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

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

The rate of "inflammaging" is also greater in men, driving a gap in male and female life expectancies.

“The rate of “inflammaging” is also greater in men [33–35], driving a gap in male and female life expectancies.”

• cites [33] Gubbels Bupp MR, Potluri T, Fink AL, Klein SL. The confluence of sex hormones and aging on immunity. Front Immunol. 2018;9:1269. sourceDisputed

  The Introduction (page unavailable) says aged females may be more inflammation-prone than aged males, and the section on age-related innate immunity reports higher inflammatory-protein concentrations in aged females. The paper does say women live longer and that some aspects of adaptive immune aging may progress faster in men, but it does not attribute the life-expectancy gap to a greater rate of inflammaging in men. (LLM, conf=0.84)

  Checked by a reasoning model — may be wrong.

  Experimental — accuracy not yet measured
• cites [34] Bonafè M, Olivieri F, Cavallone L, Giovagnetti S, Marchegiani F, Cardelli M, Pieri C, Marra M, Antonicelli R, Lisa R. A gender–dependent genetic predisposition to produce high levels of IL-6 is detrimental for longevity. Eur J Immunol. 2001;31(8):2357–61. sourceNot checked — no full text of the source
• cites [35] Bonafè M, Prattichizzo F, Giuliani A, Storci G, Sabbatinelli J, Olivieri F. Inflamm-aging: why older men are the most susceptible to SARS-CoV-2 complicated outcomes. Cytokine Growth Factor Rev. 2020;53:33–7. sourcePartly supported

  The section “In older men, accelerated inflamm-aging worsens COVID-19 infection outcomes” says men have a higher rate of inflamm-aging than women. The copy does not establish that this difference drives the gap in male and female life expectancies; its discussion of mortality concerns COVID-19 outcomes. (LLM, conf=0.86)

  Experimental — accuracy not yet measured

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

Inflammaging likely plays a critical role in the pathogenesis of age-related diseases, including Alzheimer's, influencing the manifestation of disease and survival time from diagnosis.

“Inflammaging likely plays a critical role in the pathogenesis of age-related diseases [36], including Alzheimer’s, influencing the manifestation of disease and survival time from diagnosis.”

• cites [36] Giunta B, Fernandez F, Nikolic WV, Obregon D, Rrapo E, Town T, Tan J. Inflammaging as a prodrome to Alzheimer’s disease. J Neuroinflammation. 2008;5(1):1–15. sourceSupported

May combine two claims.

As splenomegaly develops, the pink vascular spaces of the spleen and lymphoid follicles are encroached upon by infiltrating neutrophils, resulting in obstruction of venous outflow and abnormal enlargement.

“As splenomegaly developed, the pink vascular spaces of the spleen and lymphoid follicles were encroached upon by infiltrating neutrophils [46]. This results in the obstruction of venous outflow of blood and abnormal enlargement in size.”

• cites [46] Hermida MdE-R, De Melo CVB, Lima IDS, Oliveira GGDS, Dos-Santos WL. Histological disorganization of spleen compartments and severe visceral leishmaniasis. Front Cell Infect. 2018;8:394. sourcePartly supported

  The ‘Spleen disorganization in VL’ section (page unavailable) describes spleen enlargement and progressive disruption of lymphoid follicles. It identifies macrophages and plasma cells in the affected compartments, but does not say that infiltrating neutrophils encroach on vascular spaces or follicles, or that they obstruct venous outflow. Its mention of increased neutrophils concerns blood counts in dogs, not splenic infiltration. (LLM, conf=0.88)

  Experimental — accuracy not yet measured

• AssumptionRests on an assumption: Aging and inflammaging affect all body systems.

May combine two claims.

Women exhibit increased global Alzheimer's neuropathological burden and greater cognitive impairment compared to men.

“However, despite their prolonged survival, even with Alzheimer’s disease [7–9], women exhibit increased global Alzheimer’s neuropathological burden and greater cognitive impairment [10–13].”

• cites [10] Barnes LL, Wilson RS, Bienias JL, Schneider JA, Evans DA, Bennett DA. Sex differences in the clinical manifestations of Alzheimer disease pathology. Arch Gen Psychiatry. 2005;62(6):685–91. sourceNot checked — no full text of the source
• cites [11] Irvine K, Laws KR, Gale TM, Kondel TK. Greater cognitive deterioration in women than men with Alzheimer’s disease: a meta analysis. J Clin Neuropsychol. 2012;34(9):989–98. sourceNot checked — no full text of the source
• cites [12] Holland D, Desikan RS, Dale AM, McEvoy LK. Higher rates of decline for women and apolipoprotein E ε4 carriers. AJNR Am J Neuroradiol. 2013;34(12):2287–93. sourceSupported
• cites [13] Oveisgharan S, Arvanitakis Z, Yu L, Farfel J, Schneider JA, Bennett DA. Sex differences in Alzheimer’s disease and common neuropathologies of aging. Acta Neuropathol. 2018;136:887–900. sourcePartly supported

  The Results (AD pathology; page unavailable) report a higher global AD pathology score in women than men, adjusted for age and education. The paper says AD dementia is more common in women and describes cognitive testing in Methods (Clinical evaluation; page unavailable), but the passages found do not establish that women had greater cognitive impairment than men. (LLM, conf=0.84)

  Experimental — accuracy not yet measured

May combine two claims.

Males experience more unfavorable changes and a greater rate of inflammaging or innate immune response than females.

“While both sexes experience aging-associated changes in immune function [32, 33], males have been shown to experience more unfavorable changes and a greater rate of inflammaging [34, 35] or innate immune response.”

• cites [34] Bonafè M, Olivieri F, Cavallone L, Giovagnetti S, Marchegiani F, Cardelli M, Pieri C, Marra M, Antonicelli R, Lisa R. A gender–dependent genetic predisposition to produce high levels of IL-6 is detrimental for longevity. Eur J Immunol. 2001;31(8):2357–61. sourceNot checked — no full text of the source
• cites [35] Bonafè M, Prattichizzo F, Giuliani A, Storci G, Sabbatinelli J, Olivieri F. Inflamm-aging: why older men are the most susceptible to SARS-CoV-2 complicated outcomes. Cytokine Growth Factor Rev. 2020;53:33–7. sourceSupported

May combine two claims.

3xTg-AD mice display manifestations of systemic autoimmunity, including splenomegaly, hepatomegaly, elevated serum autoantibodies, reduced hematocrit, and elevated double-negative T splenocytes, which are all exacerbated in 3xTg-AD males.

“Marchese et al. and Kapadia et al. have provided strong evidence that 3xTg-AD mice display manifestations of systemic autoimmunity, including splenomegaly, hepatomegaly, elevated serum autoantibodies, reduced hematocrit, and elevated double-negative (CD4-/CD8-) T splenocytes, which are all exacerbated in 3xTg-AD males [26, 27].”

