What would it take to prove that a chronic infection is a causal agent in Alzheimer’s disease?

May combine two claims.

HSV-2 seropositivity has been associated with decreased memory performance, but appeared to be unrelated to global cognition and other cognitive domains, or the risk of all-cause dementia, AD, vascular dementia and other dementias.

“HSV-2 seropositivity has also been associated with decreased memory performance, but appeared to be unrelated to global cognition and other cognitive domains, or the risk of all-cause dementia, AD, vascular dementia and other dementias [27,28].”

• cites [27] Nimgaonkar VL (2016) Temporal Cognitive Decline Associated With Exposure to Infectious Agents in a Population-based, Aging Cohort. Alzheimer Dis Assoc Disord 30, 216– 222. 10.1097/wad.0000000000000133 26710257 PMC4919236 sourcePartly supported

  The Results section on temporal change reports that HSV-2 exposure was associated with greater decline in memory alone, supporting the memory finding and the absence of an association with decline in other domains. But the Results section on cognition at study entry reports associations with all measured cognitive domains, contrary to an unqualified claim that HSV-2 was unrelated to them. This paper does not report HSV-2 associations with the risks of the listed dementias; no page numbers were available in our copy. (LLM, conf=0.88)

  Experimental — accuracy not yet measured
• cites [28] Tzeng NS (2018) Anti-herpetic Medications and Reduced Risk of Dementia in Patients with Herpes Simplex Virus Infections-a Nationwide, Population-Based Cohort Study in Taiwan. Neurotherapeutics 15, 417– 429. 10.1007/s13311-018-0611-x 29488144 PMC5935641 sourceDisputed

  The Results report that genital and non-genital HSV infections were associated with increased overall dementia risk, and that HSV infections were associated with increased risks of AD, vascular dementia, and other dementia—the opposite direction from the cited sentence’s dementia-risk claim. The Discussion says the study included HSV-1 or HSV-2 infections, but also says serology data were unavailable; it therefore does not directly test HSV-2 seropositivity. The paper reports no memory-performance or cognitive-domain finding. (LLM, conf=0.75)

  Checked by a reasoning model — may be wrong.

  Experimental — accuracy not yet measured

May combine two claims.

P. gingivalis titers (or mucosa copy numbers) have not been related to performance in the MMSE or ADAS-cog, nor a risk of AD or ACD.

“However, P. gingivalis titers (or mucosa copy numbers) have not been related to performance in the MMSE or ADAS-cog, nor a risk of AD or ACD [73–75].”

• cites [73] Ide M (2016) Periodontitis and Cognitive Decline in Alzheimer’s Disease. PLoS One 11, e0151081. 10.1371/journal.pone.0151081 26963387 PMC4786266 sourcePartly supported

  The Results (Longitudinal follow up; page unavailable) found no significant association between baseline serum P. gingivalis antibody levels and subsequent change in ADAS-cog or sMMSE scores among participants who already had AD. That supports the claim about cognitive decline, but this study did not establish a lack of association with baseline test performance, mucosal copy numbers, or risk of developing AD or ACD. (LLM, conf=0.88)

  Experimental — accuracy not yet measured
• cites [74] Beydoun MA (2020) Clinical and Bacterial Markers of Periodontitis and Their Association with Incident All-Cause and Alzheimer’s Disease Dementia in a Large National Survey. J Alzheimers Dis 75, 157– 172. 10.3233/jad-200064 32280099 PMC11008556 sourceDisputed

  The Results (page not supplied) report that higher P. gingivalis IgG titers were associated with increased incident AD dementia risk, particularly among women. This contradicts the claim that the titers have not been related to AD risk. The cited passages do not report MMSE or ADAS-cog performance or mucosal copy numbers. (LLM, conf=0.90)

  Checked by a reasoning model — may be wrong.

  Experimental — accuracy not yet measured
• cites [75] Panzarella V (2022) Oral Health Status in Subjects with Amnestic Mild Cognitive Impairment and Alzheimer’s Disease: Data from the Zabút Aging Project. J Alzheimers Dis 87, 173– 183. 10.3233/jad-200385 32508326 PMC9277678 sourcePartly supported

  Results, Table 3, and the Discussion report no significant difference in subgingival P. gingivalis load among controls, aMCI, and AD groups. The paper reports MMSE scores separately but does not test their relationship to P. gingivalis load; it does not report ADAS-cog results or assess future risk of AD or ACD. Its group comparison therefore supports only part of the attributed claim. (LLM, conf=0.86)

  Experimental — accuracy not yet measured

May combine two claims.

High titers of P. gingivalis have been associated with decreased performance in delayed verbal memory as well as serial subtraction, while P. gingivalis seropositivity has been related to decreased ADAS-cog performance.

“High titers of P. gingivalis have been associated with decreased performance in delayed verbal memory as well as serial subtraction, while P. gingivalis seropositivity has been related to decreased ADAS-cog performance [73].”

• cites [73] Ide M (2016) Periodontitis and Cognitive Decline in Alzheimer’s Disease. PLoS One 11, e0151081. 10.1371/journal.pone.0151081 26963387 PMC4786266 sourceDisputed

  The Results (Longitudinal follow up; page unavailable) report no significant association between baseline P. gingivalis antibody levels and the rate of ADAS-cog decline. The Discussion reiterates that finding. The paper does not report the claimed delayed verbal memory or serial subtraction associations. (LLM, conf=0.85)

  Checked by a reasoning model — may be wrong.

  Experimental — accuracy not yet measured

May combine two claims.

Although mucosa copy numbers of Campylobacter rectus and Treponema denticola are unrelated to AD risk, titer levels of these pathogens are linked to increased risk of ACD.

“Although mucosa copy numbers of Campylobacter rectus and Treponema denticola are unrelated to AD risk, titer levels of these pathogens are linked to increased risk of ACD [74,75].”

• cites [74] Beydoun MA (2020) Clinical and Bacterial Markers of Periodontitis and Their Association with Incident All-Cause and Alzheimer’s Disease Dementia in a Large National Survey. J Alzheimers Dis 75, 157– 172. 10.3233/jad-200064 32280099 PMC11008556 sourcePartly supported

  The Results section reports that C. rectus IgG titers were associated with increased all-cause dementia risk. It reports only a marginal association among women for a multi-pathogen cluster containing T. denticola, not an individual T. denticola titer association. The Methods describe serum IgG measurements, not mucosal copy numbers, so the claimed lack of association between copy numbers and AD risk is unsupported. (LLM, conf=0.88)

  Experimental — accuracy not yet measured
• cites [75] Panzarella V (2022) Oral Health Status in Subjects with Amnestic Mild Cognitive Impairment and Alzheimer’s Disease: Data from the Zabút Aging Project. J Alzheimers Dis 87, 173– 183. 10.3233/jad-200385 32508326 PMC9277678 sourceDisputed

  The Discussion (page unavailable) says a cited study found no significant differences in antibody levels against selected bacteria, including Treponema denticola, between groups—contrary to the claimed link between pathogen titers and increased risk. The Results report a higher T. denticola oral load in aMCI than in AD, while the Methods do not list Campylobacter rectus among the organisms tested. The paper does not establish the claimed pattern for both pathogens. (LLM, conf=0.86)

  Checked by a reasoning model — may be wrong.

  Experimental — accuracy not yet measured

May combine two claims.

Studies using electronic health records have found a link between VZV and risk of all-cause dementia, AD, vascular dementia, with antivirals decreasing all-cause dementia risk.

“Studies using electronic health records have found a link between VZV and risk of all-cause dementia, AD, vascular dementia, with antivirals decreasing all-cause dementia risk [23,36–40].”

