Alzheimer Disease: An Update on Pathobiology and Treatment Strategies

In the paper

“Aβ is produced by sequential cleavage of β-amyloid precursor protein (APP) by β-secretase and γ-secretase”

What the sources say

• Supported

  The Abstract states that Aβ is produced in the amyloidogenic pathway by the consecutive action of β-secretase and γ-secretase. It specifies that β-secretase first generates an APP fragment, which γ-secretase then cleaves. (LLM, conf=0.95)

  cites Haass et al., 2012 source

In the paper

“Several lines of evidence suggest Aβ deposition may be required for progression of tau pathology in AD”

What the sources say

• Supported

  The Discussion (page unavailable in our copy) reports no measurable change in flortaucipir signal in amyloid-β− subjects, in contrast to a significant change in amyloid-β+ subjects. It explicitly suggests that amyloid deposition may be a necessary antecedent for tau spread beyond the temporal lobe in Alzheimer’s disease, supporting the claim’s hedged wording. (LLM, conf=0.95)

  cites Pontecorvo et al., 2019 source
• Not checked yetcites Price and Morris, 1999
• Partly supported

  The Introduction (page not provided) describes a hypothesis that Aβ precedes and accelerates neocortical tau pathology. The Discussion reports that Aβ increases were associated with later tau changes, but also observes tau increases in people with low Aβ. The paper supports a role for Aβ in tau progression, not the stronger suggestion that Aβ deposition is required for it. (LLM, conf=0.84)

  cites Hanseeuw et al., 2019 sourceExperimental — accuracy not yet measured

In the paper

“A recent detailed morphological analysis of microglial activation state in brain specimens from two cohorts of cognitive aging found that the proportion of activated microglia (PAM) strongly correlated with presence of pathologic AD (Felsky et al., 2019).”

What the sources say

• Partly supported

  The Results section (“Active microglia discriminate pathological AD”) reports a strong association between PAM and pathological AD in the midfrontal and inferior temporal cortices. The Discussion specifies that activation was elevated in cortical but not subcortical structures, a regional limit omitted from the citing sentence. (LLM, conf=0.88)

  cites Felsky et al., 2019 sourceExperimental — accuracy not yet measured

In the paper

“A non-synonymous coding variant in PCLG2, a gene with suspected immune function, has been associated with decreased risk of AD (van der Lee et al., 2019).”

What the sources say

• Supported

  The Discussion states that the authors replicated an association between a nonsynonymous PLCG2 variant and reduced Alzheimer’s disease risk. The Introduction also describes PLCG2’s role in immune signaling. The citing sentence spells the gene “PCLG2,” apparently a transposition of PLCG2. (LLM, conf=0.94)

  cites van der Lee et al., 2019 source

In the paper

“In a recent study assessing the effect of ApoE-TR in the PS19 (tauP301S) tauopathy mouse model, ApoE4 dramatically exacerbated tau-mediated neurodegeneration”

What the sources say

• Supported

  The study’s description of its P301S tauopathy mouse model reports significantly more brain atrophy and neuronal loss in mice expressing human ApoE4 than in those expressing ApoE2 or ApoE3. It concludes that ApoE4 caused more severe tau-mediated neurodegeneration. (LLM, conf=0.95)

  cites Shi et al., 2017 source

In the paper

“Areas of brain parenchyma containing deposits of HSV-1 infection also demonstrated increased Aβ deposition (Eimer et al., 2018).”

What the sources say

• Supported

  The Results section reports Aβ deposition in the brains of HSV1-infected young 5XFAD mice and says HSV1 and Aβ signals co-localized. This supports the claim for the mouse model studied; it does not establish the same finding in human brain tissue. (LLM, conf=0.91)

  cites Eimer et al., 2018 source

In the paper

“A single night of sleep deprivation leads to elevated CSF Aβ42 levels in healthy middle-aged men (Ooms et al., 2014).”