• cites [26] Marchese M, Cowan D, Head E, Ma D, Karimi K, Ashthorpe V, Kapadia M, Zhao H, Davis P, Sakic B. Autoimmune manifestations in the 3xTg-AD model of Alzheimer’s disease. J Alzheimer’s Dis. 2014;39(1):191–210. sourcePartly supported

  The Results summary reports all five listed manifestations in aged 3xTg-AD mice. However, Materials and Methods > Animals states that only males were studied, so this paper cannot establish that the manifestations are exacerbated in males relative to females. The reported worsening is age-related, not a male–female comparison; page numbers are unavailable in our copy. (LLM, conf=0.91)

  Experimental — accuracy not yet measured
• cites [27] Kapadia M, Mian MF, Michalski B, Azam AB, Ma D, Salwierz P, Christopher A, Rosa E, Zovkic IB, Forsythe P. Sex-dependent differences in spontaneous autoimmunity in adult 3xTg-AD mice. J Alzheimer’s Dis. 2018;63(3):1191–205. sourcePartly supported

  Sections 3.1 and 3.3 report more severe splenomegaly, higher serum autoantibodies, and lower hematocrit in six-month-old 3xTg-AD males than females. Section 3.2 reports reduced CD3+, CD8+, and CD4+ splenic T-cell populations, but does not report elevated double-negative T splenocytes; the retrieved organ-weight results do not report hepatomegaly. Page numbers were not available in our copy. (LLM, conf=0.90)

  Experimental — accuracy not yet measured

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

3xTg-AD mice are one of the only models to develop both Aβ plaques and NFTs, in addition to exhibiting stark sexual dimorphism.

“They are one of the only models to develop both Aβ plaques and NFTs, in addition to exhibiting stark sexual dimorphism [18–22].”

• cites [18] Oddo S, Caccamo A, Kitazawa M, Tseng BP, LaFerla FM. Amyloid deposition precedes tangle formation in a triple transgenic model of Alzheimer’s disease. Neurobiol Aging. 2003;24(8):1063–70. sourceNot checked — no full text of the source
• cites [19] Clinton LK, Billings LM, Green KN, Caccamo A, Ngo J, Oddo S, McGaugh JL, LaFerla FM. Age-dependent sexual dimorphism in cognition and stress response in the 3xTg-AD mice. Neurobiol Dis. 2007;28(1):76–82. sourcePartly supported

  The Introduction reports that 3xTg-AD mice develop plaques and tangles, and the Results and Discussion describe age-dependent sex differences in cognition and stress response. The paper does not establish that they are one of the only models with both lesions; it also reports no significant sex difference in Aβ or tau pathology. (LLM, conf=0.87)

  Experimental — accuracy not yet measured
• cites [20] Giménez-Llort L, Arranz L, Maté I, De la Fuente M. Gender-specific neuroimmunoendocrine aging in a triple-transgenic 3× Tg-AD mouse model for Alzheimer’s disease and its relation with longevity. Neuroimmunomodulation. 2008;15(4–6):331–43. sourceNot checked — no full text of the source
• cites [21] Kane AE, Shin S, Wong AA, Fertan E, Faustova NS, Howlett SE, Brown RE. Sex differences in healthspan predict lifespan in the 3xTg-AD mouse model of Alzheimer’s disease. Front Aging Neurosci. 2018;10:172. sourcePartly supported

  The Introduction says 3xTg-AD mice develop both amyloid beta plaques and tangles, and the Discussion describes sex differences in pathology, frailty, and mortality. Our copy does not establish that this is one of the only models to develop both plaques and tangles. (LLM, conf=0.84)

  Experimental — accuracy not yet measured
• cites [22] Belfiore R, Rodin A, Ferreira E, Velazquez R, Branca C, Caccamo A, Oddo S. Temporal and regional progression of Alzheimer’s disease-like pathology in 3xTg-AD mice. Aging Cell. 2019;18(1):e12873. sourcePartly supported

  The Introduction says 3xTg-AD mice accumulate plaques and tangles, and the Discussion contrasts their Aβ and tau pathology with that of most other mouse models. The Animals section says only females were studied because males in this colony showed substantial neuropathological variability; it does not establish stark sexual dimorphism through a male–female comparison. No page numbers are available in our copy. (LLM, conf=0.86)

  Experimental — accuracy not yet measured

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

The PHG has been shown to carry the strongest molecular signal of late-onset Alzheimer's disease.

“The PHG has been shown to carry the strongest molecular signal of late-onset Alzheimer’s disease [50].”

• cites [50] Neff RA, Wang M, Vatansever S, Guo L, Ming C, Wang Q, Wang E, Horgusluoglu-Moloch E, Song W-M, Li A. Molecular subtyping of Alzheimer’s disease using RNA sequencing data reveals novel mechanisms and targets. Sci Adv. 2021;7(2):eabb5398. sourceSupported

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

Chronic immunosuppression limits manifestations of autoimmunity in 3xTg-AD mice.

“The group proposed that this sex-dependent autoimmune mechanism may be interfering with the development of plaques and tangles in the male 3xTg-AD brain and have shown that chronic immunosuppression limits said manifestations of autoimmunity [28].”

• cites [28] Kapadia M, Mian MF, Ma D, Hutton CP, Azam A, Narkaj K, Cao C, Brown B, Michalski B, Morgan D, et al. Differential effects of chronic immunosuppression on behavioral, epigenetic, and Alzheimer’s disease-associated markers in 3xTg-AD mice. Alzheimers Res Ther. 2021;13(1):30. sourceSupported

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

ComBat-seq was applied to adjust for sequencing batch effects.

“To adjust for sequencing batch effects within our total sample population, ComBat-seq was applied as previously described [37].”

• cites [37] Zhang Y, Parmigiani G, Johnson WE. ComBat-seq: batch effect adjustment for RNA-seq count data. Nar Genom Bioinform. 2020;2(3):lqaa078. sourceSupported

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

Strong evidence has implicated the complement system in the pathogenesis of Alzheimer's disease.

“Strong evidence has implicated the complement system in the pathogenesis of Alzheimer’s disease [72–76]”

• cites [72] Eikelenboom P, Stam F. An immunohistochemical study on cerebral vascular and senile plaque amyloid in Alzheimer’s dementia. Virchows Arch B. 1984;47:17–25. sourceNot checked — no full text of the source
• cites [73] Walker DG, McGeer PL. Complement gene expression in human brain: comparison between normal and Alzheimer disease cases. Brain Res Mol Brain Res. 1992;14(1–2):109–16. sourceNot checked — no full text of the source
• cites [74] Stoltzner SE, Grenfell TJ, Mori C, Wisniewski KE, Wisniewski TM, Selkoe DJ, Lemere CA. Temporal accrual of complement proteins in amyloid plaques in Down’s syndrome with Alzheimer’s disease. Am J Pathol. 2000;156(2):489–99. sourceSupported
• cites [75] Lambracht-Washington D, Fu M, Manouchehri N, Hynan LS, Stuve O, Rosenberg RN. Glial cell transcriptome analyses in 3xTg-AD mice: effects of aging, disease progression, and anti-Aβ immunotherapy. Aging Brain. 2023;3:100066. sourcePartly supported

  The Results (Differential expression of glial genes in brain; page unavailable) identify complement genes as upregulated in 3xTg-AD mice and complement activation among pathways enriched in AD-pathology-associated genes. This implicates the complement system in the mouse model, but the paper’s transcriptomic findings do not establish the broader claim of strong evidence for its role in Alzheimer’s disease pathogenesis. (LLM, conf=0.83)

  Experimental — accuracy not yet measured
• cites [76] Morgan BP. Complement in the pathogenesis of Alzheimer’s disease. Springer Semin Immunopathol. 2018;40(1):113–24. sourceSupported

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

The deficiency of complement factors such as C1q, C3, C3ar1, C5aR, and Cd59, has exacerbated neuropathology in some studies and reduced neuropathology in others.

“The deficiency of complement factors such as C1q, C3, C3ar1, C5aR, and Cd59, has exacerbated neuropathology in some studies [84–86] and reduced neuropathology in others [87–89].”