• cites [23] Lopatko Lindman K (2021) Herpesvirus infections, antiviral treatment, and the risk of dementia-a registry-based cohort study in Sweden. Alzheimers Dement (N Y) 7, e12119. 10.1002/trc2.12119 33614892 PMC7882534 sourcePartly supported

  The Discussion reports an association between VZV diagnosis and increased dementia risk, and an association between antiviral treatment and reduced dementia risk. But it says the study did not analyze AD and vascular dementia separately because dementia subtypes were often misclassified; it does not establish a VZV link to each subtype. The reported antiviral effect is observational, not proof that treatment caused the reduction. (LLM, conf=0.90)

  Experimental — accuracy not yet measured
• cites [36] Bae S (2021) Association of herpes zoster with dementia and effect of antiviral therapy on dementia: a population-based cohort study. Eur Arch Psychiatry Clin Neurosci 271, 987– 997. 10.1007/s00406-020-01157-4 32613564 sourceNot checked — no full text of the source
• cites [37] Chen VC (2018) Herpes Zoster and Dementia: A Nationwide Population-Based Cohort Study. J Clin Psychiatry 79. 10.4088/JCP.16m11312 29244265 sourceNot checked — no full text of the source
• cites [38] Schnier C (2021) Antiherpetic medication and incident dementia: Observational cohort studies in four countries. Eur J Neurol 28, 1840– 1848. 10.1111/ene.14795 33657269 sourcePartly supported

  The Introduction reports studies linking VZV infection to incident dementia, and the Dementia incidence results find a small association between antiherpetic medication and lower dementia incidence in some cohorts. The paper does not establish a VZV-specific link to Alzheimer disease or vascular dementia: its findings for those subtypes concern medication exposure, not VZV infection. It also cautions in the Discussion that the medication association was heterogeneous and may reflect confounding, rather than a demonstrated reduction caused by antivirals. Page numbers were not provided in our copy. (LLM, conf=0.88)

  Experimental — accuracy not yet measured
• cites [39] Levine KS (2023) Virus exposure and neurodegenerative disease risk across national biobanks. Neuron 111, 1086– 1093.e1082. 10.1016/j.neuron.2022.12.029 36669485 PMC10079561 sourcePartly supported

  The Results report a replicated association between varicella-zoster virus (VZV) and vascular dementia, but do not report a VZV infection association with all-cause dementia or AD. The Discussion says some studies suggest antivirals may reduce dementia risk in patients with VZV; it does not establish that antivirals decrease the risk. Its separate statement about reduced dementia and AD risk concerns shingles vaccination, not VZV infection. (LLM, conf=0.86)

  Experimental — accuracy not yet measured
• cites [40] Tsai MC (2017) Increased risk of dementia following herpes zoster ophthalmicus. PLoS One 12, e0188490. 10.1371/journal.pone.0188490 29166672 PMC5699837 sourcePartly supported

  The Discussion reports an association between herpes zoster ophthalmicus and subsequent dementia in a population-based cohort. It does not report separate VZV associations with Alzheimer’s disease or vascular dementia, and explicitly says the study did not compare antiviral treatment with subsequent dementia risk. No page numbers are provided in our copy. (LLM, conf=0.90)

  Experimental — accuracy not yet measured

May combine two claims.

Adding antibiotics to standard of care produced similar benefits and provided strong evidence for H. pylori as a causal agent to subsequent disease.

“Similar benefits from adding antibiotics to the standard of care were obtained by other investigators [13–16], providing strong evidence for H. pylori as a causal agent to subsequent disease.”

• cites [13] George LL (1990) Cure of duodenal ulcer after eradication of Helicobacter pylori. Med J Aust 153, 145– 149. 10.5694/j.1326-5377.1990.tb136833.x 1974027 sourceNot checked — no full text of the source
• cites [14] Graham DY (1991) Effect of triple therapy (antibiotics plus bismuth) on duodenal ulcer healing. A randomized controlled trial. Ann Intern Med 115, 266– 269. 10.7326/0003-4819-115-4-266 1854110 sourceNot checked — no full text of the source
• cites [15] Graham DY (1992) Effect of treatment of Helicobacter pylori infection on the long-term recurrence of gastric or duodenal ulcer. A randomized, controlled study. Ann Intern Med 116, 705– 708. 10.7326/0003-4819-116-9-705 1558340 sourceNot checked — no full text of the source
• cites [16] Hosking SW (1992) Randomised controlled trial of short term treatment to eradicate Helicobacter pylori in patients with duodenal ulcer. Bmj 305, 502– 504. 10.1136/bmj.305.6852.502 1392995 PMC1882868 sourceSupported

May combine two claims.

HSV-1 has been related to increased risk of all-cause dementia, AD, vascular dementia, and other dementias, with antivirals decreasing this risk.

“while HSV-1 has additionally been related to increased risk of all-cause dementia, AD, vascular dementia, and other dementias, with antivirals decreasing this risk [23,24].”

• cites [23] Lopatko Lindman K (2021) Herpesvirus infections, antiviral treatment, and the risk of dementia-a registry-based cohort study in Sweden. Alzheimers Dement (N Y) 7, e12119. 10.1002/trc2.12119 33614892 PMC7882534 sourcePartly supported

  The Background links HSV-1 to increased AD risk, and the Results associate untreated herpes infection with increased overall dementia risk and antiviral treatment with decreased overall risk. However, the Methods and Discussion show that the study did not distinguish HSV-1 from other HSV infections or analyze AD, vascular dementia, and other dementia subtypes separately. The Conclusion also cautions that the observed antiviral association does not establish a causal reduction in risk (page numbers unavailable). (LLM, conf=0.90)

  Experimental — accuracy not yet measured
• cites [24] Sipilä PN (2021) Hospital-treated infectious diseases and the risk of dementia: a large, multicohort, observational study with a replication cohort. Lancet Infect Dis 21, 1557– 1567. 10.1016/s1473-3099(21)00144-4 34166620 PMC8592915 sourcePartly supported

  The Results report increased dementia risk after hospital-treated herpes-virus infections, and increased risks of all-cause, Alzheimer’s, vascular, and other dementias after hospital-treated infections generally. They do not establish those subtype associations specifically for HSV-1. The Introduction mentions HSV-1 animal models, but the paper does not report that antivirals decrease dementia risk. (LLM, conf=0.88)

  Experimental — accuracy not yet measured

May combine two claims.

A study on individuals with a history of symptomatic herpetic infections found accelerated white matter atrophy, but another study found no longitudinal evidence of HSV1-related whole-brain atrophy among carriers of familial AD mutations.

“A study on individuals with a history of symptomatic herpetic infections found accelerated white matter atrophy, but another study found no longitudinal evidence of HSV1-related whole-brain atrophy among carriers of familial AD mutations [46,47].”

• cites [46] Warren-Gash C (2022) Herpes simplex virus and rates of cognitive decline or whole brain atrophy in the Dominantly Inherited Alzheimer Network. Ann Clin Transl Neurol 9, 1727– 1738. 10.1002/acn3.51669 36189728 PMC9639627 sourceSupported
• cites [47] Duggan MR (2022) Herpes Viruses in the Baltimore Longitudinal Study of Aging: Associations With Brain Volumes, Cognitive Performance, and Plasma Biomarkers. Neurology 99, e2014– e2024. 10.1212/wnl.0000000000201036 35985823 PMC9651463 sourceSupported

May combine two claims.

HHV6 seropositivity does not appear to be related to AD risk, although HHV6 titers among individuals co-infected with HSV-1 can be associated with increased risk of all-cause dementia.

“HHV6 seropositivity does not appear to be related to AD risk, although there is evidence that HHV6 titers among individuals co-infected with HSV-1 can be associated with increased risk of all-cause dementia [25].”

• cites [25] Mekli K (2022) Investigation of the association between the antibody responses to neurotropic viruses and dementia outcomes in the UK Biobank. PLoS One 17, e0274872. 10.1371/journal.pone.0274872 36223333 PMC9555633 sourcePartly supported

  The Results (page unavailable) report only a marginal association between overall HHV6 seropositivity and all-cause dementia, and an increased dementia risk for people seropositive for four viruses, including HHV6 and HSV1. The paper does not establish the claim about HHV6 seropositivity and AD risk, or report that HHV6 titers specifically predict dementia among people co-infected with HSV1; its Methods describe using binary seropositivity variables. (LLM, conf=0.85)

  Experimental — accuracy not yet measured

May combine two claims.

