Alzheimer Disease: An Update on Pathobiology and Treatment Strategies

In the paper

“The presence of extracellular amyloid-β deposition as neuritic plaques and intracellular accumulation of hyperphosphorylated tau as neurofibrillary tangles remain the primary neuropathologic criteria for AD diagnosis.”

• Also stated in: § INTRODUCTION · plain

  “AD as a distinct entity is now defined biologically by the presence of a specific neuropathological profile (Jack et al., 2018a): extracellular deposition of amyloid-β (Aβ) in the form of diffuse and neuritic plaques and the presence of intraneuronal neurofibrillary tangles and neuropil threads within dystrophic neurites consisting of aggregated hyperphosphorylated tau protein (Duyckaerts et al.,”

What the sources say

• Not checked yetcites Jack et al., 2018a
• Not checked yetcites Duyckaerts et al., 2009

In the paper

“Tau protein is subject to numerous post-translational modifications, including phosphorylation, acetylation, glycation, O-GlcNAcylation, nitration, SUMOylation, ubiquitination and truncation”

• Also stated in: § Tau · plain

  “In many cases, aberrant phosphorylation results in decreased binding affinity for microtubules”

What the sources say

• Not checked yetcites Marcelli et al., 2018
• Not checked yetcites Biernat et al., 1993
• Not checked yetcites Mandelkow et al., 2007

In the paper

“In summary, the available data still strongly supports the central role of pathologic Aβ accumulation in mediating AD pathogenesis as outlined in the original description of the amyloid cascade hypothesis, although its mechanism may be less direct than originally anticipated”

In the paper

“The γ-secretase complex consists of four protein subunits: presenilin (PSEN), presenilin enhancer (PEN), APH and Nicastrin.”

In the paper

“This extension proposes that accumulation of cerebral amyloid and tau pathology (the “biochemical phase”) is a slow, gradual process that is tolerated by CNS cells early in the course of disease, serving as a risk factor for development of clinical disease, but that the disease is only manifest clinically when cellular homeostatic mechanisms fail, leading to impaired clearance of aggregated”

What the sources say

• Not checked yetcites De Strooper and Karran, 2016 source

In the paper

“Hypoxia can induce increased Aβ production, possibly via increased BACE1 expression (Sun et al., 2006), suggesting the possibility of a pathological feedforward loop.”

What the sources say

• Not checked yetcites Sun et al., 2006 source

In the paper

“it seems clear that Aβ is necessary but not sufficient and that there are other downstream factors that play a key role.”

In the paper

“Longitudinal assessment of amyloid and tau PET imaging suggests that rate of amyloid accumulation predicts onset of tau accumulation whereas rate of tau accumulation predicts onset of cognitive impairment”

What the sources say

• Not checked yetcites Hanseeuw et al., 2019 source

In the paper

“These findings have led to the hypothesis that cognitive decline and neurodegeneration in AD is primarily driven by onset and spread of tau pathology.”

In the paper

“Tau acetylation has been shown to reduce degradation of phosphorylated tau and increase tau pathology”

What the sources say

• Not checked yetcites Min et al., 2010 source

In the paper

“A 3D in vitro culture system consisting of human neurons differentiated from induced pluripotent stem cells overexpressing human APP containing FAD mutations generates robust Aβ42 production and amyloid deposition. Importantly, this model also develops elevated phospho-tau levels and fibrillary tau aggregates, suggesting that elevated Aβ levels alone are sufficient to drive tau pathology in human”

What the sources say

• Not checked yetcites Choi et al., 2014 source

In the paper

“Soluble oligomers isolated from AD brain have been shown to potently inhibit long-term potentiation (LTP), enhance long-term depression (LTD) and reduce dendritic spine density in rodent hippocampal slice cultures”

What the sources say

• Not checked yetcites Kamenetz et al., 2003 source
• Not checked yetcites Shankar et al., 2007 source
• Not checked yetcites Wei et al., 2010 source

In the paper

“Clinico-neuropathologic correlation analyses have demonstrated that tau pathology propagates throughout the AD brain in a stereotyped fashion across neuroanatomically connected networks (Figure 2C) forming the basis of Braak staging”

What the sources say

• Not checked yetcites Braak and Braak, 1991 source

In the paper

“The hypothesis is supported by the discovery that exclusively genetic forms of AD, such as in autosomal dominant AD (ADAD), Down syndrome (trisomy 21), or APP locus duplications, cause an increase in the Aβ42/40 ratio, increased total Aβ production, or increased Aβ fibrillinogenic properties and are sufficient to induce typical AD pathology”

