The amyloid hypothesis in Alzheimer disease: new insights from new therapeutics

May combine two claims.

Fifteen potential therapeutics aimed at amyloid-beta have been tested in phase III trials, and eleven of them clearly failed to show clinical efficacy.

“fifteen potential therapeutics intended to target the role of Aβ in AD in various ways, including inhibition of enzymes involved in Aβ production and removal of Aβ from the brain using antibodies, have been tested in phase III trials (Table 1).Yet so far, eleven of these have clearly failed to demonstrate clinical efficacy.”

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

A hypothetical anti-Aβ antibody with a normalized rate of amyloid removal of 10 CL/4 wk/10mg/kg has 88 weeks remaining post amyloid negativity.

“10 | 16 | 88”

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

A hypothetical anti-Aβ antibody with a normalized rate of amyloid removal of 1.0 CL/4 wk/10mg/kg takes 160 weeks to reach 20 CL from a baseline of 100 CL.

“1.0 | 160 | 0”

Probably not a substantial claim: may not pass S3 (load-bearing). The quote only partly states this claim.

A hypothetical anti-Aβ antibody with a normalized rate of amyloid removal of 5 CL/4 wk/10mg/kg takes 32 weeks to reach 20 CL from a baseline of 100 CL.

“5 | 32 | 72”

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

A hypothetical anti-Aβ antibody with a normalized rate of amyloid removal of 5 CL/4 wk/10mg/kg has 72 weeks remaining post amyloid negativity.

“5 | 32 | 72”

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

A hypothetical anti-Aβ antibody with a normalized rate of amyloid removal of 2.5 CL/4 wk/10mg/kg takes 64 weeks to reach 20 CL from a baseline of 100 CL.

“2.5 | 64 | 40”

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

A hypothetical anti-Aβ antibody with a normalized rate of amyloid removal of 10 CL/4 wk/10mg/kg takes 16 weeks to reach 20 CL from a baseline of 100 CL.

“10 | 16 | 88”

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

A hypothetical anti-Aβ antibody with a normalized rate of amyloid removal of 2.5 CL/4 wk/10mg/kg has 40 weeks remaining post amyloid negativity.

“2.5 | 64 | 40”

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

A hypothetical anti-Aβ antibody with a normalized rate of amyloid removal of 1.0 CL/4 wk/10mg/kg has 0 weeks remaining post amyloid negativity.

“1.0 | 160 | 0”

May combine two claims.

The data support the idea that amyloid provokes tau pathology spread, which ultimately causes neuronal loss.

“in aggregate the data strongly support the concept that amyloid provokes the spread of tau pathology that ultimately causes neuronal loss”

• cites [22] De Strooper, B. & Karran, E. The cellular phase of Alzheimer’s disease. Cell 164, 603–615 (2016). sourceNot checked yet

  Not checked in the free run.

May combine two claims.

There is both a spatial and temporal separation between the main pathologies of Alzheimer disease.

“Thus, there is both a spatial and temporal disconnect between the cardinal pathologies of AD.”

May combine two claims.

The spread of neurofibrillary tangle pathology correlates best with, and possibly causes, substantial cognitive impairment in Alzheimer disease.

“it has become evident that it is the spread of NFT pathology that correlates best, and possibly causes, substantial cognitive impairment in AD”

• cites [20] Lowe, V. J. et al. Cross-sectional associations of tau-PET signal with cognition in cognitively unimpaired adults. Neurology 93, e29–e39 (2019). sourceNot checked yet

  Not checked in the free run.

• cites [21] Pontecorvo, M. J. et al. Relationships between flortaucipir PET tau binding and amyloid burden, clinical diagnosis, age and cognition. Brain 140, 748–763 (2017).Not checked yet

  Not checked in the free run.

May combine two claims.

In participants with varied ages, cognitive status, and amyloid loads, tau pathology first appeared in the transentorhinal cortex and spread into the neocortex at amyloid burdens above 40 centiloids.

“They demonstrated that the initial site of tau pathology was in the transentorhinal cortex and that further spreading into neocortex occurred at amyloid burdens of >40 CL.”

• cites [27] Sanchez, J. S. et al. The cortical origin and initial spread of medial temporal tauopathy in Alzheimer’s disease assessed with positron emission tomography. Sci. Transl. Med. 13, eabc0655 (2021). sourceNot checked yet

  Not checked in the free run.

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

A therapeutic hypothesis that is poorly defined cannot be readily falsified.

“A therapeutic hypothesis that is poorly defined is not readily falsified.”

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

The therapeutic hypothesis for anti-amyloid approaches is poorly defined.

“there is a poorly defined therapeutic hypothesis that reducing either soluble (oligomeric) Aβ, or amyloid plaques, or both, in the brain to non-pathological levels -that is, below the level that provokes tau pathology spread -will mediate a therapeutic benefit”

• AssumptionThe authors state this as an assumption: Lowering soluble or oligomeric amyloid-beta, amyloid plaques, or both to a non-pathological level below the threshold that triggers tau pathology spread will produce a therapeutic benefit.

May combine two claims.

Individuals vary in their response to amyloid, but once a threshold is exceeded, tau pathology spread accelerates.

“It is likely that individuals have a variable response to amyloid, but that once a threshold is surpassed, the spread of tau pathology is accelerated.”

May combine two claims.

Reductions in monomeric amyloid-beta, and by extension oligomeric forms, are not efficacious in the patient populations tested and do not cause substantial plaque removal.