Recent analyses of post-mortem samples indicate HHV6 may be more abundant in the brains of AD individuals, but these results were contrasted by a re-analysis of the same samples using different bioinformatic techniques.

“Although recent analyses of post-mortem samples indicate HHV6 may be more abundant in the brains of AD individuals, these results were contrasted by a re-analysis of the same samples using different bioinformatic techniques [43,44].”

• cites [43] Allnutt MA (2020) Human Herpesvirus 6 Detection in Alzheimer’s Disease Cases and Controls across Multiple Cohorts. Neuron 105, 1027– 1035.e1022. 10.1016/j.neuron.2019.12.031 31983538 PMC7182308 sourceSupported
• cites [44] Readhead B (2018) Multiscale Analysis of Independent Alzheimer’s Cohorts Finds Disruption of Molecular, Genetic, and Clinical Networks by Human Herpesvirus. Neuron 99, 64– 82.e67. 10.1016/j.neuron.2018.05.023 29937276 PMC6551233 sourcePartly supported

  The Results section reports increased HHV-6A abundance in post-mortem brain samples from people with Alzheimer’s disease. The cited paper does not report a contrasting re-analysis of the same samples using different bioinformatic techniques, so it supports only the first part of the sentence. (LLM, conf=0.88)

  Experimental — accuracy not yet measured

May combine two claims.

A link between HSV-1 seropositivity and AD has been found, and a recent prospective cohort study showed HSV-1 infection can double AD risk.

“On the one hand, a link between HSV-1 seropositivity and AD has been found, and a recent prospective cohort study showed HSV-1 infection can double AD risk [25,26].”

• cites [25] Mekli K (2022) Investigation of the association between the antibody responses to neurotropic viruses and dementia outcomes in the UK Biobank. PLoS One 17, e0274872. 10.1371/journal.pone.0274872 36223333 PMC9555633 sourcePartly supported

  The Results (Association between seropositivity status and dementia risk; page unavailable) report an association between HSV-1 seropositivity and dementia (OR 2.14), but do not give that estimate for Alzheimer’s disease specifically. The Discussion describes prospective-cohort evidence of increased AD risk only among APOE-ε4 carriers with particular antibody findings; it does not report a doubling of AD risk in that cohort. (LLM, conf=0.88)

  Experimental — accuracy not yet measured
• cites [26] Vestin E (2024) Herpes Simplex Viral Infection Doubles the Risk of Dementia in a Contemporary Cohort of Older Adults: A Prospective Study. J Alzheimers Dis 97, 1841– 1850. 10.3233/jad-230718 38306033 PMC10894565 sourcePartly supported

  The Introduction reports an association between HSV-1 and dementia risk and discusses associations between HSV seropositivity and AD or dementia risk. But the Discussion says this cohort found more than doubled incident dementia risk, not a statistically significant association with AD; its AD hazard ratio was similar in magnitude. Thus the claim substitutes AD risk for the study’s demonstrated dementia-risk finding. (LLM, conf=0.91)

  Experimental — accuracy not yet measured

May combine two claims.

A higher infectious burden of five infections, including CMV, was related to worse executive function at baseline and cognitive decline in memory.

“Among stroke-free participants with repeated cognitive testing on a subset, a higher infectious burden of five infections, including CMV, was related to worse executive function at baseline and cognitive decline in memory [58].”

• cites [58] Wright CB (2015) Infectious Burden and Cognitive Decline in the Northern Manhattan Study. J Am Geriatr Soc 63, 1540– 1545. 10.1111/jgs.13557 26289683 PMC4878014 sourceSupported

May combine two claims.

In mouse models of β-amyloidosis, experimental sepsis was shown to increase the formation of fibrillar amyloid plaques, promote neuroinflammation, and exacerbate cognitive impairment.

“In mouse models of β-amyloidosis, experimental sepsis was shown to increase the formation of fibrillar amyloid plaques, promote neuroinflammation, and exacerbate cognitive impairment [101].”

• cites [101] Basak JM (2021) Bacterial sepsis increases hippocampal fibrillar amyloid plaque load and neuroinflammation in a mouse model of Alzheimer’s disease. Neurobiol Dis 152, 105292. 10.1016/j.nbd.2021.105292 33556539 PMC8057119 sourcePartly supported

  The Abstract Results and Discussion report increased hippocampal fibrillar amyloid plaques and plaque-related neuroinflammation after experimental sepsis in APP/PS1 mice. They do not report that sepsis exacerbated cognitive impairment in those mice; the Discussion presents accelerated symptomatic decline as a possibility, not a measured result. (LLM, conf=0.90)

  Experimental — accuracy not yet measured

May combine two claims.

Mucosa copy numbers of Fusobacterium nucleatum have been related to increased AD, and evidence suggests lower titers of Actinomyces naeslundii in AD.

“Mucosa copy numbers of Fusobacterium nucleatum have been related to increased AD, and evidence suggests lower titers of Actinomyces naeslundii in AD [74,75].”

• cites [74] Beydoun MA (2020) Clinical and Bacterial Markers of Periodontitis and Their Association with Incident All-Cause and Alzheimer’s Disease Dementia in a Large National Survey. J Alzheimers Dis 75, 157– 172. 10.3233/jad-200064 32280099 PMC11008556 sourcePartly supported

  The Results section on pathogen factors links a composite that includes F. nucleatum IgG titers to increased AD mortality risk in adults aged 65 or older. It does not report mucosal F. nucleatum copy numbers or establish an individual F. nucleatum association with AD incidence. The Methods describe serum IgG measurements for A. naeslundii, but the passages found do not link lower titers to AD. (LLM, conf=0.85)

  Experimental — accuracy not yet measured
• cites [75] Panzarella V (2022) Oral Health Status in Subjects with Amnestic Mild Cognitive Impairment and Alzheimer’s Disease: Data from the Zabút Aging Project. J Alzheimers Dis 87, 173– 183. 10.3233/jad-200385 32508326 PMC9277678 sourcePartly supported

  The Results and Discussion report significantly higher Fusobacterium nucleatum load in AD subjects than in controls. However, the Methods specify subgingival plaque sampling, not mucosal sampling, and list the organisms tested without Actinomyces naeslundii. This source therefore does not support the claim about lower A. naeslundii titers in AD. (LLM, conf=0.90)

  Experimental — accuracy not yet measured

May combine two claims.

Brains from COVID patients also show ischemic and hemorrhagic lesions, as well as microglial activation, which can be seen in many AD patients with cerebral amyloid angiopathy.

“Additionally, brains from COVID patients also show ischemic and hemorrhagic lesions, as well as microglial activation [79], which can be seen in many AD patients with cerebral amyloid angiopathy [80].”

• cites [79] Agrawal S (2022) Brain autopsies of critically ill COVID-19 patients demonstrate heterogeneous profile of acute vascular injury, inflammation and age-linked chronic brain diseases. Acta Neuropathol Commun 10, 186. 10.1186/s40478-022-01493-7 36528671 PMC9758667 sourceSupported
• cites [80] Greenberg SM (2020) Cerebral amyloid angiopathy and Alzheimer disease - one peptide, two pathways. Nat Rev Neurol 16, 30– 42. 10.1038/s41582-019-0281-2 31827267 PMC7268202 sourcePartly supported

  The “Brain injury in CAA and AD” section describes hemorrhagic and presumed ischemic CAA-related lesions and says CAA and AD frequently co-occur. It does not establish microglial activation as a common feature in these patients; instead, it says inflammation does not seem to be a major component of CAA-related microhemorrhage or microinfarction, apart from an autoimmune subtype. The COVID-patient findings are cited separately to [79], not to this source. (LLM, conf=0.87)

  Experimental — accuracy not yet measured

May combine two claims.

Aβ42 can also suppress influenza A virus replication in vitro, and significantly increase the uptake of these viruses by neutrophils.

“Aβ42 can also suppress influenza A virus replication in vitro, and significantly increase the uptake of these viruses by neutrophils [112].”