What the sources say

• Not checked yetcites Tcw and Goate, 2017

In the paper

“Exogenously supplied fibrils will seed aggregation of transgenic human and endogenous mouse tau fibrils in mouse tauopathy models by enhancing nucleation of new fibrils. These aggregates then spread transsynaptically to remote anatomically connected brain regions inducing further seeding and aggregation”

What the sources say

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

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

  cites Clavaguera et al., 2009, 2013
• Not checked yetcites Frost et al., 2009 source

In the paper

“These data suggest that while amyloid accumulation may be key in beginning the pathological process, other downstream events such as neuroinflammation and tau accumulation may be the main drivers of neurodegeneration.”

In the paper

“Based on a number of lines of evidence, Hardy and Higgins proposed the amyloid cascade hypothesis in 1992, positing that deposition of Aβ in the brain is the initiating step of AD pathogenesis, leading to subsequent tau deposition, neuron and synaptic loss and cognitive decline”

What the sources say

• Not checked yetcites Hardy and Higgins, 1992 source

In the paper

“In these studies, tau pathology and neurodegeneration is enhanced in mice with both pathologies, whereas amyloid pathology is generally unaffected”

What the sources say

• Not checked yetcites Bolmont et al., 2007
• Not checked yetcites Götz et al., 2001
• Not checked yetcites Hurtado et al., 2010

In the paper

“Hyperphosphorylated tau is also redirected from the axonal compartment to the somatodendritic compartment where it can impair synaptic function by inhibiting glutamate receptor trafficking or synaptic anchoring”

What the sources say

• Not checked yetcites Hoover et al., 2010 source

In the paper

“GABAergic inhibitory networks are impaired in AD and may contribute to cognitive impairment”

• Also stated in: § ApoE · plain

  “ApoE4-TR mice have decreased numbers of GABAergic interneurons in the hippocampus and this correlates with learning deficits.”

What the sources say

• Not checked yetcites Najm et al., 2019 source

In the paper

“Detailed in vivo microdialysis and stable isotope labeling kinetics experiments have demonstrated that ApoE regulates clearance of Aβ in the brain in an isoform-dependent manner (ApoE4-TR mice have diminished Aβ clearance relative to other TR mice), whereas Aβ production was not influenced by ApoE isoform”

What the sources say

• Not checked yetcites Castellano et al., 2011 source

In the paper

“A single inherited copy of the APOE ε4 allele increases risk of developing LOAD by approximately 3-4 fold, while two inherited copies increases risk by ~12-fold”

• Also stated in: § ApoE · plain

  “Inheritance of the APOE ε2 allele is protective.”

What the sources say

• Not checked yetcites Roses, 1996

In the paper

“Importantly, there was also a reduction in plaque-associated microglia with associated impairments in plaque compaction and increased levels of dystrophic neurites around plaques (Leyns et al., 2017; Song 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; Song et al., 2018

In the paper

“Single nuclear transcriptomic techniques have recently been applied to human AD brain specimens and have identified microglial subtypes with increased Apoe expression but have failed to identify DAM or MGnD subpopulations similar to what has been seen in the mouse brain (Mathys et al., 2019).”

What the sources say

• Not checked yetcites Mathys et al., 2019 source

In the paper

“ApoE expression in microglia is required for the phenotypic expression of disease-associated microglia”

• Also stated in: § ApoE · plain

  “ApoE also promotes microglial clustering around Aβ plaques”

What the sources say

• Not checked yetcites Ulrich et al., 2018 source

In the paper

“This may be because of disease stage specific effects with activation being protective in the setting of amyloid deposition and damaging in the setting of tau accumulation (Figure 4B).”

In the paper

“Termed microglial neurodegenerative phenotype (MGnD) or disease-associated microglia (DAM), these cells are defined by a unique expression profile consisting of upregulation of certain inflammatory transcripts (e.g. Apoe, Trem2, Clec7a) and downregulation of homeostatic transcripts (e.g. P2ry12, Tmeml19).”

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

“In TREM2 deletion and haploinsufficiency studies using mouse models of Aβ deposition (APPPS1-21 and 5xFAD), levels of Aβ were decreased at 2 months of age (before plaque deposition) but increased at 8.5 months of age (after plaque deposition), suggesting an age or amyloid burden effect (Ulrich et al., 2014).”