What the sources say

• Supported

  The Conclusions state that one night of total sleep deprivation increased CSF Aβ42 relative to normal sleep in healthy middle-aged men. The Discussion clarifies that deprivation abolished the morning decrease seen after sleep, so the elevation is relative to the normal-sleep group. (LLM, conf=0.94)

  cites Ooms et al., 2014 source

In the paper

“In mice overexpressing Aβ, acute sleep deprivation caused a significant increase in amyloid plaque deposition.”

What the sources say

• Partly supported

  The passage describing the plaque experiment (section labelled Abstract, p. not provided) reports greater plaque deposition in transgenic mice after 21 days of chronic sleep restriction. The passage on acute sleep deprivation reports increased interstitial-fluid Aβ levels, not plaque deposition. The claim substitutes an acute intervention for the chronic intervention used in the plaque experiment. (LLM, conf=0.90)

  cites Kang et al., 2009 sourceExperimental — accuracy not yet measured

In the paper

“Two γ-secretase inhibitors (GSI) have been tested clinically as disease modifying therapies for AD and each have failed due to lack of efficacy or worsening of cognition combined with dose-limiting adverse side effects.”

What the sources say

• Partly supported

  The Discussion (page not available in our copy) reports that avagacestat showed no signal of efficacy and had dose-limiting safety and tolerability effects. It mentions similar adverse-event trends with semagacestat, but does not establish that the second inhibitor failed because of lack of efficacy or worsening cognition combined with dose-limiting adverse effects. (LLM, conf=0.86)

  cites Coric et al., 2015 sourceExperimental — accuracy not yet measured
• Not checked yetcites Doody et al., 2013 source

In the paper

“Any putative benefit attributed to methylene blue has been thought to be secondary to reduced tau fibrillization and aggregation and induction of autophagy, which leads to reduced tau pathology and neuron death in mouse models of tauopathy (Congdon et al., 2012; Crowe et al., 2013; Wischik et al., 1996).”

What the sources say

• Partly supported

  The Results and discussion report that methylene blue induces autophagy and reduces total and phosphorylated tau in tauopathy mice; the Results also show reduced aggregated tau in mouse-derived slice cultures. The paper says aggregated tau did not significantly decrease in live mice, and it does not establish that these mechanisms reduced neuronal death in its mouse experiment. The discussion cites an earlier study for attenuated neurodegeneration in a tau-transgenic line. (LLM, conf=0.87)

  cites Congdon et al., 2012 sourceExperimental — accuracy not yet measured
• Partly supported

  In “Tau Fibrillization Inhibitors Promote Disulfide Formation” (page unavailable), Crowe et al. report that methylene blue inhibits 4-R tau fibrillization in vitro and note studies suggesting it enhances autophagic degradation of tau. They also say autophagy may reduce tau inclusions independently of fibrillization inhibition. Our copy does not establish that these mechanisms together reduce tau pathology or neuronal death in mouse tauopathy models. (LLM, conf=0.88)

  cites Crowe et al., 2013 sourceExperimental — accuracy not yet measured
• Partly supported

  The Results report that methylene blue inhibits tau–tau binding and reverses the proteolytic stability of paired helical filaments in vitro. The paper does not report induction of autophagy or reduced tau pathology and neuronal death in mouse tauopathy models, so it supports only the aggregation-related part of the attributed claim. (LLM, conf=0.88)

  cites Wischik et al., 1996 sourceExperimental — accuracy not yet measured

In the paper

“An alternative means of inhibiting amyloidogenic processing of Aβ by γ-secretase is to use γ-secretase modulators (GSM) that alter processing of APP (lower Aβ42 and higher Aβ40 levels) without influencing processing of other substrates (Xia, 2019).”

