Unraveling sex differences in Alzheimer's disease and related endophenotypes with brain proteomes

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

An integrated proteomic and metabolomic study of 43 hippocampal samples identified significant sex differences in insulin signaling and serine metabolism.

“An integrated proteomic and metabolomic study of 43 hippocampal samples identified significant sex differences in insulin signaling and serine metabolism.”

• cites [23] Mangold CA, Wronowski B, Du M, et al. Sexually divergent induction of microglial‐associated neuroinflammation with hippocampal aging. J Neuroinflammation. 2017; 14(1): 141. 28732515 PMC5521082 sourceDisputed

  The Methods (Microarray analysis; page unavailable) describe transcriptomic microarray analysis of 24 mouse hippocampal samples, not an integrated proteomic and metabolomic study of 43 samples. The Results (Sex differences in hippocampal gene expression across the lifespan; page unavailable) report sex differences chiefly in inflammatory and microglial gene expression, not the claimed insulin-signaling and serine-metabolism findings. (LLM, conf=0.90)

  Checked by a reasoning model — may be wrong.

  Experimental — accuracy not yet measured

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

Prior work examined the effect of biological sex on protein expression and its genetic regulation in human brain proteomes.

“Our prior work examined the effect of biological sex on protein expression and its genetic regulation in human brain proteomes.”

• cites [24] Wingo AP, Liu Y, Gerasimov ES, et al. Sex differences in brain protein expression and disease. Nat Med. 2023; 29(9): 2224‐ 2232. 37653343 PMC10504083 sourceSupported

May combine two claims.

Sex differences have been observed in the progression, diagnosis, and clinical presentations of AD.

“Despite the mixed findings from these incidence studies, sex differences have been observed in the progression, diagnosis, and clinical presentations of AD.”

• cites [12] Mielke MM, Vemuri P, Rocca WA. Clinical epidemiology of Alzheimer's disease: assessing sex and gender differences. Clin Epidemiol. 2014; 6: 37‐ 48. 24470773 PMC3891487 sourceSupported
• cites [13] Nebel RA, Aggarwal NT, Barnes LL, et al. Understanding the impact of sex and gender in Alzheimer's disease: a call to action. Alzheimers Dement. 2018; 14(9): 1171‐ 1183. 29907423 PMC6400070 sourceSupported
• cites [14] Ferretti MT, Iulita MF, Cavedo E, et al. Sex differences in Alzheimer disease—the gateway to precision medicine. Nat Rev Neurol. 2018; 14(8): 457‐ 469. 29985474 sourceNot checked — no full text of the source

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

Estrogen-related receptor beta is differentially expressed between male and female AD across four brain regions.

“For instance, estrogen‐related receptor beta was found to be differentially expressed between male and female AD across four brain regions.”

• cites [15] Sun LL, Yang SL, Sun H, Li WD, Duan SR. Molecular differences in Alzheimer's disease between male and female patients determined by integrative network analysis. J Cell Mol Med. 2019; 23(1): 47‐ 58. 30394676 PMC6307813 sourceSupported

May combine two claims.

Female-specific pathways are enriched in immune response, insulin signaling, and tau phosphorylation.

“Female‐specific pathways were found to be enriched in immune response, 17 , 18 , 19 insulin signaling, 20 , 21 and tau phosphorylation, 22”

• cites [17] Paranjpe MD, Belonwu S, Wang JK, et al. Sex‐specific cross tissue meta‐analysis identifies immune dysregulation in women with Alzheimer's disease. Front Aging Neurosci. 2021; 13: 735611. 34658838 PMC8515049 sourceSupported
• cites [20] Santiago JA, Quinn JP, Potashkin JA. Sex‐specific transcriptional rewiring in the brain of Alzheimer's disease patients. Front Aging Neurosci. 2022; 14: 1009368. 36389068 PMC9659968 sourceSupported
• cites [22] Cáceres A, González JR. Female‐specific risk of Alzheimer's disease is associated with tau phosphorylation processes: a transcriptome‐wide interaction analysis. Neurobiol Aging. 2020; 96: 104‐ 108. 32977080 sourceNot checked — no full text of the source

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

Male-specific pathways are linked to nicotine addiction, adipocytokine signaling, and alcoholism.

“while male‐specific pathways were linked to nicotine addiction, adipocytokine signaling, and alcoholism. 20”

• cites [20] Santiago JA, Quinn JP, Potashkin JA. Sex‐specific transcriptional rewiring in the brain of Alzheimer's disease patients. Front Aging Neurosci. 2022; 14: 1009368. 36389068 PMC9659968 sourceSupported

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

Females account for two-thirds of AD patients and have a higher lifetime risk of developing AD than males.

“Females account for two‐thirds of AD patients and experience a higher lifetime risk of developing AD compared to males.”

• cites [1] 2024 Alzheimer's Disease Facts and Figures. Alzheimers Dement, 2024. 20(5): 3708‐ 3821. 38689398 PMC11095490 sourcePartly supported

  The Prevalence section reports that almost two-thirds of Americans with Alzheimer’s are women and estimates a higher lifetime risk for women than men using Framingham Heart Study data. The citing sentence presents these U.S.-based figures without a geographic qualifier; the paper does not establish them for all AD patients worldwide. (LLM, conf=0.86)

  Experimental — accuracy not yet measured

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

The DLPFC controls working memory and executive function and is a key neocortical region affected in AD.

“The DLPFC controls working memory and executive function and is a key neocortical region affected in AD.”