• cites [112] White MR (2014) Alzheimer’s associated β-amyloid protein inhibits influenza A virus and modulates viral interactions with phagocytes. PLoS One 9, e101364. 10.1371/journal.pone.0101364 24988208 PMC4079246 sourceSupported

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

Constituting ~45% of the human and rodent genomes, transposable elements are routinely repressed in somatic cells to prevent their mobilization, which otherwise can have deleterious effects.

“Constituting ~45% of the human and rodent genomes, transposable elements are routinely repressed in somatic cells to prevent their mobilization, which otherwise can have deleterious effects [119,120].”

• cites [119] Bourque G (2018) Ten things you should know about transposable elements. Genome Biol 19, 199. 10.1186/s13059-018-1577-z 30454069 PMC6240941 sourcePartly supported

  The sections on TE expression and repression and on insertional mutagenesis describe host mechanisms that keep TEs in check and harmful insertions that can occur in somatic cells. The paper says TEs occupy a substantial portion of genomes, but the passages found do not give the claimed ~45% figure for human and rodent genomes. It also documents somatic TE activity, so repression should not be read as preventing all mobilization. (LLM, conf=0.87)

  Experimental — accuracy not yet measured
• cites [120] Makalowski W (2019) Transposable Elements: Classification, Identification, and Their Use As a Tool For Comparative Genomics. In Evolutionary Genomics: Statistical and Computational Methods (Anisimova M, ed), pp. 177– 207, Springer 31278665 sourceFetching the cited paper…

May combine two claims.

Fecal microbiota transplantation studies demonstrate that AD pathological features can be largely transferred to a healthy host via the gut microbiota, indicating a possible causal role of commensal microbes in AD.

“Fecal microbiota transplantation studies demonstrate that AD pathological features can be largely transferred to a healthy host via the gut microbiota, indicating a possible causal role of commensal microbes in AD.”

• cites [98] Grabrucker S (2023) Microbiota from Alzheimer’s patients induce deficits in cognition and hippocampal neurogenesis. Brain 146, 4916– 4934. 10.1093/brain/awad303 37849234 PMC10689930 sourcePartly supported

  The Discussion reports that microbiota from Alzheimer’s patients transferred cognitive and neurogenic alterations to healthy young rats and describes this as evidence for a causal role of gut microbiota. But the Results report no amyloid plaque deposition in the recipient rats, so the broader assertion that AD pathological features were largely transferred overstates what the study showed. Page numbers are unavailable in our copy. (LLM, conf=0.88)

  Experimental — accuracy not yet measured
• cites [99] Kim N (2021) Transplantation of gut microbiota derived from Alzheimer’s disease mouse model impairs memory function and neurogenesis in C57BL/6 mice. Brain Behav Immun 98, 357– 365. 10.1016/j.bbi.2021.09.002 34500036 sourceNot checked — no full text of the source

May combine two claims.

Autopsy has revealed that SARS-CoV-2 is detected in subcortical white matter but without infiltration of lymphocytes or leukocytes, although not all post-mortem studies have detected SARS-CoV-2 in the brain.

“For example, autopsy has revealed that SARS-CoV-2 is detected in subcortical white matter but without infiltration of lymphocytes or leukocytes [78], although not all post-mortem studies have detected SARS-CoV-2 in the brain.”

• cites [78] Song E (2021) Neuroinvasion of SARS-CoV-2 in human and mouse brain. J Exp Med 218. 10.1084/jem.20202135 PMC7808299 33433624 sourceSupported

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

Bacterial sepsis is linked to systemic inflammation, mainly through LPS engagement with Toll-like receptors (TLR), which may result in acute brain dysfunction, particularly in older patients.

“Bacterial sepsis is linked to systemic inflammation, mainly through LPS engagement with Toll-like receptors (TLR), which may result in acute brain dysfunction, particularly in older patients [100].”

• cites [100] Manabe T and Heneka MT (2022) Cerebral dysfunctions caused by sepsis during ageing. Nat Rev Immunol 22, 444– 458. 10.1038/s41577-021-00643-7 34764472 PMC8582341 sourcePartly supported

  The ‘Acute phase of sepsis’ section describes inflammation through innate immune receptors, and ‘Immediate neuroinflammation’ says circulating LPS can activate TLR2 and TLR4, contributing to brain inflammation. The paper also reports acute cerebral dysfunction after sepsis and heightened responses with ageing. It does not establish that LPS–TLR engagement is the main route of systemic inflammation; it describes other triggers and pathways as well. Page numbers were not available in our copy. (LLM, conf=0.86)

  Experimental — accuracy not yet measured

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

Increased dementia risk may be driven just by general inflammation itself.

“as increased dementia risk may be driven just by general inflammation itself [24].”

• cites [24] Sipilä PN (2021) Hospital-treated infectious diseases and the risk of dementia: a large, multicohort, observational study with a replication cohort. Lancet Infect Dis 21, 1557– 1567. 10.1016/s1473-3099(21)00144-4 34166620 PMC8592915 sourceSupported

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

Periodontal disease, commonly characterized by gum damage and potential tooth loss, is caused by infection of periodontal bacteria, which consist of up to 700 different species including Porphyromonas gingivalis.

“Periodontal disease, commonly characterized by gum damage and potential tooth loss, is caused by infection of periodontal bacteria, which consist of up to 700 different species including Porphyromonas gingivalis [4].”

• cites [4] Socransky SS and Haffajee AD (2005) Periodontal microbial ecology. Periodontol 2000 38, 135– 187. 10.1111/j.1600-0757.2005.00107.x 15853940 sourcePartly supported

  The paper’s “Microbial composition of biofilms in periodontal health and disease” section reports that P. gingivalis is more frequently detected, and present at higher levels, in people with periodontitis. But “Species abundance” estimates approximately 500 species in subgingival biofilms, not 700. The cited passages do not establish tooth loss or the sentence’s unqualified claim that bacterial infection causes periodontal disease. (LLM, conf=0.87)

  Experimental — accuracy not yet measured

May combine two claims.

Chronically elevated levels of IL-1β in the brain has been shown to provoke BBB breakdown, to induce the expression of amyloid precursor protein and to exacerbate tau phosphorylation.

“Chronically elevated levels of IL-1β in the brain has been shown to provoke BBB breakdown, to induce the expression of amyloid precursor protein and to exacerbate tau phosphorylation [96], further contributing to AD pathology.”

• cites [96] Ghosh S (2013) Sustained interleukin-1β overexpression exacerbates tau pathology despite reduced amyloid burden in an Alzheimer’s mouse model. J Neurosci 33, 5053– 5064. 10.1523/jneurosci.4361-12.2013 23486975 PMC3637949 sourcePartly supported

  The Discussion reports elevated phospho-tau after sustained IL-1β overexpression in an Alzheimer’s mouse model, supporting the tau portion. It reports APP increases only in earlier in vitro or acute-exposure studies; in this study, basal APP expression did not change. The passages found do not report blood–brain barrier breakdown. (LLM, conf=0.90)

  Experimental — accuracy not yet measured

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

The causes of neuroborreliosis are not fully understood, and it can also include meningitis, inflammation, dementia-like cognitive deficits, and encephalopathy.

“The causes of neuroborreliosis are not fully understood, and it can also include meningitis, inflammation, dementia-like cognitive deficits, and encephalopathy [61,62].”

• cites [61] Kristoferitsch W (2018) Secondary dementia due to Lyme neuroborreliosis. Wien Klin Wochenschr 130, 468– 478. 10.1007/s00508-018-1361-9 30046879 PMC6096534 sourcePartly supported

  The Pathogenesis section says the mechanism of chronic encephalomyelitis in Lyme neuroborreliosis is not fully understood and describes focal inflammation and leptomeningitis. The Conclusion identifies dementia-like syndromes as a rare manifestation. But the claim broadens that uncertainty to the causes of neuroborreliosis generally, and the Discussion explicitly distinguishes this disorder from Lyme encephalopathy rather than listing encephalopathy as a manifestation. (LLM, conf=0.88)

  Experimental — accuracy not yet measured
• cites [62] Miklossy J (2008) Biology and neuropathology of dementia in syphilis and Lyme disease. Handb Clin Neurol 89, 825– 844. 10.1016/s0072-9752(07)01272-9 18631798 sourceNot checked — no full text of the source

May combine two claims.