• cites [84] Maier M, Peng Y, Jiang L, Seabrook TJ, Carroll MC, Lemere CA. Complement C3 deficiency leads to accelerated amyloid β plaque deposition and neurodegeneration and modulation of the microglia/macrophage phenotype in amyloid precursor protein transgenic mice. J Neurosci. 2008;28(25):6333–41. sourceSupported
• cites [85] Wyss-Coray T, Yan F, Lin AH-T, Lambris JD, Alexander JJ, Quigg RJ, Masliah E. Prominent neurodegeneration and increased plaque formation in complement-inhibited Alzheimer’s mice. Proc Natl Acad Sci USA. 2002;99(16):10837–42. sourcePartly supported

  The Abstract and Discussion report that inhibiting C3 activation with sCrry increased amyloid deposition and neurodegeneration in hAPP mice, supporting the exacerbation part of the sentence. This study did not make the mice deficient in the listed complement factors or report reduced neuropathology from such deficiencies. (LLM, conf=0.86)

  Experimental — accuracy not yet measured
• cites [86] El Gaamouch F, Audrain M, Lin W-J, Beckmann N, Jiang C, Hariharan S, Heeger PS, Schadt EE, Gandy S, Ehrlich ME. VGF-derived peptide TLQP-21 modulates microglial function through C3aR1 signaling pathways and reduces neuropathology in 5xFAD mice. Mol Neurodegener. 2020;15(1):1–19. sourcePartly supported

  The Discussion (page not provided) reports that C3aR1-null mice had reduced pathology in a PS19 tauopathy model. It does not report that deficiency of C1q, C3, C5aR, or Cd59 exacerbated neuropathology, or establish the claimed pattern of opposing outcomes across those factors. The paper’s own reduced amyloid load followed C3aR1 activation, not deficiency. (LLM, conf=0.84)

  Experimental — accuracy not yet measured
• cites [87] Shi Q, Chowdhury S, Ma R, Le KX, Hong S, Caldarone BJ, Stevens B, Lemere CA. Complement C3 deficiency protects against neurodegeneration in aged plaque-rich APP/PS1 mice. Sci Transl Med. 2017;9(392):eaaf6295. sourceSupported
• cites [88] Czirr E, Castello NA, Mosher KI, Castellano JM, Hinkson IV, Lucin KM, Baeza-Raja B, Ryu JK, Li L, Farina SN. Microglial complement receptor 3 regulates brain Aβ levels through secreted proteolytic activity. J Exp Med. 2017;214(4):1081–92. sourceSupported
• cites [89] Fonseca MI, Ager RR, Chu S-H, Yazan O, Sanderson SD, LaFerla FM, Taylor SM, Woodruff TM, Tenner AJ. Treatment with a C5aR antagonist decreases pathology and enhances behavioral performance in murine models of Alzheimer’s disease. J Immunol Res. 2009;183(2):1375–83. sourcePartly supported

  The Discussion (page not provided) reports less neuropathology in a C1q-knockout Alzheimer’s mouse model and accelerated pathology in C3-deficient models, supporting the claim that complement deficiency has had differing effects. This paper tested a C5aR antagonist, not C5aR deficiency, and the cited passages do not establish outcomes for C3ar1 or Cd59 deficiency. (LLM, conf=0.87)

  Experimental — accuracy not yet measured

May combine two claims.

A clinical study of over 450,000 participants revealed that males were more likely to experience liver fibrosis and exhibited higher associations between liver fibrosis and most cognitive performance tests.

“A clinical study of over 450,000 participants [62] revealed that males were more likely to experience liver fibrosis and exhibited higher associations between liver fibrosis and most cognitive performance tests”

• cites [62] Jiang R, Wu J, Rosenblatt M, Dai W, Rodriguez RX, Sui J, Qi S, Liang Q, Xu B, Meng Q, Calhoun VD, Scheinost D. Elevated C-reactive protein mediates the liver-brain axis: a preliminary study. EBioMedicine. 2023;93:104679. sourcePartly supported

  The Results (Population characteristics) report that people with liver fibrosis were more likely to be male. The Results (Associations between liver fibrosis and cognitive functions) report stronger associations with most cognitive tests in males than in females. But the behavioural analysis included up to 447,626 participants, not over 450,000. (LLM, conf=0.91)

  Experimental — accuracy not yet measured

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

The accumulation of senescent cells drives chronic immune induction, which in turn impairs the clearance of senescent cells, creating a detrimental cycle that fuels inflammaging.

“The accumulation of senescent cells drives chronic immune induction, which in turn impairs the clearance of senescent cells, creating a detrimental cycle that fuels inflammaging [63].”

• cites [63] Olivieri F, Prattichizzo F, Grillari J, Balistreri CR. Cellular senescence and inflammaging in age-related diseases. Mediators Inflamm. 2018;2018:9076485. sourcePartly supported

  In “Cellular Senescence and Inflammaging in Age-Related Diseases” (page not provided), the paper says senescent-cell accumulation promotes immune activation and describes a vicious circle that fuels inflammaging. It says chronic immune induction is *associated with* reduced senescent-cell clearance, however, rather than establishing that it impairs clearance. (LLM, conf=0.84)

  Experimental — accuracy not yet measured

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

Non-alcoholic fatty liver disease has been linked to an increased risk of dementia.

“non-alcoholic fatty liver disease has been linked to an increased risk of dementia [61]”

• cites [61] Shang Y, Widman L, Hagström H. Nonalcoholic fatty liver disease and risk of dementia: a population-based cohort study. Neurology. 2022;99(6):e574–82. sourceSupported

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

Others find the opposite sex-difference in females.

“while others find the opposite sex-difference in females [81–83].”

• cites [81] Yang H, Oh C-K, Amal H, Wishnok JS, Lewis S, Schahrer E, Trudler D, Nakamura T, Tannenbaum SR, Lipton SA. Mechanistic insight into female predominance in Alzheimer’s disease based on aberrant protein S-nitrosylation of C3. Sci Adv. 2022;8(50):eade0764. sourceSupported
• cites [82] Mangold CA, Wronowski B, Du M, Masser DR, Hadad N, Bixler GV, Brucklacher RM, Ford MM, Sonntag WE, Freeman WM. Sexually divergent induction of microglial-associated neuroinflammation with hippocampal aging. J Neuroinflammation. 2017;14:1–19. sourceSupported
• cites [83] Nelson LH, Warden S, Lenz KM. Sex differences in microglial phagocytosis in the neonatal hippocampus. Brain Behav Immun. 2017;64:11–22. sourceSupported

May combine two claims.

These results align with published literature and reinforce the translatability of the 3xTg-AD model.

“Together, these results align with published literature [20, 21, 23, 24, 26, 27] and reinforce the translatability of the 3xTg-AD model.”

