Sex-specific DNA methylation differences in Alzheimer’s disease pathology

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

Although caffeine reduces the risk for AD in both men and women, the protective effect seems to be greater in women.

“Although caffeine reduces the risk for AD [68, 69] in both men and women, the protective effect seems to be greater in women [70].”

• cites [68] Driscoll I, Shumaker SA, Snively BM, Margolis KL, Manson JE, Vitolins MZ, Rossom RC, Espeland MA (2016) Relationships between caffeine intake and risk for probable dementia or global cognitive impairment: the women’s health initiative memory study. J Gerontol A Biol Sci Med Sci 71(12):1596–1602 sourcePartly supported

  The Results report a lower incidence of probable dementia among women with higher caffeine intake. The Discussion cites a study finding a protective relationship with cognition in women but not men, while explicitly saying this study cannot generalize to men. It does not establish that protection against Alzheimer’s disease is greater in women than in men. (LLM, conf=0.84)

  Experimental — accuracy not yet measured
• cites [69] Kim JW, Byun MS, Yi D, Lee JH, Jeon SY, Jung G, Lee HN, Sohn BK, Lee JY, Kim YK, Shin SA, Sohn CH, Lee DY, Group KR (2019) Coffee intake and decreased amyloid pathology in human brain. Transl Psychiatry 9(1):270 sourceDisputed

  Citation [70] is attached to the claim that the protective effect is greater in women. In the Results section on moderating effects (page unavailable), the paper reports no significant interaction between gender and lifetime coffee intake for amyloid positivity. It studied coffee intake rather than isolating caffeine’s effect. (LLM, conf=0.88)

  Checked by a reasoning model — may be wrong.

  Experimental — accuracy not yet measured
• cites [70] Jee HJ, Lee SG, Bormate KJ, Jung YS (2020) Effect of caffeine consumption on the risk for neurological and psychiatric disorders: sex differences in human. Nutrients 12(10):3080 sourcePartly supported

  Section 3.3 (Dementia) says steady caffeine intake seems to reduce dementia risk in both men and women, with a greater effect in women; the Conclusions repeat the greater reduction in women. The cited paper does not establish that this sex difference applies specifically to Alzheimer’s disease (AD), rather than dementia more broadly. Page numbers are not available in our copy. (LLM, conf=0.84)

  Experimental — accuracy not yet measured

May combine two claims.

Recently, multiple studies have shown that reduced levels of platelet-derived growth factors (PDGFs) in plasma significantly correlate with mild cognitive impairment and have proposed PDGFs as a potential biomarker for AD.

“Recently, multiple studies have shown that reduced levels of platelet-derived growth factors (PDGFs) in plasma significantly correlate with mild cognitive impairment and have proposed PDGFs as a potential biomarker for AD [95, 96].”

• cites [95] Bjorkqvist M, Ohlsson M, Minthon L, Hansson O (2012) Evaluation of a previously suggested plasma biomarker panel to identify Alzheimer’s disease. PLoS ONE 7(1):e29868 sourceDisputed

  The Discussion (page unavailable) says an earlier study found reduced PDGF-BB in AD, but this paper found increased levels in AD cases instead. Its mention of mild cognitive impairment concerns an 18-protein panel, not a correlation with reduced PDGF levels; the Discussion also finds that panel unsuitable for clinical AD diagnosis. (LLM, conf=0.88)

  Checked by a reasoning model — may be wrong.

  Experimental — accuracy not yet measured
• cites [96] Ray S, Britschgi M, Herbert C, Takeda-Uchimura Y, Boxer A, Blennow K, Friedman LF, Galasko DR, Jutel M, Karydas A, Kaye JA, Leszek J, Miller BL, Minthon L, Quinn JF, Rabinovici GD, Robinson WH, Sabbagh MN, So YT, Sparks DL, Tabaton M, Tinklenberg J, Yesavage JA, Tibshirani R, Wyss-Coray T (2007) Classification and prediction of clinical Alzheimer’s diagnosis based on plasma signaling proteins. Nat Med 13(11):1359–1362 sourceNot checked — no full text of the source

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

Men with AD have an increased risk for death.

“it has also been reported men with AD have an increased risk for death [9–11]”

• cites [9] Davis EJ, Broestl L, Abdulai-Saiku S, Worden K, Bonham LW, Minones-Moyano E, Moreno AJ, Wang D, Chang K, Williams G, Garay BI, Lobach I, Devidze N, Kim D, Anderson-Bergman C, Yu GQ, White CC, Harris JA, Miller BL, Bennett DA, Arnold AP, De Jager PL, Palop JJ, Panning B, Yokoyama JS, Mucke L, Dubal DB (2020) A second X chromosome contributes to resilience in a mouse model of Alzheimer’s disease. Sci Transl Med 12:558 sourceSupported
• cites [10] Lapane KL, Gambassi G, Landi F, Sgadari A, Mor V, Bernabei R (2001) Gender differences in predictors of mortality in nursing home residents with AD. Neurology 56(5):650–654 sourceNot checked — no full text of the source
• cites [11] Stern Y, Tang MX, Albert MS, Brandt J, Jacobs DM, Bell K, Marder K, Sano M, Devanand D, Albert SM, Bylsma F, Tsai WY (1997) Predicting time to nursing home care and death in individuals with Alzheimer disease. JAMA 277(10):806–812 sourceSupported

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

The bacon method estimates inflation in EWAS based on empirical null distributions.

“Iterson et al. [32] developed a Bayesian method that estimates inflation in EWAS based on empirical null distributions, which is implemented in the Bioconductor package bacon”

• cites [32] van Iterson M, van Zwet EW, Consortium B, Heijmans BT (2017) Controlling bias and inflation in epigenome- and transcriptome-wide association studies using the empirical null distribution. Genome Biol 18(1):19 sourceSupported

May combine two claims.

After diagnosis, women progress faster with more rapid cognitive and functional declines.

“After diagnosis, women also progress faster with more rapid cognitive and functional declines [3–8]”

• cites [3] Koran MEI, Wagener M, Hohman TJ, I. Alzheimer’s Neuroimaging (2017) Sex differences in the association between AD biomarkers and cognitive decline. Brain Imaging Behav 11(1):205–213 sourcePartly supported

  The Discussion reports faster decline in memory and executive function among women with biomarker levels indicating greater AD pathology. It does not report functional decline, and the finding is conditional on biomarker levels rather than a general finding that women progress faster after diagnosis; the reported sex difference was most pronounced among participants with MCI. (LLM, conf=0.86)

  Experimental — accuracy not yet measured
• cites [4] Tschanz JT, Corcoran CD, Schwartz S, Treiber K, Green RC, Norton MC, Mielke MM, Piercy K, Steinberg M, Rabins PV, Leoutsakos JM, Welsh-Bohmer KA, Breitner JC, Lyketsos CG (2011) Progression of cognitive, functional, and neuropsychiatric symptom domains in a population cohort with Alzheimer dementia: the Cache County Dementia Progression study. Am J Geriatr Psychiatry 19(6):532–542 sourcePartly supported

  The Results (Association between Predictors and Rate of Change; page not provided) report that women declined faster than men on the MMSE, a measure of cognition. For the CDR-sb, the paper reports greater impairment among women at onset, not a faster rate of functional decline. (LLM, conf=0.90)