While most ERVs are defective and unable to produce infectious viral particles, some ERVs can.

“While most ERVs are defective and unable to produce infectious viral particles, some ERVs can [7,121].”

• cites [7] Dopkins N and Nixon DF (2024) Activation of human endogenous retroviruses and its physiological consequences. Nat Rev Mol Cell Biol 25, 212– 222. 10.1038/s41580-023-00674-z 37872387 sourceNot checked — no full text of the source
• cites [121] Shimode S (2015) Multiple invasions of an infectious retrovirus in cat genomes. Sci Rep 5, 8164. 10.1038/srep08164 25641657 PMC4313119 sourceSupported

May combine two claims.

IFN-I is important for controlling an HSV-1 infection and reactivation in the CNS, as HSV-1 DNA is sensed by the innate immune cGAS-STING pathway in microglia, which orchestrates IFN-I production and a potent antiviral defense program.

“IFN-I is important for controlling an HSV-1 infection and reactivation in the CNS, as HSV-1 DNA is sensed by the innate immune cGAS–STING pathway in microglia, which orchestrates IFN-I production and a potent antiviral defense program [93].”

• cites [93] Reinert LS (2016) Sensing of HSV-1 by the cGAS-STING pathway in microglia orchestrates antiviral defence in the CNS. Nat Commun 7, 13348. 10.1038/ncomms13348 27830700 PMC5109551 sourcePartly supported

  The Results (section 'STING-dependent type I IFN production by microglia'; page not provided) show that HSV-1-infected microglia produce type I IFN through cGAS and STING. The Discussion (page not provided) describes how this response limits viral replication and spreads antiviral activity to other CNS cells. The cited passages address HSV-1 infection, but do not establish a role in controlling reactivation. (LLM, conf=0.88)

  Experimental — accuracy not yet measured

May combine two claims.

Several groups have independently detected elevated TE transcripts in human AD, adding to an intriguing phenomenon of TE dysregulation in neurodegenerative diseases.

“Several groups have independently detected elevated TE transcripts in human AD [122–124], adding to an intriguing phenomenon of TE dysregulation in neurodegenerative diseases [125–128].”

• cites [122] Guo C (2018) Tau Activates Transposable Elements in Alzheimer’s Disease. Cell Rep 23, 2874– 2880. 10.1016/j.celrep.2018.05.004 29874575 PMC6181645 sourceSupported
• cites [123] Macciardi F (2022) A retrotransposon storm marks clinical phenoconversion to late-onset Alzheimer’s disease. Geroscience 44, 1525– 1550. 10.1007/s11357-022-00580-w 35585302 PMC9213607 sourceSupported
• cites [124] Sun W (2018) Pathogenic tau-induced piRNA depletion promotes neuronal death through transposable element dysregulation in neurodegenerative tauopathies. Nat Neurosci 21, 1038– 1048. 10.1038/s41593-018-0194-1 30038280 PMC6095477 sourceSupported
• cites [125] Ochoa Thomas E (2020) Awakening the dark side: retrotransposon activation in neurodegenerative disorders. Curr Opin Neurobiol 61, 65– 72. 10.1016/j.conb.2020.01.012 32092528 PMC7198348 sourceSupported
• cites [126] Jönsson ME (2020) Transposable Elements: A Common Feature of Neurodevelopmental and Neurodegenerative Disorders. Trends Genet 36, 610– 623. 10.1016/j.tig.2020.05.004 32499105 sourceSupported
• cites [127] Saleh A (2019) Transposable Elements, Inflammation, and Neurological Disease. Front Neurol 10, 894. 10.3389/fneur.2019.00894 31481926 PMC6710400 sourceSupported
• cites [128] Reilly MT (2013) The role of transposable elements in health and diseases of the central nervous system. J Neurosci 33, 17577– 17586. 10.1523/jneurosci.3369-13.2013 24198348 PMC3818539 sourceSupported

May combine two claims.

Both spirochetes and senile plaques contain biofilm elements, and in vitro, B. burgdorferi contains Aβ.

“Interestingly, both spirochetes and senile plaques contain biofilm elements, and in vitro, B. burgdorferi contains Aβ [64].”

• cites [64] Miklossy J (2016) Bacterial Amyloid and DNA are Important Constituents of Senile Plaques: Further Evidence of the Spirochetal and Biofilm Nature of Senile Plaques. J Alzheimers Dis 53, 1459– 1473. 10.3233/jad-160451 27314530 PMC4981904 sourceSupported

May combine two claims.

GMC101 nematodes have Aβ in the gut, and this amyloid is protective against a S. typhimurium infection.

“Interestingly, GMC101 nematodes have Aβ in the gut, and this amyloid is protective against a S. typhimurium infection [106].”

• cites [106] Kumar DK (2016) Amyloid-β peptide protects against microbial infection in mouse and worm models of Alzheimer’s disease. Sci Transl Med 8, 340ra372. 10.1126/scitranslmed.aaf1059 PMC5505565 27225182 sourceSupported

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

Transposable elements are endogenous mobile genetic elements that can move and integrate into different locations within the genome.

“Contrary to the exogenous infectious agents discussed above, transposable elements are endogenous mobile genetic elements that can move and integrate into different locations within the genome [117,118].”

• cites [117] Fueyo R (2022) Roles of transposable elements in the regulation of mammalian transcription. Nat Rev Mol Cell Biol 23, 481– 497. 10.1038/s41580-022-00457-y 35228718 PMC10470143 sourceSupported
• cites [118] Wells JN and Feschotte C (2020) A Field Guide to Eukaryotic Transposable Elements. Annu Rev Genet 54, 539– 561. 10.1146/annurev-genet-040620-022145 32955944 PMC8293684 sourceSupported

May combine two claims.

Chronic activation of Aβ can cause hyperphosphorylation of tau and the creation of neurofibrillary tangles that lead to AD pathology in aged individuals, due to their reduced efficiency in Aβ and tau clearance.

“Chronic activation of Aβ can cause hyperphosphorylation of tau and the creation of neurofibrillary tangles [109] that lead to AD pathology in aged individuals [104,110], due to their reduced efficiency in Aβ and tau clearance [110].”

• cites [109] Roda AR (2022) Amyloid-beta peptide and tau protein crosstalk in Alzheimer’s disease. Neural Regen Res 17, 1666– 1674. 10.4103/1673-5374.332127 35017413 PMC8820696 sourcePartly supported

  The amyloid cascade hypothesis section (Figure 2; page unavailable) says impaired Aβ clearance can contribute to Aβ accumulation, and that Aβ oligomers induce tau hyperphosphorylation and eventual neurofibrillary tangles. The Introduction identifies AD as a major cause of disability among elderly people. Neither passage says that aging reduces clearance of both Aβ and tau, so the sentence’s proposed explanation for pathology in aged individuals is unsupported. (LLM, conf=0.86)

  Experimental — accuracy not yet measured
• cites [104] Moir RD (2018) The antimicrobial protection hypothesis of Alzheimer’s disease. Alzheimers Dement 14, 1602– 1614. 10.1016/j.jalz.2018.06.3040 30314800 sourceNot checked — no full text of the source
• cites [110] Vojtechova I (2022) Infectious origin of Alzheimer’s disease: Amyloid beta as a component of brain antimicrobial immunity. PLoS Pathog 18, e1010929. 10.1371/journal.ppat.1010929 36395147 PMC9671327 sourcePartly supported

  In “Protective role of amyloid beta > Fungi” (page unavailable), the paper says chronic Aβ accumulation may lead to tau hyperphosphorylation and tangles, and that impaired clearance of Aβ and hyperphosphorylated tau can sustain pathology. Its discussion of aging links reduced clearance specifically to Aβ deposits, not explicitly to reduced tau clearance in aged individuals. The claim therefore combines supported mechanisms but overstates the age-related clearance explanation. (LLM, conf=0.85)

  Experimental — accuracy not yet measured

May combine two claims.

