Association of rare APOE missense variants with Alzheimer's disease in the Japanese population

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

Specific APOE rare missense variants (p.L46P, p.R154S, p.R163C, p.V254E, p.R269G) have been reported in Western populations and suggest potential resistance to amyloid-β accumulation, phosphorylated tau pathology, or the effects of the APOE ε4 allele.

“For example, RMVs such as p.L46P (p.L28P; rs769452 [Pittsburgh]), 17 p.R154S (p.R136S; rs121918393 [Christchurch]), 18 p.R163C (p.R145C; rs769455), 19 p.V254E (p.V236E; rs199768005 [Jacksonville]), 20 and p.R269G (p.R251G; rs267606661) 21 have been reported in Western populations, suggesting potential resistance to amyloid-β (Aβ) accumulation, phosphorylated tau pathology, or the effects of the AP”

• cites [17] Kamboh MI Aston CE Perez-Tur J, et al. A novel mutation in the apolipoprotein E gene (APOE*4 Pittsburgh) is associated with the risk of late-onset Alzheimer’s disease. Neurosci Lett 1999; 263: 129– 132. 10213152 sourceNot checked — no full text of the source
• cites [18] Arboleda-Velasquez JF Lopera F O’Hare M, et al. Resistance to autosomal dominant Alzheimer’s disease in an APOE3 Christchurch homozygote: a case report. Nat Med 2019; 25: 1680– 1683. 31686034 PMC6898984 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 [19] Le Guen Y Raulin AC Logue MW, et al. Association of African ancestry-specific APOE missense variant R145C with risk of Alzheimer disease. JAMA 2023; 329: 551– 560. 36809323 PMC9945061 sourceDisputed

  Split into 2 atoms — 1 confirmed, 0 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.

rs140808909 (p.E262K) and rs190853081 (p.E263K) have been previously identified in Japanese patients with dyslipidemia and atherosclerosis and are defined as the APOE ε7 allele.

“Both variants have been previously identified in Japanese patients with dyslipidemia and atherosclerosis and is defined as the APOE ε7 allele.29–31”

• cites [29] Yamamura T Yamamoto A Sumiyoshi T, et al. New mutants of apolipoprotein E associated with atherosclerotic diseases but not to type III hyperlipoproteinemia. J Clin Invest 1984; 74: 1229– 1237. 6480826 PMC425289 sourcePartly supported

  The Introduction and Results describe apo E mutants found in patients with hyperlipidemia and atherosclerotic disease; the discussion suggests these mutants may be limited to the Japanese population. But the paper does not identify rs140808909 or rs190853081, establish the E262K or E263K substitutions, or define either as the APOE ε7 allele. It calls the new allele apo E-Suita; E-VII denotes a protein band, not an allele name. (LLM, conf=0.88)

  Experimental — accuracy not yet measured
• cites [30] Maeda H Nakamura H Kobori S, et al. Identification of human apolipoprotein E variant gene: apolipoprotein Ε7 (Glu244,245----Lys244,245). J Biochem 1989; 105: 51– 54. 2738044 sourceNot checked — no full text of the source
• cites [31] Tajima S Yamamura T Menju M, et al. Analysis of apolipoprotein E7 (apolipoprotein E-Suita) gene from a patient with hyperlipoproteinemia. J Biochem 1989; 105: 249– 253. 2470732 sourceNot checked — no full text of the source

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

Rasmussen et al. identified 20 APOE rare missense variants in an analysis involving more than 100,000 participants and demonstrated their association with plasma APOE levels and Alzheimer's disease onset.

“Rasmussen et al. 22 identified 20 APOE RMVs in an analysis involving more than 100,000 participants and demonstrated their association with plasma APOE levels and AD onset.”

• cites [22] Rasmussen KL Tybjaerg-Hansen A Nordestgaard BG, et al. APOE And dementia - resequencing and genotyping in 105,597 individuals. Alzheimers Dement 2020; 16: 1624– 1637. 32808727 PMC7984319 sourcePartly supported

  The Methods and Results describe 105,597 participants, 27 rare APOE variants identified by resequencing, and nine rare amino-acid–changing variants further genotyped—not 20 rare missense variants analyzed for the stated associations. The Results link some of the nine variants to plasma apoE levels and assess their association with Alzheimer's disease risk, but do not demonstrate an association with age of onset. Page numbers are unavailable in our copy. (LLM, conf=0.89)

  Experimental — accuracy not yet measured

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

APOE remains the most significant genetic risk factor for Alzheimer's disease across populations.