What the sources say

• Not checked yetcites Ulrich et al., 2014 source

In the paper

“Longitudinal CSF, MRI and PET imaging studies of the preclinical phase of AD have established that APOE ε4 allele carriers develop enhanced cerebral amyloid deposition with age, do so at an earlier age and accumulate amyloid at a more rapid rate relative to non-carriers”

What the sources say

• Not checked yetcites Bussy et al., 2019
• Not checked yetcites Grimmer et al., 2010
• Not checked yetcites Mishra et al., 2018

In the paper

“PAM was also strongly associated with total Aβ load and number of neuritic plaques and less strongly associated with amount of PHF tau.”

What the sources say

• Not checked yetcites Felsky et al., 2019 source

In the paper

“ApoE4 may also mediate neuropathological effects by directly modulating BBB integrity”

• Also stated in: § ApoE · boosted

  “Studies in the Zlokovic lab have demonstrated that ApoE4 does not efficiently engage LRP1 on pericytes.”

What the sources say

• Not checked yetcites Bell et al., 2012 source
• Not checked yetcites Zlokovic, 2013

In the paper

“TREM2 protein is expressed on microglia, promotes microglial phagocytosis, modulates inflammatory signaling and promotes microglial survival.”

In the paper

“These data suggest that ApoE4 may cause neuronal dysfunction via direct neurotoxic effects and by promoting hyperactivity in hippocampal neuronal networks.”

In the paper

“In APP transgenic-ApoE targeted replacement (ApoE-TR) mice, where human apoE isoforms are expressed under the influence of endogenous murine ApoE regulatory sequences, ApoE isoforms have differential effects on amyloid pathology. ApoE4-TR mice have enhanced amyloid deposition and higher Aβ levels”

What the sources say

• Not checked yetcites Bales et al., 2009

In the paper

“Either TREM2 KO or TREM2 R47H transgene expression in mice that develop amyloid deposition results in enhanced amyloid seeding as well as enhanced tau seeding and spreading near neuritic plaques (Leyns et al., 2019; Parhizkar et al., 2019).”

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., 2019; Parhizkar et al., 2019

In the paper

“ApoE4-TR mice have enhanced neural activity in the hippocampus and entorhinal cortex, as evidenced by hypermetabolism on fMRI, increased high frequency oscillations measured by in vivo electrophysiology, and reduced inhibitory input to neurons of entorhinal cortex”

What the sources say

• Not checked yetcites Nuriel et al., 2017

In the paper

“A recent study failed to replicate the neurotoxic effect of ApoE4 in tauopathy mice.”

• Also stated in: § ApoE · plain

  “They found that ApoE2 mice, rather than ApoE4, had enhanced tau pathology, astrogliosis and behavioral impairment”

What the sources say

• Not checked yetcites Zhao et al., 2018 source

In the paper

“ApoE directly binds to Aβ present in plaques”

• Also stated in: § ApoE · hedged

  “APP transgenic animal models demonstrate markedly reduced fibrillar Aβ deposition and Aβ levels in the setting of ApoE KO, suggesting ApoE inhibits clearance and/or promotes Aβ seeding”

What the sources say

• Not checked yetcites Namba et al., 1991
• Not checked yetcites Bales et al., 1997, 1999
• Not checked yetcites Huynh et al., 2017b

In the paper

“TREM2 also binds to soluble oligomers of Aβ and promotes phagocytosis of Aβ.”

In the paper

“In one study, MGnD could be induced in WT mouse brain by injection of apoptotic neurons, and required ApoE expression for induction (Keren-Shaul et al., 2017; Krasemann 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 Keren-Shaul et al., 2017; Krasemann et al., 2017

In the paper

“NLRP3 and caspase-1 genetic deletion results in decreased Aβ deposition, reduced IL-1β release from microglia and improved cognitive performance in APPPS1 mice (Heneka et al., 2013).”

What the sources say

• Not checked yetcites Heneka et al., 2013 source

In the paper

“NLRP3 inflammasome is activated in AD and mild cognitive impairment (MCI) brains and in APPPS1 mice.”

In the paper

“These experiments have led to the antimicrobial protection hypothesis of AD that suggests intracerebral infection by certain pathogens may induce Aβ fibrillization as an antimicrobial defense mechanism, leading to amyloid seeding and deposition, thereby initiating the amyloid cascade. (Moir et al., 2018).”

