Genome-wide analysis identifies novel loci influencing plasma apolipoprotein E concentration and Alzheimer’s disease risk

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

LXR is a member of a group of nuclear receptors, PPARs, each of which upon activation heterodimerizes with RXR to form a functional transcription factor along with coactivators that regulate expression of many genes, including those involved in AD pathogenesis.

“LXR is a member of a group of nuclear receptors, peroxisome proliferator-activated receptors (PPARs; other members are PPARγ and PPARδ), each of which upon activation heterodimerizes with retinoid X receptor (RXR) to form a functional transcription factor along with coactivators that act to regulate expression of many genes, including those involved in AD pathogenesis [34].”

• cites [34] Mandrekar-Colucci S, Landreth GE. Nuclear receptors as therapeutic targets for Alzheimer’s disease. Expert Opin Ther Targets. 2011;15:1085–97. sourceDisputed

  Split into 2 atoms — 0 confirmed, 1 partially supported, 1 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

  Checked by a reasoning model — may be wrong.

  Experimental — accuracy not yet measured

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

The APOE polymorphism is the most studied, successfully replicated, and well-established risk factor for Alzheimer's disease, with APOE*2 protective and APOE*4 risk compared to APOE*3.

“The APOE polymorphism is the most studied, successfully replicated, and well-established risk factor for AD where APOE*2 is the protective allele and APOE*4 is the risk allele as compared to APOE*3 [7–10].”

• cites [7] Seshadri S. Apolipoprotein E ε4 allele and the lifetime risk of Alzheimer’s disease. Arch Neurol. 1995;52:1074–9. sourceNot checked — no full text of the source
• cites [8] Farrer LA, Cupples LA, Haines JL, Hyman B, Kukull WA, Mayeux R, et al. Effects of age, sex, and ethnicity on the association between apolipoprotein E genotype and Alzheimer disease. A meta-analysis. ApoE and Alzheimer disease meta analysis consortium. JAMA. 1997;278:1349–56. sourceNot checked — no full text of the source
• cites [9] Kamboh MI. Molecular genetics of late-onset Alzheimer’s disease. Ann Hum Genet. 2004;68:381–404. sourceSupported
• cites [10] Genin E, Hannequin D, Wallon D, Sleegers K, Hiltunen M, Combarros O, et al. ApoE and Alzheimer disease: a major gene with semi-dominant inheritance. Mol Psychiatry. 2011;16:903–7. sourcePartly supported

  The Introduction reports higher Alzheimer’s disease odds for APOE 3/4 and 4/4 than for APOE 3/3, and a protective effect of APOE 2 in Caucasian subjects. The Results say the APOE 4/4 estimate is consistent with previous estimates, supporting a replicated association. The paper does not establish the comparative claim that APOE is the most studied risk factor. (LLM, conf=0.84)

  Experimental — accuracy not yet measured

May combine two claims.

Only 5 of the 12 SNPs in the APOE region were present in the amyloid-PET GWAS data, and all 5 were associated with amyloid deposition.

“Only 5 of the 12 SNPs in the APOE region were present in the amyloid-PET GWAS data [25] and all 5 were also associated with amyloid deposition.”

• cites [25] Yan Q, Nho K, Del-Aguila JL, Wang X, Risacher SL, Fan KH, et al. Genome-wide association study of brain amyloid deposition as measured by Pittsburgh Compound-B (PiB)-PET imaging. Mol Psychiatry. 2021;26:309–21. sourcePartly supported

  The Results section (‘Conditional analysis in the APOE region’; page unavailable) reports APOE-region SNPs associated with PiB retention, supporting the general association with amyloid deposition. It does not identify the citing paper’s set of 12 SNPs or establish that exactly five of them were present in this GWAS, so the specific five-of-twelve claim is not supported by our copy. (LLM, conf=0.82)

  Experimental — accuracy not yet measured

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

The effect of APOE*4 on Alzheimer's disease risk is dose-dependent; one and two copies increase AD risk by 3.5- and 14.5-fold, respectively.

“The effect of APOE*4 is dose-dependent; one and two copies of E*4 increase the AD risk by 3.5- and 14.5-fold, respectively [10].”

• cites [10] Genin E, Hannequin D, Wallon D, Sleegers K, Hiltunen M, Combarros O, et al. ApoE and Alzheimer disease: a major gene with semi-dominant inheritance. Mol Psychiatry. 2011;16:903–7. sourcePartly supported

  The Results report an odds ratio of 14.49 for two APOE*4 copies relative to APOE 3/3, supporting the 14.5 figure and the dose-dependent association. The Introduction gives 3.2, not 3.5, for one copy and explicitly distinguishes odds ratios from an individual's actual disease risk. No page numbers are available in our copy. (LLM, conf=0.87)

  Experimental — accuracy not yet measured

Probably not a substantial claim: may not pass S3 (load-bearing).