• cites [20] Giménez-Llort L, Arranz L, Maté I, De la Fuente M. Gender-specific neuroimmunoendocrine aging in a triple-transgenic 3× Tg-AD mouse model for Alzheimer’s disease and its relation with longevity. Neuroimmunomodulation. 2008;15(4–6):331–43. sourceNot checked — no full text of the source
• cites [21] Kane AE, Shin S, Wong AA, Fertan E, Faustova NS, Howlett SE, Brown RE. Sex differences in healthspan predict lifespan in the 3xTg-AD mouse model of Alzheimer’s disease. Front Aging Neurosci. 2018;10:172. sourceSupported
• cites [23] Carroll JC, Rosario ER, Kreimer S, Villamagna A, Gentzschein E, Stanczyk FZ, Pike CJ. Sex differences in β-amyloid accumulation in 3xTg-AD mice: role of neonatal sex steroid hormone exposure. Brain Res. 2010;1366:233–45. sourceSupported
• cites [24] Hirata-Fukae C, Li H-F, Hoe H-S, Gray AJ, Minami SS, Hamada K, Niikura T, Hua F, Tsukagoshi-Nagai H, Horikoshi-Sakuraba Y. Females exhibit more extensive amyloid, but not tau, pathology in an Alzheimer transgenic model. Brain Res. 2008;1216:92–103. sourceNot checked — no full text of the source
• cites [26] Marchese M, Cowan D, Head E, Ma D, Karimi K, Ashthorpe V, Kapadia M, Zhao H, Davis P, Sakic B. Autoimmune manifestations in the 3xTg-AD model of Alzheimer’s disease. J Alzheimer’s Dis. 2014;39(1):191–210. sourceSupported
• cites [27] Kapadia M, Mian MF, Michalski B, Azam AB, Ma D, Salwierz P, Christopher A, Rosa E, Zovkic IB, Forsythe P. Sex-dependent differences in spontaneous autoimmunity in adult 3xTg-AD mice. J Alzheimer’s Dis. 2018;63(3):1191–205. sourceSupported

Classified as probably not a substantial claim.

Evidence has pointed to the liver as a target organ in Alzheimer's due to its role in regulating metabolism and supporting the immune system.

“Evidence has pointed to the liver as a target organ in Alzheimer’s due to its role in regulating metabolism and supporting the immune system [54–56]”

• cites [54] Lam V, Takechi R, Hackett MJ, Francis R, Bynevelt M, Celliers LM, Nesbit M, Mamsa S, Arfuso F, Das S. Synthesis of human amyloid restricted to liver results in an Alzheimer disease–like neurodegenerative phenotype. PLoS Biol. 2021;19(9):e3001358. sourcePartly supported

  The Discussion links liver-derived amyloid and its peripheral metabolism to neurovascular damage relevant to Alzheimer’s disease. It does not identify the liver’s role in supporting the immune system as a reason to target it; the inflammation discussed is neurovascular inflammation. (LLM, conf=0.84)

  Experimental — accuracy not yet measured
• cites [55] Kim D-G, Krenz A, Toussaint LE, Maurer KJ, Robinson S-A, Yan A, Torres L, Bynoe MS. Non-alcoholic fatty liver disease induces signs of Alzheimer’s disease (AD) in wild-type mice and accelerates pathological signs of AD in an AD model. J Neuroinflammation. 2016;13:1–18. sourceSupported
• cites [56] Nho K, Kueider-Paisley A, Ahmad S, MahmoudianDehkordi S, Arnold M, Risacher SL, Louie G, Blach C, Baillie R, Han X. Association of altered liver enzymes with Alzheimer disease diagnosis, cognition, neuroimaging measures, and cerebrospinal fluid biomarkers. JAMA Netw Open. 2019;2(7):e197978. sourcePartly supported

  The Introduction (page unavailable) links the liver’s metabolic activity to Alzheimer’s disease and says the evidence highlights the liver’s importance in AD pathophysiology. The Conclusions (page unavailable) also report associations between liver-function markers and AD biomarkers. Neither passage establishes the claimed role of the liver in supporting the immune system as a reason to regard it as a target organ in AD. (LLM, conf=0.85)

  Experimental — accuracy not yet measured

May combine two claims.

Marchese et al. showed that 3xTg-AD male mice exhibit elevated serum autoantibodies, reduced hematocrit, increased double-negative T splenocytes, splenomegaly, and hepatomegaly, which progress between 2 and 12 months of age.

“Marchese et al. showed that 3xTg-AD male mice exhibit elevated serum autoantibodies, reduced hematocrit, increased double-negative T splenocytes, splenomegaly, and hepatomegaly, which progress between 2 and 12 months of age [26].”

• cites [26] Marchese M, Cowan D, Head E, Ma D, Karimi K, Ashthorpe V, Kapadia M, Zhao H, Davis P, Sakic B. Autoimmune manifestations in the 3xTg-AD model of Alzheimer’s disease. J Alzheimer’s Dis. 2014;39(1):191–210. sourceSupported

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

Hepatomegaly has been previously reported in the 3xTg-AD model.

“Hepatomegaly has been previously reported in the 3xTg-AD model [26, 27, 52]”

• cites [26] Marchese M, Cowan D, Head E, Ma D, Karimi K, Ashthorpe V, Kapadia M, Zhao H, Davis P, Sakic B. Autoimmune manifestations in the 3xTg-AD model of Alzheimer’s disease. J Alzheimer’s Dis. 2014;39(1):191–210. sourceSupported
• cites [27] Kapadia M, Mian MF, Michalski B, Azam AB, Ma D, Salwierz P, Christopher A, Rosa E, Zovkic IB, Forsythe P. Sex-dependent differences in spontaneous autoimmunity in adult 3xTg-AD mice. J Alzheimer’s Dis. 2018;63(3):1191–205. sourceCould not verify

  Section 3.1 (Body and organ weights; page unavailable) reports splenomegaly in 3xTg-AD mice, not hepatomegaly. Searches for hepatomegaly, liver enlargement, and liver weight found no passage in our copy addressing liver enlargement. (LLM, conf=0.72)

  Experimental — accuracy not yet measured
• cites [52] Fraile-Ramos J, Garrit A, Reig-Vilallonga J, Giménez-Llort L. Hepatic oxi-inflammation and neophobia as potential liver-brain axis targets for Alzheimer’s disease and aging, with strong sensitivity to sex, isolation, and obesity. Cells. 2023;12(11):1517. sourceSupported

May combine two claims.

Chronic immunosuppression resulted in reduced hepatosplenomegaly, autoantibody levels, and regulatory T cell proportions relative to effector T cell populations.

“Chronic immunosuppression resulted in reduced hepatosplenomegaly, autoantibody levels, and regulatory T cell proportions relative to effector T cell populations.”

• cites [28] Kapadia M, Mian MF, Ma D, Hutton CP, Azam A, Narkaj K, Cao C, Brown B, Michalski B, Morgan D, et al. Differential effects of chronic immunosuppression on behavioral, epigenetic, and Alzheimer’s disease-associated markers in 3xTg-AD mice. Alzheimers Res Ther. 2021;13(1):30. sourceSupported

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

Several studies point to more potent and plentiful complement factors, and higher rates of microglial phagocytosis in males.