• cites [27] Blumenfeld RS, Ranganath C. Dorsolateral prefrontal cortex promotes long‐term memory formation through its role in working memory organization. J Neurosci. 2006; 26(3): 916‐ 925. 16421311 PMC6675388 sourcePartly supported

  The Introduction and fMRI results link the DLPFC to organizing information in working memory, supporting its role in working-memory control. Our copy does not establish that it is a key neocortical region affected in Alzheimer’s disease (AD); a search for AD-related passages found none. (LLM, conf=0.88)

  Experimental — accuracy not yet measured
• cites [28] De Jager PL, Ma Y, Mccabe C, et al. A multi‐omic atlas of the human frontal cortex for aging and Alzheimer's disease research. Sci Data. 2018; 5: 180142. 30084846 PMC6080491 sourceSupported

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

These findings are in line with prior work showing robust differences in brain protein expression by sex.

“These findings are in line with our prior work showing robust differences in brain protein expression by sex.”

• cites [24] Wingo AP, Liu Y, Gerasimov ES, et al. Sex differences in brain protein expression and disease. Nat Med. 2023; 29(9): 2224‐ 2232. 37653343 PMC10504083 sourceSupported

May combine two claims.

MDK, SMOC1, and NTN1 have been shown to colocalize with Aβ plaque and are promising biomarkers associated with AD pathology.

“These proteins have been shown to colocalize with Aβ plaque and are promising biomarkers associated with AD pathology.”

• cites [43] Johnson ECB, Carter EK, Dammer EB, et al. Large‐scale deep multi‐layer analysis of Alzheimer's disease brain reveals strong proteomic disease‐related changes not observed at the RNA Level. Nat Neurosci. 2022; 25(2): 213‐ 225. 35115731 PMC8825285 sourcePartly supported

  The Results section (‘Modules Enriched in Proteins Co-localized with Plaques and Tangles’; page unavailable) names SMOC1, MDK and NTN1 as possible plaque-associated proteins and reports MDK staining consistent with plaque co-localization. It does not establish co-localization for all three individually. The Discussion (page unavailable) says proteins in their module may be promising AD biofluid biomarkers, citing elevated SMOC1 in AD cerebrospinal fluid. (LLM, conf=0.83)

  Experimental — accuracy not yet measured
• cites [51] Bai B, Wang X, Li Y, et al. Deep multilayer brain proteomics identifies molecular networks in Alzheimer's disease progression. Neuron. 2020; 105(6): 975‐991 e7. 31926610 PMC7318843 sourcePartly supported

  The Results section on amyloid plaque pathology reports that MDK and NTN1 are highly colocalized with Aβ plaques, while SMOC1 is partially colocalized. The Results section on CSF proteomics identifies SMOC1 among proteins changed in AD cerebrospinal fluid, but does not establish MDK or NTN1 as biomarker candidates. Thus the colocalization claim is supported, but calling all three promising biomarkers goes beyond the evidence in our copy. Page numbers are unavailable. (LLM, conf=0.86)

  Experimental — accuracy not yet measured
• cites [52] Zhou M, Haque RU, Dammer EB, et al. Targeted mass spectrometry to quantify brain‐derived cerebrospinal fluid biomarkers in Alzheimer's disease. Clin Proteomics. 2020; 17: 19. 32514259 PMC7257173 sourcePartly supported

  The Results and Discussion identify SMOC1 as a promising CSF biomarker associated with AD pathology. Our copy does not report that SMOC1 colocalizes with Aβ plaques, or establish the stated findings for MDK and NTN1 (searched: colocalization, plaques, MDK, and NTN1). (LLM, conf=0.87)

  Experimental — accuracy not yet measured

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

MARCKS is a cellular substrate for protein kinase C (PKC).

“MARCKS is a cellular substrate for protein kinase C (PKC) (Figure S5) and the phosphorylation level of MARCKS is associated with AD. 53 , 54”

• cites [53] Chen Z, Zhang W, Selmi C, et al. The myristoylated alanine‐rich C‐kinase Substrates (MARCKS): a membrane‐anchored mediator of the cell function. Autoimmun Rev. 2021; 20(11): 102942. 34509657 PMC9746065 sourceSupported
• cites [54] Fujita K, Motoki K, Tagawa K, et al. HMGB1, a pathogenic molecule that induces neurite degeneration via TLR4‐MARCKS, is a potential therapeutic target for Alzheimer's Disease. Sci Rep. 2016; 6: 31895. 27557632 PMC4997258 sourceSupported

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

TRIM46 is associated with proper microtubule functions.

“Among these proteins, TOGARAM1 and TRIM46 are associated with proper microtubule functions, 55 , 56 and MTFR1L is associated with mitochondrial fusion processes. 57”

• cites [55] Latour BL, et al. Dysfunction of the Ciliary ARMC9/TOGARAM1 protein module causes Joubert Syndrome. J Clin Invest. 2020; 130(8): 4423‐ 4439. 32453716 PMC7410078 sourceCould not verify

  The paper’s discussion of ciliary microtubules and tubulin modifications concerns ARMC9 and TOGARAM1, not TRIM46. A search of our full-text copy for “TRIM46” and “TRIM46 microtubule functions” found no passage addressing TRIM46’s role; page numbers were not available for the indexed passages. (LLM, conf=0.72)

  Experimental — accuracy not yet measured
• cites [56] van Beuningen SFB, et al. TRIM46 controls neuronal polarity and axon specification by driving the formation of parallel microtubule arrays. Neuron. 2015; 88(6): 1208‐ 1226. 26671463 sourceSupported

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

The phosphorylation level of MARCKS is associated with AD.