  Experimental — accuracy not yet measured
• cites [5] Ardekani BA, Convit A, Bachman AH (2016) Analysis of the MIRIAD data shows sex differences in hippocampal atrophy progression. J Alzheimers Dis 50(3):847–857 sourceNot checked — no full text of the source
• cites [6] Holland D, Desikan RS, Dale AM, McEvoy LK, I. Alzheimer’s Disease Neuroimaging (2013) Higher rates of decline for women and apolipoprotein E epsilon4 carriers. AJNR Am J Neuroradiol 34(12):2287–2293 sourcePartly supported

  The Results (Rates of Decline in MCI; page unavailable) report faster decline for women on CDR-SB and ADAS-Cog, supporting the claim for participants with MCI. But the Results (Rates of Decline in AD; page unavailable) report no significant sex effect on any cognitive measure in participants diagnosed with Alzheimer disease. The paper therefore does not support the unqualified claim of faster cognitive and functional decline after an AD diagnosis. (LLM, conf=0.88)

  Experimental — accuracy not yet measured
• cites [7] Lin KA, Choudhury KR, Rathakrishnan BG, Marks DM, Petrella JR, Doraiswamy PM, I. Alzheimer’s Disease Neuroimaging (2015) Marked gender differences in progression of mild cognitive impairment over 8 years. Alzheimers Dement (N Y) 1(2):103–110 sourcePartly supported

  The Discussion and Conclusions report faster cognitive and functional decline in women than men with mild cognitive impairment (MCI). The claim says only “after diagnosis,” without specifying MCI; the paper does not establish the same finding for women diagnosed with Alzheimer’s disease or other conditions. (LLM, conf=0.82)

  Experimental — accuracy not yet measured
• cites [8] Hua X, Hibar DP, Lee S, Toga AW, Jack CR Jr, Weiner MW, Thompson PM (2010) Sex and age differences in atrophic rates: an ADNI study with n=1368 MRI scans. Neurobiol Aging 31(8):1463–1480 sourcePartly supported

  The Introduction says women with Alzheimer’s disease may have greater cognitive impairment and functional disability than men. Results §3.1 finds faster brain atrophy in women, but the paper does not establish that women have faster cognitive and functional declines after diagnosis; those are different outcomes from impairment levels and atrophy rates. The indexed passages provide section labels but no page numbers. (LLM, conf=0.88)

  Experimental — accuracy not yet measured

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

Alterations of DNA methylation levels have been implicated in multiple neurological disorders including AD.

“Importantly, alterations of DNA methylation levels have also been implicated in multiple neurological disorders including AD [18–22]”

• cites [18] De Jager PL, Srivastava G, Lunnon K, Burgess J, Schalkwyk LC, Yu L, Eaton ML, Keenan BT, Ernst J, McCabe C, Tang A, Raj T, Replogle J, Brodeur W, Gabriel S, Chai HS, Younkin C, Younkin SG, Zou F, Szyf M, Epstein CB, Schneider JA, Bernstein BE, Meissner A, Ertekin-Taner N, Chibnik LB, Kellis M, Mill J, Bennett DA (2014) Alzheimer’s disease: early alterations in brain DNA methylation at ANK1, BIN1, RHBDF2 and other loci. Nat Neurosci 17(9):1156–1163 sourceSupported
• cites [19] Lunnon K, Smith R, Hannon E, De Jager PL, Srivastava G, Volta M, Troakes C, Al-Sarraj S, Burrage J, Macdonald R, Condliffe D, Harries LW, Katsel P, Haroutunian V, Kaminsky Z, Joachim C, Powell J, Lovestone S, Bennett DA, Schalkwyk LC, Mill J (2014) Methylomic profiling implicates cortical deregulation of ANK1 in Alzheimer’s disease. Nat Neurosci 17(9):1164–1170 sourcePartly supported

  The paper’s discussion (page unavailable in our copy) reports extensive differences in DNA methylation across brain regions in AD. It does not establish the broader claim about multiple neurological disorders; this source supports the AD example only. (LLM, conf=0.86)

  Experimental — accuracy not yet measured
• cites [20] Smith RG, Hannon E, De Jager PL, Chibnik L, Lott SJ, Condliffe D, Smith AR, Haroutunian V, Troakes C, Al-Sarraj S, Bennett DA, Powell J, Lovestone S, Schalkwyk L, Mill J, Lunnon K (2018) Elevated DNA methylation across a 48-kb region spanning the HOXA gene cluster is associated with Alzheimer’s disease neuropathology. Alzheimer’s Dementia 14(12):1580–1588 sourcePartly supported

  The Introduction and Discussion report altered DNA methylation associated with AD neuropathology, supporting the AD portion of the claim. The paper mentions differential methylation in Down syndrome, but does not establish DNA methylation alterations across multiple neurological disorders as the sentence states. (LLM, conf=0.85)

  Experimental — accuracy not yet measured
• cites [21] Gasparoni G, Bultmann S, Lutsik P, Kraus TFJ, Sordon S, Vlcek J, Dietinger V, Steinmaurer M, Haider M, Mulholland CB, Arzberger T, Roeber S, Riemenschneider M, Kretzschmar HA, Giese A, Leonhardt H, Walter J (2018) DNA methylation analysis on purified neurons and glia dissects age and Alzheimer’s disease-specific changes in the human cortex. Epigenetics Chromatin 11(1):41 sourcePartly supported

  The Abstract Results report disease-related DNA methylation changes associated with Alzheimer’s disease, supporting the AD portion of the claim. The passages from the paper do not establish the broader claim about multiple neurological disorders. (LLM, conf=0.85)

  Experimental — accuracy not yet measured
• cites [22] Zhang L, Silva TC, Young JI, Gomez L, Schmidt MA, Hamilton-Nelson KL, Kunkle BW, Chen X, Martin ER, Wang L (2020) Epigenome-wide meta-analysis of DNA methylation differences in prefrontal cortex implicates the immune processes in Alzheimer’s disease. Nat Commun 11(1):6114 sourcePartly supported

  The Introduction states that there is growing evidence for a role of DNA methylation in AD, and the Discussion reports methylation differences in pathological AD. This supports the AD example, but the paper does not establish the broader claim about multiple neurological disorders. (LLM, conf=0.86)

  Experimental — accuracy not yet measured

Classified as probably not a substantial claim.

Previous studies have shown that epigenetics is an important contributor to the sex differences in brain functions and vulnerability to diseases.

“Previous studies have shown that epigenetics is an important contributor to the sex differences in brain functions and vulnerability to diseases [12–16]”

• cites [12] Dunn GA, Morgan CP, Bale TL (2011) Sex-specificity in transgenerational epigenetic programming. Horm Behav 59(3):290–295 sourceNot checked — no full text of the source
• cites [13] Menger Y, Bettscheider M, Murgatroyd C, Spengler D (2010) Sex differences in brain epigenetics. Epigenomics 2(6):807–821 sourceNot checked — no full text of the source
• cites [14] McCarthy MM, Nugent BM (2015) At the frontier of epigenetics of brain sex differences. Front Behav Neurosci 9:221 sourcePartly supported

  The Abstract says epigenetic modifications have been found to be important for sexual differentiation of the brain, including behavioral differences. It also cautions that evidence of their role remains limited. The paper does not establish that epigenetics contributes to sex differences in disease vulnerability; a related possibility appears only in the title of another work listed in the References. Page numbers are not available in our copy. (LLM, conf=0.85)

  Experimental — accuracy not yet measured
• cites [15] Burghardt KJ, Pilsner JR, Bly MJ, Ellingrod VL (2012) DNA methylation in schizophrenia subjects: gender and MTHFR 677C/T genotype differences. Epigenomics 4(3):261–268 sourcePartly supported