APOE*4 is associated with Alzheimer's disease-related proteinopathies, including amyloid-β, tau, α-synuclein, and TDP-43.

“APOE*4 is also associated with AD-related proteinopathies, including amyloid-β, tau, α-synuclein, and TDP-43 [11, 12].”

• cites [11] Belloy ME, Napolioni V, Greicius MD. A quarter century of APOE and alzheimer’s disease: progress to date and the path forward. Neuron 2019;101:820–38. sourcePartly supported

  The review’s AD pathogenesis section reports an established association between APOE4 and amyloid accumulation. Its APOE and Sex section discusses an APOE4–tau pathology association, and Other Neurodegenerative Disorders reports evidence linking APOE4 to TDP-43 pathology. The α-synuclein part is less firmly supported: that section links APOE4 to dementia with Lewy bodies but treats an independent link to its pathology as likely rather than established, and says APOE has not clearly been associated with other synucleinopathies. Page numbers were not available in our copy. (LLM, conf=0.83)

  Experimental — accuracy not yet measured
• cites [12] Long JM, Holtzman DM. Alzheimer disease: an update on pathobiology and treatment strategies. Cell 2019;179:312–39. sourcePartly supported

  The Pathophysiology of AD > ApoE section links APOE ε4 to increased amyloid-β deposition and discusses ApoE4 effects in tauopathy models, while noting conflicting tau findings. The passages do not establish an APOE ε4 association with α-synuclein or TDP-43; searches for both terms found no supporting passage. Page numbers were not available in our copy. (LLM, conf=0.88)

  Experimental — accuracy not yet measured

May combine two claims.

ApoE promotes metabolic steps in reverse cholesterol by rapidly clearing HDL from circulation when present on HDL in the absence of ApoC3, while coexisting ApoC3 with ApoE on HDL attenuates this beneficial effect on coronary heart disease.

“While ApoE promotes metabolic steps in reverse cholesterol by rapidly clearing HDL from circulation when present on HDL in the absence of ApoC3, coexisting of ApoC3 with ApoE on HDL attenuates this beneficial effect on CHD [32].”

• cites [32] Morton AM, Koch M, Mendivil CO, Furtado JD, Tjønneland A, Overvad K, et al. Apolipoproteins E and CIII interact to regulate HDL metabolism and coronary heart disease risk. JCI Insight. 2018;3:98045. sourceSupported

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

GBA3 is involved in glucose metabolism pathways and its genetic variation has been reported to be associated with fasting glucose and insulin levels.

“GBA3 is involved in glucose metabolism pathways and its genetic variation has been reported to be associated with fasting glucose and insulin levels [35].”

• cites [35] Buchanan VL, Wang Y, Blanco E, Graff M, Albala C, Burrows R, et al. Genome‐wide association study identifying novel variant for fasting insulin and allelic heterogeneity in known glycemic loci in chilean adolescents: the santiago longitudinal study. Pediatr Obes. 2021;16:e12765. sourcePartly supported

  The Discussion (page unavailable) says GBA3 is involved in galactose metabolism, not specifically glucose metabolism, and places it among genes containing variants with suggestive associations with the study’s glycemic traits. It does not establish that GBA3 variation is associated with both fasting glucose and fasting insulin; the Results (page unavailable) distinguish suggestive loci for the two traits without assigning both to GBA3. (LLM, conf=0.87)

  Experimental — accuracy not yet measured

May combine two claims.

ApoE4 association with lower ApoE level is more likely due to misfolding and accumulation of ApoE protein in the endoplasmic reticulum from an ionic interaction between Arg-61 in the N-terminal domain and Glu-255 in the C-terminal domain in the E4 isoform; this domain interaction is not present in the other two ApoE isoforms.

“ii) more likely, it is the result of misfolding and accumulation of ApoE protein in endoplasmic reticulum due to an ionic interaction between Arg-61 in the N-terminal domain and Glu-255 in the C-terminal domain in the E4 isoform; this domain interaction is not present in the other two ApoE isoforms [3, 4].”

• cites [3] Mahley RW. Central nervous system lipoproteins: ApoE and regulation of cholesterol metabolism. Arterioscler Thromb Vasc Biol. 2016;36:1305–15. sourcePartly supported

  Split into 2 atoms — 1 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

  Experimental — accuracy not yet measured
• cites [4] Marais AD. Apolipoprotein E in lipoprotein metabolism, health and cardiovascular disease. Pathology. 2019;51:165–76. sourceNot checked — no full text of the source

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

The AVIL-TSFM-CYP27B1-TSPAN31 locus is gene-dense and has previously been implicated with multiple distinct autoimmune disorders.