What the sources say

• Not checked yetcites Moir et al., 2018

In the paper

“This can be reversed by genetic deletion of ASC or use of an anti-ASC neutralizing antibody (Venegas et al., 2017).”

What the sources say

• Not checked yetcites Venegas et al., 2017 source

In the paper

“This suggests a role of Trem2 function in suppressing amyloid-induced local toxicity that also inhibits tau seeding/spreading.”

In the paper

“C1q binds to synapses and, in the presence of soluble Aβ oligomers, promotes microglia phagocytosis of synaptic contents (Hong et al., 2016)”

What the sources say

• Not checked yetcites Hong et al., 2016 source

In the paper

“Depletion of microglia or pharmacological inhibition of exosome secretion led to reduced tau spreading in this model.”

What the sources say

• Not checked yetcites Asai et al., 2015 source

In the paper

“Extracellular ASC specks have been found to bind to Aβ and can cross-seed Aβ oligomerization and plaque formation in APPPS1 mice (Figure 4C).”

What the sources say

• Not checked yetcites Venegas et al., 2017 source

In the paper

“Dating back to 1991, studies have demonstrated the presence of herpesvirus in brains of patients with AD, as well as within amyloid plaques (Carbone et al., 2014; Jamieson et al., 1991, 1992; Wozniak et al., 2009).”

What the sources say

• Not checked yetcites Carbone et al., 2014; Jamieson et al., 1991, 1992; Wozniak et al., 2009

In the paper

“Follow-up analyses in AD brain specimens found detectable human herpesvirus (HHV)-6 and herpes simplex virus (HSV)-1 DNA in 3 separate cohorts, and identified many putative viral-host interactions that regulate gene networks pertinent to AD biology, including innate immunity and APP processing (Readhead et al., 2018)”

What the sources say

• Not checked yetcites Readhead et al., 2018 source

In the paper

“Indeed, one study demonstrated that APP/PS1ΔE9 mice chronically administered a cocktail of high dose antibiotics to modulate microbiome composition had significantly reduced Aβ plaque load, reduced plaque size, increased soluble Aβ42 levels and reduced plaque-associated microglia and reactive astrocytes (Minter et al., 2016).”

What the sources say

• Not checked yetcites Minter et al., 2016 source

In the paper

“In the J20 amyloid mouse model, CD33 expression resulted in reduced microglial-mediated phagocytosis of Aβ, and increased amyloid pathology (Bradshaw et al., 2013; Griciuc 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 Bradshaw et al., 2013; Griciuc et al., 2013

In the paper

“Germ-free mice develop microglia with an immature phenotype, blunted response to inflammatory stimuli and defective immune response to infection (Erny et al., 2015).”

What the sources say

• Not checked yetcites Erny et al., 2015 source

In the paper

“These data in models of Aβ deposition would suggest that dysfunctional microglia are less able to sequester Aβ pathology within compact plaques and less able to inhibit amyloid and tau seeding near plaques, resulting in neuronal damage.”

In the paper

“5xFAD mice survived longer with less severe disease than WT mice, while APP KO mice had slightly increased mortality compared to WT mice.”

What the sources say

• Not checked yetcites Kumar et al., 2016 source

In the paper

“CD33 KO results in decreased amyloid pathology and improved cognition in 5xFAD mice.”

What the sources say

• Not checked yetcites Griciuc et al., 2019 source

In the paper

“Synthetic and AD-brain derived Aβ peptide fibrils significantly inhibit the growth of gram positive and gram negative bacteria, fungus (Soscia et al., 2010) and herpesvirus, and inhibits the entry of herpesvirus into cells (Bourgade et al., 2015).”

What the sources say

• Not checked yetcites Soscia et al., 2010; Bourgade et al., 2015

In the paper

“Activated microglia can directly secrete toxic proinflammatory cytokines (Colonna and Butovsky, 2017; Kinney et al., 2018) or secrete indirect mediators that stimulate astrocytes to secrete a neurotoxic substance (Liddelow 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 Colonna and Butovsky, 2017; Kinney et al., 2018; Liddelow et al., 2017

In the paper

“The current AD clinical pipeline has over 100 different compounds currently being tested in various phases of clinical trials (Hara et al., 2019).”

What the sources say

• Not checked yetcites Hara et al., 2019

In the paper

“However, after Aβ plaque formation, there is an impaired sleep-wake cycle and loss of diurnal fluctuation in ISF/CSF Aβ levels (Roh et al., 2012).”