  The Discussion reports gender differences in DNA methylation among people with schizophrenia and suggests these may contribute to women's higher metabolic-syndrome risk. It explicitly says causality cannot be established. The paper does not show that epigenetics is an established contributor to sex differences in brain function or to disease vulnerability generally. Page numbers were not available in our copy. (LLM, conf=0.86)

  Experimental — accuracy not yet measured
• cites [16] Xia Y, Dai R, Wang K, Jiao C, Zhang C, Xu Y, Li H, Jing X, Chen Y, Jiang Y, Kopp RF, Giase G, Chen C, Liu C (2019) Sex-differential DNA methylation and associated regulation networks in human brain implicated in the sex-biased risks of psychiatric disorders. Mol Psychiatry sourcePartly supported

  The Introduction says DNA methylation plays important roles in sexually differential characteristics of the human brain. It also says whether the associated regulatory networks influence sex bias in psychiatric disorders was unknown; the study investigates potential involvement and reports associations with disorder-related genes, rather than establishing epigenetics as a contributor to disease vulnerability. The claim states that contribution more firmly and broadly than this paper supports. (LLM, conf=0.82)

  Experimental — accuracy not yet measured

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

Chromatin states were shown to vary across sex, tissue type, and developmental age.

“which were shown to vary across sex, tissue type, and developmental age [39]”

• cites [39] Yen A, Kellis M (2015) Systematic chromatin state comparison of epigenomes associated with diverse properties including sex and tissue type. Nat Commun 6:7973 sourceSupported

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

Almost two-thirds of AD patients in the U.S. are women.

“Almost two-thirds of AD patients in the U.S. are women [2]”

• cites [2] Hebert LE, Weuve J, Scherr PA, Evans DA (2013) Alzheimer disease in the United States (2010–2050) estimated using the 2010 census. Neurology 80(19):1778–1783 sourceCould not verify

  The Abstract reports the total estimated number of U.S. adults aged 65 or older with AD dementia, and the methods describe calculations by sex. Neither those passages nor the Results table gives the proportion of patients who are women. Searches for “two-thirds,” “women,” and sex-specific prevalence did not find the claimed figure in our copy. (LLM, conf=0.72)

  Experimental — accuracy not yet measured

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

DNA methylation is an important epigenetic modification that regulates gene transcription and is involved in Alzheimer's disease.

“DNA methylation is an important epigenetic modification that regulates gene transcription and is known to be involved in AD”

• cites [18] De Jager PL, Srivastava G, Lunnon K, Burgess J, Schalkwyk LC, Yu L, Eaton ML, Keenan BT, Ernst J, McCabe C, Tang A, Raj T, Replogle J, Brodeur W, Gabriel S, Chai HS, Younkin C, Younkin SG, Zou F, Szyf M, Epstein CB, Schneider JA, Bernstein BE, Meissner A, Ertekin-Taner N, Chibnik LB, Kellis M, Mill J, Bennett DA (2014) Alzheimer’s disease: early alterations in brain DNA methylation at ANK1, BIN1, RHBDF2 and other loci. Nat Neurosci 17(9):1156–1163 sourcePartly supported

  The Introduction reports altered DNA methylation at 71 CpGs associated with AD pathology and says transcription of genes in those regions is independently associated with AD pathology. This supports a link between methylation, transcription and AD, but does not establish that the observed methylation changes regulate transcription; the section on cognitively non-impaired subjects says whether they contribute to the disease process remains open. Page numbers were not supplied in our copy. (LLM, conf=0.86)

  Experimental — accuracy not yet measured
• cites [19] Lunnon K, Smith R, Hannon E, De Jager PL, Srivastava G, Volta M, Troakes C, Al-Sarraj S, Burrage J, Macdonald R, Condliffe D, Harries LW, Katsel P, Haroutunian V, Kaminsky Z, Joachim C, Powell J, Lovestone S, Bennett DA, Schalkwyk LC, Mill J (2014) Methylomic profiling implicates cortical deregulation of ANK1 in Alzheimer’s disease. Nat Neurosci 17(9):1164–1170 sourceSupported
• cites [20] Smith RG, Hannon E, De Jager PL, Chibnik L, Lott SJ, Condliffe D, Smith AR, Haroutunian V, Troakes C, Al-Sarraj S, Bennett DA, Powell J, Lovestone S, Schalkwyk L, Mill J, Lunnon K (2018) Elevated DNA methylation across a 48-kb region spanning the HOXA gene cluster is associated with Alzheimer’s disease neuropathology. Alzheimer’s Dementia 14(12):1580–1588 sourcePartly supported

  The Introduction and Discussion report that altered DNA methylation is associated with AD neuropathology, supporting the AD-related part of the claim. The paper does not establish that DNA methylation regulates gene transcription; the Discussion says gene-expression analyses are still needed to interpret the methylation differences observed in HOXA. (LLM, conf=0.84)

  Experimental — accuracy not yet measured
• cites [21] Gasparoni G, Bultmann S, Lutsik P, Kraus TFJ, Sordon S, Vlcek J, Dietinger V, Steinmaurer M, Haider M, Mulholland CB, Arzberger T, Roeber S, Riemenschneider M, Kretzschmar HA, Giese A, Leonhardt H, Walter J (2018) DNA methylation analysis on purified neurons and glia dissects age and Alzheimer’s disease-specific changes in the human cortex. Epigenetics Chromatin 11(1):41 sourcePartly supported

  The Background (page unavailable) calls DNA methylation an extensively studied epigenetic mark, and the Abstract Results report methylation changes associated with Alzheimer’s disease. The Results also place methylation differences at genes with cell-type-specific expression, but the retrieved passages do not establish that methylation regulates gene transcription. (LLM, conf=0.82)

  Experimental — accuracy not yet measured
• cites [22] Zhang L, Silva TC, Young JI, Gomez L, Schmidt MA, Hamilton-Nelson KL, Kunkle BW, Chen X, Martin ER, Wang L (2020) Epigenome-wide meta-analysis of DNA methylation differences in prefrontal cortex implicates the immune processes in Alzheimer’s disease. Nat Commun 11(1):6114 sourceSupported

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

The TYROBP causal network was previously inferred from a large-scale network analysis of human late-onset AD brains.

“The TYROBP causal network was previously inferred from a large-scale network analysis of human late-onset AD brains [56]”

• cites [56] Zhang B, Gaiteri C, Bodea LG, Wang Z, McElwee J, Podtelezhnikov AA, Zhang C, Xie T, Tran L, Dobrin R, Fluder E, Clurman B, Melquist S, Narayanan M, Suver C, Shah H, Mahajan M, Gillis T, Mysore J, MacDonald ME, Lamb JR, Bennett DA, Molony C, Stone DJ, Gudnason V, Myers AJ, Schadt EE, Neumann H, Zhu J, Emilsson V (2013) Integrated systems approach identifies genetic nodes and networks in late-onset Alzheimer’s disease. Cell 153(3):707–720 sourceSupported

May combine two claims.