“which is gene-dense and previously been implicated with multiple distinct autoimmune disorders [48].”

• cites [48] Alcina A, Fedetz M, Fernández O, Saiz A, Izquierdo G, Lucas M, et al. Identification of a functional variant in the KIF5A-CYP27B1-METTL1-FAM119B locus associated with multiple sclerosis. Med Genet. 2013;50:25–33. sourceSupported

May combine two claims.

The cited finding provides confirmation to our independent observation and affirms the association of ZPR1/rs964184 with ApoE level being genuine.

“This provides confirmation to our independent observation and affirms the association of ZPR1/rs964184 with ApoE level being genuine.”

• cites [41] Steffen BT, Pankow JS, Norby FL, Lutsey PL, Demmer RT, Guan W, et al. Proteomics analysis of genetic liability of abdominal aortic aneurysm identifies plasma neogenin and kit Ligand: the ARIC Study. Arterioscler Thromb Vasc Biol. 2023;43:367–78. sourceCould not verify

  The Results section, “Associations of proteins and AAA-related SNPs” (page unavailable), reports that rs964184 was associated with 33 plasma proteins, highlighting apolipoprotein A-V and protein phosphatase inhibitor 2. Neither that passage nor the additional passages searched for rs964184 and apolipoprotein E establish an association with ApoE levels; the paper discusses an APOE-linked variant, rs429358, separately. (LLM, conf=0.70)

  Experimental — accuracy not yet measured

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

ZPR1/ZNF259 promoter region has the binding sequence for PPARs, which may activate genes involved in glucose and cholesterol metabolism, including APOE, via hepatocyte nuclear factor 4 alpha activation.

“ZPR1/ZNF259 promoter region has the binding sequence for PPARs, which may activate genes involved in glucose and cholesterol metabolism, including APOE, via hepatocyte nuclear factor 4 alpha activation [39].”

• cites [39] Guan F, Niu Y, Zhang T, Liu S, Ma L, Qi T, et al. Two-stage association study to identify the genetic susceptibility of a novel common variant of rs2075290 in ZPR1 to type 2 diabetes. Sci Rep. 2016;6:29586. sourcePartly supported

  The paper’s introductory passage (indexed under Abstract; no page number provided) says the ZPR1/ZNF259 promoter binds PPARG proteins 1 and 2, which bind HNF4α; it says HNF4α activates genes involved in glucose and cholesterol metabolism. It does not identify APOE as one of those genes. The Discussion mentions a different gene, APOA5, adjacent to ZPR1. (LLM, conf=0.88)

  Experimental — accuracy not yet measured

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

PLK2 binds and phosphorylates Thr-668 and Ser-675 residues of amyloid precursor protein, which instigate Aβ production in hippocampal neurons, suggesting that PLK2 may be an important target molecule for AD treatment.

“PLK2 (polo-like kinase 2) that binds and phosphorylates Thr-668 and Ser-675 residues of amyloid precursor protein, which instigate Aβ production in hippocampal neurons, suggesting that PLK2 may be an important target molecule for AD treatment [46].”

• cites [46] Lee Y, Lee JS, Lee KJ, Turner RS, Hoe H-S, Pak DTS. Polo-like kinase 2 phosphorylation of amyloid precursor protein regulates activity-dependent amyloidogenic processing. Neuropharmacology 2017;117:387–400. sourceSupported

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

rs964184 has been associated with triglycerides, type 2 diabetes, and abdominal aortic aneurysm.

“has been associated with triglycerides [39, 40], type 2 diabetes [39] and abdominal aortic aneurysm (AAA) [41].”

• cites [39] Guan F, Niu Y, Zhang T, Liu S, Ma L, Qi T, et al. Two-stage association study to identify the genetic susceptibility of a novel common variant of rs2075290 in ZPR1 to type 2 diabetes. Sci Rep. 2016;6:29586. sourceSupported
• cites [40] Bandesh K, Prasad G, Giri AK, Kauser Y, Upadhyay M, INDICO, et al. Genome-wide association study of blood lipids in Indians confirms universality of established variants. J Hum Genet. 2019;64:573–87. sourceNot checked — no full text of the source
• cites [41] Steffen BT, Pankow JS, Norby FL, Lutsey PL, Demmer RT, Guan W, et al. Proteomics analysis of genetic liability of abdominal aortic aneurysm identifies plasma neogenin and kit Ligand: the ARIC Study. Arterioscler Thromb Vasc Biol. 2023;43:367–78. sourceSupported

May combine two claims.

The mechanism of BMP2-mediated upregulation of ApoE operates through a novel PPARγ/ApoE axis downstream of BMP2 and its receptor BMP-R2; BMP2/BMP-R2 signaling leads to activation of PPARγ and resulting production and secretion of ApoE.