What the sources say

• Partly supported

  The section “Modulating γ-secretase and neuroinflammation” (page unavailable) says GSMs can alter APP cleavage and lower Aβ42 while sparing Notch processing. But its example reports increased Aβ38 with no change in Aβ40—not higher Aβ40—and describes reduced effects on other substrates, not an absence of effects on all of them. (LLM, conf=0.90)

  cites Xia, 2019 sourceExperimental — accuracy not yet measured

In the paper

“This is especially critical after a recent study in the preclinical literature demonstrated APOE2 expression via viral delivery exacerbated pathology in tauopathy mice (Zhao et al., 2018).”

What the sources say

• Partly supported

  The Introduction and Results report more severe tau pathology in apoE2 mice than in apoE3 or apoE4 mice. But the Results specify that the virus delivered mutant human tau into mice already carrying the human apoE2 allele; APOE2 itself was not delivered virally. Page numbers are not provided in our copy. (LLM, conf=0.90)

  cites Zhao et al., 2018 sourceExperimental — accuracy not yet measured

In the paper

“Longitudinal studies of cognitive function and CSF and neuroimaging biomarker changes in ADAD and LOAD have identified a significant preclinical phase of disease preceding onset of clinical symptoms by at least 10-20 years”

What the sources say

• Not checked yetcites Vermunt et al., 2019 source

In the paper

“Recent studies demonstrate the ability to detect CNS Aβ deposition via the use of plasma assessment of Aβ species”

What the sources say

• Not checked yetcites Nakamura et al., 2018 source
• Not checked yetcites Ovod et al., 2017 source
• Not checked yetcites Palmqvist et al., 2019 source

In the paper

“Despite this, no disease modifying treatment currently exists and numerous phase 3 clinical trials have failed to demonstrate benefit.”

• Also stated in: § INTRODUCTION · plain

  “There is a dire need for disease modifying therapies that may prevent or slow rate of disease progression, but unfortunately none are currently available.”

In the paper

“Synaptic and neuronal loss in the entorhinal cortex generally correlates well with onset of cognitive impairment”

What the sources say

• Not checked yetcites Gómez-Isla et al., 1996 source

In the paper

“Antemortem AD neuropathologic diagnoses can now be made with reasonable validity using cerebrospinal fluid (CSF) or positron emission tomography (PET) imaging biomarkers as surrogate markers for cerebral Aβ and tau deposition”

What the sources say

• ?Not matched

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

  cites Brier et al., 2016
• ?Not matched

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

  cites Fagan et al., 2006, 2007
• Not checked yetcites Lowe et al., 2019 source

In the paper

“characterized by early deposition of Aβ in the precuneus and other cortical regions comprising the default mode network, followed sequentially by regional cortical hypometabolism, accumulation of tau pathology, hippocampal volume loss, and onset of symptomatic cognitive impairment”

What the sources say

• Not checked yetcites Bateman et al., 2012 source
• ?Not matched

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

  cites Fagan et al., 2006, 2007
• Not checked yetcites Hanseeuw et al., 2019 source

In the paper

“Studies of both ADAD and LOAD have demonstrated that rate of change in CSF and plasma NfL levels correlate with cortical thickness on structural MRI and cognitive performance”

What the sources say

• Not checked yetcites Mattsson et al., 2019 source
• Not checked yetcites Preische et al., 2019 source

In the paper

“numerous phase 3 clinical trials have failed to demonstrate benefit”

• Also stated in: § INTRODUCTION · boosted

  “The history of pharmaceutical development for AD has been plagued by a seemingly endless parade of mid-to-late-stage clinical trial failures.”

In the paper

“Unlike Aβ, the stage of tau pathology correlates well with progression of cognitive impairment”

What the sources say

• Not checked yetcites Giannakopoulos et al., 2003 source
• Not checked yetcites Nelson et al., 2012 source

In the paper

“Neuropathological studies in humanshave demonstrated that tau pathology generally does not progress from the entorhinal cortex into the neocortex in the absence of co-occurring amyloid pathology”

What the sources say

• Not checked yetcites Pontecorvo et al., 2019 source
• Not checked yetcites Price and Morris, 1999
• Not checked yetcites Price et al., 2009 source

In the paper

“For example, there is minimal correlation between phases of amyloid deposition and degree of cognitive decline”

What the sources say

• Not checked yetcites Nelson et al., 2012 source

In the paper

“Owing to increased hydrophobicity of its expanded C-terminus, Aβ42 has a greater propensity for aggregation.”