“we conclude that reductions in monomeric Aβ, and by extension, oligomeric forms of Aβ 53 , are not efficacious in the patient populations tested and also do not mediate significant removal of plaque”

• cites [53] Brothers, H. M., Gosztyla, M. L. & Robinson, S. R. The physiological roles of amyloid-β peptide hint at new ways to treat Alzheimer’s disease. Front. Aging Neurosci. 10, 118 (2018). sourceNot checked yet

  Not checked in the free run.

May combine two claims.

About one third of the aducanumab trial duration was used to titrate up to 10 mg/kg to reduce ARIA-E, so patients only approached amyloid negativity near the end of Emerge and did not reach it in Engage.

“In the protocol, about one third of the duration of the trials was used in titrating up to the 10mg/kg dose to minimize the incidence of ARIA-E, such that patients were only approaching amyloid negativity towards the end of the 78-week trial in Emerge and were not at amyloid negativity in Engage.”

May combine two claims.

In dominantly inherited Alzheimer disease, gantenerumab lowered amyloid from 38 to 22 centiloids in asymptomatic patients and from 102 to 80 centiloids in symptomatic patients.

“In the asymptomatic cohort, gantenerumab lowered amyloid from a baseline of 38 CL to 22 CL; and in the symptomatic cohort, from a baseline of 102 CL to 80 CL.”

• cites [47] Ultsch, M. et al. Structure of crenezumab complex with Abeta shows loss of beta-hairpin. Sci. Rep. 6, 39374 (2016). sourceNot checked yet

  Not checked in the free run.

May combine two claims.

In the Marguerite Road open-label extension, at 2 years about half of patients were amyloid-negative, and in mild AD patients first receiving drug during the extension amyloid was reduced from baseline by 78 centiloids.

“At the 2-year time point, approximately 50% of the patients were deemed to be amyloid-negative (defined as <24 CL by the sponsor) and in those patients with mild AD who started receiving drug for the first time during the open-label extension, amyloid had been reduced from baseline by 78 CL.”

May combine two claims.

The decrease in amyloid of about 5 centiloids from baseline with 1.0 mg/kg bapineuzumab was very modest and therapeutically irrelevant.

“The decrease in amyloid (~5 CL) from baseline in the 1.0 mg/kg group was very modest and therapeutically irrelevant.”

• cites [61] Bohrmann, B. et al. Gantenerumab: a novel human anti-Abeta antibody demonstrates sustained cerebral amyloid-beta binding and elicits cell-mediated removal of human amyloid-beta. J. Alzheimers Dis. 28, 49–69 (2012). sourceNot checked yet

  Not checked in the free run.

May combine two claims.

Strong suppression of amyloid-beta production by BACE inhibition reduced amyloid deposition by about 20% and produced a modest increase in cognitive impairment, probably through unwanted on-target effects.

“Strong suppression of Aβ production, via BACE inhibition, reduced amyloid deposition by about 20% and resulted in a modest increase in cognitive impairment, probably due to unwanted on-target effects mediated via inhibiting other BACE substrates”

• cites [39] Hampel, H. et al. The β-secretase BACE1 in Alzheimer’s disease. Biol. Psychiatry 89, 745–756 (2021). sourceNot checked yet

  Not checked in the free run.

May combine two claims.

Anti-amyloid monoclonal antibodies that mainly bind monomeric amyloid-beta do not cause substantial plaque removal and lack clinical efficacy.

“anti-Aβ mAbs that predominantly bind to monomeric Aβ do not mediate substantial removal of plaque and lack clinical efficacy”

• cites [42] Honig, L. S. et al. Trial of solanezumab for mild dementia due to Alzheimer’s disease. N. Engl. J. Med. 378, 321–330 (2018). sourceNot checked yet

  Not checked in the free run.

• cites [43] Siemers, E. R. et al. Phase 3 solanezumab trials: secondary outcomes in mild Alzheimer’s disease patients. Alzheimers Dement. 12, 110–120 (2016). sourceNot checked yet

  Not checked in the free run.

May combine two claims.

Emerge showed a statistically significant benefit on the CDR scale at the 10 mg/kg every 4 weeks dose of aducanumab, while Engage did not.

“Emerge showed statistically significant benefit using the CDR assessment scale at the 10 mg/kg QW4 dose of aducanumab, while the other study, Engage, did not.”

May combine two claims.

In the dominantly inherited Alzheimer disease study, asymptomatic patients did not show cognitive decline, so efficacy could not be demonstrated, and gantenerumab was without efficacy in the symptomatic cohort.

“In this study, the asymptomatic patients did not demonstrate cognitive decline, and hence there was no possibility of the drug demonstrating efficacy.In the symptomatic cohort, gantenerumab was without efficacy.”

• cites [47] Ultsch, M. et al. Structure of crenezumab complex with Abeta shows loss of beta-hairpin. Sci. Rep. 6, 39374 (2016). sourceNot checked yet

  Not checked in the free run.

May combine two claims.

In Emerge, 64 centiloids of amyloid were removed, bringing levels to 21 centiloids by 78 weeks; in Engage, 54 centiloids were removed, bringing levels to 37 centiloids.

“In Emerge, 64 CL of amyloid were removed at the 10mg/kg QW4 dose, bringing levels down to 21 CL by the end of the 78-week study 77 .In Engage, rather less amyloid was removed, 54 CL, bringing amyloid levels to 37 CL at 78 weeks.”

• cites [77] Saido, T. C. et al. Dominant and differential deposition of distinct beta-amyloid peptide species, A beta N3(pE), in senile plaques. Neuron 14, 457–466 (1995). sourceNot checked yet

  Not checked in the free run.

May combine two claims.