“The mechanism of BMP2-mediated upregulation of ApoE is operated through a novel PPARγ/ApoE axis down stream of BMP2 and its receptor, BMP-R2. The BMP2/BMP-R2 signaling leads to activation of PPARγ and the resulting production and secretion of ApoE [43].”

• cites [43] Hansmann G, de Jesus Perez VA, Alastalo TP, Alvira CM, Guignabert C, Bekker JM, et al. An antiproliferative BMP-2/PPARγ/apoE axis in human and murine SMCs and its role in pulmonary hypertension. J Clin Invest. 2008; 118:1846–57. sourceSupported

May combine two claims.

In addition to the established and opposite associations of APOE*4 and APOE*2 with both AD risk and ApoE level, multiple additional independent AD-associated SNPs reported in the APOE region and reported SNPs in some known non-APOE AD loci are also associated with plasma ApoE level.

“We show here that in addition to the established and opposite associations of APOE*4 and APOE*2 with both AD risk and ApoE level, multiple additional independent AD-associated SNPs reported in the APOE region [23] as well as reported SNPs in some known non-APOE AD loci [5], are also associated with plasma ApoE level.”

• cites [23] Jansen IE, Savage JE, Watanabe K, Bryois J, Williams DM, Steinberg S, et al. Genome-wide meta-analysis identifies new loci and functional pathways influencing Alzheimer’s disease risk. Nat Genet. 2019;51:404–13. sourcePartly supported

  Split into 2 atoms — 0 confirmed, 2 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

  Experimental — accuracy not yet measured
• cites [5] Kamboh MI. Genomics and functional genomics of alzheimer’s disease. Neurotherapeutics. 2022;19:152–72. sourceSupported

May combine two claims.

Murine data in targeted replacement APOE mice and APOE knock-in mice support this observation, wherein reduced brain ApoE level and reduced basal dendritic spine density in the entorhinal cortex were found in ApoE4 mice compared with ApoE3 mice.

“The murine data in targeted replacement APOE mice and APOE knock-in mice support this observation, wherein reduced brain ApoE level and reduced basal dendritic spine density in the entorhinal cortex were found in ApoE4 mice compared with ApoE3 mice [49].”

• cites [49] Sepulveda J, Luo N, Nelson M, Ng CAS, Rebeck GW. Independent APOE4 knock-in mouse models display reduced brain APOE protein, altered neuroinflammation, and simplification of dendritic spines. J Neurochem. 2022;163:247–59. sourceSupported

Classified as probably not a substantial claim.

To determine the association of plasma ApoE level with risk of incident dementia, hazard ratios per 1-SD lower ApoE level were obtained in 3031 subjects using Cox regression adjusted for baseline age, sex, ethnicity, education, BMI, and research site.

“To determine the association of plasma ApoE level with risk of incident dementia, we obtained hazard ratios (HRs) per 1-standard deviation (SD) lower ApoE level in 3031 subjects using the Cox regression model [21] adjusted for baseline age, sex, ethnicity, education, BMI, and the research site.”

• cites [21] Koch M, DeKosky ST, Goodman M, Sun J, Furtado JD, Fitzpatrick AL, et al. Association of apolipoprotein E in lipoprotein subspecies with risk of dementia. JAMA Netw Open. 2020;3:e209250. sourceSupported

May combine two claims.

In the GEM study, lower baseline whole plasma ApoE concentration was not associated with incident dementia (HR = 1.00; 95% CI 0.91-1.10) or Alzheimer's disease (HR = 1.01; 95% CI 0.92-1.12).

“While lower ApoE concentration in whole plasma was not associated with either incident dementia (HR = 1.00; 95% CI: 0.91–1.10) or AD (HR = 1.01: 95% CI: 0.92 to 1.12)”

Probably not a substantial claim: may not pass S3 (load-bearing).

In the GEM study, exposure to Ginkgo biloba showed no impact on plasma ApoE level (P = 0.769).

“exposure to Ginkgo biloba showed no impact on plasma ApoE level (P = 0.769; Fig. S2).”

May combine two claims.

Plasma ApoE level-associated independent variants, especially in the APOE region, were also associated with Alzheimer's disease risk and amyloid deposition in the brain.

“Plasma ApoE level-associated independent variants, especially in the APOE region, were also associated with AD risk and amyloid deposition in the brain”

Probably not a substantial claim: may not pass S3 (load-bearing).

In the GEM study, plasma ApoE level was significantly higher in females than males (P = 1.18E-24).

“ApoE level was significantly higher in females than males (P = 1.18E-24; Fig. S1b)”

Probably not a substantial claim: may not pass S1 (asserted), S3 (load-bearing), S4 (based).