In the paper

“There is strong evidence that human-to-human transmission of amyloid pathology is possible.”

What the sources say

• Not checked yetcites Jaunmuktane et al., 2015 source
• Not checked yetcites Purro et al., 2018 source

In the paper

“Multiple lines of evidence suggest that aggregated, hyperphosphorylated forms of tau may be a primary driver of neurodegeneration in AD.”

In the paper

“Aβ fibrillization can be “seeded” in a prion-like manner by the presence of small assemblies of misfolded beta-sheet-containing Aβ seeds that template the formation of larger amyloid aggregates”

What the sources say

• Not checked yetcites Walker and Jucker, 2015 source

In the paper

“Numerous studies over the last decade have demonstrated the “prion-like” ability of aggregated human tau fibrils to self-propagate, for both synthetically-prepared fibrils and those derived from human AD brain.”

In the paper

“In addition, the strongest genetic risk factor for LOAD, apolipoprotein E, APOE, in large part appears to increase risk via influencing Aβ seeding and clearance”

What the sources say

• Not checked yetcites Bales et al., 1997 source
• Not checked yetcites Castellano et al., 2011 source
• Not checked yetcites Verghese et al., 2013 source

In the paper

“Thus, prion-like seeding and spreading may represent a mechanism whereby tau pathology propagates from the entorhinal cortex to the neocortex in AD”

What the sources say

• Not checked yetcites DeVos et al., 2018 source

In the paper

“A recent study shows that the presence of Aβ also causes capillary constriction in human cortical slices by acting on pericytes to generate reactive oxygen species (ROS) leading to endothelin-1 release”

What the sources say

• Not checked yetcites Nortley et al., 2019 source

In the paper

“Finally, despite decades of investment by the pharmaceutical industry in anti-amyloid therapies and numerous phase 3 clinical trials, no amyloid-targeting therapy has been successful in limiting progression of cognitive impairment in symptomatic AD.”

In the paper

“Aβ may also lead to cognitive impairment in ways independent from its effects on tau.”

In the paper

“Cognitive impairment in AD is only noted when tau spreads from the entorhinal cortex into the neocortex in neuropathological studies”

What the sources say

• Not checked yetcites Price and Morris, 1999
• Not checked yetcites Price et al., 2009 source

In the paper

“APOE is the strongest genetic risk factor for LOAD”

What the sources say

• Not checked yetcites Corder et al., 1993 source
• Not checked yetcites Strittmatter et al., 1993 source
• Not checked yetcites Kunkle et al., 2019 source

In the paper

“ApoE4 may have direct pathologic effects on neurons and neuronal networks independent of effects on amyloid and tau pathology”

What the sources say

• Not checked yetcites Najm et al., 2019 source

In the paper

“ApoE4 may mediate risk for AD though modulation of immune and microglial responses.”

In the paper

“Causal mediation modeling generated a model consistent with a proposed pathologic sequence of increased PAM triggering increased PHF tau accumulation, leading to cognitive decline.”

What the sources say

• Not checked yetcites Felsky et al., 2019 source

In the paper

“In both studies, these microglia were found to be in close association with neuritic plaques.”

What the sources say

• ?Not matched

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

  cites Keren-Shaul et al., 2017; Krasemann et al., 2017

In the paper

“Instead, ApoE regulates clearance of Aβ by competitively binding to Aβ receptors, such as LDLR-related protein 1 (LRP1) on the surface of astrocytes, and blocking Aβ uptake.”

What the sources say

• Not checked yetcites Verghese et al., 2013 source

In the paper

“ApoE likely regulates AD risk in large part via effects on amyloid pathology”

What the sources say

• Not checked yetcites Huynh et al., 2017a

In the paper

“As an example, TREM2 is an AD risk gene with a rare variant allele R47H associated with significantly increased risk of AD (Gratuze et al., 2018).”