“Several studies point to more potent and plentiful complement factors, and higher rates of microglial phagocytosis in males [77–80]”

• cites [77] Kamitaki N, Sekar A, Handsaker RE, De Rivera H, Tooley K, Morris DL, Taylor KE, Whelan CW, Tombleson P, Loohuis LMO. Complement genes contribute sex-biased vulnerability in diverse disorders. Nature. 2020;582(7813):577–81. sourcePartly supported

  The passage labeled Abstract (page unavailable) reports higher C4 and C3 protein levels in men than women, particularly at ages 20–50, supporting the claim that these complement factors are more plentiful in males. It does not establish that the factors are more potent or that males have higher rates of microglial phagocytosis. (LLM, conf=0.86)

  Experimental — accuracy not yet measured
• cites [78] Poppelaars F, Mollnes TE, Tedesco F, Wuerzner R, Trouw LA, Truedsson L, Daha MR, Roos A, Seelen MA. Age and sex-associated changes of complement activity and complement levels in a healthy Caucasian population. Front Immunol. 2018;9:2664. sourcePartly supported

  The Results section reports higher alternative-pathway activity and higher levels of several complement components in healthy Caucasian males, though classical- and lectin-pathway activity did not differ by sex. The paper does not report rates of microglial phagocytosis, so it does not support that part of the sentence. (LLM, conf=0.88)

  Experimental — accuracy not yet measured
• cites [79] Guillot-Sestier M-V, Araiz AR, Mela V, Gaban AS, O’Neill E, Joshi L, Chouchani ET, Mills EL, Lynch MA. Microglial metabolism is a pivotal factor in sexual dimorphism in Alzheimer’s disease. Commun Biol. 2021;4(1):711. sourcePartly supported

  The Discussion reports reduced Aβ phagocytosis by microglia from female versus male APP/PS1 mice, supporting the male-higher phagocytosis portion in that model. The Results also report greater CD68 staining in male AD patients, but use it as a proxy rather than a direct measure of phagocytosis. The passages do not support the claim about more potent or plentiful complement factors in males (searched: complement). (LLM, conf=0.88)

  Experimental — accuracy not yet measured
• cites [80] Yanguas-Casás N, Crespo-Castrillo A, Arevalo MA, Garcia-Segura LM. Aging and sex: impact on microglia phagocytosis. Aging Cell. 2020;19(8):e13182. sourcePartly supported

  The Discussion (page unavailable) reports higher uptake of E. coli bioparticles by newborn male microglia, supporting a male advantage for one type of phagocytosis. It also reports higher nonspecific and neural-debris phagocytosis in newborn females and similar basal activity in adult males and females. The cited paper does not establish that males generally have higher phagocytosis rates or more potent and plentiful complement factors. (LLM, conf=0.87)

  Experimental — accuracy not yet measured

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

This process likely plays a key role in the pathogenesis of age-related diseases, including Alzheimer's.

“This process likely plays a key role in the pathogenesis of age-related diseases, including Alzheimer’s [36].”

• cites [36] Giunta B, Fernandez F, Nikolic WV, Obregon D, Rrapo E, Town T, Tan J. Inflammaging as a prodrome to Alzheimer’s disease. J Neuroinflammation. 2008;5(1):1–15. sourceSupported

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

In Alzheimer's disease, neuroinflammation is primarily thought to be a consequence of a series of damage signals including trauma, oxidation, oligomers of Aβ and tau, and more.

“In Alzheimer’s disease, neuroinflammation is primarily thought to be a consequence of a series of damage signals including trauma, oxidation, oligomers of Aβ and tau, and more [67].”

• cites [67] Morales I, Guzmán-Martínez L, Cerda-Troncoso C, Farías GA, Maccioni RB. Neuroinflammation in the pathogenesis of Alzheimer’s disease. A rational framework for the search of novel therapeutic approaches. Front Cell Neurosci. 2014;8:112. sourcePartly supported

  The Neuroinflammation section describes inflammation as generally secondary to an initial event such as trauma, and the Microglial cell section says Aβ protofibrils and pathological tau aggregates can activate microglia. The paper does not clearly identify oxidation as an initiating damage signal; its Neuroinflammation table instead lists oxidative stress as an effect of inflammatory products. No page numbers are available in our copy. (LLM, conf=0.85)

  Experimental — accuracy not yet measured

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

Studies manipulating the complement system have yielded mixed results.

“Further, studies manipulating the complement system have yielded mixed results.”

• cites [84] Maier M, Peng Y, Jiang L, Seabrook TJ, Carroll MC, Lemere CA. Complement C3 deficiency leads to accelerated amyloid β plaque deposition and neurodegeneration and modulation of the microglia/macrophage phenotype in amyloid precursor protein transgenic mice. J Neurosci. 2008;28(25):6333–41. sourceSupported
• cites [85] Wyss-Coray T, Yan F, Lin AH-T, Lambris JD, Alexander JJ, Quigg RJ, Masliah E. Prominent neurodegeneration and increased plaque formation in complement-inhibited Alzheimer’s mice. Proc Natl Acad Sci USA. 2002;99(16):10837–42. sourceSupported
• cites [86] El Gaamouch F, Audrain M, Lin W-J, Beckmann N, Jiang C, Hariharan S, Heeger PS, Schadt EE, Gandy S, Ehrlich ME. VGF-derived peptide TLQP-21 modulates microglial function through C3aR1 signaling pathways and reduces neuropathology in 5xFAD mice. Mol Neurodegener. 2020;15(1):1–19. sourceSupported
• cites [87] Shi Q, Chowdhury S, Ma R, Le KX, Hong S, Caldarone BJ, Stevens B, Lemere CA. Complement C3 deficiency protects against neurodegeneration in aged plaque-rich APP/PS1 mice. Sci Transl Med. 2017;9(392):eaaf6295. sourceSupported
• cites [88] Czirr E, Castello NA, Mosher KI, Castellano JM, Hinkson IV, Lucin KM, Baeza-Raja B, Ryu JK, Li L, Farina SN. Microglial complement receptor 3 regulates brain Aβ levels through secreted proteolytic activity. J Exp Med. 2017;214(4):1081–92. sourceSupported
• cites [89] Fonseca MI, Ager RR, Chu S-H, Yazan O, Sanderson SD, LaFerla FM, Taylor SM, Woodruff TM, Tenner AJ. Treatment with a C5aR antagonist decreases pathology and enhances behavioral performance in murine models of Alzheimer’s disease. J Immunol Res. 2009;183(2):1375–83. sourceSupported

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

Multiple studies have shown that complement factor inhibition ameliorates synapse and neuron loss.

“Additionally, multiple studies have shown that complement factor inhibition ameliorates synapse and neuron loss [90–93].”

• cites [90] Carpanini SM, Torvell M, Bevan RJ, Byrne RA, Daskoulidou N, Saito T, Saido TC, Taylor PR, Hughes TR, Zelek WM. Terminal complement pathway activation drives synaptic loss in Alzheimer’s disease models. Acta Neuropathol Commun. 2022;10(1):1–16. sourcePartly supported

  The Introduction reports that inhibiting or deleting complement components reduced pathological synapse loss in Alzheimer’s disease mouse models. The Results also show protection against synaptic loss with C7 inhibition or C6 deficiency. The paper treats synapse loss as an early index of neurodegeneration, but these passages do not establish that its interventions reduced neuron loss. (LLM, conf=0.86)

  Experimental — accuracy not yet measured
• cites [91] Britschgi M, Takeda-Uchimura Y, Rockenstein E, Johns H, Masliah E, Wyss-Coray T. Deficiency of terminal complement pathway inhibitor promotes neuronal tau pathology and degeneration in mice. J Neuroinflammation. 2012;9(1):1–6. sourcePartly supported

  The Findings (page unavailable) report that mice lacking the complement inhibitor CD59a had greater neuronal and synaptic degeneration, while expression of another complement inhibitor reduced phosphorylated-tau-positive neurons. The paper proposes that terminal-pathway inhibition may be beneficial, but it does not show that inhibition ameliorated synapse and neuron loss or report multiple studies demonstrating that outcome. (LLM, conf=0.86)

  Experimental — accuracy not yet measured
• cites [92] Fonseca MI, Zhou J, Botto M, Tenner AJ. Absence of C1q leads to less neuropathology in transgenic mouse models of Alzheimer’s disease. J Neurosci. 2004;24(29):6457–65. sourcePartly supported