The APOE-region independent signals together explained about 22% of the variance in plasma ApoE level.

“together they explained about 22% of the variance in plasma ApoE level”

• Also stated in: § Discussion · plain

  “Altogether, the 11 independent SNPs in the APOE region explained about 22% of the variance of plasma ApoE level.”

May combine two claims. The quote only partly states this claim.

Conditional analyses identified ten independent signals in the APOE region, including five with lowering effect and five with elevating effect, plus one partially independent signal.

“we identified 10 independent signals, including five with lowering effect: APOC4/rs35136575(intergenic), APOE/rs429358(p.Cys112Arg), APOE/rs4055 09(promoter), APOC1/rs157595(intergenic) and APOC1P1/rs5112 (ncRNA-exonic); and five with elevating effect: APOE/rs7412 (p.Arg158Cys), APOE/rs769446(promoter), CBLC/rs148933445(intronic), APOC1/rs144311893(intergenic), and APOC1P/rs114448690 (ncRNA-intron”

May combine two claims.

On chromosome 11, three additional independent signals were identified: BUD13/rs180326 (P = 2.62E-07), SIK3/rs4936359 (P = 4.85E-07), and ZPR1/rs35120633(p.A264V) (P = 3.48E-07).

“we identified three additional independent signals: BUD13/rs180326 (P = 2.62E-07), SIK3/rs4936359 (P = 4.85E-07); and ZPR1/rs35120633(p.A264V) (P = 3.48E-07).”

May combine two claims.

Three SNPs in the partially independent signal are potentially functional: PVRL2/rs6857 (3'UTR), TOMM40/rs71352238 (promoter), and TOMM40/rs11556505 (p.Phe131Leu).

“Three of these are potentially functional: PVRL2/rs6857(3’UTR), TOMM40/rs71352238 (promoter), TOMM40/rs11556505 (p.Phe131Leu).”

May combine two claims.

In the APOE region, APOC1P1-APOC4/rs35136575 was the most significant SNP associated with lower ApoE levels (β = −0.3799; P = 6.34E-24), showing a stronger effect than APOE*4.

“APOC1P1-APOC4/rs35136575 was the most significant SNP associated with lower ApoE levels (β = −0.3799; P = 6.34E-24), showing an even stronger effect than APOE*4.”

May combine two claims.

Six regions on chromosomes 1, 4, 7, 11, 19, and 20 showed genome-wide significant signals (P < 5E-08) along with a subthreshold GWS signal on chromosome 5 (P = 5.49E-08).

“Six regions on chromosomes 1, 4, 7, 11, 19, and 20 showed genome-wide significant (GWS) signals (P < 5E-08) along with a subthreshold GWS signal (P = 5.49E-08) on chromosome 5”

May combine two claims.

PVRL2/rs6857 is in LD (R2 = 0.69) with APOE*4/rs429358, while TOMM40/rs71352238 and rs11556505 are in moderate LD (R2 = 0.46-0.48) with APOE*4.

“While PVRL2/rs6857 is in LD (R2 = 0.69) with APOE*4/rs429358, the other two are only in a moderate LD (R2 = 0.46– 0.48) with the latter”

Probably not a substantial claim: may not pass S3 (load-bearing).

Of the novel loci, no expression data were available for PPARGC1A, GBA3, and BMP2 genes in GTEx.

“Of the novel loci, no expression data were available for PPARGC1A, GBA3, and BMP2 genes in GTEx.”

Probably not a substantial claim: may not pass S3 (load-bearing).

APOE and other genes in the APOE region have relatively high expression in the brain.

“APOE along with other genes in this region have relatively high expression in the brain (Fig. S6).”

May combine two claims.

All 8 Jansen et al. Alzheimer's disease-risk SNPs showed the expected association with plasma ApoE level in this study, where the AD risk allele was associated with lower ApoE level and the AD protective allele with higher ApoE level.

“All these SNPs showed the expected association with plasma ApoE level in our study where AD risk allele was associated with lower ApoE level and AD protective allele with higher ApoE level (Table S6).”

May combine two claims.

Baseline low plasma ApoE level present in HDL lacking ApoC3 was a risk factor for incident dementia and worse cognitive function, but not in HDL having ApoC3.

“Baseline low plasma ApoE level present in HDL lacking ApoC3 was a risk factor for incident dementia and worse cognitive function, but not in HDL having ApoC3.”

May combine two claims.

FUMA SNP2GENE mapped 116 pre-defined SNPs with GWS or suggestive associations to 79 coding genes, including 49 in novel regions and 17 in the APOE region.

“A total of 116 pre-defined SNPs with GWS or suggestive associations (Table S3) with ApoE levels were used as input to SNP2GENE that mapped to 79 coding genes, including 49 in the novel regions and 17 in the APOE region”

May combine two claims.