“MARCKS is a cellular substrate for protein kinase C (PKC) (Figure S5) and the phosphorylation level of MARCKS is associated with AD. 53 , 54”

• cites [53] Chen Z, Zhang W, Selmi C, et al. The myristoylated alanine‐rich C‐kinase Substrates (MARCKS): a membrane‐anchored mediator of the cell function. Autoimmun Rev. 2021; 20(11): 102942. 34509657 PMC9746065 sourceSupported
• cites [54] Fujita K, Motoki K, Tagawa K, et al. HMGB1, a pathogenic molecule that induces neurite degeneration via TLR4‐MARCKS, is a potential therapeutic target for Alzheimer's Disease. Sci Rep. 2016; 6: 31895. 27557632 PMC4997258 sourceSupported

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

TOGARAM1 is associated with proper microtubule functions.

“Among these proteins, TOGARAM1 and TRIM46 are associated with proper microtubule functions, 55 , 56 and MTFR1L is associated with mitochondrial fusion processes. 57”

• cites [55] Latour BL, et al. Dysfunction of the Ciliary ARMC9/TOGARAM1 protein module causes Joubert Syndrome. J Clin Invest. 2020; 130(8): 4423‐ 4439. 32453716 PMC7410078 sourceSupported
• cites [56] van Beuningen SFB, et al. TRIM46 controls neuronal polarity and axon specification by driving the formation of parallel microtubule arrays. Neuron. 2015; 88(6): 1208‐ 1226. 26671463 sourceCould not verify

  The section on parallel microtubule organization in the proximal axon describes TRIM46’s role in microtubule organization, not TOGARAM1’s. Searches of our copy for “TOGARAM1” and its expanded name found no passage addressing TOGARAM1’s function, so this source does not verify the specific claim attributed to it. (LLM, conf=0.74)

  Experimental — accuracy not yet measured

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

Functional enrichment used all quality-control-passed proteins as the background set and Benjamini-Hochberg FDR correction.

“All proteins that passed the quality control (n = 10,030) were used as the background set. The z‐score was used to determine overrepresentation of ontologies and one‐sided Fisher's exact test (Benjamini–Hochberg false discover rate [FDR] corrected) was used to assess the significance of the z‐score.”

• cites [46] Yu G, Wang L‐G, Han Y, He Q‐Y. clusterProfiler: an R package for comparing biological themes among gene clusters. OMICS. 2012; 16(5): 284‐ 287. 22455463 PMC3339379 sourcePartly supported

  The Materials and Methods section describes functional enrichment tests and FDR control, but specifies Storey q-values rather than Benjamini–Hochberg correction. It does not say that quality-control-passed proteins were used as the background set; the Results instead describe an example analysis of gene clusters. (LLM, conf=0.84)

  Experimental — accuracy not yet measured

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

Surrogate variable analysis was used to detect hidden technical or biological factors that may influence brain protein expression, and significant surrogate variables were adjusted for as covariates.

“The surrogate variable analysis (SVA) method in the sva R package (version 3.52.0) 45 was used to detect potentially hidden variables that may influence brain protein expression.”

• cites [45] Leek JT, Johnson WE, Parker HS, Jaffe AE, Storey JD. The sva Package for removing batch effects and other unwanted variation in high‐throughput experiments. Bioinformatics. 2012; 28(6): 882‐ 883. 22257669 PMC3307112 sourceSupported

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

SLC22A5 is a carnitine transporter involved in neurotransmitter synthesis.

“SLC22A5 is a carnitine transporter involved in neurotransmitter synthesis, and expression of SLC22A5 is regulated by estrogen receptors. 62”

• cites [62] Wang C, Uray IP, Mazumdar A, Mayer JA, Brown PH. SLC22A5/OCTN2 expression in breast cancer is induced by estrogen via a novel intronic estrogen‐response element (ERE). Breast Cancer Res Treat. 2012; 134(1): 101‐ 115. 22212555 PMC3416040 sourcePartly supported

  The Results section identifies SLC22A5 as a carnitine transporter, and the Abstract reports that estrogen stimulates its expression in an estrogen receptor-dependent manner. The paper discusses carnitine transport and lipid metabolism, but does not support the attributed involvement in neurotransmitter synthesis; a search for that phrase found no relevant passage. Page numbers were not provided in our copy. (LLM, conf=0.90)

  Experimental — accuracy not yet measured

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

DCUN1D5 is involved in the neddylation pathway that regulates protein homeostasis.

“DCUN1D5 is involved in the neddylation pathway that regulates protein homeostasis, 58 and S100A12 is a pro‐inflammatory mediator that modulates neuroinflammation. 59”

• cites [58] Zhang S, Yu Q, Li Z, Zhao Y, Sun Y. Protein neddylation and its role in health and diseases. Signal Transduct Target Ther. 2024; 9(1): 85. 38575611 PMC10995212 sourceSupported

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

PLCD3 is a phospholipase C (PLC) isozyme activated by G protein-coupled estrogen receptor (GPER) and is involved in phosphoinositide turnover and PKC activation.

