APOE region molecular signatures of Alzheimer's disease across races/ethnicities

Kulminski, Alexander M.; Shu, Leonardo; Loika, Yury; Nazarian, Alireza; Arbeev, Konstantin G.; Ukraintseva, Svetlana V.; Yashin, Anatoliy I.; Culminskaya, Irina

doi:10.1016/j.neurobiolaging.2019.11.007

Cited by 28 publications

(38 citation statements)

References 41 publications

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“…The analyses focused on the same 32 SNPs representing the BCAM‐NECTIN2‐TOMM40‐APOE‐APOC1 (19q13.3) region (Table S1) as in previous studies 26 . We selected SNPs available from common GWAS arrays, which were genotyped directly in at least two cohorts and which were not in strong LD in the mega sample of all studies ( r 2 <0.8).…”

Section: Methodsmentioning

confidence: 99%

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Haplotype architecture of the Alzheimer's risk in the APOE region via co‐skewness

Kulminski

Philipp

Loika

et al. 2020

Alzheimer's & Dementia: Diagnosis, Assessment &

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Introduction As a multifactorial polygenic disorder, Alzheimer's disease (AD) can be associated with complex haplotypes or compound genotypes. Methods We examined associations of 4960 single nucleotide polymorphism (SNP) triples, comprising 32 SNPs from five genes in the apolipoprotein E gene ( APOE ) region with AD in a sample of 2789 AD‐affected and 16,334 unaffected subjects. Results We identified a large number of 1127 AD‐associated triples, comprising SNPs from all five genes, in support of definitive roles of complex haplotypes in predisposition to AD. These haplotypes may not include the APOE ε4 and ε2 alleles. For triples with rs429358 or rs7412, which encode these alleles, AD is characterized mainly by strengthening connections of the ε4 allele and weakening connections of the ε2 allele with the other alleles in this region. Discussion Dissecting heterogeneity attributed to AD‐associated complex haplotypes in the APOE region will target more homogeneous polygenic profiles of people at high risk of AD.

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Section: Methodsmentioning

confidence: 99%

“…Some studies attempted to access the differences in LD structures in the APOE region between AD‐affected and unaffected subjects qualitatively 22,23 . Recently we reported significant associations of both the entire SNP patterns and specific SNPs pairs in the APOE region with AD in populations of different ancestries 24–26 …”

Section: Introductionmentioning

confidence: 99%

Haplotype architecture of the Alzheimer's risk in the APOE region via co‐skewness

Kulminski

Philipp

Loika

et al. 2020

Alzheimer's & Dementia: Diagnosis, Assessment &

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“…Recently, Kulminski et al (2019Kulminski et al ( , 2020 and Wolters et al (2019) documented new AD risk variants in 11 more genes in 19q13.3 (Table 3) Together with its AD-associated genes, the 19q13.3 locus includes more than 50 other genes with diverse functions (Table 3), including lipid metabolism and transport (ApoC1), inflammatory mediators (NFkB, PVRL2), reproductive hormones (luteinizing hormone), and transcription factors (NFkB, zinc finger). While many of these genes do not have reported AD associations, we include them because of the possibilities of co-regulation.…”

Section: Apoe Genotype and The Chromosome 19q13 Gene Clustermentioning

confidence: 99%

“…The linkage disequilibrium (LD) showed that the roles of the ε4and ε2coding SNPs in AD were dependent on the other SNPs in this locus. Differences between white and nonwhite populations in LD structure and changes in LD between the AD-affected and -unaffected subjects may explain differences in risks of AD for these alleles in these populations (Kulminski et al, 2020).…”

Section: Apoe Genotype and The Chromosome 19q13 Gene Clustermentioning

confidence: 99%

APOE Alleles and Diet in Brain Aging and Alzheimer’s Disease

Yassine

Finch

2020

Front. Aging Neurosci.

101

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The APOE gene alleles modify human aging and the response to the diet at many levels with diverse pleotropic effects from gut to brain. To understand the interactions of APOE isoforms and diet, we analyze how cellular trafficking of apoE proteins affects energy metabolism, the immune system, and reproduction. The age-accelerating APOE4 allele alters the endosomal trafficking of cell surface receptors that mediate lipid and glucose metabolism. The APOE4 allele is the ancestral human allele, joined by APOE3 and then APOE2 in the human species. Under conditions of high infection, uncertain food, and shorter life expectancy, APOE4 may be adaptive for reducing mortality. As humans transitioned into modern less-infectious environments and longer life spans, APOE4 increased risks of aging-related diseases, particularly impacting arteries and the brain. The association of APOE4 with glucose dysregulation and body weight promotes many aging-associated diseases. Additionally, the APOE gene locus interacts with adjacent genes on chromosome 19 in haplotypes that modify neurodegeneration and metabolism, for which we anticipate complex gene-environment interactions. We summarize how diet and Alzheimer's disease (AD) risk are altered by APOE genotype in both animal and human studies and identify gaps. Much remains obscure in how APOE alleles modify nutritional factors in human aging. Identifying risk variant haplotypes in the APOE gene complex will clarify homeostatic adaptive responses to environmental conditions.

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“…TOMM40 was the first APOE gene neighbor with AD risk variants, 3 joined by APOC1 , APOC2 , APOC4 , and NECTIN2 in complex AD haplotypes. More than 30 single nucleotide variants (SNPs) in coding and non‐coding adjacent sequences are AD‐associated; subsets may act in cis combination with APOE or independently 4–6 . APOE cluster genes encode diverse functions: lipoproteins ( APOE , APOC1 , ‐ C2, ‐C4 ), inflammation ( RELB , TGFB1 ), metabolism ( IGFL1 , TOMM40 ), brain development (NTF4 ), reproduction via gonadotrophins ( CGB , LHB ), and viral resistance ( APOE , NECTIN2 ).…”

Section: Narrativementioning

confidence: 99%

The APOE gene cluster responds to air pollution factors in mice with coordinated expression of genes that differs by age in humans

Haghani

Thorwald

Morgan

et al. 2020

Alzheimer's & Dementia

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Little is known of gene–environment interactions for Alzheimer's disease (AD) risk factors. Apolipoprotein E (APOE) and neighbors on chromosome 19q13.3 have variants associated with risks of AD, but with unknown mechanism. This study describes novel links among the APOE network, air pollution, and age‐related diseases. Mice exposed to air pollution nano‐sized particulate matter (nPM) had coordinate responses of Apoe‐Apoc1‐Tomm40 in the cerebral cortex. In humans, the AD vulnerable hippocampus and amygdala had stronger age decline in APOE cluster expression than the AD‐resistant cerebellum and hypothalamus. Using consensus weighted gene co‐expression network, we showed that APOE has a conserved co‐expressed network in rodent and primate brains. SOX1, which has AD‐associated single nucleotide polymorphisms, was among the co‐expressed genes in the human hippocampus. Humans and mice shared 87% of potential binding sites for transcription factors in APOE cluster promoter, suggesting similar inducibility and a novel link among environment, APOE cluster, and risk of AD.

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APOE region molecular signatures of Alzheimer's disease across races/ethnicities

Cited by 28 publications

References 41 publications

Haplotype architecture of the Alzheimer's risk in the APOE region via co‐skewness

Haplotype architecture of the Alzheimer's risk in the APOE region via co‐skewness

APOE Alleles and Diet in Brain Aging and Alzheimer’s Disease

The APOE gene cluster responds to air pollution factors in mice with coordinated expression of genes that differs by age in humans

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