumulating evidence from in vitro, in vivo, and human-based studies has corroborated and extended this association, promoting ABCA7 as one of the most important risk genes of both early-onset and late-onset AD, harboring both common and rare risk variants with relatively large effect on AD risk. Within this review, we provide a comprehensive assessment of the literature on ABCA7, with a focus on AD-related human -omics studies (e.g. genomics, transcriptomics, and methylomics). In European and African American populations, indirect ABCA7 GWAS associations are explained by expansion of an ABCA7 variable number tandem repeat (VNTR), and a common premature termination codon (PTC) variant, respectively. Rare ABCA7 PTC variants are strongly enriched in AD patients, and some of these have displayed inheritance patterns resembling autosomal dominant AD. In addition, rare missense variants are more frequent in AD patients than healthy controls, whereas a common ABCA7 missense variant may protect from disease. Methylation at several CpG sites in the ABCA7 locus is significantly associated with AD. Furthermore, ABCA7 contains many different isoforms and ABCA7 splicing has been shown to associate with AD. Besides associations with disease status, these genetic and epigenetic ABCA7 markers also showed significant correlations with AD endophenotypes; in particular amyloid deposition and brain morphology. In conclusion, human-based -omics studies provide converging evidence of (partial) ABCA7 loss as an AD pathomechanism, and future studies should make clear if interventions on ABCA7 expression can serve as a valuable therapeutic target for AD.
MeSH term(s)	ATP-Binding Cassette Transporters/deficiency ; ATP-Binding Cassette Transporters/genetics ; ATP-Binding Cassette Transporters/physiology ; Alzheimer Disease/ethnology ; Alzheimer Disease/genetics ; Amyloid/metabolism ; Animals ; Atrophy ; Brain/metabolism ; Brain/pathology ; Codon, Nonsense ; Cognition/physiology ; CpG Islands ; DNA Methylation ; Disease Models, Animal ; Ethnic Groups/genetics ; Female ; Genes, Dominant ; Genetic Predisposition to Disease ; Genomics ; Humans ; Lipid Metabolism/genetics ; Male ; Mice ; Minisatellite Repeats ; Mutation, Missense ; Polymorphism, Single Nucleotide ; Risk ; Transcriptome
Chemical Substances	ABCA7 protein, human ; ATP-Binding Cassette Transporters ; Abca7 protein, mouse ; Amyloid ; Codon, Nonsense
Language	English
Publishing date	2019-03-22
Publishing country	Germany
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	1079-0
ISSN	1432-0533 ; 0001-6322
ISSN (online)	1432-0533
ISSN	0001-6322
DOI	10.1007/s00401-019-01994-1
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Article ; Online: Genetic variations underlying Alzheimer's disease: evidence from genome-wide association studies and beyond.

Cuyvers, Elise / Sleegers, Kristel

The Lancet. Neurology

2016 Volume 15, Issue 8, Page(s) 857–868

Abstract: With the advent of genome-wide association studies (GWAS) and next-generation sequencing, more than 20 risk loci that affect Alzheimer's disease have been identified. These loci are estimated to explain about 28% of the heritability of liability, 30% of ... ...

Abstract	With the advent of genome-wide association studies (GWAS) and next-generation sequencing, more than 20 risk loci that affect Alzheimer's disease have been identified. These loci are estimated to explain about 28% of the heritability of liability, 30% of familial risk, and over 50% of sibling recurrence risk of developing Alzheimer's disease. These estimates are high in comparison with those for other complex diseases for which more risk loci have been discovered, such as type 2 diabetes, which is mostly a result of the strong effect of APOE ɛ4 and to a lesser extent the rare variant TREM2 p.Arg47His. The search for functionally relevant genetic variants in risk loci detected in GWAS has revealed that the genetic variations underlying Alzheimer's disease include common variants affecting expression and splicing, a functional intragenic copy number variation, and rare pathogenic variants in risk loci, some of which might lead to familial Alzheimer's disease. An understanding of the contribution of these variants to the development of Alzheimer's disease has several clinical implications, including enhancing diagnostic accuracy and providing targets for the development of novel treatments.
MeSH term(s)	Alzheimer Disease/genetics ; Apolipoproteins E/genetics ; Genetic Predisposition to Disease/genetics ; Genetic Variation/genetics ; Genome-Wide Association Study ; Humans ; Membrane Glycoproteins/genetics ; Receptors, Immunologic/genetics
Chemical Substances	Apolipoproteins E ; Membrane Glycoproteins ; Receptors, Immunologic ; TREM2 protein, human
Language	English
Publishing date	2016
Publishing country	England
Document type	Journal Article ; Review ; Research Support, Non-U.S. Gov't
ZDB-ID	2079704-7
ISSN	1474-4465 ; 1474-4422
ISSN (online)	1474-4465
ISSN	1474-4422
DOI	10.1016/S1474-4422(16)00127-7
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Article ; Online: CSF biomarker analysis of ABCA7 mutation carriers suggests altered APP processing and reduced inflammatory response.