  The Results report that C1q-deficient APP mice had less loss of synaptophysin, a synaptic marker, and higher MAP-2 staining than APP mice at later ages. But the Results and Discussion explicitly report no detectable neuronal cell loss, so this study does not show that C1q deficiency ameliorates neuron loss. The study concerns C1q deficiency in transgenic mice, not complement-factor inhibition generally. (LLM, conf=0.90)

  Experimental — accuracy not yet measured
• cites [93] Hong S, Beja-Glasser VF, Nfonoyim BM, Frouin A, Li S, Ramakrishnan S, Merry KM, Shi Q, Rosenthal A, Barres BA. Complement and microglia mediate early synapse loss in Alzheimer mouse models. Science. 2016;352(6286):712–6. sourcePartly supported

  The paper reports that inhibiting C1q, C3, or CR3 rescues early synapse loss in Alzheimer mouse models (passage 7, section labelled Abstract; page not provided). It does not report that complement inhibition ameliorates neuron loss. The claim’s reference to multiple studies is a collective attribution to citations [90–93], not a finding this individual paper must establish. (LLM, conf=0.88)

  Experimental — accuracy not yet measured

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

Researchers have proposed that impaired liver function due to chronic liver diseases and inflammation leads to an imbalance in peripheral Aβ clearance, exacerbating amyloid burden and Alzheimer's pathology.

“Researchers have proposed that impaired liver function due to chronic liver diseases and inflammation leads to an imbalance in peripheral Aβ clearance, exacerbating amyloid burden and Alzheimer’s pathology [57, 58]”

• cites [57] Estrada LD, Ahumada P, Cabrera D, Arab JP. Liver dysfunction as a novel player in Alzheimer’s progression: looking outside the brain. Front Aging Neurosci. 2019;11:174. sourceSupported
• cites [58] Huang Z, Lin HW, Zhang Q, Zong X. Targeting Alzheimer’s disease: the critical crosstalk between the liver and brain. Nutrients. 2022;14(20):4298. sourcePartly supported

  Section 4.2 reports that cirrhosis is associated with elevated plasma Aβ and suggests liver dysfunction may reduce peripheral Aβ clearance; the Conclusions say disturbed peripheral Aβ metabolism may contribute to AD progression. But the paper does not establish inflammation as the cause of impaired clearance, and Section 6 says whether liver dysfunction directly exacerbates brain Aβ burden remains unclear. (LLM, conf=0.86)

  Experimental — accuracy not yet measured

May combine two claims.

SASP is a damaging byproduct of senescent cells, and a potential driver of Alzheimer's pathogenesis.

“A key contributor to the development and progression of inflammaging is the senescence associated secretory phenotype (SASP) – a damaging byproduct of senescent cells [63], and a potential driver of Alzheimer’s pathogenesis [64].”

• cites [63] Olivieri F, Prattichizzo F, Grillari J, Balistreri CR. Cellular senescence and inflammaging in age-related diseases. Mediators Inflamm. 2018;2018:9076485. sourceSupported
• cites [64] Zhang P, Kishimoto Y, Grammatikakis I, Gottimukkala K, Cutler RG, Zhang S, Abdelmohsen K, Bohr VA, Misra Sen J, Gorospe M. Senolytic therapy alleviates Aβ-associated oligodendrocyte progenitor cell senescence and cognitive deficits in an Alzheimer’s disease model. Nat Neurosci. 2019;22(5):719–28. sourceSupported

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

Heightened levels of CD45+ and F4/80+ cells have been described in the livers of 24-month-old male C57BL/6 mice and Fischer rats.

“Heightened levels of CD45 + and F4/80 + cells have been described in the livers of 24-month-old male C57BL/6 mice [59] and Fischer rats [60].”

• cites [59] Mohammed S, Thadathil N, Selvarani R, Nicklas EH, Wang D, Miller BF, Richardson A, Deepa SS. Necroptosis contributes to chronic inflammation and fibrosis in aging liver. Aging Cell. 2021;20(12):e13512. sourceSupported
• cites [60] Hilmer SN, Cogger VC, Couteur DGL. Basal activity of Kupffer cells increases with old age. J Gerontol A Biol Sci Med Sci. 2007;62(9):973–8. sourceNot checked — no full text of the source

May combine two claims.

The authors' analyses of clinical data from patients with sporadic late onset Alzheimer's disease further validated the translational relevance of and lessened the limitations associated with the 3xTg-AD model in the context of this study.

“our analyses of clinical data from patients with sporadic late onset Alzheimer’s disease further validated the translational relevance of and lessened the limitations associated with the 3xTg-AD model in the context of this study.”

• cites [39] Wang M, Beckmann ND, Roussos P, Wang E, Zhou X, Wang Q, Ming C, Neff R, Ma W, Fullard JF, et al. The Mount Sinai cohort of large-scale genomic, transcriptomic and proteomic data in Alzheimer’s disease. Sci Data. 2018;5(1):180185. sourceSupported

Classified as probably not a substantial claim.

In response to LPS injection, male C57BL/6 microglia elicit an aged phenotype characterized by heightened upregulation of immune gene expression relative to female-derived microglia.

“This work showed that in response to LPS injection, male C57BL/6 microglia elicit an aged phenotype characterized by heightened upregulation of immune gene expression relative to female derived microglia.”

• cites [103] Hanamsagar R, Alter MD, Block CS, Sullivan H, Bolton JL, Bilbo SD. Generation of a microglial developmental index in mice and in humans reveals a sex difference in maturation and immune reactivity. Glia. 2017;65(9):1504–20. sourcePartly supported

  The Methods (Animals; LPS treatments and tissue collection) identify C57BL/6 mice and an LPS injection. The Results (Sex difference in microglial developmental index response to LPS challenge) report that male, but not female, microglia shifted toward a more mature developmental profile after LPS; the Results (Gene expression changes in microglia following an immune challenge are related to development) link that profile to immune-related genes. The paper does not call it an aged phenotype, and it says the overall magnitude of the male and female transcriptional responses was similar, rather than establishing heightened immune-gene upregulation in males overall. (LLM, conf=0.88)

  Experimental — accuracy not yet measured

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

Current "disease-modifying" FDA-approved therapies for Alzheimer's are anti-amyloid antibody drugs, which successfully eliminate amyloid fibrils from the brain and produce an overall significant difference in performance on cognitive assessment scales.

“Current “disease- modifying” FDA-approved therapies for Alzheimer’s are anti-amyloid antibody drugs, which successfully eliminate amyloid fibrils from the brain and produce an overall significant difference in performance on cognitive assessment scales [105].”

• cites [105] Van Dyck CH, Swanson CJ, Aisen P, Bateman RJ, Chen C, Gee M, et al. Lecanemab in early Alzheimer’s disease. New Eng J Med. 2023;388(1):9–21. sourcePartly supported

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

  Experimental — accuracy not yet measured

Classified as probably not a substantial claim.

Microglial coverage of amyloid plaques is highest in male APOE3 mice and reduced by female sex and APOE4 genotype.

“They discovered that microglial coverage of amyloid plaques is highest in male APOE3 mice and reduced by female sex and APOE4 genotype.”

• cites [104] Stephen TL, Cacciottolo M, Balu D, Morgan TE, LaDu MJ, Finch CE, Pike CJ. APOE genotype and sex affect microglial interactions with plaques in Alzheimer’s disease mice. Acta Neuropathol Commun. 2019;7(1):82. sourceSupported

May combine two claims.

All complement-related DEGs had greater log-fold change and more statistical significance in 3xTg-AD males compared to females.

“All complement-related DEGs had greater log-fold change and more statistical significance in 3xTg-AD males compared to females”

May combine two claims.