“PLCD3 is a phospholipase C (PLC) isozyme activated by G protein‐coupled estrogen receptor (GPER) and is involved in phosphoinositide turnover and protein kinase C (PKC) activation. 60 , 61”

• cites [60] Roque C, Mendes‐Oliveira J, Duarte‐Chendo C, Baltazar G. The Role of G protein‐coupled estrogen receptor 1 on neurological disorders. Front Neuroendocrinol. 2019; 55: 100786. 31513775 sourceNot checked — no full text of the source
• cites [61] Prossnitz ER, Barton M. The G protein‐coupled oestrogen receptor GPER in health and disease: an update. Nat Rev Endocrinol. 2023; 19(7): 407‐ 424. 37193881 PMC10187525 sourcePartly supported

  The Molecular signalling mediated by GPER section (page unavailable) describes a GPER-initiated PLCβ–PKC pathway and PKC activation following calcium mobilization. It does not identify PLCD3 as the PLC isozyme activated by GPER or describe PLCD3-mediated phosphoinositide turnover. (LLM, conf=0.88)

  Experimental — accuracy not yet measured

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

PANK4 is one of the pantothenate kinase isozymes implicated in coenzyme A biosynthesis.

“Of these two proteins, PANK4 showed a sex‐biased association with global AD pathology and is one of the pantothenate kinase isozymes implicated in coenzyme A biosynthesis. 63”

• cites [63] Munshi MI, Yao SJ, Ben Mamoun C. Redesigning therapies for pantothenate kinase‐associated neurodegeneration. J Biol Chem. 2022; 298(3): 101577. 35041826 PMC8861153 sourcePartly supported

  The Models of PKAN section identifies PANK4 as one of four human PANK-like genes, and the therapeutic-strategies section describes how its activity may affect the availability of CoA precursors. But the paper distinguishes PANK4 from the three active pantothenate kinases: it lacks the residues required for kinase activity and instead has phosphatase activity. Calling it a pantothenate kinase isozyme therefore overstates the source. (LLM, conf=0.86)

  Experimental — accuracy not yet measured

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

MTFR1L is associated with mitochondrial fusion processes.

“Among these proteins, TOGARAM1 and TRIM46 are associated with proper microtubule functions, 55 , 56 and MTFR1L is associated with mitochondrial fusion processes. 57”

• cites [57] Tilokani L, Russell FM, Hamilton S, et al. AMPK‐dependent phosphorylation of MTFR1L regulates mitochondrial morphology. Sci Adv. 2022; 8(45): eabo7956. 36367943 PMC9651865 sourceSupported

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

PLCD3 is a phospholipase C (PLC) isozyme activated by G protein-coupled estrogen receptor (GPER).

“Both PLCD3 and SLC22A5 are associated with estrogen‐related signaling pathways (Figure S5), with PLCD3 being a phospholipase C (PLC) isozyme activated by G protein‐coupled estrogen receptor (GPER) 60 , 61 and SLC22A5 being a carnitine transport protein transcriptionally regulated by estrogen receptors. 62”

• cites [60] Roque C, Mendes‐Oliveira J, Duarte‐Chendo C, Baltazar G. The Role of G protein‐coupled estrogen receptor 1 on neurological disorders. Front Neuroendocrinol. 2019; 55: 100786. 31513775 sourceNot checked — no full text of the source
• cites [61] Prossnitz ER, Barton M. The G protein‐coupled oestrogen receptor GPER in health and disease: an update. Nat Rev Endocrinol. 2023; 19(7): 407‐ 424. 37193881 PMC10187525 sourcePartly supported

  The ‘Molecular signalling mediated by GPER’ section describes GPER signalling through a PLCβ–PKC pathway, supporting a connection between GPER and a phospholipase C isozyme. It does not identify PLCD3 or say that GPER activates PLCD3 specifically; the named isozyme is PLCβ. No page number is available in our copy. (LLM, conf=0.86)

  Experimental — accuracy not yet measured

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

PLCD is highly expressed in the brain and has been associated with AD and neurodegenerative diseases.

“PLCD is highly expressed in the brain and has been associated with AD and neurodegenerative diseases. 72”

• cites [72] Lim K‐H, Yang S, Kim S‐H, Ko E, Kang M, Joo J‐Y. Cryptic mutations of PLC family members in brain disorders: recent discoveries and a deep‐learning‐based Approach. Brain. 2023; 146(4): 1267‐ 1280. 36448305 PMC10115239 sourceSupported

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

SOS1 is a guanine nucleotide exchange factor that activates the RAS signaling cascade.

“SOS1 showed a significant sex interaction with CAA and is a guanine nucleotide exchange factor that activates the RAS signaling cascade. 64”

• cites [64] Baltanás FC, Zarich N, Rojas‐Cabañeros JM, Santos E. SOS GEFs in health and disease. Biochim Biophys Acta Rev Cancer. 2020; 1874(2): 188445. 33035641 sourceSupported

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

S100A12 is a pro-inflammatory protein localized within Aβ plaques.

“For instance, S100A12 is a pro‐inflammatory protein localized within Aβ plaques. 59 , 77”

• cites [59] Shepherd CE, Goyette J, Utter V, et al. Inflammatory S100A9 and S100A12 proteins in Alzheimer's disease. Neurobiol Aging. 2006; 27(11): 1554‐ 1563. 16253391 sourceNot checked — no full text of the source
• cites [77] Cristóvão JS, Gomes CM. S100 proteins in Alzheimer's disease. Front Neurosci. 2019; 13: 463. 31156365 PMC6532343 sourcePartly supported

  The S100A12 section reports S100A12 hexamers associated with senile plaques in AD brains, and the Outlook says S100A12 is found within amyloid plaques. The S100 Protein Family section describes pro-inflammatory activity for some S100 proteins, but the copy does not establish that activity specifically for S100A12. (LLM, conf=0.85)

  Experimental — accuracy not yet measured

May combine two claims.