In the DIAD gantenerumab trial, 60% of enrolled patients were cognitively normal (CDR=0), and the placebo group's amyloid level rose from 39 CL at baseline to 51 CL over 4 years without cognitive decline.

“In the DIAD trial of gantenerumab, 60% of the patients enrolled were cognitively normal (CDR=0) with a baseline amyloid level in the placebo group of 39 CL that increased to 51 CL over the course of the 4-year study.These patients failed to demonstrate cognitive decline.”

May combine two claims.

In TRAILBLAZER-ALZ, donanemab reduced amyloid by 68 centiloids from a baseline of 108 centiloids by 24 weeks, with 40% of patients amyloid-negative, and by 78 weeks 68% were amyloid-negative.

“By 24 weeks, donanemab treatment resulted in a 68 CL reduction in amyloid from a starting baseline of 108 CL, and 40% of patients were amyloid-negative (defined by the sponsor as <24 CL).By 78 weeks, 68% of patients were amyloid-negative.”

• cites [84] Clark, C. M. et al. Cerebral PET with florbetapir compared with neuropathology at autopsy for detection of neuritic amyloid-β plaques: a prospective cohort study. Lancet Neurol. 11, 669–678 (2012). sourceNot checked yet

  Not checked in the free run.

May combine two claims.

In the DIAD trial, placebo patients who were symptomatic at baseline (CDR >= 0.5) declined cognitively, with amyloid increasing from 97 CL to 104 CL.

“Those patients in the placebo arm that were symptomatic (CDR ≥ 0.5) at baseline further declined during the course of the study: their baseline amyloid was 97 CL and increased to 104 CL.”

May combine two claims.

In cognitively normal subjects aged 65-85, there is no increase in annualized tau PET signal below 21 centiloids, but above 68 centiloids tau PET signal significantly increases.

“Knopman et al. 26 have shown that there is no increase in annualized tau PET signal in cognitively normal subjects aged 65-85 years below a threshold of 21 CL, but that above 68 CL, tau PET signal significantly increases.”

• cites [26] Knopman, D. S. et al. Association of initial beta-amyloid levels with subsequent flortaucipir positron emission tomography changes in persons without cognitive impairment. JAMA Neurol. 78, 217–228 (2021). sourceNot checked yet

  Not checked in the free run.

May combine two claims.

The composite flortaucipir tau PET signal was not significantly lowered in donanemab-treated patients, although individual regions of interest did show significant reductions.

“while the composite flortaucipir tau PET signal was not statistically significantly lowered in donanemab-treated patients, individual regions of interest did show significant reductions”

• cites [84] Clark, C. M. et al. Cerebral PET with florbetapir compared with neuropathology at autopsy for detection of neuritic amyloid-β plaques: a prospective cohort study. Lancet Neurol. 11, 669–678 (2012). sourceNot checked yet

  Not checked in the free run.

May combine two claims.

In cognitively unimpaired subjects, there is no meaningful increase in tau PET signal below 22 centiloids, although a 20% increase in amyloid PET SUVr up to about 35 centiloids was associated with a statistically significant increase in annualized tau PET signal.

“Jack et al. 89 have shown there is no meaningful increase in tau PET signal in cognitively unimpaired subjects below 22 CL, although an increase amyloid PET SUVr signal of 20% (up to ~35 CL) was associated with a statistically significant increase in annualized tau PET signal.”

• cites [89] Klein, G. et al. Gantenerumab reduces amyloid-beta plaques in patients with prodromal to moderate Alzheimer’s disease: a PET substudy interim analysis. Alzheimers Res. Ther. 11, 101 (2019). sourceNot checked yet

  Not checked in the free run.

Probably not a substantial claim: may not pass S1 (asserted), S3 (load-bearing), S4 (based).

The acceleration of tau pathology caused by increasing amyloid burden may differ in magnitude from the deceleration caused by therapeutic amyloid reduction, because in the latter case tau pathology is more extensive and has more opportunity to propagate.

“The acceleration of tau pathology progression mediated by the increase in amyloid burden may be different in magnitude to its deceleration consequent to a therapeutically mediated reduction in amyloid, because in the latter case tau pathology will be more extensive with a greater opportunity to propagate further.”

May combine two claims.

There are signs of clinical efficacy with anti-amyloid plaque antibodies, but these must be interpreted cautiously.

“There are signs of clinical efficacy with these antibodies, but we must still be cautious in our interpretation of these.”

May combine two claims.

Donanemab met the primary outcome measure in TRAILBLAZER-ALZ, but the clinical meaningfulness of the iADRS has not been established.

“Donanemab met the primary outcome measure, although the clinical meaningfulness of the iADRS has not yet been established”

• cites [84] Clark, C. M. et al. Cerebral PET with florbetapir compared with neuropathology at autopsy for detection of neuritic amyloid-β plaques: a prospective cohort study. Lancet Neurol. 11, 669–678 (2012). sourceNot checked yet

  Not checked in the free run.

May combine two claims.

The anti-Aβ antibodies have quite different propensities to cause ARIA-E, which limits the dose administered and determines whether dose titration is required.

“The antibodies have quite different propensities to cause ARIA-E, which will limit the dose administered and determine whether dose titration is required.”

May combine two claims.

The antibodies differ in discriminating properties including targeted Aβ epitope, presence of the epitope in CAA, parenchymal plaque and soluble Aβ, affinity, brain exposure, non-specific binding, half-life, and dose-limiting side effects such as ARIA-E.