What the sources say

• Not checked yetcites Gratuze et al., 2018 source

In the paper

“Of note, many of these immune-related AD risk factor SNPs or coding variants (Apoe, Trem2, Cd33, Ms4a6d) have been identified as genes differentially expressed in models of Aβ deposition as compared to tauopathy, suggesting they may represent amyloid response genes (Matarin et al., 2015).”

What the sources say

• Not checked yetcites Matarin et al., 2015 source

In the paper

“R47H is thought to be a loss of function variant (Gratuze et al., 2018; Shi and Holtzman, 2018).”

What the sources say

• ?Not matched

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

  cites Gratuze et al., 2018; Shi and Holtzman, 2018

In the paper

“Numerous SNPs and rare coding variants in immune-related genes thought to be implicated in microglial function have been identified as risk factors for AD in whole genome sequencing and GWAS analyses (see for review (Efthymiou and Goate, 2017; Karch and Goate, 2015), including TREM2, CR1, SHIP1, BIN1, CD33, PICALM, CLU, and theMS4A gene cluster.”

What the sources say

• ?Not matched

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

  cites Efthymiou and Goate, 2017; Karch and Goate, 2015

In the paper

“ApoE also has modulatory effects on tau pathology and tau-related neurodegeneration”

What the sources say

• Not checked yetcites Shi and Holtzman, 2018 source

In the paper

“Single cell transcriptomic methods have been employed to identify unique microglial phenotypes associated with Aβ plaque deposition in animal models of amyloidosis (APP/PS1 and 5XFAD) (Figure 4A).”

What the sources say

• ?Not matched

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

  cites Keren-Shaul et al., 2017; Krasemann et al., 2017

In the paper

“APOE ε4 carriers have a stronger systemic inflammatory response to an intravenous LPS challenge, including more intense hyperthermia and higher levels of TNF secretion in whole blood”

What the sources say

• Not checked yetcites Gale et al., 2014 source

In the paper

“Systems-level analyses of gene regulatory networks in post-mortem human LOAD brain specimens have identified the immune/microglial molecular network as most highly associated with pathophysiology in LOAD (Zhang et al., 2013).”

What the sources say

• Not checked yetcites Zhang et al., 2013 source

In the paper

“Multiple lines of evidence suggest that activation of immune mediators is a critical regulator of AD pathology.”

In the paper

“Gut microbiota may also modulate the microglial response to pathology.”

In the paper

“The presence of Aβ in brain parenchyma is linked with protection against infectious bacterial encephalomyelitis experimentally induced by intracerebral inoculation with Salmonella enterica typhimurium bacteria in 4-week old 5xFAD mice.”

What the sources say

• Not checked yetcites Kumar et al., 2016 source

In the paper

“This risk was nearly eliminated in patients that received antiherpetic treatment (Tzeng et al., 2018).”

What the sources say

• Not checked yetcites Tzeng et al., 2018 source

In the paper

“These data would suggest that microglia contribute to neuron death in models of tau-mediated neurodegeneration.”

In the paper

“Alternatively, phagocytosis of Aβ by microglia can lead to microglial activation.”

In the paper

“In support of this theory, HSV-1 viral particles have recently been shown to directly catalyze the fibrillization of Aβ42 in vitro by nucleating aggregation via contact with the viral surface (Ezzat et al., 2019).”

What the sources say

• Not checked yetcites Ezzat et al., 2019 source

In the paper

“At sites of bacterial deposition in the brain, significant Aβ deposition was also noted. (Kumar et al., 2016).”

What the sources say

• Not checked yetcites Kumar et al., 2016 source

In the paper

“A recent systems-level molecular network analysis of preclinical AD brain identified a set of network driver genes noted to be enriched for viral susceptibility genes.”