Females with MCI or AD dementia show greater cognitive decline and are outperformed by males in several cognitive domains.

“Research has shown that females with MCI or AD dementia shows greater cognitive decline and are outperformed by males in several cognitive domains. 68 , 69”

• cites [68] Sohn D, Shpanskaya K, Lucas JE, et al. Sex differences in cognitive decline in subjects with high likelihood of mild cognitive impairment due to Alzheimer's disease. Sci Rep. 2018; 8(1): 7490. 29748598 PMC5945611 sourcePartly supported

  The Results section reports significantly greater ADAS-Cog11 worsening in females than males with a high likelihood of MCI due to AD. The Introduction describes faster decline after MCI or AD onset as emerging evidence, but this study did not examine AD dementia. The Discussion says other cognitive domains still need examination, so it does not establish that males outperform females in several domains. Page numbers are unavailable in our copy. (LLM, conf=0.87)

  Experimental — accuracy not yet measured
• cites [69] Laws KR, Irvine K, Gale TM. Sex differences in cognitive impairment in Alzheimer's disease. World J Psychiatry. 2016; 6(1): 54‐ 65. 27014598 PMC4804268 sourcePartly supported

  The Conclusion (page not provided) says men with AD outperform women across multiple cognitive domains, and a later passage says female patients with MCI show increased vulnerability to cognitive impairment earlier in the illness. But the Conclusion describes evidence that females deteriorate faster as limited and calls for longitudinal studies; the claim presents greater cognitive decline across MCI or AD dementia more definitively than the review does. (LLM, conf=0.86)

  Experimental — accuracy not yet measured

May combine two claims.

SLC22A5 is a carnitine transport protein transcriptionally regulated by estrogen receptors.

“Both PLCD3 and SLC22A5 are associated with estrogen‐related signaling pathways (Figure S5), with PLCD3 being a phospholipase C (PLC) isozyme activated by G protein‐coupled estrogen receptor (GPER) 60 , 61 and SLC22A5 being a carnitine transport protein transcriptionally regulated by estrogen receptors. 62”

• cites [62] Wang C, Uray IP, Mazumdar A, Mayer JA, Brown PH. SLC22A5/OCTN2 expression in breast cancer is induced by estrogen via a novel intronic estrogen‐response element (ERE). Breast Cancer Res Treat. 2012; 134(1): 101‐ 115. 22212555 PMC3416040 sourceSupported

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

SOS1 activates the RAS signaling pathway.

“SOS1 activates the RAS signaling pathway, and its expression level is elevated in the blood of AD patients. 78”

• cites [78] Sim K‐Y, Park S‐H, Choi KY, et al. High‐throughput epitope profiling of antibodies in the plasma of Alzheimer's disease patients using random peptide microarrays. Sci Rep. 2019; 9(1): 4587. 30872784 PMC6418098 sourcePartly supported

  The Discussion and Table 2 report increased SOS1 expression in pyramidal neurons of AD patients, not in their blood. The Discussion mentions RAS only as the renin–angiotensin signalling pathway; it does not say that SOS1 activates it or another RAS pathway. The Results identify SOS1 as a potential target of antibodies upregulated in plasma, which is not a measurement of blood SOS1 expression. (LLM, conf=0.88)

  Experimental — accuracy not yet measured

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

Sex differences in mitochondrial metabolism have been reported in AD.

“Although sex differences in immune response 17 , 18 , 19 and mitochondrial metabolism 79 have been reported in AD, other molecular processes identified here remain understudied.”

• cites [79] Zhao L, Mao Z, Woody SK, Brinton RD. Sex differences in metabolic aging of the brain: insights into female susceptibility to Alzheimer's Disease. Neurobiol Aging. 2016; 42: 69‐ 79. 27143423 PMC5644989 sourcePartly supported

  The Results report sex differences in age-related expression of genes involved in energy metabolism, including mitochondrial electron transport and oxidative phosphorylation. But the Abstract and Discussion describe measurements in aging mice relevant to preclinical AD risk, not mitochondrial metabolism measured in people with AD; “in AD” extends the finding beyond the studied population and condition. (LLM, conf=0.85)

  Experimental — accuracy not yet measured

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

Sex differences in immune response have been reported in AD.

“Although sex differences in immune response 17 , 18 , 19 and mitochondrial metabolism 79 have been reported in AD, other molecular processes identified here remain understudied.”

• cites [17] Paranjpe MD, Belonwu S, Wang JK, et al. Sex‐specific cross tissue meta‐analysis identifies immune dysregulation in women with Alzheimer's disease. Front Aging Neurosci. 2021; 13: 735611. 34658838 PMC8515049 sourceSupported
• cites [18] Brooks LRK, Mias GI. Data‐driven analysis of age, sex, and tissue effects on gene expression variability in Alzheimer's Disease. Front Neurosci. 2019; 13: 392. 31068785 PMC6491842 sourcePartly supported

  Results §3.3 reports a significant sex-by-disease interaction for CXCR4, and Discussion §4.2 identifies it as a chemokine receptor involved in inflammatory and neuroinflammatory signaling. This supports a sex difference in an immune-related gene in AD, but the paper does not directly establish a sex difference in immune response more broadly. No page numbers are available in our copy. (LLM, conf=0.82)

  Experimental — accuracy not yet measured
• cites [19] Barber AJ, Del Genio CL, Swain AB, et al. Age, Sex and Alzheimer's Disease: a Longitudinal Study of 3xTg‐AD mice reveals sex‐specific disease trajectories and inflammatory responses mirrored in postmortem brains from Alzheimer's patients. Alzheimers Res Ther. 2024; 16(1): 134. 38909241 PMC11193202 sourceSupported

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

MTFR1L is associated with mitochondrial metabolism.