Duchateau, Lena / Küҫükali, Fahri / De Roeck, Arne / Wittens, Mandy M J / Temmerman, Joke / Weets, Ilse / Timmers, Maarten / Engelborghs, Sebastiaan / Bjerke, Maria / Sleegers, Kristel

Alzheimer's research & therapy

2023 Volume 15, Issue 1, Page(s) 195

Abstract: Background: The Alzheimer's disease (AD) risk gene ABCA7 has suggested functions in lipid metabolism and the immune system. Rare premature termination codon (PTC) mutations and an expansion of a variable number of tandem repeats (VNTR) polymorphism in ... ...

Abstract	Background: The Alzheimer's disease (AD) risk gene ABCA7 has suggested functions in lipid metabolism and the immune system. Rare premature termination codon (PTC) mutations and an expansion of a variable number of tandem repeats (VNTR) polymorphism in the gene, both likely cause a lower ABCA7 expression and hereby increased risk for AD. However, the exact mechanism of action remains unclear. By studying CSF biomarkers reflecting different types of AD-related pathological processes, we aim to get a better insight in those processes and establish a biomarker profile of mutation carriers. Methods: The study population consisted of 229 AD patients for whom CSF was available and ABCA7 sequencing and VNTR genotyping had been performed. This included 28 PTC mutation and 16 pathogenic expansion carriers. CSF levels of Aβ Results: Carriers of ABCA7 expansion mutations had significantly lower Aβ Conclusions: Our results are suggestive for an effect on APP processing by repeat expansions given the changes in the amyloid-related CSF biomarkers that were found in carriers. The decrease in YKL-40 levels in expansion carriers moreover suggests that these patients potentially have a reduced inflammatory response to AD damage. Moreover, our findings suggest the existence of a mechanism, independent of lowered expression, affecting neuropathology in expansion carriers.
MeSH term(s)	Humans ; Alzheimer Disease/pathology ; ATP-Binding Cassette Transporters/genetics ; Biomarkers ; Chitinase-3-Like Protein 1/metabolism ; Codon, Nonsense ; Mutation/genetics ; Amyloid/metabolism
Chemical Substances	ABCA7 protein, human ; ATP-Binding Cassette Transporters ; Biomarkers ; Chitinase-3-Like Protein 1 ; Codon, Nonsense ; Amyloid
Language	English
Publishing date	2023-11-09
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2506521-X
ISSN	1758-9193 ; 1758-9193
ISSN (online)	1758-9193
ISSN	1758-9193
DOI	10.1186/s13195-023-01338-y
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Article ; Online: Molecular genetics of early-onset Alzheimer's disease revisited.

Cacace, Rita / Sleegers, Kristel / Van Broeckhoven, Christine

Alzheimer's & dementia : the journal of the Alzheimer's Association

2016 Volume 12, Issue 6, Page(s) 733–748

Abstract: As the discovery of the Alzheimer's disease (AD) genes, APP, PSEN1, and PSEN2, in families with autosomal dominant early-onset AD (EOAD), gene discovery in familial EOAD came more or less to a standstill. Only 5% of EOAD patients are carrying a ... ...

Abstract	As the discovery of the Alzheimer's disease (AD) genes, APP, PSEN1, and PSEN2, in families with autosomal dominant early-onset AD (EOAD), gene discovery in familial EOAD came more or less to a standstill. Only 5% of EOAD patients are carrying a pathogenic mutation in one of the AD genes or a apolipoprotein E (APOE) risk allele ε4, most of EOAD patients remain unexplained. Here, we aimed at summarizing the current knowledge of EOAD genetics and its role in ongoing approaches to understand the biology of AD and disease symptomatology as well as developing new therapeutics. Next, we explored the possible molecular mechanisms that might underlie the missing genetic etiology of EOAD and discussed how the use of massive parallel sequencing technologies triggered novel gene discoveries. To conclude, we commented on the relevance of reinvestigating EOAD patients as a means to explore potential new avenues for translational research and therapeutic discoveries.
MeSH term(s)	Alzheimer Disease/diagnosis ; Alzheimer Disease/genetics ; Amyloid beta-Protein Precursor/genetics ; Apolipoproteins E/genetics ; Humans ; Models, Molecular ; Molecular Biology/methods ; Mutation/genetics ; Presenilin-1/genetics ; Presenilin-2/genetics
Chemical Substances	Amyloid beta-Protein Precursor ; Apolipoproteins E ; Presenilin-1 ; Presenilin-2
Language	English
Publishing date	2016-06
Publishing country	United States
Document type	Journal Article ; Review
ZDB-ID	2211627-8
ISSN	1552-5279 ; 1552-5260
ISSN (online)	1552-5279
ISSN	1552-5260
DOI	10.1016/j.jalz.2016.01.012
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