What the sources say

• Not checked yetcites Readhead et al., 2018 source

In the paper

“This is abrogated by additional TREM2 KO, however CD33 KO does not reciprocally abrogate effects of TREM2 KO, suggesting that CD33 acts upstream of TREM2 (Griciuc et al.,2019 .”

What the sources say

• Not checked yetcites Griciuc et al., 2019 source

In the paper

“However, data regarding role of activated microglia in animal models suggest possibly divergent effects depending on disease context.”

In the paper

“Increased surface CD33 expression results in decreased microglial activation.”

In the paper

“In the PS19 tauopathy mouse, TREM2 deletion significantly reduced tau-mediated neurodegeneration and astrogliosis (Leyns et al., 2017; Sayed et al., 2018).”

What the sources say

• ?Not matched

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

  cites Leyns et al., 2017; Sayed et al., 2018

In the paper

“Various aspects of CNS physiology are regulated by the microbiome, including microglial maturation and function (Abdel-Haq et al., 2019).”

What the sources say

• Not checked yetcites Abdel-Haq et al., 2019 source

In the paper

“Complement binding (C1q) and microglial phagocytosis leads to early synapse loss in a mouse model with Aβ plaque deposition (J20 model).”

What the sources say

• Not checked yetcites Hong et al., 2016 source

In the paper

“There is increasing evidence that interactions between the gut microbiome and the CNS innate immune system (gut-brain axis) may modulate AD pathogenesis.”

What the sources say

• Not checked yetcites Abdel-Haq et al., 2019 source

In the paper

“Therefore, phagocytosis of Aβ by microglia may be a double-edged sword: it may serve to limit spread of amyloid pathology in certain contexts or alternatively may promote spread of amyloid pathology via the mechanisms described above.”

In the paper

“One study demonstrated a significantly increased risk of developing all-cause dementia (~3-fold increase) in patients greater than 50 years of age following a new HSV infection.”

What the sources say

• Not checked yetcites Tzeng et al., 2018 source

In the paper

“Microglial-derived exosomes appear necessary for tau propagation in a model of tau spreading using AAV viral transduced expression of P301Ltau to induce rapid tau spreading from the entorhinal cortex to the dentate gyrus of the hippocampus (Asai et al., 2015).”

What the sources say

• Not checked yetcites Asai et al., 2015 source

In the paper

“Several studies have profiled the composition of the gut microbiota in both mouse models of amyloidosis (APP/PS1) and in human participants with dementia due to AD and have found significant differences in the overall abundance and diversity of microbial species relative to WT animals or non-demented control participants, respectively (Bäuerl et al., 2018; Saji et al., 2019; Vogt et al., 2017).”

What the sources say

• ?Not matched

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

  cites Bäuerl et al., 2018; Saji et al., 2019; Vogt et al., 2017

In the paper

“Aβ exhibits characteristics of an antimicrobial peptide.”

In the paper

“Aβ also forms fibrils that entrap bacteria and fungal cells, leading to agglutination in vitro (Kumar et al., 2016; Spitzer et al., 2016).”

What the sources say

• ?Not matched

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

  cites Kumar et al., 2016; Spitzer et al., 2016

In the paper

“Similarly, presence of parenchymal Aβ in 5xFAD mice results in decreased mortality following direct intracerebral HSV inoculation.”

What the sources say

• Not checked yetcites Eimer et al., 2018 source

In the paper

“In summary, activation of the innate immune system undoubtedly plays a role in AD pathophysiology.”

In the paper

“Following phagocytosis by microglia, Aβ activates the NLRP3 inflammasome leading to caspase-1 activation and IL-1β maturation and release (Halle et al., 2008).”

What the sources say

• Not checked yetcites Halle et al., 2008 source

In the paper

“Their symptomatic benefit in AD has been confirmed via meta-analyses assessing both cognitive performance and global functioning (Birks, 2006).”

What the sources say

• Not checked yetcites Birks, 2006

In the paper

“Studies from the lab of Maiken Nedergaard suggest that glymphatic clearance is slower during wakefulness vs. sleep (Iliff et al., 2012; Xie et al., 2013).”