“Both MTFR1L and PANK4 are associated with mitochondrial metabolism, with MTFR1L implicated in mitochondrial fusion process 57 and PANK4 involved in coenzyme A biosynthesis. 63”

• cites [57] Tilokani L, Russell FM, Hamilton S, et al. AMPK‐dependent phosphorylation of MTFR1L regulates mitochondrial morphology. Sci Adv. 2022; 8(45): eabo7956. 36367943 PMC9651865 sourceSupported

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

PANK4 is associated with mitochondrial metabolism.

“Both MTFR1L and PANK4 are associated with mitochondrial metabolism, with MTFR1L implicated in mitochondrial fusion process 57 and PANK4 involved in coenzyme A biosynthesis. 63”

• cites [63] Munshi MI, Yao SJ, Ben Mamoun C. Redesigning therapies for pantothenate kinase‐associated neurodegeneration. J Biol Chem. 2022; 298(3): 101577. 35041826 PMC8861153 sourceSupported

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

DCUN1D5 regulates the protein neddylation pathway that has been linked to AD.

“Moreover, TRIM46 and TOGARAM1 are proteins that play roles in microtubule functions, 55 , 56 and DCUN1D5 regulates the protein neddylation pathway that has been linked to AD. 58”

• cites [58] Zhang S, Yu Q, Li Z, Zhao Y, Sun Y. Protein neddylation and its role in health and diseases. Signal Transduct Target Ther. 2024; 9(1): 85. 38575611 PMC10995212 sourceSupported

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

SOS1 expression level is elevated in the blood of AD patients.

“SOS1 activates the RAS signaling pathway, and its expression level is elevated in the blood of AD patients. 78”

• cites [78] Sim K‐Y, Park S‐H, Choi KY, et al. High‐throughput epitope profiling of antibodies in the plasma of Alzheimer's disease patients using random peptide microarrays. Sci Rep. 2019; 9(1): 4587. 30872784 PMC6418098 sourcePartly supported

  The Discussion reports increased SOS1 expression in pyramidal neurons of AD patients, not in their blood. The Results identify SOS1 as a potential target of upregulated antibodies in plasma; they do not report elevated blood SOS1 expression. The cited passages also do not establish that SOS1 activates RAS signaling. (LLM, conf=0.87)

  Experimental — accuracy not yet measured

May combine two claims.

SMOC1, NTN1, and MDK are strongly associated with amyloid plaques and are considered hub proteins in both AsymAD and AD.

“These proteins are strongly associated with amyloid plaques and are considered hub proteins in both AsymAD and AD. 43 , 51 , 80”

• cites [43] Johnson ECB, Carter EK, Dammer EB, et al. Large‐scale deep multi‐layer analysis of Alzheimer's disease brain reveals strong proteomic disease‐related changes not observed at the RNA Level. Nat Neurosci. 2022; 25(2): 213‐ 225. 35115731 PMC8825285 sourcePartly supported

  The Results section on plaque- and tangle-associated modules identifies SMOC1, NTN1, and MDK as plaque-associated proteins, and the Discussion says they correlate with Aβ. Extended Data calls MDK a hub protein of the M42 module, which the Results report is elevated in both AsymAD and AD. Our copy does not identify all three proteins as hubs in both conditions. (LLM, conf=0.86)

  Experimental — accuracy not yet measured
• cites [51] Bai B, Wang X, Li Y, et al. Deep multilayer brain proteomics identifies molecular networks in Alzheimer's disease progression. Neuron. 2020; 105(6): 975‐991 e7. 31926610 PMC7318843 sourcePartly supported

  The Results section, “Pathway Ranking and Top-ranked Proteins in Amyloid Plaque Pathology” (page unavailable), reports plaque accumulation of MDK, NTN1, and SMOC1 in AD; MDK and NTN1 were highly colocalized with plaques, while SMOC1 was only partially colocalized. The cited passages do not establish that all three are hub proteins in both asymptomatic AD (AsymAD) and AD. (LLM, conf=0.88)

  Experimental — accuracy not yet measured
• cites [80] Higginbotham L, Ping L, Dammer EB, et al. Integrated proteomics reveals brain‐based cerebrospinal fluid biomarkers in asymptomatic and symptomatic Alzheimer's disease. Sci Adv. 2020; 6(43). PMC7577712 33087358 sourcePartly supported

  The Results sections ‘Disease-related brain modules are preserved in AsymAD’ and ‘Overlap between brain protein and RNA networks’ report changes in SMOC1 and MDK in AsymAD and AD, and describe strong amyloid-plaque associations as a likely explanation for changes that include NTN1 and MDK. They do not identify the three proteins as hub proteins in both conditions, establish a plaque association for SMOC1, or specifically report an AsymAD change for NTN1. Page numbers are unavailable in our copy. (LLM, conf=0.86)

  Experimental — accuracy not yet measured

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

CHRM3 is involved in the acetylcholine pathway.

“Similarly, the muscarinic cholinergic receptor CHRM3, which is involved in the acetylcholine pathway, 84 was significantly upregulated in both AD and Lewy body pathology.”

• cites [84] Kruse AC, Kobilka BK, Gautam D, Sexton PM, Christopoulos A, Wess J. Muscarinic acetylcholine receptors: novel opportunities for drug development. Nat Rev Drug Discov. 2014; 13(7): 549‐ 560. 24903776 PMC5818261 sourceSupported

May combine two claims.