The top SNP in each of the 21 non-APOE AD loci was associated at nominal significance with plasma ApoE level, with the strongest association in the ABCA7 region (P = 9.88E-05).

“The top SNP in each AD region in our plasma ApoE GWAS was associated at nominal significance with ApoE level (Table S7) with the strongest association observed in the ABCA7 region (P = 9.88E-05).”

May combine two claims.

Genes at novel loci were implicated with delirium on chromosome 11 (P = 3.15E-08) and hippocampal volume on chromosomes 11 and 12 (P = 3.50E-14).

“genes at novel loci were implicated with delirium on chromosome 11 (P = 3.15E-08) and hippocampal volume on chromosomes 11 and 12 (P = 3.50E-14; Table S5).”

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

Brain expression of OPRD1, PLK2, PHF14 and ZPR1/ZNF259 was modest, while multiple candidate genes on chromosomes 11 and 12 showed high expression.

“While the brain expression of OPRD1, PLK2, PHF14 and ZPR1/ZNF259 was modest, multiple candidate genes on chromosomes 11 and 12 showed high expression.”

May combine two claims.

Chromosome 12 signal rs2470341 is intergenic and located near the AVIL-TSFM-CYP27B1-TSPAN31 locus.

“Chromosome 12 signal, rs2470341, is intergenic and located near the AVIL-TSFM-CYP27B1-TSPAN31 locus”

May combine two claims.

This GWAS, in addition to confirming the previously reported association of APOE*2 and APOE*4, has identified additional independent signals in the APOE region as well as seven new loci on other chromosomes affecting plasma ApoE level.

“This is the largest GWAS on plasma ApoE level that, in addition to confirming the previously reported association of APOE*2 and APOE*4, has identified additional independent signals in the APOE region as well as seven new loci on other chromosomes affecting plasma ApoE level.”

May combine two claims.

The ApoE level-associated independent variants, especially in the APOE region, are associated with AD risk and amyloid deposition.

“We also found that the ApoE level-associated independent variants, especially in the APOE region, are associated with AD risk and amyloid deposition”

May combine two claims.

Before this study, no large genome-wide association study on plasma ApoE level had been reported; only a small GWAS of 570 subjects had identified the known APOE region signal.

“Previously a small genome-wide association study (GWAS) was carried out on only 570 subjects with plasma ApoE level that identified only the known signal in the APOE region [16].”

• cites [16] Cruchaga C, Kauwe JSK, Nowotny P, Bales K, Pickering EH, Mayo K, et al. Cerebrospinal fluid APOE levels: an endophenotype for genetic studies for alzheimer’s disease. Hum Mol Genet. 2012;21:4558–71. sourceNot checked — no full text of the source

May combine two claims.

APOE polymorphism is associated with variation in plasma ApoE concentration; APOE*4 is associated with lower and APOE*2 with higher plasma ApoE level compared to APOE*3.

“APOE polymorphism is also associated with variation in plasma ApoE concentration; APOE*4 is associated with lower and APOE*2 with higher level as compared to the common APOE*3 allele [13, 14].”

• cites [13] Kaprio J, Ferrell RE, Kottke BA, Kamboh MI, Sing CF. Effects of polymorphisms in apolipoproteins E, A-IV, and H on quantitative traits related to risk for cardiovascular disease. Arterioscler Thromb. 1991;11:1330–48. sourceNot checked — no full text of the source
• cites [14] Rasmussen KL, Tybjærg-Hansen A, Nordestgaard BG, Frikke-Schmidt R. Plasma levels of apolipoprotein E and risk of dementia in the general population. Ann Neurol. 2015;77:301–11. sourceNot checked — no full text of the source

May combine two claims.

Complementary data suggest that at least a part of the Alzheimer's disease genetic risk and amyloid deposition is mediated by genetically determined plasma ApoE variation, especially in the APOE region.

“These complementary data suggest that at least a part of the AD genetic risk and amyloid deposition is mediated by genetically determined plasma ApoE variation, especially in the APOE region.”

May combine two claims.

APOC4/rs35136575 has a RegulomeDB score of 1d and can affect transcription binding.

“APOC4/rs35136575 with a RegulomeDB score of 1d, can affect transcription binding.”

May combine two claims.

Another independent signal represented by three LD-linked SNPs (rs157595, rs439401, rs584007) has RegulomeDB scores of 1f, 1c, and 1f, respectively, indicating that these SNPs have regulatory functions as they can affect transcription binding and expression of a gene target.

“Another independent signal represented by three LD-linked SNPs (rs157595, rs439401 and rs584007) have RegulomeDB scores of 1f, 1c, and 1f, respectively, indicating that these SNPs have regulatory functions as they can affect transcription binding and expression of a gene target.”