Compared to controls, male 3xTg-AD life expectancy was 12 months shorter on average, while female 3xTg-AD life expectancy was 6 months shorter on average.

“Compared to their respective controls, male 3xTg-AD life expectancy was 12 months shorter on average, while female 3xTg-AD life expectancy was 6 months shorter on average.”

May combine two claims.

Tau expression progressed with age, more significantly in 3xTg-AD females compared to males.

“We found that tau expression progressed with age, more significantly in 3xTg-AD females compared to males (Fig. 2e).”

May combine two claims.

The complement system was altered in both female and male 3xTg-AD mice, with the highest ratio of differentially expressed genes.

“the complement system was altered in both female and male 3xTg-AD mice, with the highest ratio of differentially expressed genes”

May combine two claims.

Extracellular Aβ plaques were first detectable at 12 months in the hippocampal formation of female 3xTg-AD mice, and plaque accumulation progressed significantly with age.

“We observed that extracellular Aβ plaques were first detectable at 12-months-old in the hippocampal formation of female 3xTg-AD mice, and plaque accumulation progressed significantly with age (Fig. 2a).”

May combine two claims.

Severe splenomegaly was present in aged 3xTg-AD males and associated with abnormal histology.

“severe splenomegaly was present in aged 3xTg-AD males and associated with abnormal histology”

May combine two claims.

Phospho-tau pathology started in 15-month-old 3xTg-AD female mice and progressed significantly with age.

“We observed that phospho-tau pathology started in 15-month-old 3xTg-AD female mice and progressed significantly with age (Fig. 2c).”

May combine two claims.

C1QA, C1QB, and C1QC reached statistical significance in males while only C1QC reached statistical significance in females in human AD PHG.

“C1QA, C1QB, and C1QC reached statistical significance in males while only C1QC reached statistical significance in females”

May combine two claims.

3xTg-AD male mice exhibited significantly enlarged spleens, with an average weight of 4.6 g in 18-month-old mice, 36× the size of age-matched control spleens, and nearly 15% of their total body weight.

“3xTg-AD male mice exhibited significantly enlarged spleens, with an average weight of 4.6 g in 18-month-old 3xTg-AD male mice, 36 × the size of age-matched control spleens, and nearly 15% of their total body weight (Fig. 3a).”

• AssumptionRests on an assumption: Aging and inflammaging affect all body systems.

The quote only partly states this claim.

Additional immune-related biological processes were further enriched at 21- and 24-months-old in 3xTg-AD females.

“Additional immune-related biological processes were further enriched at 21- and 24-months-old.”

May combine two claims.

3xTg-AD males exhibit no Aβ plaque pathology and very minimal tangle pathology, if any, in old age.

“3xTg-AD males exhibit no Aβ plaque pathology and very minimal tangle pathology, if any, in old age”

May combine two claims.

WT mice experienced no natural mortality events up to 2 years of age, with animals surviving past 30 months.

“WT mice experienced no natural mortality events up to 2-years of age (730 days), with animals surviving past 30 months.”

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

Escalating presence of Alzheimer's neuropathology in female 3xTg-AD mice from 12-months of age onward.

“given the escalating presence of Alzheimer’s neuropathology in female 3xTg-AD mice from 12-months of age onward”

May combine two claims.

Progressive plaque and tangle pathology were first observed in 3xTg-AD females at 12 months and 15 months of age respectively, subsequently followed by escalating neuroinflammation between 18 and 24 months of age.

“Progressive plaque and tangle pathology were first observed in 3xTg-AD females at 12 months and 15 months of age respectively, subsequently followed by escalating neuroinflammation between 18 and 24 months of age”

May combine two claims.

Male 3xTg-AD mice exhibit significant chronic hepatic inflammation throughout adulthood, while females exhibit milder hepatic inflammation in old age.

“We discovered that male 3xTg-AD mice exhibit significant chronic hepatic inflammation throughout adulthood, while females exhibit milder hepatic inflammation in old age”

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

3xTg-AD mice exhibit sex-dependent and age-dependent alterations in double-negative T cell populations.

“Catorce et al. further showed that 3xTg-AD mice exhibit not only sex-dependent, but also age-dependent alterations in double-negative T cell populations [29].”

• cites [29] Catorce MN, Acero G, Gevorkian G. Age-and sex-dependent alterations in the peripheral immune system in the 3xTg-AD mouse model of Alzheimer’s disease: Increased proportion of CD3+ CD4-CD8-double-negative T cells in the blood. J Neuroimmunol. 2021;360:577720. sourceNot checked — no full text of the source

Classified as probably not a substantial claim.

Differential expression p-values were adjusted for multiple comparisons with the Benjamini-Hochberg method.

“Differential expression p-values were adjusted for multiple comparisons with the Benjamini-Hochberg method.”

May combine two claims.

3xTg-AD male mice exhibit accelerated upregulation of immune-related gene expression over the course of disease progression, presenting with significant molecular dysfunction 6-months prior to 3xTg-AD females.

“Further, 3xTg-AD male mice exhibit accelerated upregulation of immune-related gene expression over the course of disease progression, presenting with significant molecular dysfunction 6-months prior to 3xTg-AD females.”

Classified as probably not a substantial claim.

Diagnoses of AD or control in clinical data were determined based on the clinical dementia rating scale, Mini Mental State Exam, and Braak staging.

“Diagnoses of AD or control (CT) were determined based on the clinical dementia rating scale, Mini Mental State Exam, and Braak staging.”

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

Blood samples from sentinel mice underwent quarterly and yearly serology testing to confirm the absence of pathogens.

“Blood samples obtained from sentinel mice underwent quarterly and yearly serology testing with the Multiplexed Fluorometric ImmunoAssay at Charles River Research Animal Diagnostic Services to confirm the absence of pathogens (see Supplementary Table 1, Additional file 1 for list of tested agents).”

May combine two claims.

Sex likely impacts the severity of complement overactivation, with males exhibiting increased upregulation of most complement DEGs, and reduced expression of complement inhibitors, relative to females.

“suggest that sex likely impacts the severity of complement overactivation, with males exhibiting increased upregulation of most complement DEGs, and reduced expression of complement inhibitors, relative to females.”

• AssumptionRests on an assumption: C4 is involved in classical and lectin activation pathways.

May combine two claims.

The brains of 3xTg-AD mice exhibit highly modulated transcriptomic profiles that worsened with age and can be largely characterized by an upregulation of immune-related processes.

“These results indicate that the brains of 3xTg-AD mice exhibit highly modulated transcriptomic profiles that worsened with age and can be largely characterized by an upregulation of immune-related processes.”

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

Intra-assay precision quality controls indicated 2.9% coefficient of variation.

“Intra-assay precision quality controls indicated 2.9% coefficient of variation.”

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

CD45 antigen is expressed on almost all hematopoietic cells except for mature erythrocytes.

“CD45 antigen, or leukocyte common antigen, is expressed on almost all hematopoietic cells except for mature erythrocytes [47]”

• cites [47] Nakano A, Harada T, Morikawa S, Kato Y. Expression of leukocyte common antigen (CD45) on various human leukemia/lymphoma cell lines. Pathol Int. 1990;40(2):107–15. sourceNot checked — no full text of the source

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

Inflammaging is low-grade chronic, systemic inflammation in aging associated with increased proinflammatory cytokine production, and is a substantial risk factor for morbidity and mortality in older adults.

“Franceschi et al. coined the term “inflammaging” to describe low-grade chronic, systemic, inflammation in aging associated with increased proinflammatory cytokine production, which is a substantial risk factor for morbidity and mortality in older adults [31].”