For males, no significant GO terms were identified at 25% FDR; the strongest enrichment with nominal P<0.001 involved immune responses to accumulation of amyloid-β in the brain, such as regulation of T cell activation via T cell receptor contact with antigen bound to MHC molecule on antigen presenting cell, and other biological processes recently implicated in AD such as response to angiotensin [

“For males, we did not identify any significant GO terms at 25% FDR; the strongest enrichment with nominal P-value less than 0.001 involved immune responses to the accumulation of amyloid-β (Aβ) in the brain, such as regulation of T cell activation via T cell receptor contact with antigen bound to MHC molecule on antigen presenting cell, and other biological processes recently implicated in AD such”

• cites [57] Cosarderelioglu C, Nidadavolu LS, George CJ, Oh ES, Bennett DA, Walston JD, Abadir PM (2020) Brain renin-angiotensin system at the intersect of physical and cognitive frailty. Front Neurosci 14:586314 sourcePartly supported

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

  Experimental — accuracy not yet measured
• cites [58] Benigni A, Cassis P, Remuzzi G (2010) Angiotensin II revisited: new roles in inflammation, immunology and aging. EMBO Mol Med 2(7):247–257 sourcePartly supported

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

  Experimental — accuracy not yet measured
• cites [59] Manoharan S, Guillemin GJ, Abiramasundari RS, Essa MM, Akbar M, Akbar MD (2016) The role of reactive oxygen species in the pathogenesis of Alzheimer’s disease. Parkinson’s disease, and Huntington’s disease: a mini review. Oxid Med Cell Longev 2016:8590578 sourcePartly supported

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

  Experimental — accuracy not yet measured
• cites [60] Chen YY, Wang MC, Wang YN, Hu HH, Liu QQ, Liu HJ, Zhao YY (2020) Redox signaling and Alzheimer’s disease: from pathomechanism insights to biomarker discovery and therapy strategy. Biomark Res 8:42 sourceCould not verify

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

  Experimental — accuracy not yet measured

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

During aging, human brain DNA methylation levels gradually increase at genomic loci located at CpG islands and gene promoters, whereas intergenic CpG sites are marked with hypomethylation.

“These observations are consistent with the knowledge that during aging, human brain DNA methylation levels gradually increase (hypermethylation) at genomic loci located at CpG islands and gene promoters, whereas intergenic CpG sites are marked with hypomethylation [50, 51].”

• cites [50] Prasad R, Jho EH (2019) A concise review of human brain methylome during aging and neurodegenerative diseases. BMB Rep 52(10):577–588 sourcePartly supported

  The Introduction (page not provided) reports gradually increasing methylation at many loci in the aging human cerebral cortex, but does not identify those loci generally as CpG islands or gene promoters. The genome-wide aging section (page not provided) reports intergenic hypomethylation and CpG-island hypermethylation in a comparison of newborns and centenarians; it does not establish that this whole pattern occurs gradually in the human brain or at gene promoters. (LLM, conf=0.84)

  Experimental — accuracy not yet measured
• cites [51] Heyn H, Li N, Ferreira HJ, Moran S, Pisano DG, Gomez A, Diez J, Sanchez-Mut JV, Setien F, Carmona FJ, Puca AA, Sayols S, Pujana MA, Serra-Musach J, Iglesias-Platas I, Formiga F, Fernandez AF, Fraga MF, Heath SC, Valencia A, Gut IG, Wang J, Esteller M (2012) Distinct DNA methylomes of newborns and centenarians. Proc Natl Acad Sci U S A 109(26):10522–10527 sourcePartly supported

  The Results and Discussion (page not provided) report greater methylation at CpG-island promoters and lower methylation in intergenic regions in centenarian CD4+ T cells than in newborn cells. Middle-aged blood samples showed intermediate methylation at many age-associated sites. The paper does not establish this pattern in human brain, and its findings do not support an increase at gene promoters generally: CpG-poor promoters were less methylated with age. (LLM, conf=0.89)

  Experimental — accuracy not yet measured

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

These inflation values are comparable to those obtained in other recent large-scale EWAS.

“These values are comparable to those obtained in other recent large-scale EWAS [49]”

• cites [49] Viana J, Hannon E, Dempster E, Pidsley R, Macdonald R, Knox O, Spiers H, Troakes C, Al-Saraj S, Turecki G, Schalkwyk LC, Mill J (2017) Schizophrenia-associated methylomic variation: molecular signatures of disease and polygenic risk burden across multiple brain regions. Hum Mol Genet 26(1):210–225 sourceSupported

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

HLA-DPA1 encodes microglia receptors involved in antigen presentation and is regulated by PU.1.

“which encodes microglia receptors involved in antigen presentation and is regulated by PU.1 [61].”

• cites [61] Rustenhoven J, Smith AM, Smyth LC, Jansson D, Scotter EL, Swanson MEV, Aalderink M, Coppieters N, Narayan P, Handley R, Overall C, Park TIH, Schweder P, Heppner P, Curtis MA, Faull RLM, Dragunow M (2018) PU.1 regulates Alzheimer’s disease-associated genes in primary human microglia. Mol Neurodegener 13(1):44 sourceSupported

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

PRC2 silences genes involved in neurodegeneration and its deficiency leads to de-repression of developmental regulators such as Hox gene clusters, which manifest in progressive and fatal neurodegeneration in mice.

“PRC2 silences genes involved in neurodegeneration and its deficiency leads to the de-repression of developmental regulators such as the Hox gene clusters, which manifest in progressive and fatal neurodegeneration in mice [54].”

• cites [54] von Schimmelmann M, Feinberg PA, Sullivan JM, Ku SM, Badimon A, Duff MK, Wang Z, Lachmann A, Dewell S, Ma’ayan A, Han MH, Tarakhovsky A, Schaefer A (2016) Polycomb repressive complex 2 (PRC2) silences genes responsible for neurodegeneration. Nat Neurosci 19(10):1321–1330 sourceSupported

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

Synapse loss significantly correlates with cognitive impairment and has been observed to be an early feature of AD pathogenesis.

“Notably, synapse loss significantly correlates with cognitive impairment [76, 77] and has been observed to be an early feature of AD pathogenesis [78, 79].”

• cites [76] DeKosky ST, Scheff SW (1990) Synapse loss in frontal cortex biopsies in Alzheimer’s disease: correlation with cognitive severity. Ann Neurol 27(5):457–464 sourceNot checked — no full text of the source
• cites [77] Terry RD, Masliah E, Salmon DP, Butters N, DeTeresa R, Hill R, Hansen LA, Katzman R (1991) Physical basis of cognitive alterations in Alzheimer’s disease: synapse loss is the major correlate of cognitive impairment. Ann Neurol 30(4):572–580 sourceNot checked — no full text of the source
• cites [78] Masliah E, Mallory M, Alford M, DeTeresa R, Hansen LA, McKeel DW Jr, Morris JC (2001) Altered expression of synaptic proteins occurs early during progression of Alzheimer’s disease. Neurology 56(1):127–129 sourceSupported
• cites [79] Scheff SW, Price DA, Schmitt FA, DeKosky ST, Mufson EJ (2007) Synaptic alterations in CA1 in mild Alzheimer disease and mild cognitive impairment. Neurology 68(18):1501–1508 sourceNot checked — no full text of the source

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

The PRKCA gene encodes protein kinase Cα (PKCα), which participates in synaptic loss resulting from the accumulation of amyloid-β in AD neuropathology.

“The PRKCA gene encodes protein kinase Cα (PKCα), which participates in synaptic loss resulting from the accumulation of amyloid-β (Aβ) in AD neuropathology [73, 74].”