“However, they have other discriminating properties: the Aβ epitope targeted by the antibody, and whether the epitope is present in CAA, parenchymal plaque and soluble Aβ; the affinity of the antibody for its epitope; the antibody exposure in the brain; extent of non-specific binding; half-life in the circulation; and dose-limiting side effects (for example, ARIA-E).”

Classified as probably not a substantial claim.

The authors hypothesize that the rate of amyloid removal in the aducanumab trials was not fast enough to provide convincing clinical benefit within the study duration.

“Further, we hypothesize that the rate of amyloid removal was not fast enough to provide convincing clinical benefit within the duration of the study.”

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

The reduction of brain amyloid is the major therapeutic hypothesis for all four antibodies, with the possible exception of lecanemab.

“As the reduction in brain amyloid represents the major therapeutic hypothesis for all four antibodies (with the potential exception of lecanemab)”

Classified as probably not a substantial claim.

The longer a clinical trial takes, the larger the group sizes needed to ensure sufficient statistical power because of patient attrition.

“Firstly, given the normal patient attrition rate from clinical trials, the longer the trial takes to conduct, the greater the group sizes need to be to ensure sufficient statistical power at the trial's conclusion.”

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

The faster amyloid is removed, the more rapidly patients would show amelioration of tau pathology propagation and consequent cognitive decline.

“then the faster this is achieved, the more rapidly patients would manifest an amelioration of tau pathology propagation and consequent cognitive decline.”

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

The authors' comparison of antibody-mediated amyloid clearance and ARIA-E incidence should be treated cautiously because some data are based on small sample sizes.

“These data should be treated cautiously because in some cases they are based on a small sample size.”

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

All anti-Aβ antibodies discussed are of the same IgG1 isotype.

“All of the anti-Aβ antibodies discussed here are the same IgG1 isotype.”

Classified as probably not a substantial claim.

The authors propose a 'lead and lag' scenario in which amyloid removal leads and clinical benefit lags.

“Therefore, we propose a 'lead and lag' scenario: amyloid removal will lead and the clinical benefit will lag (Figure 3).”

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

AD is a complex interplay of cellular pathology probably involving multiple cell types and cellular processes.

“We have previously highlighted that AD is a complex interplay of cellular pathology probably involving multiple cell types and cellular processes 22”

• cites [22] De Strooper, B. & Karran, E. The cellular phase of Alzheimer’s disease. Cell 164, 603–615 (2016). sourceNot checked yet

  Not checked in the free run.

May combine two claims.

Amyloid removal is faster in patients with high baseline amyloid levels, which confounds direct comparison of anti-Aβ antibodies.

“There is also evidence that amyloid removal is faster in those patients with high baseline levels, further confounding a direct comparison of anti-Aβ antibodies 90 .”

• cites [90] Boche, D., Denham, N., Holmes, C. & Nicoll, J. A. Neuropathology after active Abeta42 immunotherapy: implications for Alzheimer’s disease pathogenesis. Acta Neuropathol. 120, 369–384 (2010). sourceNot checked yet

  Not checked in the free run.

Probably not a substantial claim: may not pass S4 (based). May combine two claims.

Clinical efficacy will be demonstrated after TΔA, the time taken to reduce amyloid to a low level such as <=20 CL; thereafter full clinical benefit will manifest and at TΔE a sufficient separation between placebo and treated groups will be evidenced.

“Clinical efficacy will be demonstrated after TΔA -the time taken to reduce amyloid to a low level, for example, ≤ 20 CL.Thereafter, the full clinical benefit of amyloid negativity will be manifested and at TΔE a sufficient separation between the placebo and treated groups will be evidenced.”

May combine two claims.

All four anti-Aβ antibodies might eventually render patients amyloid negative, but they may not be equivalent in their ability to provide clinical efficacy over the same duration.

“Thus, while all 4 anti-Aβ antibodies under consideration might be able to render patients 'amyloid negative' over time, they may not be equivalent in their ability to provide clinical efficacy over the same time duration.”

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

The relationship between plaque removal and clinical benefit is likely to be complex.

“The relationship between the removal of plaque and demonstrating a clinical benefit, if that is possible, is likely to be complex, as we have discussed.”

Probably not a substantial claim: may not pass S2 (checkable), S4 (based).

A period of low or no amyloid status would be required to enable the brain to restore homeostasis.

“it seems reasonable to believe that a period of low/no amyloid status would be required to enable the brain to restore homeostasis.”

May combine two claims.

Anti-Aβ antibodies that slowly reduce amyloid to negativity may eventually ameliorate cognitive decline, but this will be challenging to demonstrate.

“Anti-Aβ antibodies that reduce amyloid levels slowly to an amyloid-negative status may also eventually demonstrate an amelioration in cognitive decline, but this will be challenging to demonstrate for a variety of reasons.”

May combine two claims.

Donanemab has a high incidence of ARIA (27%), which was not evident in preclinical studies.

“Interestingly, donanemab has a high incidence of ARIA (27%), although this was not evident in preclinical studies 56 .”

• cites [56] Sperling, R. A. et al. Amyloid-related imaging abnormalities in amyloid-modifying therapeutic trials: recommendations from the Alzheimer’s Association Research Roundtable Workgroup. Alzheimers Dement. 7, 367–385 (2011). sourceNot checked yet

  Not checked in the free run.

May combine two claims.

PiB may bind preferentially to amyloid plaques containing pE3Aβ, and if other amyloid PET ligands do the same, this preferential binding might overestimate the extent of amyloid clearance.

“There are data that show that the amyloid PET ligand PiB may bind preferentially to amyloid plaques containing the pE3Aβ species 93,94 and although it is not known whether this is the case for other amyloid PET ligands, such preferential binding might over-estimate the extent of amyloid clearance.”