What the sources say

• Not checked yetcites Roh et al., 2012 source

In the paper

“Oral infection of WT mice with Porphyromsonas gingivalis resulted in elevated intraparenchymal Aβ levels, and inhibition of gingipain activity led to reduced intracerebral bacterial burden, decreased Aβ levels and reduced neuroinflammation (Dominy et al., 2019).”

What the sources say

• Not checked yetcites Dominy et al., 2019 source

In the paper

“Memantine is a uncompetitive NMDA receptor modulator that may act to inhibit glutamate-mediated neurotoxicity that develops as neurons die during AD progression, although the precise mechanism of its effect is unclear (Greenamyre et al., 1988; Livingston et al., 2017).”

What the sources say

• Not checked yetcites Greenamyre et al., 1988; Livingston et al., 2017

In the paper

“However, as with ChEI, the effect size is quite small and the medication has no effect on long-term disease progression.”

In the paper

“In summary, these studies provide compelling evidence that sleep deprivation stimulates increased levels of Aβ and tau in human CSF and animal model brains and enhances intracerebral pathology.”

In the paper

“However, the overall effect size is modest (mean difference in MiniMental State Examination (MMSE) of 1.37 points after 6 months treatment), and there is no effect on long-term disease progression.”

In the paper

“Effects in mild-to-moderate stage disease were marginal and therefore, it is not recommended that this medication be prescribed to patients with mild AD.”

In the paper

“At this stage of disease pathogenesis, significant and irreversible synaptic and neuronal loss has occurred and the pathological cascade would likely be very difficult to reverse (Gómez-Isla et al., 1996).”

What the sources say

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

In the paper

“Available data does not support the use of ChEI in very mild AD (i.e. mild cognitive impairment), and in fact ChEI may worsen cognition at this early clinical stage (Han et al., 2019).”

What the sources say

• Not checked yetcites Han et al., 2019

In the paper

“While the underlying evidence for the amyloid cascade hypothesis remains solid, new discoveries should continually inform and update our understanding of disease pathobiology, eventually leading to the development of novel treatment approaches.”

In the paper

“In a recent study of amyloid kinetics in human CSF using stable isotope labeling, there was an increase in Aβ levels following sleep deprivation but no change in rate of Aβ clearance.”

What the sources say

• Not checked yetcites Lucey et al., 2018 source

In the paper

“In animal microdialysis experiments, interstitial fluid (ISF) Aβ levels correlate with wakefulness and significantly increase following acute sleep deprivation or orexin infusion.”

What the sources say

• Not checked yetcites Kang et al., 2009 source

In the paper

“However, in a recent study of partial sleep deprivation lasting 5-8 days, no changes in AD CSF biomarkers were noted although that study did not alter the quantity of slow-wave sleep (Olsson et al., 2018).”

What the sources say

• Not checked yetcites Olsson et al., 2018

In the paper

“They differ primarily in their pharmacokinetic profiles (donepezil has a much longer half-life than the others and is dosed once daily) and formulation (rivastigmine is available as a continuous release transdermal patch) but not in overall efficacy.”

In the paper

“More than 20 compounds have completed large phase 3 double-blind randomized control trials in cohorts of patients at various stages of AD and none has demonstrated any efficacy in slowing cognitive decline or improving global functioning (Table 1).”

What the sources say

• Not checked yetcites Table 1

In the paper

“Aducanumab is a fully human IgG1 antibody that binds a specific conformational epitope of Aβ. There was initial excitement for this antibody, as it was demonstrated to actively engage and clear amyloid plaques both in transgenic APP models and in human participants with prodromal or mild AD based on florbetapir-PET imaging.”

What the sources say

• Not checked yetcites Sevigny et al., 2016 source

In the paper

“Ideally, BACE1 inhibition would be the preferred target for primary prevention studies, as blocking Aβ production prior to onset of pathology would be sufficient to prevent the development of pathology.”

In the paper

“In mouse amyloidosis model, BACE1 inhibition limits initiation of new plaque formation but does not prevent growth of established plaques (Peters et al., 2018).”

What the sources say

• Not checked yetcites Peters et al., 2018

In the paper

“Gantenerumab is a fully human IgG1 antibody that binds to a conformational epitope on aggregated Aβ fibrils within plaques and triggers Fc-mediated microglial phagocytosis of Aβ.”