“Among the AD susceptibility genes/loci identified to date, APOE remains the most significant genetic risk factor across populations.”

• cites [8] Farrer LA Cupples LA Haines JL, 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– 1356. 9343467 sourceNot checked — no full text of the source
• cites [9] Bertram L McQueen MB Mullin K, et al. Systematic meta-analyses of Alzheimer disease genetic association studies: the AlzGene database. Nat Genet 2007; 39: 17– 23. 17192785 sourceNot checked — no full text of the source
• cites [10] Belloy ME Andrews SJ Le Guen Y, et al. APOE Genotype and Alzheimer disease risk across age, sex, and population ancestry. JAMA Neurol 2023; 80: 1284– 1294. 37930705 PMC10628838 sourceSupported
• cites [11] Ridge PG Hoyt KB Boehme K, et al. Assessment of the genetic variance of late-onset Alzheimer’s disease. Neurobiol Aging 2016; 41: 200.e13– 200.e20. PMC4948179 27036079 sourcePartly supported

  The Results (section 3; page unavailable) identify APOE as the dominant contributor among the known AD variants examined: it explained 13% of phenotypic variance, versus almost 3% for other genes combined. The paper does not establish that APOE is the most significant genetic risk factor across populations; that extension is unsupported by this analysis. (LLM, conf=0.85)

  Experimental — accuracy not yet measured

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

rs121918392 (p.E21K) was defined as the APOE ε5 allele.

“rs121918392 (p.E21K) was defined as the APOE ε5 allele29,32–34”

• cites [29] Yamamura T Yamamoto A Sumiyoshi T, et al. New mutants of apolipoprotein E associated with atherosclerotic diseases but not to type III hyperlipoproteinemia. J Clin Invest 1984; 74: 1229– 1237. 6480826 PMC425289 sourcePartly supported

  The Introduction identifies apo E-5, and the discussion says it is controlled by an additional APOE allele. The paper does not identify that allele as rs121918392 or p.E21K; it says peptide-sequence analysis was still underway and tentatively suggests a deletion instead. (LLM, conf=0.88)

  Experimental — accuracy not yet measured
• cites [32] Yamamura T Yamamoto A Hiramori K, et al. A new isoform of apolipoprotein E--apo E-5--associated with hyperlipidemia and atherosclerosis. Atherosclerosis 1984; 50: 159– 172. 6712769 sourceNot checked — no full text of the source
• cites [33] Tajima S Yamamura T Yamamoto A. Analysis of apolipoprotein E5 gene from a patient with hyperlipoproteinemia. J Biochem 1988; 104: 48– 52. 2851587 sourceNot checked — no full text of the source
• cites [34] Maeda H Nakamura H Kobori S, et al. Molecular cloning of a human apolipoprotein E variant: E5 (Glu3----Lys3). J Biochem 1989; 105: 491– 493. 2760009 sourceNot checked — no full text of the source

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

rs121918392 (p.E21K) was also associated with dyslipidemia and atherosclerosis.

“rs121918392 (p.E21K) was also associated with dyslipidemia and atherosclerosis.29,32–34”

• cites [29] Yamamura T Yamamoto A Sumiyoshi T, et al. New mutants of apolipoprotein E associated with atherosclerotic diseases but not to type III hyperlipoproteinemia. J Clin Invest 1984; 74: 1229– 1237. 6480826 PMC425289 sourcePartly supported

  The Results and Discussion (page unavailable) associate apo E-5 and apo E-Suita with hyperlipidemia and atherosclerotic disease. But the paper does not identify either mutant as rs121918392 (p.E21K); the Discussion says peptide sequence analysis was still underway. It therefore supports the disease association for the mutants studied, not its attribution to that specific variant. (LLM, conf=0.88)

  Experimental — accuracy not yet measured
• cites [32] Yamamura T Yamamoto A Hiramori K, et al. A new isoform of apolipoprotein E--apo E-5--associated with hyperlipidemia and atherosclerosis. Atherosclerosis 1984; 50: 159– 172. 6712769 sourceNot checked — no full text of the source
• cites [33] Tajima S Yamamura T Yamamoto A. Analysis of apolipoprotein E5 gene from a patient with hyperlipoproteinemia. J Biochem 1988; 104: 48– 52. 2851587 sourceNot checked — no full text of the source
• cites [34] Maeda H Nakamura H Kobori S, et al. Molecular cloning of a human apolipoprotein E variant: E5 (Glu3----Lys3). J Biochem 1989; 105: 491– 493. 2760009 sourceNot checked — no full text of the source

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

Large-scale genome-wide association studies have identified 90 susceptibility genes/loci for Alzheimer's disease.