What the sources say

• ?Not matched

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

  cites Iliff et al., 2012; Xie et al., 2013

In the paper

“During the course of AD pathogenesis, cholinergic neurons in the nucleus basalis of Meynert and other septal nuclei that project widely throughout the cortex are lost, causing a general cholinergic deficit (Bartus et al., 1982).”

What the sources say

• Not checked yetcites Bartus et al., 1982 source

In the paper

“When seeded with recombinant synthetic tau fibrils, sleep deprived animals had more significant tau spreading relative to non-sleep deprived animals.”

What the sources say

• Not checked yetcites Holth et al., 2019

In the paper

“Sleep impairment can lead to impaired attention, concentration, and working memory but may also influence development of underlying AD pathology.”

In the paper

“Meta-analysis confirms the efficacy of memantine in moderate-to-severe AD on measures of cognition, activities of daily living (ADL) and neuropsychiatric symptoms (McShane et al., 2006).”

What the sources say

• Not checked yetcites McShane et al., 2006

In the paper

“Three ChEI are currently approved for use in mild-to-moderate AD: donepezil, rivastigmine and galantamine.”

In the paper

“Despite enormous efforts by the pharmaceutical industry, there remains no effective disease modifying therapy available today.”

In the paper

“Again, a significant decrease in dementia risk was observed in patients that received antiherpetic treatment (HR 0.47) (Chen et al., 2018).”

What the sources say

• Not checked yetcites Chen et al., 2018 source

In the paper

“Increased synaptic and network activity has been previously shown to stimulate release of extracellular Aβ and tau from neurons (Bero et al., 2011; Brody et al., 2008; Cirrito et al., 2005; Yamada et al., 2014).”

What the sources say

• ?Not matched

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

  cites Bero et al., 2011; Brody et al., 2008; Cirrito et al., 2005; Yamada et al., 2014

In the paper

“Several recent large scale clinical trials have adopted a secondary or primary prevention paradigm: the Dominantly Inherited Alzheimer Network Trials Unit (DIAN-TU) drawing from the large DIAN cohort of ADAD patients (Bateman et al., 2017), the A4 trial enrolling participants with confirmed preclinical AD by biomarker assessment (Sperling et al., 2014), and the Alzheimer Prevention initiative (API”

What the sources say

• ?Not matched

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

  cites Bateman et al., 2017; Sperling et al., 2014; Reiman et al., 2011

In the paper

“Cholinesterase inhibitors (ChEI) work to reverse this deficiency by increasing synaptic levels of acetylcholine.”

In the paper

“A second study demonstrated a very slight increased risk of developing all-cause dementia after zoster infection (HR 1.12).”

What the sources say

• Not checked yetcites Chen et al., 2018 source

In the paper

“In mice overexpressing Aβ, sleep-wake cycle and diurnal fluctuations in ISF and CSF Aβ levels are normal before an age when animals develop amyloid plaque formation.”

What the sources say

• Not checked yetcites Roh et al., 2012 source

In the paper

“In this study, periodontal bacterial proteins (gingipains) and DNA were identified in human AD brain.”

What the sources say

• Not checked yetcites Dominy et al., 2019 source

In the paper

“Though this represents an intermediate phase of clinical disease, this is actually an advanced stage of the biological disease when considering that pathology accumulates in the AD brain 15-20 years prior to onset of clinical symptoms (Vermunt et al., 2019).”

What the sources say

• Not checked yetcites Vermunt et al., 2019 source

In the paper

“This suggests the mechanism for increased Aβ is increased production (Lucey et al., 2018).”

What the sources say

• Not checked yetcites Lucey et al., 2018 source

In the paper

“The goal of many Aβ-directed therapies is to lower levels of parenchymal Aβ and amyloid deposits in the AD brain.”