• cites [93] Higuchi, M. Visualization of brain amyloid and microglial activation in mouse models of Alzheimer’s disease. Curr. Alzheimer Res. 6, 137–143 (2009). sourceNot checked yet

  Not checked in the free run.

• cites [94] Insel, P. S. et al. Determining clinically meaningful decline in preclinical Alzheimer disease. Neurology 93, e322–e333 (2019). sourceNot checked yet

  Not checked in the free run.

May combine two claims.

The donanemab phase II trial met its primary endpoint for slowing decline on the iADRS, indicating that the amyloid load threshold for clinical benefit was reached.

“However, this phase II trial also met its primary endpoint regarding slowing decline measured using the iADRS indicating that the amyloid load threshold to see clinical benefit was reached in this study.”

May combine two claims.

Early therapeutic intervention in AD is more likely to demonstrate clinical benefit, but demonstrating that benefit becomes increasingly difficult and expensive.

“While therapeutic intervention early in the disease process is more likely to demonstrate clinical benefit, demonstrating that benefit becomes increasingly more difficult and expensive.”

Classified as probably not a substantial claim.

For an amyloid-removing therapy, unless a prevention trial is being considered, patients who are amyloid positive must be selected.

“For a therapeutic removing amyloid, unless a preventative trial is being considered, then patients who are amyloid positive will have to be selected.”

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

The iADRS and preclinical Alzheimer cognitive composite are clinical instruments designed to reveal treatment effects with greater sensitivity.

“One response to these problems has been the design of clinical instruments that purport to be able to reveal treatment effects with greater sensitivity: for example, the iADRS 83 or the preclinical Alzheimer cognitive composite 96 .”

• cites [83] Mintun, M. A. et al. Donanemab in early Alzheimer’s disease. N. Engl. J. Med. 384, 1691–1704 (2021). sourceNot checked yet

  Not checked in the free run.

• cites [96] Zetterberg, H. & Blennow, K. Moving fluid biomarkers for Alzheimer’s disease from research tools to routine clinical diagnostics. Mol. Neurodegener. 16, 10 (2021). sourceNot checked yet

  Not checked in the free run.

May combine two claims.

Recruiting participants below the ~67 CL amyloid threshold might result in slow or no cognitive decline in the placebo arm, requiring large group sizes and long-duration trials.

“Recruiting participants below this threshold might result in slow/no cognitive decline in the placebo arm, requiring large group sizes and long duration trials as discussed above.”

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

Donanemab induces a 90% anti-drug antibody response, which might be connected to the incidence of ARIA.

“Donanemab also induces a 90% anti-drug antibody response, and it might be that this, in some way, is connected to the incidence of ARIA.”

May combine two claims.

Recruiting participants who already have cognitive impairment reduces screen failure rates because they are more likely to have advanced disease, but it reduces the likelihood of slowing disease progression.

“While recruiting participants that already have cognitive impairment reduces the trial enrollment screen failure rate, as they are more likely to have pathologically advanced disease, this will, however, reduce the likelihood of slowing disease progression.”

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

The Aβ epitope targeted by the antibody is important, and current anti-Aβ antibodies are effectively plaque-specific.

“The Aβ epitope targeted by the antibody is important and current anti-Aβ antibodies are effectively plaque-specific.”

May combine two claims.

pE3Aβ is present at low concentrations but is often associated with dense core plaques.

“The pE3Aβ is present at low concentrations, but often associated with dense core plaques 56,78 .”

• cites [56] Sperling, R. A. et al. Amyloid-related imaging abnormalities in amyloid-modifying therapeutic trials: recommendations from the Alzheimer’s Association Research Roundtable Workgroup. Alzheimers Dement. 7, 367–385 (2011). sourceNot checked yet

  Not checked in the free run.

• cites [78] Kuo, Y.-M., Emmerling, M. R., Woods, A. S., Cotter, R. J. & Roher, A. E. Isolation, chemical characterization, and quantitation of Aβ 3-pyroglutamyl peptide from neuritic plaques and vascular amyloid deposits. Biochem Biophys Res. Commun. 237, 188–191 (1997). sourceNot checked yet

  Not checked in the free run.

May combine two claims.

Bapineuzumab caused significant ARIA-E but removed very little amyloid.

“For example, bapinezumab caused significant ARIA-E but removed very little amyloid 61 .”

• cites [61] Bohrmann, B. et al. Gantenerumab: a novel human anti-Abeta antibody demonstrates sustained cerebral amyloid-beta binding and elicits cell-mediated removal of human amyloid-beta. J. Alzheimers Dis. 28, 49–69 (2012). sourceNot checked yet

  Not checked in the free run.

May combine two claims.

Vascular amyloid is somewhat different in composition and potentially conformation from parenchymal Aβ plaques.

“interestingly vascular amyloid is somewhat different in its composition 79 and potentially, its conformation from the parenchymal Aβ plaques 92 .”

• cites [79] Lowe, S. L. et al. Donanemab (LY3002813) dose-escalation study in Alzheimer’s disease. Alzheimers Dementia 7, e12112 (2021).Not checked yet

  Not checked in the free run.

• cites [92] Maeda, J. et al. Longitudinal, quantitative assessment of amyloid, neuroinflammation, and anti-amyloid treatment in a living mouse model of Alzheimer’s disease enabled by positron emission tomography. J. Neurosci. 27, 10957–10968 (2007). sourceNot checked yet

  Not checked in the free run.