• cites [73] Alfonso SI, Callender JA, Hooli B, Antal CE, Mullin K, Sherman MA, Lesne SE, Leitges M, Newton AC, Tanzi RE, Malinow R (2016) Gain-of-function mutations in protein kinase Calpha (PKCalpha) may promote synaptic defects in Alzheimer’s disease. Sci Signal 9(427):ra47 sourcePartly supported

  The Abstract identifies PRKCA as the gene encoding PKCα, and the Results (‘PKCα is necessary for the synaptic effects of Aβ’) show that PKCα is required for Aβ-related synaptic depression in mouse hippocampal slices. The Discussion links Aβ accumulation with synaptic loss in AD, but the study does not directly show that PKCα causes synaptic loss in human AD. (LLM, conf=0.82)

  Experimental — accuracy not yet measured
• cites [74] John A, Reddy PH (2020) Synaptic basis of Alzheimer’s disease: Focus on synaptic amyloid beta. P-tau and mitochondria. Ageing Res Rev 65:101208 sourcePartly supported

  The “Amyloid Beta and Alzheimer’s Disease” section states that Aβ accumulation induces synaptic damage in AD neurons, supporting that part of the claim. The passages found for PRKCA, PKCα, and protein kinase C do not identify PRKCA as encoding PKCα or link PKCα to that damage, so the protein-specific attribution is unsupported by our copy. Page numbers were not available. (LLM, conf=0.86)

  Experimental — accuracy not yet measured

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

In recent GWAS, a genetic variant on TMEM39A was discovered and replicated as an important risk locus for multiple sclerosis, an autoimmune condition of the central nervous system.

“In recent GWAS, a genetic variant on TMEM39A was discovered and replicated as an important risk locus for multiple sclerosis, an autoimmune condition of the central nervous system [80, 81].”

• cites [80] C. International Multiple Sclerosis Genetics (2010) Comprehensive follow-up of the first genome-wide association study of multiple sclerosis identifies KIF21B and TMEM39A as susceptibility loci. Hum Mol Genet 19(5): 953–962 sourceSupported
• cites [81] Varade J, Comabella M, Ortiz MA, Arroyo R, Fernandez O, Pinto-Medel MJ, Fedetz M, Izquierdo G, Lucas M, Gomez CL, Rabasa AC, Alcina A, Matesanz F, Alloza I, Antiguedad A, Garcia-Barcina M, Otaegui D, Olascoaga J, Saiz A, Blanco Y, Montalban X, Vandenbroeck K, Urcelay E (2012) Replication study of 10 genes showing evidence for association with multiple sclerosis: validation of TMEM39A, IL12B and CBLB [correction of CLBL] genes. Mult Scler 18(7):959–965 sourceNot checked — no full text of the source

May combine two claims.

Consistent with previous studies, we observed the majority of these sex-specific differences were hyper-methylated in samples with AD neuropathology, for which methylation levels increased as the AD Braak stage increased.

“Consistent with previous studies [18, 19, 86, 87], we observed the majority of these sex-specific differences were hyper-methylated in samples with AD neuropathology, for which methylation levels increased as the AD Braak stage increased”

• cites [18] De Jager PL, Srivastava G, Lunnon K, Burgess J, Schalkwyk LC, Yu L, Eaton ML, Keenan BT, Ernst J, McCabe C, Tang A, Raj T, Replogle J, Brodeur W, Gabriel S, Chai HS, Younkin C, Younkin SG, Zou F, Szyf M, Epstein CB, Schneider JA, Bernstein BE, Meissner A, Ertekin-Taner N, Chibnik LB, Kellis M, Mill J, Bennett DA (2014) Alzheimer’s disease: early alterations in brain DNA methylation at ANK1, BIN1, RHBDF2 and other loci. Nat Neurosci 17(9):1156–1163 sourcePartly supported

  In ‘Discovery study to identify differentially methylated chromosomal regions’ (page unavailable), the paper reports that 82% of its differentially methylated regions were more methylated in subjects with a neuropathologic AD diagnosis. ‘Validation of the associated CpG in an independent sample set’ (page unavailable) reports associations using Braak staging, but does not establish that methylation increased with each successive stage. The paper does not identify the citing authors’ sex-specific differences as the regions it studied. (LLM, conf=0.84)

  Experimental — accuracy not yet measured
• cites [19] Lunnon K, Smith R, Hannon E, De Jager PL, Srivastava G, Volta M, Troakes C, Al-Sarraj S, Burrage J, Macdonald R, Condliffe D, Harries LW, Katsel P, Haroutunian V, Kaminsky Z, Joachim C, Powell J, Lovestone S, Bennett DA, Schalkwyk LC, Mill J (2014) Methylomic profiling implicates cortical deregulation of ANK1 in Alzheimer’s disease. Nat Neurosci 17(9):1164–1170 sourcePartly supported

  The paper reports that hypermethylation at two ANK1-associated sites increases with Braak score in cortical regions (main text, page not provided). It does not establish that a majority of AD-associated differences are hypermethylated or that the differences are sex-specific; the Online Methods say sex effects were regressed out. (LLM, conf=0.86)

  Experimental — accuracy not yet measured
• cites [86] Watson CT, Roussos P, Garg P, Ho DJ, Azam N, Katsel PL, Haroutunian V, Sharp AJ (2016) Genome-wide DNA methylation profiling in the superior temporal gyrus reveals epigenetic signatures associated with Alzheimer’s disease. Genome Med 8(1):5 sourcePartly supported

  The Results and discussion section (page unavailable) reports that most AD-associated differentially methylated regions were hypermethylated in AD cases, supporting the cited background comparison. The paper does not report that these changes were sex-specific or that methylation increased with Braak stage; its Methods section gives only average Braak stages for cases and controls. (LLM, conf=0.86)

  Experimental — accuracy not yet measured
• cites [87] Bakulski KM, Dolinoy DC, Sartor MA, Paulson HL, Konen JR, Lieberman AP, Albin RL, Hu H, Rozek LS (2012) Genome-wide DNA methylation differences between late-onset Alzheimer’s disease and cognitively normal controls in human frontal cortex. J Alzheimers Dis 29(3):571–588 sourcePartly supported

  The Results and Discussion report hypermethylation in some genes and pathways in AD cases, supporting the general direction of the comparison. The cited paper does not establish that a majority of sex-specific differences were hypermethylated or that methylation increased with Braak stage; its analysis adjusted for sex rather than reporting that pattern. (LLM, conf=0.84)

  Experimental — accuracy not yet measured

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

Recent studies suggested TYROBP-mediated signaling is involved in multiple important functions as aggregating Aβ activates microglia, including enhanced phagocytosis of damaged neurons and suppression of inflammatory responses, as well as neuronal pruning activity.

“Recent studies suggested TYROBP-mediated signaling is involved in multiple important functions as aggregating Aβ activates microglia, including enhanced phagocytosis of damaged neurons [56, 90] and suppression of inflammatory responses [94], as well as neuronal pruning activity [56].”