• cites [31] Franceschi C, Bonafè M, Valensin S, Olivieri F, De Luca M, Ottaviani E, De Benedictis G. Inflamm-aging: an evolutionary perspective on immunosenescence. Ann NY Acad Sci. 2000;908(1):244–54. sourceNot checked — no full text of the source

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

MASP1 is activated by the lectin complement pathway which is initiated by the binding of mannose-binding lectin to bacterial surfaces with mannose-containing polysaccharides.

“MASP1, activated by the lectin complement pathway which is initiated by the binding of mannose-binding lectin to bacterial surfaces with mannose-containing polysaccharides [51]”

• cites [51] Dunkelberger JR, Song W-C. Complement and its role in innate and adaptive immune responses. Cell Res. 2010;20(1):34–50. sourceNot checked — no full text of the source

May combine two claims.

3xTg-AD mice have a significantly shortened lifespan, which is further exacerbated in male mice.

“Overall, our results demonstrate that the 3xTg-AD mice have a significantly shortened lifespan, which is further exacerbated in male mice.”

May combine two claims.

3xTg-AD male mice experience immense splenomegaly, possibly as a result of peripheral organ inflammation, at the end of their lives.

“Overall, these results suggest that 3xTg-AD male mice experience immense splenomegaly, possibly as a result of peripheral organ inflammation, at the end of their lives.”

• AssumptionRests on an assumption: Aging and inflammaging affect all body systems.

May combine two claims.

The Alzheimer's-associated immune response, clearly exacerbated in males, resembles the downstream effects of LPS stimulation.

“we propose a model in which the Alzheimer’s-associated immune response, clearly exacerbated in males, resembles the downstream effects of LPS stimulation”

Classified as probably not a substantial claim.

3xTg-AD mice carry APP, MAPT, and PSEN1 gene mutations.

“3xTg-AD mice are a widely used transgenic model to study Alzheimer’s which carry APP, MAPT, and PSEN1 gene mutations [17].”

• cites [17] Oddo S, Caccamo A, Shepherd JD, Murphy MP, Golde TE, Kayed R, Metherate R, Mattson MP, Akbari Y, LaFerla FM. Triple-transgenic model of Alzheimer’s disease with plaques and tangles: intracellular Aβ and synaptic dysfunction. Neuron. 2003;39(3):409–21. sourceNot checked — no full text of the source

May combine two claims.

This process prompts the sustained upregulation of complement system genes, possibly contributing to observed systemic inflammation, hepatic inflammation, and splenomegaly, driving increased mortality.

“This process prompts the sustained upregulation of complement system genes, possibly contributing to observed systemic inflammation, hepatic inflammation, and splenomegaly, driving increased mortality.”

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

Neuroinflammation becomes chronic, initiating a cyclic cascade of glial priming, proinflammatory factor release, and neuronal damage.

“Eventually, however, neuroinflammation becomes chronic, initiating a cyclic cascade of glial priming, proinflammatory factor release, and neuronal damage [68].”

• cites [68] Calsolaro V, Edison P. Neuroinflammation in Alzheimer’s disease: current evidence and future directions. Alzheimer’s Dement. 2016;12(6):719–32. sourceNot checked — no full text of the source

May combine two claims.

3xTg-AD males exhibited more extensive complement system overactivation than females, as differentially expressed complement genes were more statistically significant with greater log-fold changes.

“Interestingly, 3xTg-AD males exhibited more extensive complement system overactivation than females, as differentially expressed complement genes were more statistically significant with greater log-fold changes.”

Classified as probably not a substantial claim.

Liver diseases such as cirrhosis and hepatitis are one of the most common causes of splenomegaly clinically.

“liver diseases such as cirrhosis and hepatitis are one of the most common causes of splenomegaly clinically [53]”

• cites [53] Chapman J, Goyal A, Azevedo AM. Splenomegaly. 2017.Not matched

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

May combine two claims.

Neuroinflammation in 3xTg-AD males does not follow this timeline, suggesting that an earlier trigger kicks off an unrelenting immune cascade, driven by earlier disease abnormalities as opposed to later stage disease pathology.

“However, neuroinflammation in 3xTg-AD males does not follow this timeline, suggesting that an earlier trigger kicks off an unrelenting immune cascade, driven by earlier disease abnormalities as opposed to later stage disease pathology.”

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

Age is likely a key variable between these experiments, which is especially difficult to capture in in-vitro studies, and strongly influences sex-specific results.

“Similar to other immune system studies previously described, age is likely a key variable between these experiments, which is especially difficult to capture in in-vitro studies, and strongly influences sex-specific results.”

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

The complement system is a vital element of the immune system that enhances the opsonization of pathogens and initiates a series of inflammatory responses to help fight infection.

“an overactive complement system, a vital element of the immune system that enhances the opsonization of pathogens and initiates a series of inflammatory responses to help fight infection [51].”

• cites [51] Dunkelberger JR, Song W-C. Complement and its role in innate and adaptive immune responses. Cell Res. 2010;20(1):34–50. sourceNot checked — no full text of the source

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

The hepatic inflammation observed in male 3xTg-AD mice could be the result of an accelerated aging phenotype in the male Alzheimer's disease trajectory.

“the hepatic inflammation observed in male 3xTg-AD mice could be the result of an accelerated aging phenotype in the male Alzheimer’s disease trajectory.”

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

The research could not be conducted with a comparable longitudinal experimental design in humans.

“Our research could not be conducted with comparable longitudinal experimental design in humans.”

May combine two claims.

The authors' results suggest that females are less impacted by pathogens, an endogenous pathogen-like trigger, or an autoimmune response, and that males are more susceptible to an infectious or inflammatory mode of Alzheimer's initiation.

“our results suggest that females are less impacted by pathogens, an endogenous pathogen-like trigger, or an autoimmune response, and that males are more susceptible to an infectious or inflammatory mode of Alzheimer’s initiation.”

May combine two claims.

Either the male immune system is more effective at clearing and preventing protein aggregation, or advanced pathological burden in the female brain reaches a point of no return.

“suggests that either the male immune system is more effective at clearing and preventing protein aggregation, or that advanced pathological burden in the female brain reaches a point of no return.”

May combine two claims.

Despite constraints on sample size, the histology data established age and sex-specific effects of moderate and large size and the sequencing data revealed differentially expressed genes with a high degree of statistical significance.

“Despite constraints on sample size, our histology data established age and sex-specific effects of moderate and large size and our sequencing data revealed differentially expressed genes with a high degree of statistical significance.”

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

Despite reaching statistical significance, the clinical impact of treatment on individual patients and caregivers remains unclear.

“However, despite reaching statistical significance, the clinical impact of treatment on individual patients and caregivers remains unclear [106].”

• cites [106] Lin GA, Whittington MD, Wright A, Agboola F, Herron-Smith S, Pearson SD, Rind DM. Beta-amyloid antibodies for early Alzheimer’s disease: effectiveness and value; evidence report. Institute for Clinical and Economic Review; 2023. https://icer.org/assessment/alzheimers-disease-2022/#timeline.Not checked yet

  Not checked in the free run.

May combine two claims.

In both the 3xTg-AD mouse model and humans with Alzheimer's, sex-specific disease phenotypes are primarily driven by compromised neuronal function in females and aggravated immune response in males.

“In both the 3xTg-AD mouse model, and in humans with Alzheimer’s, we see sex-specific disease phenotypes primarily driven by compromised neuronal function in females and aggravated immune response in males.”