“Large-scale genome-wide association studies (GWAS) have identified 90 susceptibility genes/loci for AD.”

• cites [3] Lambert JC Ramirez A Grenier-Boley B, et al. Step by step: towards a better understanding of the genetic architecture of Alzheimer’s disease. Mol Psychiatry 2023; 28: 2716– 2727. 37131074 PMC10615767 sourceSupported

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

APOE plays a crucial role in the pathophysiology of AD, particularly in relation to Aβ and tau.

“APOE plays a crucial role in the pathophysiology of AD, particularly in relation to Aβ and tau.43,44”

• cites [43] Yamazaki Y Zhao N Caulfield TR, et al. Apolipoprotein E and Alzheimer disease: pathobiology and targeting strategies. Nat Rev Neurol 2019; 15: 501– 518. 31367008 PMC7055192 sourceSupported
• cites [44] 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– 838. 30844401 PMC6407643 sourceSupported

May combine two claims.

This substitution reduces the binding affinity of the ε7 isoform to the LDL receptor (LDLR) and increases its affinity for heparin.

“This substitution reduces the binding affinity of the ε7 isoform to the LDL receptor (LDLR) and increases its affinity for heparin. 38”

• cites [38] Yamamura T Dong LM Yamamoto A. Characterization of apolipoprotein E7 (Glu(244)-->Lys, Glu(245)--->Lys), a mutant apolipoprotein E associated with hyperlipidemia and atherosclerosis. J Lipid Res 1999; 40: 253– 259. 9925654 sourceSupported

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

As LDLR and heparin play critical roles in Aβ clearance and tau aggregation, the ε7 isoform may influence AD pathology through these pathways.

“As these molecules play critical roles in Aβ clearance and tau aggregation,41,42 the ε7 isoform may influence AD pathology through these pathways.”

• cites [41] Kanekiyo T Xu H Bu G. ApoE and Aβ in Alzheimer’s disease: accidental encounters or partners? Neuron 2014; 81: 740– 754. 24559670 PMC3983361 sourcePartly supported

  In “ApoE in Aβ clearance” (page unavailable), the paper says LDLR mediates brain-to-blood Aβ clearance. In “ApoE and Aβ in endocytic trafficking” (page unavailable), it links heparan sulfate proteoglycans to cellular uptake of tau, but does not say that heparin plays a critical role in tau aggregation. The ε7 proposal follows the citation and is the citing authors’ inference. (LLM, conf=0.86)

  Experimental — accuracy not yet measured
• cites [42] Shi Y Andhey PS Ising C, et al. Overexpressing low-density lipoprotein receptor reduces tau-associated neurodegeneration in relation to apoE-linked mechanisms. Neuron 2021; 109: 2413– 2426. 34157306 PMC8349883 sourcePartly supported

  The Introduction (page unavailable) identifies LDLR as a receptor involved in clearing apoE lipoproteins, and the Discussion (page unavailable) reports that LDLR overexpression protects against tau pathology. The cited paper does not establish the attributed roles in Aβ clearance or tau aggregation, and the passages do not address heparin. The ε7 proposal is the citing authors’ own inference, not a finding attributed to this source. (LLM, conf=0.82)

  Experimental — accuracy not yet measured

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

The ε7 allele has been linked to dyslipidemia and atherosclerosis.

“Notably, the ε7 allele has been linked to dyslipidemia and atherosclerosis,29–31 yet few studies have examined its binding to LDLR and heparin. 38”

• cites [29] Yamamura T Yamamoto A Sumiyoshi T, et al. New mutants of apolipoprotein E associated with atherosclerotic diseases but not to type III hyperlipoproteinemia. J Clin Invest 1984; 74: 1229– 1237. 6480826 PMC425289 sourcePartly supported

  The Abstract and Results describe apo E-Suita in patients with hyperlipidemia and atherosclerosis, supporting the reported link. But the paper calls the inherited allele εSuita; E-VII is the name of an electrophoretic component, not an allele the paper identifies as ε7. It therefore does not establish the claim for an ε7 allele specifically. (LLM, conf=0.83)

  Experimental — accuracy not yet measured
• cites [30] Maeda H Nakamura H Kobori S, et al. Identification of human apolipoprotein E variant gene: apolipoprotein Ε7 (Glu244,245----Lys244,245). J Biochem 1989; 105: 51– 54. 2738044 sourceNot checked — no full text of the source
• cites [31] Tajima S Yamamura T Menju M, et al. Analysis of apolipoprotein E7 (apolipoprotein E-Suita) gene from a patient with hyperlipoproteinemia. J Biochem 1989; 105: 249– 253. 2470732 sourceNot checked — no full text of the source

May combine two claims.