Classified as probably not a substantial claim.

The authors consider the relationship between amyloid removal and potential clinical benefit to be more subtle than the FDA's view.

“We consider that the relationship between the removal of amyloid and potential consequent clinical benefit may be more subtle.”

May combine two claims.

The FDA granted accelerated approval to aducanumab and stated that reduction of amyloid is reasonably likely to predict clinical benefit.

“The FDA has controversially granted accelerated approval to aducanumab and has opined that the reduction of amyloid is reasonably likely to predict clinical benefit 7,9,[98][99][100][101][102][103][104][105][106][107] .”

• cites [7] Knopman, D. S., Jones, D. T. & Greicius, M. D. Failure to demonstrate efficacy of aducanumab: an analysis of the EMERGE and ENGAGE trials as reported by Biogen, December 2019. Alzheimers Dementia 17, 696–701 (2021). sourceNot checked yet

  Not checked in the free run.

• cites [9] Alexander, G. C. et al. Revisiting FDA approval of aducanumab. N. Engl. J. Med. 385, 769–771 (2021). sourceNot checked yet

  Not checked in the free run.

• cites [98] Alexander, G. C. & Karlawish, J. The problem of aducanumab for the treatment of Alzheimer disease. Ann. Intern. Med. 174, 1303–1304 (2021). sourceNot checked yet

  Not checked in the free run.

• cites [99] Cummings, J. et al. Aducanumab produced a clinically meaningful benefit in association with amyloid lowering. Alzheimers Res. Ther. 13, 98 (2021). sourceNot checked yet

  Not checked in the free run.

• cites [100] Doody, R. Editorial: Consequences of the FDA decision on aducanumab for patient care and research. J. Prev. Alzheimers Dis. 8, 393–395 (2021).Not checked yet

  Not checked in the free run.

• cites [101] Dunn, B., Stein, P. & Cavazzoni, P. Approval of aducanumab for Alzheimer disease-the FDA’s perspective. JAMA Intern. Med. 181, 1276–1278 (2021). sourceNot checked yet

  Not checked in the free run.

• cites [102] Dunn, B., Stein, P., Temple, R. & Cavazzoni, P. An appropriate use of accelerated approval- aducanumab for Alzheimer’s disease. N. Engl. J. Med. 385, 856–857 (2021). sourceNot checked yet

  Not checked in the free run.

• cites [103] Petersen, R. C. Aducanumab: what about the patient? Ann. Neurol. 90, 334–335 (2021). sourceNot checked yet

  Not checked in the free run.

• cites [104] Rabinovici, G. D. Controversy and progress in Alzheimer’s disease - FDA approval of aducanumab. N. Engl. J. Med. 385, 771–774 (2021). sourceNot checked yet

  Not checked in the free run.

• cites [105] Salloway, S. & Cummings, J. Aducanumab, amyloid lowering, and slowing of Alzheimer disease. Neurology 97, 543–544 (2021). sourceNot checked yet

  Not checked in the free run.

May combine two claims.

In tauopathies such as frontotemporal lobar dementia, tau pathology can spread without amyloid, so removing amyloid may not halt or sufficiently slow tau spread in AD to significantly ameliorate cognitive decline.

“In tauopathies such as frontal temporal lobar dementia, tau pathology can spread through the brain in the absence of amyloid, and so there is still the risk that removing amyloid will not halt, or sufficiently slow, tau pathology spread in AD to provide significant amelioration of cognitive decline.”

May combine two claims.

In the DIAN cohort, gantenerumab significantly reduced amyloid plaques and CSF total tau, phospho-tau181 and neurofilament light chain, confirming an interaction between Aβ and tau.

“In the DIAN cohort, treatment of patients with familial (caused by autosomal dominant mutations) Alzheimer disease with gantenerumab significantly reduced amyloid plaques and cerebrospinal fluid (CSF) total tau, phospho-tau181 and neurofilament light chain, confirming an interaction between Aβ and tau.”

May combine two claims.

Large cross-sectional neuropathological studies of autopsied brain suggest that tau pathology is prevalent long before amyloid pathology appears, potentially supporting the concept that tau pathology leads to amyloid pathology.

“From large cross-sectional neuropathological studies of autopsied brain 124 , it appears that tau pathology is already prevalent long before amyloid pathology appears, potentially supporting the concept that tau pathology leads to amyloid pathology 125 .”

• cites [124] Palmqvist, S. et al. Cerebrospinal fluid and plasma biomarker trajectories with increasing amyloid deposition in Alzheimer’s disease. EMBO Mol. Med. 11, e11170 (2019). sourceNot checked yet

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• cites [125] Hansson, O. Biomarkers for neurodegenerative diseases. Nat. Med. 27, 954–963 (2021). sourceNot checked yet

  Not checked in the free run.

May combine two claims.

Autosomal dominant mutations in MAPT lead to neuronal tangle pathology and frontotemporal dementia but not amyloid plaques, suggesting that tau pathology does not induce Aβ pathology.

“Autosomal dominant mutations to the MAPT (tau) gene lead to neuronal tangle pathology and frontotemporal dementia but not to amyloid plaques 122,123 , suggesting that tau pathology does not induce Aβ pathology.”

• cites [122] Arnsten, A. F. T., Datta, D., Tredici, K. D. & Braak, H. Hypothesis: Tau pathology is an initiating factor in sporadic Alzheimer’s disease. Alzheimers Dement. 17, 115–124 (2021). sourceNot checked yet

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• cites [123] Jack, C. R. Jr. et al. Hypothetical model of dynamic biomarkers of the Alzheimer’s pathological cascade. Lancet Neurol. 9, 119–128 (2010). sourceNot checked yet

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Probably not a substantial claim: may not pass S1 (asserted), S2 (checkable), S4 (based).