Classified as probably not a substantial claim.

Recent population-based epidemiological studies suggest that low plasma ApoE level may be a risk factor for incident dementia.

“recent population-based epidemiological studies suggest that low plasma ApoE level may be a risk factor for incident dementia [14, 15].”

• cites [14] Rasmussen KL, Tybjærg-Hansen A, Nordestgaard BG, Frikke-Schmidt R. Plasma levels of apolipoprotein E and risk of dementia in the general population. Ann Neurol. 2015;77:301–11. sourceNot checked — no full text of the source
• cites [15] Rasmussen KL, Tybjærg-Hansen A, Nordestgaard BG, Frikke-Schmidt R. Plasma apolipoprotein E levels and risk of dementia: a Mendelian randomization study of 106,562 individuals. Alzheimers Dement. 2018;14:71–80. sourceNot checked — no full text of the source

Classified as probably not a substantial claim. May combine two claims.

A similar mechanism may occur in the brain where lipoproteins are HDL-like, and low concentration of ApoE on HDL lacking ApoC3 may affect neuronal cholesterol uptake and clearance of Aβ and tau mediated by ApoE-binding receptors, eventually affecting cognitive function and Alzheimer's disease risk.

“A similar mechanism may occur in the brain where lipoproteins are HDL-like [33] and low concentration of ApoE on HDL lacking ApoC3 may affect the neuronal cholesterol uptake and clearance of Aβ and tau mediated by ApoE-binding receptors and eventually affecting cognitive function and AD risk.”

• cites [33] Turri M, Marchi G, Adorni MP, Calabresi, Zimetti F.Emerging role of HDL in brain cholesterol metabolism and neurodegenerative disorders.BBA Mol Cell Biol Lipids. 2022;1867:159123 sourceNot checked — no full text of the source

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

Plasma ApoE is associated with multiple lipoprotein particles, and about 50% of ApoE is present on high-density lipoprotein (HDL).

“Plasma ApoE is associated with multiple lipoprotein particles, which also contain other apolipoproteins, and about 50% of ApoE is present on high-density lipoprotein (HDL) [20].”

• cites [20] Weisgraber KH, Mahley RW. Characterization of apolipoprotein E-containing lipoproteins. Methods Enzymol. 1986;129:145–66. sourceNot checked — no full text of the source

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

NDUFA4 has been identified as one of the few significantly regulated proteins in Aβ plaques in anti-Aβ antibody aducanumab treated transgenic mice, suggesting that upregulation of NDUFA4 in plaques may inhibit Aβ toxicity and increase phagocytosis and cell viability.

“NDUFA4, that codes for a mitochondrial protein has been identified as one of the few significantly regulated proteins in Aβ plaques in anti-Aβ antibody aducanumab treated transgenic mice, suggesting that upregulation of NDUFA4 in plaques may inhibit Aβ toxicity and increase phagocytosis and cell viability [47].”

• cites [47] Bastrup J, Hansen KH, Poulsen TBG, Kastaniegaard K, Asuni AA, Christensen S, et al. Anti-Aβ antibody aducanumab regulates the proteome of senile plaques and closely surrounding tissue in a transgenic mouse model of Alzheimer’s disease. J Alzheimers Dis. 2021;79:249–65. sourceNot checked — no full text of the source

Probably not a substantial claim: may not pass S3 (load-bearing).

Elevated OPRD1 promoter methylation is suggested to be a risk factor for AD.

“elevated OPRD1 promoter methylation is suggested to be a risk factor for AD [45].”

• cites [45] Mathieu-Kia A-M, Fan L-Q, Kreek MJ, Simon EJ, Hiller JM. Μ-, δ- and κ-opioid receptor populations are differentially altered in distinct areas of postmortem brains of Alzheimer’s disease patients. Brain Res. 2001;893:121–34. sourceNot checked — no full text of the source

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

OPRD1 encodes delta-opioid receptors, which are implicated in cognitive functions.

“OPRD1 that encodes delta-opioid receptors, which are implicated in cognitive functions [44]”

• cites [44] Cruz-Gordillo P, Fedrigo O, Wray GA, Babbitt CC. Extensive changes in the expression of the opioid genes between humans and chimpanzees. Brain Behav Evol. 2010;76:154–62. sourceNot checked — no full text of the source

May combine two claims.

Variation in ApoE level is associated with AD risk, with a significant contribution from multiple signals in the APOE region.

“These data suggest that variation in ApoE level is associated with AD risk, with a significant contribution from multiple signals in the APOE region.”

Probably not a substantial claim: may not pass S3 (load-bearing).

BMP2 was originally shown to upregulate APOE in a murine-mesenchymal progenitor cell line, suggesting a possible role of APOE in organogenesis and tissue differentiation.