Compared to male participants, female participants had an older age at death and received fewer years of education.

“Compared to male participants, female participants had an older age at death (β [SE] = 2.8 [0.5]; p < 0.001) and received fewer years of education (β [SE] = −1.4 [0.3]; p < 0.001).”

Not yet classified.

Downregulated proteins in AD were enriched for synaptic signaling, axon development, and actin filament organization.

“The downregulated proteins in AD were enriched for synaptic signaling, axon development, and actin filament organization (Figure S1, Table S4).”

May combine two claims.

Females showed more severe arteriolosclerosis than males, while no significant sex differences were found in other age-related neuropathologic conditions.

“For age‐related pathologies, females showed more severe arteriolosclerosis than males (β [SE] = 0.15 [0.07]; p = 0.043) while no significant sex differences were found in other age‐related neuropathologic conditions.”

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

After quality control, 10,030 proteins were considered in the study.

“After quality control, 10,030 proteins were considered in our study.”

May combine two claims.

Among these proteins, 59% had higher abundance in cognitive stability and 41% had lower abundance in cognitive stability.

“Among these proteins, 59% had higher abundance (i.e., positive betas) in cognitive stability, while 41% had lower abundance (i.e., negative betas) in cognitive stability (Figure 1B).”

May combine two claims.

There were no significant sex differences in cognitive diagnosis or APOE ε4 status.

“There were no significant sex differences in cognitive diagnosis (p = 0.41) and APOE ε4 status (p = 0.90).”

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

All participants were of European ancestry, with an average age of 89.4 years at death and an average of 15.9 years of education.

“All participants were of European ancestry, with an average age of 89.4 at death and an average of 15.9 years of education.”

May combine two claims.

The study included 770 ROS/MAP participants with deep brain proteomic profiles, of whom 66.2% were female.

“We examined brain proteomes profiled from the dorsolateral prefrontal cortex of 770 donors (66.2% female).”

• Also stated in: § Study participants · plain

  “This study included 770 participants and their cognitive diagnosis at the time of death consisted of 33.4% no cognitive impairment (NCI), 26.9% mild cognitive impairment (MCI), and 39.7% AD dementia.”

May combine two claims.

Of the 1467 sex-differentiated proteins, 41% had higher expression in males and 59% had higher expression in females.

“Of these, 41% had higher expression in males and 59% had higher expression in females (Table S2).”

May combine two claims.

Female participants had a higher global AD pathology score and a higher neurofibrillary tangle score than males after adjusting for education and age at death.

“When comparing AD hallmark pathology by sex, female participants had a higher global AD pathology score (β [SE] = 0.11 [0.03]; p < 0.001) and a higher neurofibrillary tangle score (β [SE] = 0.38 [0.09]; p < 0.001) after adjusting for education and age at death.”

May combine two claims.

Compared to males, females had lower cognitive scores at each assessment timepoint, indicating steeper rates of decline in global cognition and cognitive abilities.

“Compared to male participants, female participants had lower cognitive scores at each assessment timepoint (i.e., negative time‐by‐sex interaction term), indicating steeper rates of decline in global cognition and cognitive abilities (Table S1).”

May combine two claims.

Both female and male participants displayed significant declines in global cognition and different cognitive domains over time.

“Both female and male participants displayed significant declines in global cognition and different cognitive domains over time.”

May combine two claims.

At baseline, females showed better episodic memory and perceptual speed, while males showed better visuospatial ability, after adjusting for age and education.

“At baseline, female participants showed better performance in episodic memory (β [SE] = 0.17 [0.06]; p = 0.002) and perceptual speed (β [SE] = 0.14 [0.06]; p = 0.024), while male participants showed better baseline visuospatial ability (β [SE] = 0.35 [0.06]; p < 0.001) after adjusting for age and education (Table S1).”

May combine two claims.

In the joint analysis of AD hallmark pathologies, 1183 proteins were associated with Aβ density, 1309 with tangle density, and 1924 with global AD pathology.

“In the joint analysis of AD hallmark pathologies, 1183 proteins were found to be associated with Aβ density, 1309 with tangle density, and 1924 with global AD pathology (Table S12‐S14).”

May combine two claims.

Joint analysis in different cognitive domains revealed 1976 differentially expressed proteins for episodic memory, 1576 for working memory, 1501 for semantic memory, 461 for perceptual speed, and four for visuospatial ability.

“Joint analysis in different cognitive domains also revealed many differentially expressed proteins, with 1976 for episodic memory, 1576 for working memory, 1501 for semantic memory, 461 for perceptual speed, and four for visuospatial ability (Figure S2, Table S7‐S11).”

May combine two claims.

Fewer proteins were associated with age-related pathologies: 98 with Lewy bodies, 67 with CAA, one with microinfarcts, and no associations with other neuropathologic conditions.

“Fewer proteins were found to be associated with age‐related pathologies: 98 were associated with Lewy bodies, 67 with CAA, one with microinfarcts, and no associations observed with other neuropathologic conditions (Figure S2, Table S17‐S23).”

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

The cognitive diagnosis at death consisted of 33.4% no cognitive impairment, 26.9% mild cognitive impairment, and 39.7% AD dementia.

“This study included 770 participants and their cognitive diagnosis at the time of death consisted of 33.4% no cognitive impairment (NCI), 26.9% mild cognitive impairment (MCI), and 39.7% AD dementia.”

• Also stated in: § Comparing AD and its endophenotypes between females and males · plain

  “The final cognitive diagnosis for these participants consisted of 39.7% AD dementia, 26.9% MCI, and 33.4% NCI.”