Neuroinflammation is a fundamental hallmark and driver of AD pathogenesis.

“Neuroinflammation is a fundamental hallmark and driver of AD pathogenesis [92].”

• cites [92] Wilson DM 3rd (2023) Hallmarks of neurodegenerative diseases. Cell 186, 693– 714. 10.1016/j.cell.2022.12.032 36803602 sourcePartly supported

  The INFLAMMATION section (p. 10) explicitly calls neuroinflammation a pathological hallmark of neurodegenerative diseases, including AD. The framework section (p. 13) says inflammation *could be considered* a major contributor to AD, while the INFLAMMATION section (p. 10) describes specific microglial mechanisms that can drive neurodegeneration. These passages support a contributory role, but the unqualified description of neuroinflammation as a fundamental driver of AD pathogenesis is stronger than the paper’s disease-level conclusion. (LLM, conf=0.83)

  Experimental — accuracy not yet measured

May combine two claims.

Similar to B. burgdorferi, T. pallidum accumulates as spirochetes that are visually indistinguishable from senile plaques in AD brains and require more advanced microscopy or chemical analysis to define these plaques.

“Similar to B. burgdorferi, T. pallidum accumulates as spirochetes that are visually indistinguishable from senile plaques in AD brains and require more advanced microscopy or chemical analysis to define these plaques [70,71].”

• cites [70] Chakravarthi ST and Joshi SG (2021) An Association of Pathogens and Biofilms with Alzheimer’s Disease. Microorganisms 10. 10.3390/microorganisms10010056 PMC8778325 35056505 sourcePartly supported

  Section 3.2 (Treponema; page not provided) says T. pallidum can form brain aggregates that highly resemble senile plaques in AD. It does not say they are visually indistinguishable or that advanced microscopy or chemical analysis is required to identify them. (LLM, conf=0.87)

  Experimental — accuracy not yet measured
• cites [71] Miklossy J (2015) Historic evidence to support a causal relationship between spirochetal infections and Alzheimer’s disease. Front Aging Neurosci 7, 46. 10.3389/fnagi.2015.00046 25932012 PMC4399390 sourcePartly supported

  In “Pathological Hallmarks of Syphilitic Dementia Compared to AD” (page unavailable), the paper describes T. pallidum colonies in the cortex of patients with general paresis as morphologically indistinguishable from some senile plaques in AD; Figure 1 shows individual spirochetes at higher magnification. It does not establish that those T. pallidum colonies occur in AD brains, or state that advanced microscopy or chemical analysis is required to define the plaques. (LLM, conf=0.86)

  Experimental — accuracy not yet measured

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

Poor periodontal habits lead to a buildup of biofilm that fosters the growth of microorganisms, triggering prolonged inflammation and contributing to surrounding tissue damage.

“Poor periodontal habits (i.e., brushing, flossing) lead to a buildup of biofilm that fosters the growth of microorganisms, triggering prolonged inflammation and contributing to surrounding tissue damage [4].”

• cites [4] Socransky SS and Haffajee AD (2005) Periodontal microbial ecology. Periodontol 2000 38, 135– 187. 10.1111/j.1600-0757.2005.00107.x 15853940 sourcePartly supported

  The Subgingival biofilm development section (page unavailable) reports rapid plaque regrowth in the absence of oral hygiene, and Microbial succession (page unavailable) describes a proposed cycle in which microbial changes promote gingivitis and further bacterial proliferation. The Microbial composition of biofilms in periodontal health and disease section (page unavailable) says colonizing species might cause inflammation and periodontal tissue loss, but does not establish that poor brushing or flossing specifically causes prolonged inflammation and tissue damage. (LLM, conf=0.82)

  Experimental — accuracy not yet measured

May combine two claims.

Paretic neurosyphilis causes cortical atrophy and dementia-like symptoms that can develop decades after the initial infection.

“Specifically, paretic neurosyphilis causes cortical atrophy and dementia-like symptoms that can develop decades after the initial infection [68].”

• cites [68] Nitrini R (2010) Did you rule out neurosyphilis? Dement Neuropsychol 4, 338– 345. 10.1590/s1980-57642010dn40400014 29213708 PMC5619069 sourceSupported

May combine two claims.

In a post-COVID-19 study, COVID-19 infection resulted in executive function and language deficits, as well as lower scores in frontal assessment battery, as in AD overall.

“This was observed in a post-COVID-19 study, wherein COVID-19 infection resulted in executive function and language deficits, as well as lower scores in frontal assessment battery [86], as in AD overall [87].”

• cites [86] Ortelli P (2022) Altered motor cortex physiology and dysexecutive syndrome in patients with fatigue and cognitive difficulties after mild COVID-19. Eur J Neurol 29, 1652– 1662. 10.1111/ene.15278 35138693 PMC9111319 sourcePartly supported

  Table 3 and the Conclusions report lower executive-function and language scores, as well as lower frontal assessment battery scores, in post-COVID-19 patients than in healthy controls. The study examined patients with fatigue and cognitive difficulties after COVID-19; this comparison does not establish that infection caused the deficits. The AD comparison is attached to a different citation and is not judged here. (LLM, conf=0.87)

  Experimental — accuracy not yet measured
• cites [87] Oshima E (2012) Frontal assessment battery and brain perfusion imaging in Alzheimer’s disease. Int Psychogeriatr 24, 994– 1001. 10.1017/s1041610211002481 22217392 sourcePartly supported

  Citation [87] supports the comparison with Alzheimer’s disease, not the preceding claim about COVID-19. The Discussion reports that some patients with mild AD show frontal dysfunction and that patients with low FAB scores can be found even in early AD. It does not establish executive and language deficits with lower FAB scores in AD overall; the Methods describe lexical fluency as a FAB subtest, but do not report a language-deficit finding. (LLM, conf=0.85)

  Experimental — accuracy not yet measured

May combine two claims.

These findings, along with reports of a latent brain virome, suggest the brain is not sterile and may harbor various microorganisms.

“These findings, along with reports of a latent brain virome [136,137], suggest the brain is not sterile and may harbor various microorganisms.”

• cites [136] Balakrishnan B (2023) Brain Virome in Neurodegenerative Disorders: Insights from Transcriptomic Data Analysis. ACS Chem Neurosci 14, 3979– 3985. 10.1021/acschemneuro.3c00432 37812144 sourceNot checked — no full text of the source
• cites [137] Dang X (2024) Characterization of the brain virome in human immunodeficiency virus infection and substance use disorder. PLoS One 19, e0299891. 10.1371/journal.pone.0299891 38630782 PMC11023569 sourcePartly supported

  The Results and discussion section, under “Qualitative and quantitative diversity of the brain virome,” reports many viral sequences in prefrontal cortex samples, supporting the reference to a brain virome. Under “Potential role of virus infection of the brain in SUD,” the authors say the viruses *may* remain latent; they do not establish that the detected virome is latent. (LLM, conf=0.84)

  Experimental — accuracy not yet measured

• AssumptionRests on an assumption: Detection of microbial sequences or antigens in post-mortem brain indicates viable microorganisms rather than contamination.

May combine two claims.

Microbial sequence analyses revealed that bacterial colonization often accompanies fungal infections in the human brain; here, the normal variety of species and their abundance under normal conditions contrast with the higher burden noted in AD brains.

“Additionally, microbial sequence analyses revealed that bacterial colonization often accompanies fungal infections in the human brain; here, the normal variety of species and their abundance under normal conditions contrast with the higher burden noted in AD brains [134,135].”

• cites [134] Pisa D (2017) Polymicrobial Infections In Brain Tissue From Alzheimer’s Disease Patients. Sci Rep 7, 5559. 10.1038/s41598-017-05903-y 28717130 PMC5514053 sourcePartly supported

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

  Experimental — accuracy not yet measured
• cites [135] Pisa D (2015) Different Brain Regions are Infected with Fungi in Alzheimer’s Disease. Sci Rep 5, 15015. 10.1038/srep15015 26468932 PMC4606562 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

May combine two claims.