“BMP2 was originally shown to upregulate APOE in a murine-mesenchymal progenitor cell line, suggesting a possible role of APOE in organogenesis and tissue differentiation [42].”

• cites [42] Bächner D, Schröder D, Betat N, Ahrens M, Gross G. Apolipoprotein E (ApoE), a Bmp-2 (bone morphogenetic protein) upregulated gene in mesenchymal progenitors (c3h10t1/2), is highly expressed in murine embryonic development. Biofactors 1999;9:11–17. sourceNot checked — no full text of the source

Classified as probably not a substantial claim.

SNP analysis was performed using a linear regression framework implemented in PLINK, including age, sex, education, and the first four PCs of ancestry as covariates.

“SNP analysis was performed using a linear regression framework implemented in PLINK, including age, sex, education, and the first four PCs of ancestry as covariates.”

May combine two claims.

Some limitations of the study include the use of an older cohort and lack of replication sample.

“Some limitations of our study include the use of an older cohort and lack of replication sample.”

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

The study was approved by the University of Pittsburgh Internal Review Board and informed consent was obtained from all subjects.

“The study was approved by the University of Pittsburgh Internal Review Board and informed consent was obtained from all subjects.”

Probably not a substantial claim: may not pass S3 (load-bearing).

All duplicate samples showed comparable values.

“All duplicate samples showed comparable values.”

Classified as probably not a substantial claim. May combine two claims.

The first four components were conservatively determined to be relevant for determination of population origin and were used as covariates in subsequent statistical association analyses.

“The first four components were conservatively determined to be relevant for the determination of population origin based on the visual examination of the principal component (PC) of ancestry plots and were used as covariates in subsequent statistical association analyses.”

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

Exclusion criteria for SNPs included minor allele frequency (MAF) <1%, high genotype failure rate, and deviation from Hardy-Weinberg expectations (P ≤ 1E-06).

“Exclusion criteria for SNPs included minor allele frequency (MAF) <1%, high genotype failure rate, and deviation from Hardy–Weinberg expectations (P ≤ 1E–06).”

Probably not a substantial claim: may not pass S3 (load-bearing).

GWAS findings in this older cohort may not be generalizable.

“GWAS findings in this older cohort may not be generalizable”

May combine two claims.

ApoE deficiency in mice has been shown to be associated with BBB dysfunction where both blood- and tissue-derived ApoE were found to be equally important for BBB function and thus relevant to age-related neurodegenerative diseases, like AD.

“ApoE deficiency in mice has also shown to be associated with BBB dysfunction where both the blood- and tissue-derived ApoE were found to be equally important for BBB function and thus relevant to age-related neurodegenerative diseases, like AD [52].”

• cites [52] Hafezi-Moghadam A, Thomas KL, Wagner DD. ApoE deficiency leads to a progressive age-dependent blood-brain barrier leakage. Am J Physiol Cell Physiol. 2007;292:C1256–C1262. sourceNot checked — no full text of the source

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

Participants with >2% genotype failure rate and cryptic relatedness (none removed) were used as exclusion criteria.

“Participants with >2% genotype failure rate and cryptic relatedness (none removed) were used as exclusion criteria.”

Classified as probably not a substantial claim.

Population stratification was analyzed using a multi-dimensional scaling-based method as implemented in PLINK using only QC-passed common variants (MAF > 0.05).

“Population stratification was analyzed using a multi-dimensional scaling-based method as implemented in PLINK using only QC-passed (n = 5,448,855 SNPs) common variants (MAF > 0.05) [55].”

• cites [55] Purcell S, Neale B, Todd-Brown K, Thomas L, Ferreira MAR, Bender D, et al. Plink: a tool set for whole-genome association and population-based linkage analyses. Am J Hum Genet. 2007;81:559–75. sourceNot checked — no full text of the source

Probably not a substantial claim: may not pass S3 (load-bearing).

The top imputed SNPs with genome-wide significant P-values were genotyped using TaqMan assays.

“The top imputed SNPs with genome-wide significant P-values were genotyped using TaqMan assays (Applied Biosystems, Thermo Fisher Scientific).”

May combine two claims.

The study used the largest sample size to date with 90% power to detect 0.0174 effect size index at GWS level, which enabled identification of multiple novel signals in the known APOE region as well as novel loci in the genome.

“The strength of our study is that we have used the largest sample size to date with 90% power to detect 0.0174 effect size index at GWS level, which has enabled the identification of multiple novel signals in the known APOE region as well as novel loci in the genome.”

Probably not a substantial claim: may not pass S3 (load-bearing).

Some ApoE level-associated variants may have been missed.

“some ApoE level-associated variants may have been missed.”