In the NIG cohort, all carriers of the seven identified APOE RMVs were heterozygous, and no homozygotes were identified.

“All carriers were heterozygous, and no homozygotes were identified.”

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

The homozygous individual for rs140808909 and rs190853081 had LDL-C, HDL-C, and TG levels of 96, 49, and 67, respectively, all within normal ranges (TC data unavailable).

“This individual exhibited LDL-C, HDL-C, and TG levels of 96, 49, and 67, respectively, all within the normal ranges (TC data were not available).”

May combine two claims.

rs140808909 (p.E262K) and rs190853081 (p.E263K) were in complete linkage disequilibrium (R2 = 1), indicating they were fully co-inherited.

“These two variants were in complete linkage disequilibrium (LD) (LD coefficient R² = 1), indicating that they were fully co-inherited (Supplemental Figure 2).”

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

Fourteen rare missense variants (RMVs) of APOE were identified in the Niigata and Tohoku cohorts, with minor allele frequency 0.02-0.73%.

“Fourteen RMVs were identified (minor allele frequency 0.02–0.73%), with 10 unique to East Asians.”

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

These five previously reported variants were more frequently observed in non-East Asian populations.

“These variants were more frequently observed in non-East Asian populations (Supplemental Table 3).”

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims. The quote only partly states this claim.

In the ToMMo cohort, all carriers of identified APOE RMVs were heterozygous, and no homozygotes were identified.

“All carriers were heterozygous, and no homozygotes were identified.”

Classified as probably not a substantial claim.

Genotype data were obtained for four APOE rare missense variants: rs121918392 (ε5), rs762461580, rs140808909 (ε7), and rs190853081 (ε7).

“Among the 14 APOE RMVs, genotype data were obtained for four variants: rs121918392 (ε5), rs762461580, rs140808909 (ε7), and rs190853081 (ε7) (Table 4, Figures 1 and 2).”

May combine two claims.

In carriers of the four RMVs analyzed, no carriers with ε2*2, ε2*4, or ε4*4 genotypes were identified, so they were excluded from analysis.

“As no carriers of APOE RMVs with the ε2*2, ε2*4, or ε4*4 genotypes were identified, they were excluded from the analysis.”

May combine two claims.

rs121918392 (p.E21K) defining the ε5 allele, and rs140808909 (p.E262K) and rs190853081 (p.E263K) defining the ε7 allele, appeared to co-segregate with the ε3 allele.

“Variant rs121918392 (p.E21K) that defines the ε5 allele, and two variants, rs140808909 (p.E262K) and rs190853081 (p.E263K), that are in complete LD and define the ε7 allele, appeared to co-segregate with the ε3 allele (Supplemental Table 2).”

May combine two claims.

In the same genotype comparison, the OR (95% CI) for All was 3.13 (2.93-3.35), but was 4.18 (1.15-14.00) for rs762461580.

“For example, in the same genotype comparison, the OR (95% CI) for All was 3.13 (2.93–3.35), but was 4.18 (1.15–14.00) for rs762461580.”

May combine two claims.

In a comparison between ε3*3 and ε3*4 genotypes, the OR (95% CI) for All was 3.13 (2.93-3.35), whereas it was 1.79 (0.78-4.26) for ε5 (rs121918392).

“For example, in a comparison between the ε3*3 and ε3*4 genotypes, the OR (95% CI) for All was 3.13 (2.93–3.35), whereas it was 1.79 (0.78–4.26) for ε5 (rs121918392).”

May combine two claims.

In Models 3 and 5, where the ε4 allele was included as a covariate, the association between rs140808909/rs190853081 and AD was no longer significant (pBonferroni = 1.000; ORs 0.87 and 0.85).