ERV activation is also observed in mammalian models of tauopathy, raising the possibility of infectious particle generation.

“ERV activation is also observed in mammalian models of tauopathy, raising the possibility of infectious particle generation [129].”

• cites [129] Ramirez P (2022) Pathogenic tau accelerates aging-associated activation of transposable elements in the mouse central nervous system. Prog Neurobiol 208, 102181. 10.1016/j.pneurobio.2021.102181 34670118 PMC8712387 sourceSupported

May combine two claims.

The same bacterial sequences were detected in the brains of immunocompromised mice, weeks after human brain tissue transplantation but not in mice given heat-treated tissue, suggesting the bacterial sequences in the human brain samples were viable.

“The same bacterial sequences were detected in the brains of immunocompromised mice, weeks after human brain tissue transplantation but not in mice given heat-treated tissue, suggesting the bacterial sequences in the human brain samples were viable [133].”

• cites [133] Branton WG (2013) Brain microbial populations in HIV/AIDS: α-proteobacteria predominate independent of host immune status. PLoS One 8, e54673. 10.1371/journal.pone.0054673 23355888 PMC3552853 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

• AssumptionRests on an assumption: Detection of microbial sequences or antigens in post-mortem brain indicates viable microorganisms rather than contamination.

May combine two claims.

The relationship between HSV-1/HSV-2 and AD may be conditional on APOE4 genotype, duration of infection, or co-infection with other herpesviruses and/or immunoglobulin type.

“However, these results may be conditional on APOE4 genotype, duration of infection, or co-infection with other herpesviruses and/or immunoglobulin type.”

May combine two claims.

In Marshall's study of 100 dyspepsia cases undergoing endoscopy, 87% of ulcer-caused dyspepsia cases had H. pylori present, whereas only 50% of non-ulcer cases had H. pylori.

“In the dyspepsia cases caused by ulcer, 87% had H. pylori present, but in other non-ulcer cases only 50% had H. pylori [10].”

• cites [10] Marshall BJ and Warren JR (1984) Unidentified curved bacilli in the stomach of patients with gastritis and peptic ulceration. Lancet 1, 1311– 1315. 10.1016/s0140-6736(84)91816-6 6145023 sourceNot checked — no full text of the source

May combine two claims.

Infection of the CNS/PNS by HHVs usually occurs via infiltration of HHV-infected lymphocytes across the BBB or by HHV retrograde axonal transport along cervical, motor, and olfactory nerves.

“Infection of the CNS/PNS by HHVs usually occurs via the infiltration of HHV-infected lymphocytes across the BBB or by HHV retrograde axonal transport along cervical, motor, and olfactory nerves [1].”

• cites [1] Pellett PE and Roizman B (2006) The Herpesviridae: a brief introduction. In Fields Virology (Knipe DM, eds), pp. 2479– 2499, Lippincott, Williams & WilkinsNot checked yet

  Not checked in the free run.

May combine two claims.

HHVs establish life-long latency in viral reservoirs persisting as extrachromosomal circular DNA, followed by asymptomatic viral shedding and recurrent reactivation.

“HHVs establish life-long latency in viral reservoirs persisting as extrachromosomal circular DNA, followed by asymptomatic viral shedding and recurrent reactivation.”

• cites [1] Pellett PE and Roizman B (2006) The Herpesviridae: a brief introduction. In Fields Virology (Knipe DM, eds), pp. 2479– 2499, Lippincott, Williams & WilkinsNot checked yet

  Not checked in the free run.

May combine two claims.

Earlier studies found substantial differences in IgG titers in AD patients compared to controls, but subsequent studies found no association in ante-mortem or post-mortem AD versus controls for CMV.

“Although earlier studies found substantial differences in IgG titers in AD patients compared to controls [51], subsequent studies found no association in ante-mortem [52] or post-mortem [53] AD versus controls for CMV.”

• cites [51] Ounanian A (1990) Antibodies to viral antigens, xenoantigens, and autoantigens in Alzheimer’s disease. J Clin Lab Anal 4, 367– 375. 10.1002/jcla.1860040510 2172499 sourceNot checked — no full text of the source
• cites [52] Renvoize EB (1987) A sero-epidemiological study of conventional infectious agents in Alzheimer’s disease. Age Ageing 16, 311– 314. 10.1093/ageing/16.5.311 3687571 sourceNot checked — no full text of the source
• cites [53] Renvoize EB and Hambling MH (1984) Cytomegalovirus infection and Alzheimer’s disease. Age Ageing 13, 205– 209. 10.1093/ageing/13.4.205 6089524 sourceNot checked — no full text of the source

May combine two claims.

Koch's criteria may work well for an acute disease with rapid onset and potential for complete clearance of the agent, but may not apply to chronic diseases evolving over decades for which there is little evidence of immune-based resolution, such as AD.

“Thus, Koch’s criteria may work well for an acute disease with a relatively rapid onset and potential for complete clearance of the agent, but may not apply to chronic diseases evolving over decades for which there is little evidence of immune-based resolution (e.g., AD).”

May combine two claims.

Increased CMV titers were related to lower mini-mental state examination scores and increased MCI risk.

“Specifically, increased CMV titers were related to lower mini-mental state examination scores and increased MCI risk [54].”

• cites [54] Strandberg TE (2004) Cognitive impairment and infectious burden in the elderly. Arch Gerontol Geriatr Suppl, 419– 423. 10.1016/j.archger.2004.04.053 15207442 sourceNot checked — no full text of the source

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

HHV recurrence can be triggered across an individual's lifespan by environmental toxins, psychological stressors, and co-infection with other pathogens.

“This recurrence can be triggered across an individual’s lifespan by a variety of factors, including environmental toxins, psychological stressors, and co-infection with other pathogens [1,22].”

• cites [1] Pellett PE and Roizman B (2006) The Herpesviridae: a brief introduction. In Fields Virology (Knipe DM, eds), pp. 2479– 2499, Lippincott, Williams & WilkinsNot checked yet

  Not checked in the free run.

• cites [22] Baldwin KJ and Cummings CL (2018) Herpesvirus Infections of the Nervous System. Continuum (Minneap Minn) 24, 1349– 1369. 10.1212/con.0000000000000661 30273243 sourceNot checked — no full text of the source

May combine two claims.

Not everyone who develops ulcers has H. pylori, and not everyone who has H. pylori develops ulcers.

“First, not everyone who develops ulcers has H. pylori, and not everyone who has H. pylori develops ulcers.”

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

Peptic ulcers, in many instances, are secondary to a chronic infection of the upper gastrointestinal tract by Helicobacter pylori.

“History gives us a somewhat parallel case in the determination that peptic ulcers, in many instances, are secondary to a chronic infection of the upper gastrointestinal tract by a bacterium called Helicobacter pylori.”

• cites [9] Warren JR and Marshall B (1983) Unidentified curved bacilli on gastric epithelium in active chronic gastritis. Lancet 1, 1273– 1275 6134060 sourceNot checked — no full text of the source
• cites [10] Marshall BJ and Warren JR (1984) Unidentified curved bacilli in the stomach of patients with gastritis and peptic ulceration. Lancet 1, 1311– 1315. 10.1016/s0140-6736(84)91816-6 6145023 sourceNot checked — no full text of the source
• cites [12] Marshall BJ (1987) Antibacterial action of bismuth in relation to Campylobacter pyloridis colonization and gastritis. Digestion 37 Suppl 2, 16– 30. 10.1159/000199555 3622946Not checked yet

  Not checked in the free run.

May combine two claims.

Several studies have found a significant association between CMV exposure and AD risk, but further work is required to elucidate this link in more detail.

“In sum, several studies have found a significant association between CMV exposure and AD risk, but further work is required to elucidate this link in more detail.”

May combine two claims.

Neuroinflammation involves microgliosis and astrogliosis, both of which are linked to the activation of immune-related genes and pathways similar to those triggered by chronic infections.

“It involves microgliosis and astrogliosis, both of which are linked to the activation of immune-related genes and pathways similar to those triggered by chronic infections.”