• cites [56] Zhang B, Gaiteri C, Bodea LG, Wang Z, McElwee J, Podtelezhnikov AA, Zhang C, Xie T, Tran L, Dobrin R, Fluder E, Clurman B, Melquist S, Narayanan M, Suver C, Shah H, Mahajan M, Gillis T, Mysore J, MacDonald ME, Lamb JR, Bennett DA, Molony C, Stone DJ, Gudnason V, Myers AJ, Schadt EE, Neumann H, Zhu J, Emilsson V (2013) Integrated systems approach identifies genetic nodes and networks in late-onset Alzheimer’s disease. Cell 153(3):707–720 sourcePartly supported

  In Results, under “Highlighting the Microglia Pathway with TYROBP as Causal Regulator” (page unavailable), the paper suggests that TYROBP may be associated with neuronal pruning activity linked to amyloid-β and Tau aggregates. It identifies pathogen-phagocytosis pathways in the microglia network, but does not report enhanced phagocytosis of damaged neurons. The suppression-of-inflammatory-responses clause is cited to [94], not this source. (LLM, conf=0.84)

  Experimental — accuracy not yet measured
• cites [90] Ma J, Jiang T, Tan L, Yu JT (2015) TYROBP in Alzheimer’s disease. Mol Neurobiol 51(2):820–826 sourceNot checked — no full text of the source
• cites [94] Sessa G, Podini P, Mariani M, Meroni A, Spreafico R, Sinigaglia F, Colonna M, Panina P, Meldolesi J (2004) Distribution and signaling of TREM2/DAP12, the receptor system mutated in human polycystic lipomembraneous osteodysplasia with sclerosing leukoencephalopathy dementia. Eur J Neurosci 20(10):2617–2628 sourcePartly supported

  The Abstract and Effects of cell stimulation (pages unavailable) identify TYROBP/DAP12 in microglia and report signaling after antibody activation of TREM2. They do not link that signaling to phagocytosis of damaged neurons, neuronal pruning, or activation by aggregated Aβ—the functions and context for which this source is cited. The separate claim about suppression of inflammatory responses is cited to [94], not this paper. (LLM, conf=0.82)

  Experimental — accuracy not yet measured

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

TYROBP is regulated by SPI1, a central hub for the network of genes involved in myeloid immune response in neurodegeneration.

“Also, TYROBP is regulated by SPI1, a central hub for the network of genes involved in myeloid immune response in neurodegeneration [93].”

• cites [93] Huang KL, Marcora E, Pimenova AA, Di Narzo AF, Kapoor M, Jin SC, Harari O, Bertelsen S, Fairfax BP, Czajkowski J, Chouraki V, Grenier-Boley B, Bellenguez C, Deming Y, McKenzie A, Raj T, Renton AE, Budde J, Smith A, Fitzpatrick A, Bis JC, DeStefano A, Adams HHH, Ikram MA, van der Lee S, Del-Aguila JL, Fernandez MV, Ibanez L, Sims R, Escott-Price V, Mayeux R, Haines JL, Farrer LA, Pericak-Vance MA, Lambert JC, van Duijn C, Launer L, Seshadri S, Williams J, Amouyel P, Schellenberg GD, Zhang B, Borecki I, Kauwe JSK, Cruchaga C, Hao K, Goate AM, P. International Genomics of Alzheimer’s, I. Alzheime sourceSupported

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

TYROBP is a transmembrane adaptor protein for TREM2, SIRPβ1, and CR3 receptors, which are known to be involved in AD pathogenesis.

“TYROBP is a transmembrane adaptor protein for TREM2, SIRPβ1, and CR3 receptors, which are known to be involved in AD pathogenesis [90–92].”

• cites [90] Ma J, Jiang T, Tan L, Yu JT (2015) TYROBP in Alzheimer’s disease. Mol Neurobiol 51(2):820–826 sourceNot checked — no full text of the source
• cites [91] Pottier C, Ravenscroft TA, Brown PH, Finch NA, Baker M, Parsons M, Asmann YW, Ren Y, Christopher E, Levitch D, van Blitterswijk M, Cruchaga C, Campion D, Nicolas G, Richard AC, Guerreiro R, Bras JT, Zuchner S, Gonzalez MA, Bu G, Younkin S, Knopman DS, Josephs KA, Parisi JE, Petersen RC, Ertekin-Taner N, Graff-Radford NR, Boeve BF, Dickson DW, Rademakers R (2016) TYROBP genetic variants in early-onset Alzheimer’s disease. Neurobiol Aging 48:2229–22215 sourcePartly supported

  The Introduction and Discussion (page not available in our copy) describe TYROBP as a transmembrane protein, identify it as a TREM2 binding partner, and link TREM2 and TYROBP to Alzheimer’s disease. The passages do not identify SIRPβ1 or CR3 as TYROBP-associated receptors or establish their involvement in AD pathogenesis. (LLM, conf=0.88)

  Experimental — accuracy not yet measured
• cites [92] Paloneva J, Manninen T, Christman G, Hovanes K, Mandelin J, Adolfsson R, Bianchin M, Bird T, Miranda R, Salmaggi A, Tranebjaerg L, Konttinen Y, Peltonen L (2002) Mutations in two genes encoding different subunits of a receptor signaling complex result in an identical disease phenotype. Am J Hum Genet 71(3):656–662 sourceNot checked — no full text of the source

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

TNXB encodes tenascin proteins, which are extracellular matrix glycoproteins demonstrated to modulate synaptic plasticity in the brain.

“TNXB encodes tenascin proteins, which are extracellular matrix glycoproteins demonstrated to modulate synaptic plasticity in the brain [83].”

• cites [83] Ferrer-Ferrer M, Dityatev A (2018) Shaping synapses by the neural extracellular matrix. Front Neuroanat 12:40 sourcePartly supported

  The “Tenascins and Synaptic Plasticity” section describes tenascins as extracellular-matrix glycoproteins that modulate synaptic plasticity, particularly tenascin-R and tenascin-C in the brain. It does not identify TNXB as encoding a tenascin or demonstrate a role for the TNXB product specifically. (LLM, conf=0.88)

  Experimental — accuracy not yet measured

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

TYROBP is a key regulator of the complement pathway in the immune/microglia network, which is activated as Aβ accumulates in LOAD brains.

“TYROBP (TYRO protein tyrosine kinase-binding protein) is a key regulator of the complement pathway in the immune/microglia network, which is activated as Aβ accumulates in LOAD brains [56, 90].”

• cites [56] Zhang B, Gaiteri C, Bodea LG, Wang Z, McElwee J, Podtelezhnikov AA, Zhang C, Xie T, Tran L, Dobrin R, Fluder E, Clurman B, Melquist S, Narayanan M, Suver C, Shah H, Mahajan M, Gillis T, Mysore J, MacDonald ME, Lamb JR, Bennett DA, Molony C, Stone DJ, Gudnason V, Myers AJ, Schadt EE, Neumann H, Zhu J, Emilsson V (2013) Integrated systems approach identifies genetic nodes and networks in late-onset Alzheimer’s disease. Cell 153(3):707–720 sourcePartly supported

  The Results section, “Highlighting the Microglia Pathway with TYROBP as Causal Regulator” (page not provided), places TYROBP in the complement pathway and calls it a key regulator of an immune/microglia network activated in LOAD. But it only proposes that complement-related activity may be reawakened via amyloid-β and tau aggregates; it does not establish that the network activates as Aβ accumulates. (LLM, conf=0.88)

  Experimental — accuracy not yet measured
• cites [90] Ma J, Jiang T, Tan L, Yu JT (2015) TYROBP in Alzheimer’s disease. Mol Neurobiol 51(2):820–826 sourceNot checked — no full text of the source

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

Recently, a number of novel agents targeting the complement system are being developed and tested in clinical trials for potential effective therapy for AD.

“Recently, a number of novel agents targeting the complement system are being developed and tested in clinical trials for potential effective therapy for AD [97].”