The challenge is to determine which elements of the disease-associated microglial response propel the disease process versus those that are merely responses to it.

“The challenge for researchers is determining those elements of the disease-associated microglial response that propel the disease process, versus those that are merely responses to it.”

May combine two claims.

The NFT tau PET signal was significantly associated with impairment on various cognitive measures, and when stratified by amyloid status there was no significant evidence that amyloid modified the effect of the NFT tau PET signal.

“The NFT tau PET signal was significantly associated with impairment of various measures of cognition, on a region-of-interest basis.When the NFT tau PET signal was stratified by amyloid status, there was no significant evidence that amyloid modified the effect of the NFT tau PET signal.”

• cites [20] Lowe, V. J. et al. Cross-sectional associations of tau-PET signal with cognition in cognitively unimpaired adults. Neurology 93, e29–e39 (2019). sourceNot checked yet

  Not checked in the free run.

May combine two claims.

In individuals with autosomal dominant mutations in APP or Presenilin, altered Aβ generation causing early plaque deposition initiates the disease, and patients invariably develop the full spectrum of tau pathology.

“In individuals with autosomal dominant mutations in genes coding for amyloid precursor protein (APP) or Presenilin 119 , alterations in Aβ generation that result in early deposition of plaque initiate the disease and patients invariably develop the full spectrum of tau pathology 120,121 .”

• cites [119] Hutton, M. et al. Association of missense and 5′-splice-site mutations in tau with the inherited dementia FTDP-17. Nature 393, 702–705 (1998). sourceNot checked yet

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• cites [120] Goedert, M., Crowther, R. A. & Spillantini, M. G. Tau mutations cause frontotemporal dementias. Neuron 21, 955–958 (1998). sourceNot checked yet

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• cites [121] Braak, H., Thal, D. R., Ghebremedhin, E. & Del Tredici, K. Stages of the pathologic process in Alzheimer disease: age categories from 1 to 100 years. J. Neuropathol. Exp. Neurol. 70, 960–969 (2011). sourceNot checked yet

  Not checked in the free run.

May combine two claims.

In a cross-sectional study, Lowe et al. studied 579 cognitively unimpaired adults; median age was 70; abnormal NFT tau PET was seen in 20% and abnormal Aβ in 34%.

“In a cross-sectional study, Lowe et al. 20 studied the association of neurofibrillary (NFT) tau PET and Aβ PET on cognition in 579 cognitively unimpaired adults.The participants' median age was 70 and abnormal NFT tau PET, defined as a signal in the entorhinal region, was seen in 20%, while abnormal Aβ was seen in 34% of the cohort.”

• cites [20] Lowe, V. J. et al. Cross-sectional associations of tau-PET signal with cognition in cognitively unimpaired adults. Neurology 93, e29–e39 (2019). sourceNot checked yet

  Not checked in the free run.

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

Because current anti-Aβ antibodies target different epitopes, they may remove different populations or types of amyloid plaques.

“It is possible that as the current anti-Aβ antibodies target different epitopes, they may remove different populations or types of amyloid plaques.”

May combine two claims.

A 7-year longitudinal study of 60 clinically normal elderly found that increases in tau PET signal were significantly associated with cognitive decline; increases in amyloid PET were associated with increases in tau PET signal but not directly with cognitive decline.

“A 7-year longitudinal study was conducted in which 60 clinically normal elderly participants received repeated tau and amyloid PET scans and cognitive assessments 132 .This analysis revealed that increases in tau PET signal were significantly associated with cognitive decline, and while increases in amyloid PET were associated with increases in tau PET signal, it was not significantly directly ass”

• cites [132] Busche, M. A. & Hyman, B. T. Synergy between amyloid-beta and tau in Alzheimer’s disease. Nat. Neurosci. 23, 1183–1193 (2020). sourceNot checked yet

  Not checked in the free run.

May combine two claims.

La Joie et al. found that a CL threshold of 12.2 provided 88% accuracy, 89% sensitivity and 86% specificity for none to sparse amyloid on the CERAD scale, and a CL threshold of 23.5 provided 89% accuracy, 86% sensitivity and 96% specificity for moderate to frequent amyloid.

“A CL threshold of 12.2 provided 88% accuracy, 89% sensitivity and 86% specificity for none to sparse amyloid in the CERAD scale, and a CL threshold of 23.5 provided 89% accuracy, 86% sensitivity and 96% specificity for moderate to frequent amyloid in the CERAD scale.”

• cites [86] Dore, V. et al. Comparison of (18)F-florbetaben quantification results using the standard centiloid, MR-based, and MR-less CapAIBL((R)) approaches: validation against histopathology. Alzheimers Dement. 15, 807–816 (2019). sourceNot checked yet

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

Clarke et al. concluded that the appropriate threshold for amyloid positivity/negativity was 24 CL (=1.1 SUVr).

“The authors concluded the appropriate threshold for amyloid positivity/negativity was 24 CL (=1.1 SUVr).”

• cites [139]Not checked yet

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• cites [140]Not checked yet

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

The Centiloid Project provides guidance to convert SUVr information from different amyloid PET ligands into a common 100-point scale.

“this prompted the Centiloid Project, which has provided guidance on how to convert SUVr information from different amyloid PET ligands into a common, 100-point scale 116 .”

• cites [116] Hardy, J. The relationship between amyloid and tau. J. Mol. Neurosci. 20, 203–206 (2003). sourceNot checked yet

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May combine two claims.