In the paper

“There are currently four FDA approved medications for the management of cognitive impairment and dysfunction in global activities in symptomatic AD. These include three cholinesterase inhibitors (ChEIs; donepezil, rivastigmine and galantamine) and memantine, an uncompetitive NMDA receptor modulator.”

In the paper

“A study exploring the effect of selective reduction of overnight slow-wave sleep via an automated detection-intervention method in healthy volunteers also demonstrated increased CSF Aβ levels in participants receiving the study intervention (Ju et al., 2017).”

What the sources say

• Not checked yetcites Ju et al., 2017

In the paper

“A decrease in amyloid plaque deposition was observed after chronic orexin receptor blockade resulting in increased sleep (Kang et al., 2009).”

What the sources say

• Not checked yetcites Kang et al., 2009 source

In the paper

“Reduced slow-wave sleep in cognitively normal elderly participants is also associated with increased CSF Aβ42 (Varga et al., 2016).”

What the sources say

• Not checked yetcites Varga et al., 2016 source

In the paper

“First, most of the failed phase 3 trials intervened on patients with mild-to-moderate symptomatic AD.”

In the paper

“Women with sleep disordered breathing have a higher risk of developing MCI or dementia relative to non-sleep disordered breathing patients (Yaffe et al., 2011).”

What the sources say

• Not checked yetcites Yaffe et al., 2011

In the paper

“Instead, disease modifying clinical interventions applied as early in the preclinical phase of disease as possible in a preventative study design might have a better chance of changing disease trajectory before the onset of frank neurodegeneration.”

In the paper

“Sleep deprivation in tauopathy mice and healthy human participants resulted in increased ISF/CSF tau levels (Holth et al., 2019).”

What the sources say

• Not checked yetcites Holth et al., 2019

In the paper

“This loss of cholinergic input is thought to contribute to early attention and memory dysfunction in AD.”

In the paper

“Importantly, each study is testing anti-amyloid therapies in cognitively normal patients who are at high risk for developing the disease.”

In the paper

“Atabecestat was discontinued after a trial in preclinical AD demonstrated frequent hepatotoxicity and worse cognitive outcomes than placebo (Henley et al., 2019).”

What the sources say

• Not checked yetcites Henley et al., 2019 source

In the paper

“Solanezumab is a humanized version of mouse antibody m226 whose epitope lies within the Aβ mid-domain and binds only to soluble Aβ, not fibrillar or plaque-based Aβ.”

In the paper

“This antibody was tested in two parallel phase 3 trials in mild-to-moderate AD patients and had no effect on cognition or ADL at the doses tested (Salloway et al., 2014).”

What the sources say

• Not checked yetcites Salloway et al., 2014 source

In the paper

“25 of 129 patients were deemed to be antibody responders.”

In the paper

“Unfortunately, two phase 3 trials in mild AD were stopped early for futility in March 2019 after interim analysis suggested no change in cognitive decline (Selkoe, 2019).”

What the sources say

• Not checked yetcites Selkoe, 2019 source

In the paper

“Four additional BACE1 inhibitors failed phase 3 clinical trials due to lack of efficacy and associated side effects (Table 1).”

What the sources say

• Not checked yetcites Table 1

In the paper

“In fact, it has been chosen by the Alzheimer’s Clinical Trials Consortium for use in upcoming primary and secondary prevention studies (along with BAN2401) (Panza et al., 2018).”

What the sources say

• Not checked yetcites Panza et al., 2018 source

In the paper

“Crenezumab is being used in the API ADAD Colombia trial of known mutation carriers (Tariot et al., 2018), whereas active immunization with CAD106 is being used in the API Generation trial of APOE ε4 homozygotes (Lopez Lopez et al., 2019).”

What the sources say

• Not checked yetcites Tariot et al., 2018 source

In the paper

“Though the data for Aβ-directed monoclonal antibodies in symptomatic AD have been discouraging, several antibodies are currently being used in primary and secondary prevention studies, where dose administration at an earlier disease stage might provide a better opportunity for disease modification.”