• cites [97] Morgan BP (2018) Complement in the pathogenesis of Alzheimer’s disease. Semin Immunopathol 40(1):113–124 sourcePartly supported

  The “Targeting complement in AD” section describes C1q-blocking antibodies developed for AD and other anti-complement drugs in development. It does not say these agents are being tested in AD clinical trials; the Concluding remarks instead call such trials urgently needed and refer to future trials. (LLM, conf=0.88)

  Experimental — accuracy not yet measured

May combine two claims.

Among 451 unique CpGs identified in our sex-stratified analysis or sex-by-Braak stage interaction analysis, only 16 were also identified in Xia et al. and none were identified in Xu et al.

“Among 451 unique CpGs identified in our sex-stratified analysis or sex-by-Braak stage interaction analysis, only 16 were also identified in Xia et al. [16] and none were identified in Xu et al. [17]”

• cites [16] Xia Y, Dai R, Wang K, Jiao C, Zhang C, Xu Y, Li H, Jing X, Chen Y, Jiang Y, Kopp RF, Giase G, Chen C, Liu C (2019) Sex-differential DNA methylation and associated regulation networks in human brain implicated in the sex-biased risks of psychiatric disorders. Mol Psychiatry sourceSupported
• cites [17] Xu H, Wang F, Liu Y, Yu Y, Gelernter J, Zhang H (2014) Sex-biased methylome and transcriptome in human prefrontal cortex. Hum Mol Genet 23(5):1260–1270 sourceSupported

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

The average number of CpGs per DMR was 6.5 ± 8.9.

“The average number of CpGs per DMR was 6.5 ± 8.9”

May combine two claims.

Among the significant CpGs and DMRs, 3.6% of unique CpGs and 12.5% of unique DMRs were significant in both sexes with the same direction of change.

“Among them, 3.6% (16 out of 441 unique FDR-significant CpGs) and 12.5% (11 out of 88 unique FDR-significant DMRs) were significant in both females and males with the same direction of change”

May combine two claims.

At 5% FDR, the meta-analysis identified 72 DMRs mapped to 66 genes in females and 27 DMRs mapped to 22 genes in males.

“Similarly, at 5% FDR, we also identified 72 and 27 DMRs, mapped to 66 and 22 genes, in female and male samples, respectively”

May combine two claims.

Only 89 out of 381 (23.4%) significant CpGs in females and 13 out of 76 (17.1%) significant CpGs in males overlapped with significant DMRs.

“Only 89 out of the 381 (23.4%) significant CpGs in females, and 13 out of the 76 (17.1%) significant CpGs in males overlapped with the significant DMRs”

May combine two claims.

At 25% FDR, significant methylation differences in females were enriched in 25 GO biological processes, many involved in inflammatory responses associated with AD pathology including CD8 positive alpha beta T cell activation and interferon alpha production, as well as other biological processes critical for AD pathogenesis such as response to platelet derived growth factor and positive regulation.

“The comparison with gene ontology (GO) terms showed at 25% FDR, significant methylation differences in females were enriched in 25 GO biological processes (Table 4, Additional file 2: Table S10), many of which are involved in inflammatory responses associated with AD pathology including CD8 positive alpha beta T cell activation and interferon alpha production, as well as other biological processes”

May combine two claims.

Among the 14 CpGs identified in our sex-by-Braak stage interaction analysis, 2 and 7 CpGs with at least one brain mQTL, corresponding to 21 and 236 significant mQTL-CpG pairs, were identified at 5% FDR in females and males, respectively.

“Among the 14 CpGs identified in our sex-by-Braak stage interaction analysis, 2 and 7 CpGs with at least one brain mQTL, corresponding to 21 and 236 significant mQTL-CpG pairs, were identified at 5% FDR in females and males, respectively”

May combine two claims.

In sex-stratified analysis, the methylation-Braak stage associations for cg13212831 were highly significant in females (P=0.006) and males (P=4.1×10−5), but did not reach 5% FDR significance (FDR female=0.413, FDR male=0.097).

“In sex-stratified analysis, although the methylation-Braak stage associations were highly significant (P-valuefemale = 0.006, P-valuemale = 4.1 × 10–5), they did not reach 5% FDR significance threshold (FDRfemale = 0.413, FDRmale = 0.097).”

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

For males, lambdas ranged from 0.906 to 1.265 by the conventional approach and from 0.957 to 1.114 by the bacon approach.

“Similarly, for males, λ ranged from 0.906 to 1.265, and λbacon ranged from 0.957 to 1.114”

May combine two claims.

While no mQTL-DMR pairs reached 5% FDR significance, we did identify 572 and 284 FDR-significant mQTL-CpG pairs associated with the sex-specific CpGs in females and males, respectively.

“While no mQTL-DMR pairs reached 5% FDR significance, we did identify 572 and 284 FDR-significant mQTL-CpG pairs associated with the sex-specific CpGs in females and males, respectively”

May combine two claims.

For females, inflation factor lambdas by the conventional approach ranged from 1.060 to 1.154, and lambdas based on the bacon approach ranged from 1.021 to 1.059.

“For females, inflation factor lambdas (λ) by the conventional approach ranged from 1.060 to 1.154, and lambdas based on the bacon approach [32] (λbacon) ranged from 1.021 to 1.059”

May combine two claims.

At 5% FDR, among FDR significant CpGs in females, all 381 CpGs were linked to a nearby gene by GREAT software, in which 14 were significantly associated with target gene expression levels, and half of them (n=7) had effects in the negative direction.

“At 5% FDR, among FDR significant CpGs in females, all 381 CpGs were linked to a nearby gene by GREAT software, in which 14 were significantly associated with target gene expression levels (Additional file 2: Table S11), and half of them (n = 7) had effects in the negative direction.”

May combine two claims.

In sex-by-Braak stage interaction analysis, significant interaction was identified at 14 CpGs, but no significant interactions at DMRs at 5% FDR.

“In sex-by-Braak stage interaction analysis, we identified significant interaction at 14 CpGs, but no significant interactions at DMRs at 5% FDR.”

May combine two claims.

At 25% FDR, significant DNA methylation differences in females were enriched in TYROBP causal network (FDR=0.014), TCR signaling in naïve CD4+ T cells (FDR=0.130) and ROBO receptors bind AKAP5 (FDR=0.160) gene sets.

“At 25% FDR, the significant DNA methylation differences in females were enriched in TYROBP causal network (FDR = 0.014), TCR signaling in naïve CD4 + T cells (FDR = 0.130) and ROBO receptors bind AKAP5 (FDR = 0.160) gene sets”

May combine two claims.

The TYROBP causal network was FDR significant (P<0.001, FDR=0.014) in females, compared to a nominal association in males (P<0.001, FDR=0.620).

“it was FDR significant (P-value < 0.001, FDR = 0.014) in females (Additional file 1: Fig. S4a), compared to a nominal association in males (P-value < 0.001, FDR = 0.620).”

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

The mean age at death ranged from 79.3 to 87.2 years in females and from 67.5 to 85.0 years in males.

“the mean age at death ranged from 79.3 to 87.2 years in females and from 67.5 to 85.0 years in males”

May combine two claims.

Among FDR significant CpGs in males, out of the 46 CpGs that were linked to a nearby gene, 2 were significantly associated with target gene expression and both were in the negative direction.

“Among FDR significant CpGs in males, out of the 46 CpGs that were linked to a nearby gene, 2 were significantly associated with target gene expression and both were in the negative direction.”

May combine two claims.

Among the top 10 CpGs in the sex-stratified analysis, a new locus at cg22632947, mapped to the gene body of the PRKCA gene, was highly significant in female samples (estimate=-0.139, P=1.50×10−7, FDR=3.00×10−3), but not significant in male samples (estimate=-0.005, P=0.857, FDR=0.995).