In the paper

“Unfortunately, many clinical trials have been inadequately designed to robustly test the amyloid hypothesis, such that negative trial results cannot be necessarily interpreted as a rejection of the amyloid hypothesis (Karran and Hardy, 2014; Karran et al., 2011).”

What the sources say

• Not checked yetcites Karran and Hardy, 2014; Karran et al., 2011

In the paper

“Two phase 3 trials of solanezumab in mild-to-moderate AD failed to demonstrate a marked benefit on cognition or ADL and did not reduce cerebral amyloid deposition (Doody et al., 2014).”

What the sources say

• Not checked yetcites Doody et al., 2014 source

In the paper

“Only one BACE1 inhibitor is now left standing in clinical trials. Elenbecestat is currently engaged in phase 3 clinical trials in biomarker positive MCI/prodromal AD and has not had issues with safety, tolerability or outcome futility to-date.”

In the paper

“The first successful demonstration of antibody-mediated clearance of Aβ was in 1999, when active immunization of PDAPP mice using full length human Aβ42 peptide resulted in a significant decrease in existing amyloid deposits in animals vaccinated at an older age and almost completely prevented the development of amyloid deposition in animals vaccinated at a younger age (Schenk et al., 1999).”

What the sources say

• Not checked yetcites Schenk et al., 1999 source

In the paper

“It was hypothesized that the antibody might alter the equilibrium between plasma and CNS Aβ, the so-called “peripheral sink” hypothesis (DeMattos et al., 2001) as well as directly binding soluble Aβ in the CNS.”

What the sources say

• Not checked yetcites DeMattos et al., 2001

In the paper

“Verubecestat failed to slow cognitive decline in a phase 3 trial of mild to moderate AD and resulted in worse cognition on some measures. (Egan et al., 2018, 2019).”

What the sources say

• ?Not matched

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

  cites Egan et al., 2018, 2019

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.”

In the paper

“Since no integrated AD animal model exists in which to definitively test the validity of the amyloid cascade hypothesis, clinical trials using Aβ-directed therapies in humans have been considered one of the most direct ways to test this.”

In the paper

“Donanemab is a monoclonal antibody developed by Lilly that uniquely targets Aβ(p3-42), a pyroglutamate form of Aβ exclusively found in plaques, in which the goal is to directly engage plaque-based Aβ for clearance and is currently in a phase 2 trial.”

In the paper

“BAN2401 is a humanized version of murine antibody mAb158 that binds large soluble Aβ protofibrils in vitro. Phase 2 trials demonstrated significant engagement and clearance of cerebral amyloid deposits and possible reduction in cognitive decline. It has now entered a phase 3 clinical trial in very mild to mild AD patients (Logovinsky et al., 2016).”

What the sources say

• Not checked yetcites Logovinsky et al., 2016

In the paper

“This is a humanized version of mouse 3D6 antibody that targets N-terminal Aβ peptide and binds to soluble and fibrillar Aβ, triggering microglial phagocytosis of Aβ deposits.”

In the paper

“Preclinical studies demonstrated that peripheral administration sequestered peripheral Aβ and led to a dramatic and rapid rise in peripheral Aβ levels.”

In the paper

“Gantenerumab entered a phase 3 clinical trial for mild AD in 2014 that ultimately stopped enrolling early due to futility. The study was continued as an open label extension at high dose for two years.”

In the paper

“Post-mortem evaluation determined that there was significant variability in degree of amyloid clearance but that some vaccinated patients had long-lasting nearly complete clearance of Aβ deposits. However, they still had prominent tau pathology with advanced Braak staging and most had severe dementia at time of death, even despite plaque clearance (Nicoll et al., 2019; Vellas et al., 2009).”

What the sources say

• Not checked yetcites Nicoll et al., 2019; Vellas et al., 2009

In the paper

“Aβ-directed immunotherapy has been explored as a disease-modifying therapy in AD for the last 20 years (Gallardo and Holtzman, 2017).”

What the sources say

• Not checked yetcites Gallardo and Holtzman, 2017

In the paper

“Lilly inhibitors LY2886721 and LY3202626 failed in phase 2 trials due to hepatotoxicity and impaired cognitive performance, respectively.”

In the paper

“Follow-up analyses demonstrated a dramatic decline in Aβ deposition in participants in the open extension, such that some became amyloid negative on imaging.”