May combine two claims.

Sex-stratified analyses between AD and control yielded 869 significant proteins in females and 68 in males at FDR < 5%, with 35 proteins significant in both analyses and displaying concordant direction of associations.

“Sex‐stratified analyses between AD and control yielded 869 significant proteins in females and 68 in males at a FDR threshold of 5%, with 35 proteins significant in both analyses and displaying concordant direction of associations (Figure 2A, Table S3).”

May combine two claims.

The replication rates for different cognitive abilities were 77% for episodic memory, 84% for working memory, and 56% for semantic memory.

“The replication rates for different cognitive abilities were 77% for episodic memory, 84% for working memory, and 56% for semantic memory.”

May combine two claims.

Diabetes and hypertension showed significant sex differences in our dataset.

“To test whether comorbid medical conditions confound the moderating effects of sex on these phenotypic outcomes, we performed a sensitivity analysis by adjusting for the presence of diabetes and hypertension, both of which showed significant sex differences in our dataset (Table 1).”

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

Multiple transcriptomic studies have identified potential molecular mechanisms underlying sex differences in AD.

“Multiple transcriptomic studies have identified potential molecular mechanisms underlying sex differences in AD.”

May combine two claims.

The data suggest the presence of sex differences in baseline cognitive performance, cognitive trajectories, and AD hallmark pathologies.

“In summary, these data suggest the presence of sex differences in baseline cognitive performance, cognitive trajectories, and AD hallmark pathologies.”

• Also stated in: § Highlights · plain

  “At the phenotypic level, we found sex differences in baseline cognitive performance, cognitive trajectories, and AD hallmark pathologies.”

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

The replication rate π1 was used to estimate consistency between sex-stratified analyses; π1 estimates the fraction of true signals and is less dependent on sample size and power.

“To determine the consistency between proteins associated with each trait, we estimated the replication rate, π1, between the sex‐stratified analyses. π1 estimates the fraction of true signals, not just significance, which makes it less dependent on sample size and power 47 and helpful when the two analyses have different sample sizes (i.e., female dataset n = 510, male dataset n = 260).”

• cites [47] Storey JD. A direct approach to false discovery rates. Journal of the Royal Statistical Society Series B‐Statistical Methodology. 2002; 64: 479‐ 498.Not matched

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

Classified as probably not a substantial claim.

Linear regression models for differential expression adjusted for age at death, education, cognitive diagnosis, and surrogate variables.

“To identify proteins differentially expressed between females and males, we performed linear regression with protein abundance as the dependent variable (Y) and sex as the independent variable and covaried for age at death, education, cognitive diagnosis, and SVs.”

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

Principal component analysis was used to remove samples with greater than four standard deviations from the mean of either the first or second principal component.

“Principal component analysis was used to remove samples with greater than four standard deviations from the mean of either the first or second principal component.”

Classified as probably not a substantial claim.

Significant proteins in the larger discovery (female) dataset at FDR < 0.05 were selected from the replication (male) dataset to estimate π1 statistics.

“Significant proteins in the larger discovery (female) dataset at FDR < 0.05 were selected from the replication (male) dataset to estimate the π1 statistics using the qvalue package (version 2.36.0). 48”

• cites [48] Storey JD, Bass A, Dabney A, Robinson D. qvalue: Q‐value Estimation for False Discovery Rate Control. R package version 2.36.0; 2024. http://github.com/jdstorey/qvalue. Available from. sourceNot checked — no full text of the source

Classified as probably not a substantial claim.

A final cognitive diagnosis was made at the time of death after review of all data blinded to neuropathology.

“A final cognitive diagnosis is made at the time of death after review of all data blinded to neuropathology.”

Classified as probably not a substantial claim.

The effects of protein sequencing batch and post mortem interval were regressed out using linear regression.

“We used linear regression to regress out the effect of protein sequencing batch and post mortem interval.”

Classified as probably not a substantial claim.

Proteins with TMT abundance values in at least 30% of samples were included in analyses.

“Proteins with TMT abundance values in at least 30% of samples were included in our analyses.”

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

S100A12 is a pro-inflammatory mediator that modulates neuroinflammation.

“DCUN1D5 is involved in the neddylation pathway that regulates protein homeostasis, 58 and S100A12 is a pro‐inflammatory mediator that modulates neuroinflammation. 59”

• cites [59] Shepherd CE, Goyette J, Utter V, et al. Inflammatory S100A9 and S100A12 proteins in Alzheimer's disease. Neurobiol Aging. 2006; 27(11): 1554‐ 1563. 16253391 sourceNot checked — no full text of the source

May combine two claims.

Our phenotypic analysis suggests the presence of sex differences in baseline cognitive performance and cognitive trajectories.

“Our phenotypic analysis suggests the presence of sex differences in baseline cognitive performance and cognitive trajectories.”

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

We expect to be best powered to detect differences in proteins from neurons and glia, the major cell types in the gray matter that are also highly relevant for AD.

“Notably, we expect to be best powered to detect differences in proteins from neurons and glia, the major cell types in the gray matter that are also highly relevant for AD.”

• AssumptionRests on an assumption: The DLPFC has a relatively lower burden of AD pathology and neuronal loss, even among individuals with advanced AD or advanced age at death.

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

The limited number of significant sex-by-trait interactions may imply a lack of statistical power.

“Second, a limited number of proteins showed significant sex‐by‐trait interactions in our analysis, which may imply a lack of statistical power.”