“However, in Models 3 and 5, where the ε4 allele was included as a covariate, the association was no longer significant: pBonferroni = 1.000 and OR (95% CI) = 0.87 (0.66–1.15) in Model 3; and pBonferroni = 1.000 and OR (95% CI) = 0.85 (0.64–1.14) in Model 5 (Table 4, Figure 1).”

May combine two claims.

Among APOE RMV carriers, several individuals had ε3*4 and ε2*3, one had ε4*4, and none had ε2*2 or ε2*4.

“Several individuals were also identified with ε3*4 and ε2*3, and one individual with ε4*4. None of the APOE RMV carriers had ε2*2 or ε2*4.”

Classified as probably not a substantial claim.

Rare missense variants of APOE have been reported to be associated with Alzheimer's disease.

“Recently, rare missense variants (RMVs) of APOE were reported to be associated with AD, shedding light on new links between APOE and AD.”

Classified as probably not a substantial claim.

Variants with an INFO score ≥ 0.7 were included in the association analysis to ensure high imputation accuracy.

“To ensure high imputation accuracy, variants with an INFO score ≥ 0.7 were included in the association analysis.”

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

Multiple loci are thought to contribute to the onset of Alzheimer's disease.

“Multiple loci are thought to contribute to the onset of AD.”

• cites [2] Daw EW Payami H Nemens EJ, et al. The number of trait loci in late-onset Alzheimer disease. Am J Hum Genet 2000; 66: 196– 204. 10631151 PMC1288326 sourceNot checked — no full text of the source

Classified as probably not a substantial claim.

The Bonferroni method was applied to correct for multiple comparisons for the APOE rare missense variants analyzed.

“The Bonferroni method was applied to correct for multiple comparisons for the APOE RMVs analyzed.”

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

A large twin epidemiological study in Sweden estimated the heritability of Alzheimer's disease to be 60-80%.

“A large twin epidemiological study in Sweden estimated the heritability of AD to be 60–80%.”

• cites [1] Gatz M Reynolds CA Fratiglioni L, et al. Role of genes and environments for explaining Alzheimer disease. Arch Gen Psychiatry 2006; 63: 168– 174. 16461860 sourceNot checked — no full text of the source

May combine two claims.

The imputation INFO scores for the four analyzed APOE rare missense variants were 0.93 for rs121918392, 0.83 for rs762461580, 0.82 for rs140808909, and 0.82 for rs190853081.

“The INFO scores for each imputed variant were as follows: rs121918392 (ε5), 0.93; rs762461580, 0.83; rs140808909 (ε7), 0.82; and rs190853081 (ε7), 0.82.”

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

A study on the ε5 and ε7 alleles revealed a trend toward higher TC (>220 mg/dL) and TG (>150 mg/dL) levels compared with controls.

“For example, a study on the ε5 and ε7 alleles revealed a trend toward higher TC (>220 mg/dL) and TG (>150 mg/dL) levels compared with those in controls. 40”

• cites [40] Matsunaga A Sasaki J Moriyama K, et al. Population frequency of apolipoprotein E5 (Glu3-->Lys) and E7 (Glu244-->Lys, Glu245-->Lys) variants in western Japan. Clin Genet 1995; 48: 93– 99. 7586659Not checked — no full text of the source

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

The association analyses adjusted for sex and age (Model 2), the ε2 allele (Model 4), and the ε4 allele (Models 3 and 5).

“Models 1 (without covariate adjustment: pBonferroni = 0.0428, and OR [95% CI] = 0.70 [0.54–0.92]), 2 (adjusted for sex and age: pBonferroni = 0.0293, and OR [95% CI] = 0.68 [0.51–0.90]), and 4 (adjusted for the ε2 allele: pBonferroni = 0.0364, and OR [95% CI] = 0.70 [0.53–0.91])”

• Also stated in: § Effect of APOE RMVs on AD · plain

  “Models 3 and 5, where the ε4 allele was included as a covariate”

May combine two claims.

Since the ε7 allele co-segregates with the ε3 allele and never with the AD risk-associated ε4 allele, its protective effect is likely attributable to the ε3 allele.

“Since the ε7 allele co-segregates with the ε3 allele and never with the AD risk-associated ε4 allele (Supplemental Table 2), its protective effect is likely attributable to the ε3 allele.”

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

No functional assays have been conducted for RMVs, including the ε7 allele, and their impact on AD pathology and molecular mechanisms remain unclear.

“Finally, no functional assays have been conducted for RMVs, including the ε7 allele, and their impact on AD pathology and the underlying molecular mechanisms remain unclear.”