What the sources say

• Not checked yetcites Ostrowitzki et al., 2017 source

In the paper

“Active vaccination strategies using Aβ peptides as immunogens are still being pursued, with CAD106 in a phase 3 trial (Table 2) and ABVac40 currently in phase 2 trials (Lacosta et al., 2018; Vandenberghe et al., 2017).”

What the sources say

• Not checked yetcites Lacosta et al., 2018; Vandenberghe et al., 2017

In the paper

“The amyloid cascade hypothesis suggests that Aβ accumulation triggers disease pathogenesis, so therapies that lower parenchymal Aβ might be expected to slow disease progression.”

In the paper

“In a phase 2a trial, four patients developed aseptic meningoencephalitis leading to the discontinuation of the trial, although ongoing neuroimaging and neuropathologic follow-up allowed for assessment of long-term treatment response.”

In the paper

“Both claim to avoid the risk of meningoencephalitis by excluding portions of the Aβ peptide responsible for inducing Th1 immune responses.”

In the paper

“Unfortunately study sponsors announced discontinuation of this arm in July 2019 when interim analysis demonstrated worse cognition, increased brain atrophy and more weight loss in the treatment group relative to placebo.”

In the paper

“With infusions of a monoclonal antibody, there is less variability in efficacy from patient to patient, and since titer levels can be more tightly controlled, there is less risk of adverse events.”

In the paper

“Crenezumab is a fully human IgG4 antibody that binds oligomeric, fibrillar and plaque-based Aβ. Two phase 3 trials were terminated early in January 2019 for futility after interim analysis failed to demonstrate any benefit.”

In the paper

“The humanized version of HJ8.5 (ABBV-8E12) has been tested in a phase 1 trial and found to be safe and has now advanced to two phase 2 trials including patients with early AD and PSP (West et al., 2017).”

What the sources say

• Not checked yetcites West et al., 2017

In the paper

“Use of anti-ApoE ASO delivered via intracerebroventricular injection in ApoE-TR/APPPS1-21 mice demonstrated dramatically reduced Aβ plaque deposition if administered prior to plaque seeding but not after.”

What the sources say

• Not checked yetcites Huynh et al., 2017b

In the paper

“Another proposed strategy is to utilize gene therapy methods to overexpress ApoE2 in APOE ε4/ε4 carriers as means to overcome loss of function associated with ApoE4 (Rosenberg et al., 2018).”

What the sources say

• Not checked yetcites Rosenberg et al., 2018

In the paper

“This strategy would only be effective if ApoE4-mediated disease mechanisms are truly due to loss of function or, if secondary to ApoE4 toxic gain of function, that ApoE2 is able to act in dominant protective fashion to inhibit ApoE4 toxic effects.”

In the paper

“Conditional BACE1 KO in adulthood mitigates many of these side effects but there remains impaired axon guidance defects (Ou-Yang et al., 2018).”

What the sources say

• Not checked yetcites Ou-Yang et al., 2018 source

In the paper

“AADvac-1 recently completed phase 1 testing and is currently undergoing phase 2 trials (Novak et al., 2019).”

What the sources say

• Not checked yetcites Novak et al., 2019

In the paper

“Indeed, there are other promising GSMs now in development that may enter human trials in the near future (Wagner et al., 2017).”

What the sources say

• Not checked yetcites Wagner et al., 2017

In the paper

“In preclinical studies, mouse anti-human tau monoclonal antibody HJ8.5 demonstrated reduced tau seeding, hyperphosphorylation and thioflavin S staining, reduced levels of detergent insoluble tau, and reduced brain atrophy and cognitive deficits in PS19 (P301S) mice, whether administered via intraventricular infusion (Yanamandra et al., 2013) or peripherally (Yanamandra et al., 2015) when administ”

What the sources say

• Not checked yetcites Yanamandra et al., 2013 source
• Not checked yetcites Yanamandra et al., 2015

In the paper

“Avagacestat phase 2 trials in mild to moderate and prodromal AD were terminated after it failed to demonstrate any reduction in cognitive decline and caused adverse effects at higher doses, such as nausea, vomiting, diarrhea, rash, pruritis and increased incidence of non-melanoma skin cancer (Coric et al., 2015).”

What the sources say

• Not checked yetcites Coric et al., 2015 source

In the paper

“A GSK-3 inhibitor, tideglusib, was shown in a preclinical study using double transgenic mice expressing human tau and APP to reduce tau phosphorylation, decrease amyloid deposition, lead to less neuronal loss and improved cognition (Serenó et al., 2009).”