Jack et al. studied 59 cognitively unimpaired amyloid-negative, 37 cognitively unimpaired amyloid-positive and 30 cognitively impaired amyloid-positive participants over 12-15 months; tau PET signal did not increase in cognitively unimpaired amyloid-negative participants but did in the other groups.

“Jack et al. 130 studied 59 cognitively unimpaired, amyloid-negative participants; 37 cognitively unimpaired amyloid-positive participants and 30 cognitively impaired amyloid-positive participants in a 12-15 month study.This study showed that in cognitively unimpaired amyloid-negative participants, tau PET signal did not increase, while it did in cognitively unimpaired amyloid-positive and cognitIV”

• cites [130] La Joie, R. et al. Prospective longitudinal atrophy in Alzheimer’s disease correlates with the intensity and topography of baseline tau-PET. Sci. Transl. Med. 12, eaau5732 (2020). sourceNot checked yet

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May combine two claims. The quote only partly states this claim.

Aschenbrenner et al. retrospectively studied 152 participants; only tau PET signal significantly predicted cognitive decline, while high amyloid levels were also associated with tau-related cognitive decline.

“Aschenbrenner et al. 131 performed a retrospective study of 152 participants who had received at least 1 flortaucipir tau PET scan and 1 florbetapir amyloid PET scan within a year, and ≥2 clinical and cognitive assessments.All participants entering the study had equal to or less than 0.5 on the CDR scale; that is, they were cognitively normal or with very mild AD.The statistical analysis demonstr”

• cites [131] Ossenkoppele, R. et al. Discriminative accuracy of [18F]flortaucipir positron emission tomography for Alzheimer disease vs other neurodegenerative disorders. JAMA 320, 1151–1162 (2018). sourceNot checked yet

  Not checked in the free run.

May combine two claims.

These and other studies strongly support the concept of AD as an amyloid-provoked or facilitated tauopathy, although there is also evidence that both pathologies act in synergy.

“These and other studies 13,24,133,134 strongly support the concept of AD as being an amyloid-provoked, or facilitated, tauopathy, although there is also evidence that both pathologies act in synergy 135 .”

• cites [13] Jagust, W. Imaging the evolution and pathophysiology of Alzheimer disease. Nat. Rev. Neurosci. 19, 687–700 (2018). sourceNot checked yet

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• cites [24] Mattsson-Carlgren, N. et al. The implications of different approaches to define AT(N) in Alzheimer disease. Neurology 94, e2233–e2244 (2020). sourceNot checked yet

  Not checked in the free run.

• cites [133] Driscoll, I. et al. Correspondence between in vivo (11)C-PiB-PET amyloid imaging and postmortem, region-matched assessment of plaques. Acta Neuropathol. 124, 823–831 (2012). sourceNot checked yet

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• cites [134] Curtis, C. et al. Phase 3 trial of flutemetamol labeled with radioactive fluorine 18 imaging and neuritic plaque density. JAMA Neurol. 72, 287–294 (2015). sourceNot checked yet

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• cites [135] Sabri, O. et al. Florbetaben PET imaging to detect amyloid beta plaques in Alzheimer’s disease: phase 3 study. Alzheimers Dement. 11, 964–974 (2015). sourceNot checked yet

  Not checked in the free run.

May combine two claims.

Amadoru et al. found the optimum threshold between low and high amyloid plaque was 21 CL, and 10 CL for none versus any.

“The optimum threshold between low vs high amyloid plaque was 21 CL; and 10 CL for none vs. any.”

• cites [88] Jack, C. R. et al. Predicting future rates of tau accumulation on PET. Brain 143, 3136–3150 (2020). sourceNot checked yet

  Not checked in the free run.

Classified as probably not a substantial claim.

A CL value of <=20 is a reasonable definition of 'amyloid negativity'.

“In summary, these studies show that a CL value of ≤ 20 is a reasonable value to define 'amyloid negativity'.”

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

Bapineuzumab has a normalized rate of amyloid removal of 0 CL/4 wk/10mg/kg.

“| Bapineuzumab | 0.3 | ~7 a /12 | 0 | 71 | 0 | 9 | - |”

• cites [60] Liu, E. et al. Amyloid-β 11C-PiB-PET imaging results from 2 randomized bapineuzumab phase 3 AD trials. Neurology 85, 692–700 (2015). sourceNot checked yet

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• cites [61] Bohrmann, B. et al. Gantenerumab: a novel human anti-Abeta antibody demonstrates sustained cerebral amyloid-beta binding and elicits cell-mediated removal of human amyloid-beta. J. Alzheimers Dis. 28, 49–69 (2012). sourceNot checked yet

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• AssumptionThe authors state this as an assumption: The calculations of normalized dose assume an average patient weight of 70 kg.

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

Bapineuzumab has an incidence of ARIA-E of 9%.

“| Bapineuzumab | 0.3 | ~7 a /12 | 0 | 71 | 0 | 9 | - |”

• cites [60] Liu, E. et al. Amyloid-β 11C-PiB-PET imaging results from 2 randomized bapineuzumab phase 3 AD trials. Neurology 85, 692–700 (2015). sourceNot checked yet

  Not checked in the free run.

• cites [61] Bohrmann, B. et al. Gantenerumab: a novel human anti-Abeta antibody demonstrates sustained cerebral amyloid-beta binding and elicits cell-mediated removal of human amyloid-beta. J. Alzheimers Dis. 28, 49–69 (2012). sourceNot checked yet

  Not checked in the free run.