“among the top 10 CpGs in the sex-stratified analysis (Table 1), a new locus at cg22632947, which mapped to the gene body of the PRKCA gene, was highly significant in female samples (estimate = − 0.139, P-value = 1.50 × 10–7, FDR = 3.00 × 10–3), but not significant in male samples (estimate = − 0.005, P-value = 0.857, FDR = 0.995)”

May combine two claims.

Another novel locus is at cg18942110 in the promoter of the CRTC3 gene, where methylation-Braak stage association was highly significant in male samples (estimate=-0.164, P=2.23×10−6, FDR=3.19×10−2), but not significant in female samples (estimate=-0.031, P=0.306, FDR=0.952).

“Another novel locus is at cg18942110 in the promoter of the CRTC3 gene, where methylation-Braak stage association was highly significant in male samples (estimate = − 0.164, P-value = 2.23 × 10–6, FDR = 3.19 × 10–2), but not significant in female samples (estimate = − 0.031, P-value = 0.306, FDR = 0.952)”

May combine two claims.

59% of the significant CpGs and 69% of the significant DMRs in females, along with 66% of the significant CpGs and 89% of the significant DMRs in males were hyper-methylated in samples with AD neuropathology.

“More specifically, 59% of the significant CpGs and 69% of the significant DMRs in females, along with 66% of the significant CpGs and 89% of the significant DMRs in males were hyper-methylated in samples with AD neuropathology”

May combine two claims.

The TYROBP causal network reached the FDR significance threshold in females (FDR=0.014) but was only nominally significant in males.

“Notably, the TYROBP causal network reached the FDR significance threshold in females (FDR = 0.014) but was only nominally significant in males.”

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

The fixed effects model for meta-analysis does not require the assumption of homogeneity.

“Even though the fixed effects model for meta-analysis does not require the assumption of homogeneity [34]”

• cites [34] Rice K, Higgins JLT (2018) A re-evaluation of fixed effect(s) meta-analysis. J R Stat Soc A 181:205–227 sourceNot checked — no full text of the source

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

Caffeine was included in cocktail therapy in AD clinical trials.

“which was included in cocktail therapy in AD clinical trials [66, 67].”

• cites [66] ClinicalTrials.gov., Drug interaction study with a potential Alzheimer's disease compound. https://clinicaltrials.gov/ct2/show/NCT00726726?id=%22NCT00692510%22OR%22NCT00726726%22&draw=2&rank=1. Accessed 31 Jan 2021Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

• cites [67] ClinicalTrials.gov., Drug interaction study between AZD3480 and cytochrome P450 (Cocktail). https://clinicaltrials.gov/ct2/show/NCT00692510?id=%22NCT00692510%22OR%22NCT00726726%22&draw=2&rank=2. Accessed 31 Jan 2021Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

Classified as probably not a substantial claim.

Because of the relatively smaller number of gene sets being tested, a 25% FDR significance threshold, instead of the conventional 5% FDR, was suggested for GSEA.

“Because of the relatively smaller number of gene sets being tested, a 25% FDR significance threshold, instead of the conventional 5% FDR, was suggested for GSEA [55].”

• cites [55] GSEA/MSigDB Team, GSEA FAQ, 2020. https://software.broadinstitute.org/cancer/software/gsea/wiki/index.php/FAQ#Why_does_GSEA_use_a_false_discovery_rate_.28FDR.29_of_0.25_rather_than_the_more_classic_0.05.3F. Accessed 24 Nov 2020Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

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

Valproic acid is a mood stabilizer often prescribed for AD patients and was shown to have different pharmacokinetic profiles between male and female subjects.

“valproic acid, a mood stabilizer often prescribed for AD patients and was shown to have different pharmacokinetic profiles between male and female subjects [65].”

• cites [65] Ibarra M, Vazquez M, Fagiolino P, Derendorf H (2013) Sex related differences on valproic acid pharmacokinetics after oral single dose. J Pharmacokinet Pharmacodyn 40(4):479–486 sourceNot checked — no full text of the source

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

Previously, drug responses for donepezil were shown to be modulated by the sex hormone estrogen receptor alpha (ESR1) genotype.

“Previously, drug responses for donepezil were shown to be modulated by the sex hormone estrogen receptor alpha (ESR1) genotype [64].”

• cites [64] Scacchi R, Gambina G, Broggio E, Corbo RM (2014) Sex and ESR1 genotype may influence the response to treatment with donepezil and rivastigmine in patients with Alzheimer’s disease. Int J Geriatr Psychiatry 29(6):610–615 sourceNot checked — no full text of the source

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

In addition to its crucial role in maintaining synaptic plasticity and facilitation of short-term memory to long-term memory, the CREB signaling pathway also mediates synapse loss induced by Aβ in AD.

“In addition to its crucial role in maintaining synaptic plasticity and facilitation of short-term memory to long-term memory, the CREB signaling pathway also mediates synapse loss induced by Aβ in AD [75].”

• cites [75] Saura CA, Valero J (2011) The role of CREB signaling in Alzheimer’s disease and other cognitive disorders. Rev Neurosci 22(2):153–169 sourceNot checked — no full text of the source

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

The associations we identified in this study do not necessarily reflect causal relationships.

“Finally, the associations we identified in this study do not necessarily reflect causal relationships.”

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

Alternatively, the lack of association might also be due to the limited coverage by the 450k array.

“Alternatively, the lack of association might also be due to the limited coverage by the 450k array.”

Classified as probably not a substantial claim.

The lack of chromosome X associations might suggest that sex differences in AD neuropathology are not primarily due to chromosome X.

“this might suggest that sex differences in AD neuropathology are not primarily due to chromosome X.”

May combine two claims.

This is probably due to different hypotheses tested in our study and the sexual dimorphism studies - while our study examined the impact of sex on methylation-Braak stage association, the previous studies examined differential methylation between the sexes, regardless of AD neuropathology.

“This is probably due to different hypotheses tested in our study and the sexual dimorphism studies – while our study examined the impact of sex on methylation-Braak stage association, the previous studies examined differential methylation between the sexes, regardless of AD neuropathology.”

Probably not a substantial claim: may not pass S2 (checkable). May combine two claims.

Our results have important implications for precision medicine-many of the sex-specific DNA methylation differences also pointed to important potential AD biomarkers and therapeutic targets, suggesting a pressing need for developing and applying sex-specific treatment strategies for AD.

“Finally, our results also have important implications for precision medicine—many of the sex-specific DNA methylation differences also pointed to important potential AD biomarkers and therapeutic targets, suggesting a pressing need for developing and applying sex-specific treatment strategies for AD.”

Classified as probably not a substantial claim.

To reduce confounding effects due to cellular heterogeneities, we included the estimated neuron proportion of each brain sample as a covariate variable in all our analyses.

“To reduce confounding effects due to cellular heterogeneities, we included the estimated neuron proportion of each brain sample as a covariate variable in all our analyses.”

Probably not a substantial claim: may not pass S2 (checkable).

Our study highlighted the importance of stratifying on sex and analyzing sex-by-disease interaction in the analysis of DNA methylation data to discover the epigenetic architectures underlying AD neuropathology.

“In summary, our study highlighted the importance of stratifying on sex and analyzing sex-by-disease interaction in the analysis of DNA methylation data to discover the epigenetic architectures underlying AD neuropathology.”