What the sources say

• Not checked yetcites Serenó et al., 2009 source

In the paper

“Semagacestat was the first GSI to enter a phase 3 trial for AD. However, the trial was halted early due to concerns of worsening cognition, increased incidence of skin cancers and infection, and weight loss relative to placebo (Doody et al., 2013).”

What the sources say

• Not checked yetcites Doody et al., 2013 source

In the paper

“ASO-based clinical treatments have demonstrated dramatic success in cases of spinal motor atrophy (Finkel et al., 2017) and are being tested in Huntington’s disease (Tabrizi et al., 2019).”

What the sources say

• Not checked yetcites Finkel et al., 2017
• Not checked yetcites Tabrizi et al., 2019

In the paper

“Delivery of this antibody centrally or peripherally reduced fibrillary amyloid plaque load and soluble and insoluble Aβ levels without reducing cerebral or plasma ApoE levels.”

What the sources say

• Not checked yetcites Liao et al., 2018

In the paper

“It is likely that if a peripherally administered anti-tau antibody is to be efficacious in a disease such as AD, such a mechanism would need to occur and an antibody would need to inhibit this process.”

In the paper

“Tau- and ApoE-directed therapeutics remain at an early stage of development and both hold great potential going foward.”

In the paper

“In one study, patients with rheumatoid arthritis treated with etanercept, TNFα decoy receptor, had lower incidence of AD, but no effect was noted with use of other anti-rheumatic medications (prednisone, sulfasalazine, rituximab) or anti-TNF agents (infliximab, adalimumab) (Chou et al., 2016).”

What the sources say

• Not checked yetcites Chou et al., 2016 source

In the paper

“However, a phase 3 trial of IVIg did not demonstrate any cognitive benefits in mild AD despite a favorable safety profile (Relkin et al., 2017).”

What the sources say

• Not checked yetcites Relkin et al., 2017

In the paper

“Recent heterochronic parabiosis experiments demonstrated that introduction of young blood in old mice led to increased neurogenesis and dendritic spine density, and improved age-related cognitive impairment, (Katsimpardi et al., 2014; Villeda et al., 2014).”

What the sources say

• Not checked yetcites Katsimpardi et al., 2014 source
• Not checked yetcites Villeda et al., 2014 source

In the paper

“Heterochronic parabiosis and direct injection of young mouse plasma in APP amyloidosis mice resulted in increased levels of synaptic protein and improvement in cognitive performance on standard tests of spatial working memory and hippocampal-dependent associative learning (Middeldorp et al., 2016)”

What the sources say

• Not checked yetcites Middeldorp et al., 2016 source

In the paper

“Interest in anti-inflammatory treatments for AD were initially stoked by findings from multiple epidemiologic studies suggesting that chronic use of NSAIDs was associated with lower incidence of AD, with the most pronounced effect seen in patients taking chronic ibuprofen (in t’ Veld et al., 2001; Vlad et al., 2008).”

What the sources say

• Not checked yetcites in t’ Veld et al., 2001
• Not checked yetcites Vlad et al., 2008 source

In the paper

“Finally, AD pathobiology is complex and the older one is, the greater likelihood that other age-related diseases contribute to cognitive decline together with AD pathology.”

In the paper

“This study found that intracisternal viral injection led to the widest area of cerebral transduction with only minimal surgery (Rosenberg et al., 2018).”

What the sources say

• Not checked yetcites Rosenberg et al., 2018

In the paper

“This approach demonstrated reduced amyloid burden and improvement in recognition memory in preclinical studies using APP/PS1 mice (Chang et al., 2017).”

What the sources say

• Not checked yetcites Chang et al., 2017

In the paper

“The AMBAR trial, a current phase 2b/3 trial, is testing this hypothesis by assessing the effect of monthly plasma exchange with albumin replacement on mild to moderate AD (Boada et al., 2019)”

What the sources say

• Not checked yetcites Boada et al., 2019

In the paper

“There is also huge potential for therapies that modulate the neuroimmune or microglial response in AD, and this class of drug development is significantly underrepresented.”

In the paper

“A phase 2 trial of etanercept in mild to moderate AD established safety but saw no significant reduction in cognitive decline on analysis of secondary clinical outcomes (Butchart et al., 2015).”

What the sources say

• Not checked yetcites Butchart et al., 2015