May combine two claims.

Human chitinases and chitinases-like proteins are among the most upregulated proteins detected in the plasma and CSF of AD patients, with levels often correlating with the disease progression.

“Intriguingly, human chitinases and chitinases-like proteins are among the most upregulated proteins detected in the plasma and CSF of AD patients, with levels often correlating with the disease progression [88].”

• cites [88] Phuna ZX and Madhavan P (2022) A closer look at the mycobiome in Alzheimer’s disease: Fungal species, pathogenesis and transmission. Eur J Neurosci 55, 1291– 1321. 10.1111/ejn.15599 35048439 sourceNot checked — no full text of the source

Probably not a substantial claim: may not pass S2 (checkable), S3 (load-bearing). May combine two claims.

As COVID has not been around long enough to predict AD incidence, associations with cognition should first be detailed.

“As COVID has not been around long enough to predict AD incidence, associations with cognition should first be detailed.”

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

Untreated individuals can develop latent syphilis or advance into the tertiary stage, where brain, nerve, and eye damage can occur, with approximately 20% of tertiary-staged individuals dying from neurological complications.

“Untreated individuals can also develop latent syphilis, where no symptoms are present, or advance into the tertiary stage, where brain, nerve, and eye damage can occur, with approximately 20% of tertiary-staged individuals dying from neurological complications.”

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

Oligomerization of Aβ may be an innate host response to entrap microbial pathogens in the brain.

“Oligomerization of Aβ may be an innate host response to entrap microbial pathogens in the brain [104].”

• cites [104] Moir RD (2018) The antimicrobial protection hypothesis of Alzheimer’s disease. Alzheimers Dement 14, 1602– 1614. 10.1016/j.jalz.2018.06.3040 30314800 sourceNot checked — no full text of the source

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

Treponema pallidum is an invasive spirochete, transmitted through sexual contact, that can infect and damage any tissue in the body.

“Treponema pallidum is an invasive spirochete, transmitted through sexual contact, that can infect and damage any tissue in the body [2].”

• cites [2] Radolf JD (1996) Treponema. In Medical Microbiology (4th edn) (Baron S, ed), University of Texas Medical Branch 21413263Not checked yet

  Not checked in the free run.

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

Borrelia burgdorferi is a spirochete that is the causative agent of Lyme disease; infection is transmitted through ticks, which implies that disease prevalence varies with geographical location.

“Borrelia burgdorferi is a spirochete that is the causative agent of Lyme disease; infection is transmitted through ticks, which implies that disease prevalence varies with geographical location [3].”

• cites [3] Shapiro ED (2014) Borrelia burgdorferi (Lyme disease). Pediatr Rev 35, 500– 509. 10.1542/pir.35-12-500 25452659 PMC5029759 sourceNot checked — no full text of the source

May combine two claims.

In a small cohort, some patients with long COVID had episodic memory deficits and had impaired global function.

“In a small cohort [77], some patients with long COVID had episodic memory deficits and had impaired global function.”

• cites [77] Serrano Del Pueblo VM (2024) Brain and cognitive changes in patients with long COVID compared with infection-recovered control subjects. Brain. 10.1093/brain/awae101 38562097 sourceNot checked — no full text of the source

May combine two claims.

These changes reflect the immunomodulatory functions impacting microglial activation, neurodegeneration and tissue repair, ultimately resulting in CNS damage.

“These changes reflect the immunomodulatory functions impacting microglial activation, neurodegeneration and tissue repair, ultimately resulting in CNS damage.”

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

The endogenous retroviruses (ERV) class of retrotransposons are remnants of viral germline infections.

“The endogenous retroviruses (ERV) class of retrotransposons are remnants of viral germline infections [7].”

• cites [7] Dopkins N and Nixon DF (2024) Activation of human endogenous retroviruses and its physiological consequences. Nat Rev Mol Cell Biol 25, 212– 222. 10.1038/s41580-023-00674-z 37872387 sourceNot checked — no full text of the source

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

Chronic infection with T. pallidum can cause syphilis with sores, rash, fever, and muscle aches.

“Chronic infection with T. pallidum can cause syphilis with sores, rash, fever, and muscle aches.”

May combine two claims.

There are cases of incorrect reporting of Lyme disease in clinical practice, resulting in false-positive diagnoses, and incidence rates should be interpreted with caution.

“It should be noted, however, there that are cases of incorrect reporting of Lyme disease in clinical practice, resulting in false-positive diagnoses of Lyme disease, and accordingly, incidence rates should be interpreted with caution [67].”

• cites [67] Webber BJ (2019) Lyme disease overdiagnosis in a large healthcare system: a population-based, retrospective study. Clin Microbiol Infect 25, 1233– 1238. 10.1016/j.cmi.2019.02.020 30802651 sourceNot checked — no full text of the source

May combine two claims.

Reports typically do not distinguish neuroborreliosis from Lyme disease, which could incorrectly estimate the actual incidence of both.

“Furthermore, reports typically do not distinguish neuroborreliosis from Lyme disease, which could incorrectly estimate the actual incidence of both.”

Classified as probably not a substantial claim.

Aβ has been suggested to be part of an anti-microbial host response.

“Aβ has been suggested to be part of an anti-microbial host response.”

• cites [104] Moir RD (2018) The antimicrobial protection hypothesis of Alzheimer’s disease. Alzheimers Dement 14, 1602– 1614. 10.1016/j.jalz.2018.06.3040 30314800 sourceNot checked — no full text of the source

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

Syphilis progresses through various stages if an individual is untreated.

“Syphilis progresses though various stages if an individual is untreated.”

May combine two claims.

All these human data are from post-mortem samples, and it is unclear when the infection occurred.

“However, all these human data are from post-mortem samples, and it is unclear when the infection occurred.”

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

Symptoms of Lyme disease include fatigue, fever, aches, nausea and tingling/numbness, as well as headaches and changes in vision, often associated with neuroborreliosis.

“Symptoms of Lyme disease include fatigue, fever, aches, nausea and tingling/numbness, as well as headaches and changes in vision, often associated with neuroborreliosis [3].”

• cites [3] Shapiro ED (2014) Borrelia burgdorferi (Lyme disease). Pediatr Rev 35, 500– 509. 10.1542/pir.35-12-500 25452659 PMC5029759 sourceNot checked — no full text of the source

Classified as probably not a substantial claim.

A substantial body of literature has reported associations between various chronic infections and Alzheimer's disease.

“As summarized in earlier sections, a substantial body of literature reported associations between various chronic infections and AD.”

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

Eradicating those pathogens could arrest the progression of Alzheimer's disease pathology and potentially even reverse it.

“one would surmise that eradicating those pathogens could arrest the progression of AD pathology and potentially even reverse it.”

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

Whether a chronic infection can be an etiologic agent in the development of AD has been a matter of controversy and debate.

“Whether a chronic infection can be an etiologic agent in the development of AD has been a matter of controversy and debate.”

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

While a putative brain microbiome may exist in equilibrium under healthy conditions, its dysregulation could trigger pathogenic cascades.

“While a putative brain microbiome may exist in equilibrium under healthy conditions, its dysregulation could trigger pathogenic cascades, making it important to survey the microbial communities present in the brain or interfaces of nasal and oral cavities to establish healthy baselines for detecting changes associated with neuropsychiatric and neurocognitive diseases, such as AD.”

Classified as probably not a substantial claim.

Infection-associated pathology may not always be actual Alzheimer's disease.

“such pathology may not always be “actual” AD”

• AssumptionRests on an assumption: Infection with these pathogens could mimic Alzheimer's disease neuropathology.

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

Several studies have detected the presence of various pathogens in post-mortem brains of AD patients, while others have not.

“Whereas several studies have detected the presence of various pathogens in post-mortem brains of AD patients, others have not.”

Probably not a substantial claim: may not pass S4 (based).

Several antibiotics and antiviral drugs effectively target at least most of the pathogens discussed in earlier sections.

“Certainly, considering there are several antibiotics and antiviral drugs effectively targeting at least most of the pathogens discussed in earlier sections”