Brain accumulation of the amyloid-β (Aβ) peptide is believed to be the initial event in the Alzheimer disease (AD) process. Aβ accumulation begins 15–20 years before clinical symptoms occur, mainly owing to defective brain clearance of the peptide. Over the past 20 years, we have seen intensive efforts to decrease the levels of Aβ monomers, oligomers, aggregates and plaques using compounds that decrease production, antagonize aggregation or increase brain clearance of Aβ. Unfortunately, these approaches have failed to show clinical benefit in large clinical trials involving patients with mild to moderate AD. Clinical trials in patients at earlier stages of the disease are ongoing, but the initial results have not been clinically impressive. Efforts are now being directed against Aβ oligomers, the most neurotoxic molecular species, and monoclonal antibodies directed against these oligomers are producing encouraging results. However, Aβ oligomers are in equilibrium with both monomeric and aggregated species; thus, previous drugs that efficiently removed monomeric Aβ or Aβ plaques should have produced clinical benefits. In patients with sporadic AD, Aβ accumulation could be a reactive compensatory response to neuronal damage of unknown cause, and alternative strategies, including interference with modifiable risk factors, might be needed to defeat this devastating disease.
Genetic, biochemical, histopathological, biomarker and cognitive studies have suggested that brain accumulation of the amyloid-β (Aβ) peptide is the initial event in the Alzheimer disease (AD) process.
Over the past 15 years, several drugs that decrease Aβ production, antagonize Aβ aggregation or increase brain Aβ clearance have been tested in patients with mild to moderate AD but without success.
Anti-Aβ drugs have also produced disappointing results in individuals at earlier stages of the disease who have biomarker evidence of Aβ brain deposition.
This series of clinical failures has raised the possibility that Aβ accumulation represents an epiphenomenon rather than a cause of AD, casting doubt on the prevailing amyloid cascade hypothesis of AD.
Aducanumab, a potent monoclonal antibody specifically directed against Aβ oligomers, produced encouraging preliminary results in patients with prodromal or mild AD, suggesting that oligomeric Aβ species may represent a valid biological target.
As accumulation of Aβ in the brain starts 15–20 years before the onset of clinical symptoms, drugs are now being tested in preclinical or asymptomatic stages of AD and in cognitively healthy individuals at risk of AD.
Other promising approaches directed against key elements of the disease, such as CNS inflammation, brain insulin resistance and tau aggregation, must be more intensively pursued to avoid a therapeutic vacuum should the present anti-Aβ therapies fail even in asymptomatic individuals.
Access optionsAccess options
Subscribe to Journal
Get full journal access for 1 year
only $17.75 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Murphy, S. L., Xu, J., Kochanek, K. D., Curtin, S. C. & Arias, E. Deaths: final data for 2015. Natl Vital Stat. Rep. 66, 1–75 (2017).
Alzheimer’s Association. 2017 Alzheimer’s disease facts and figures. Alzheimers Dement. 13, 325–373 (2017).
Beyreuther, K. & Masters, C. L. Amyloid precursor protein (APP) and βA4 amyloid in the etiology of Alzheimer’s disease: precursor–product relationships in the derangement of neuronal function. Brain Pathol. 1, 241–251 (1991).
Hardy, J. & Allsop, D. Amyloid deposition as the central event in the aetiology of Alzheimer’s disease. Trends Pharmacol. Sci. 12, 383–388 (1991).
Selkoe, D. J. The molecular pathology of Alzheimer’s disease. Neuron 6, 487–498 (1991).
Hardy, J. A. & Higgins, G. A. Alzheimer’s disease: the amyloid cascade hypothesis. Science 256, 184–185 (1992).
Karran, E., Mercken, M. & De Strooper, B. The amyloid cascade hypothesis for Alzheimer’s disease: an appraisal for the development of therapeutics. Nat. Rev. Drug Discov. 10, 698–712 (2011).
Jonsson, T. et al. A mutation in APP protects against Alzheimer’s disease and age-related cognitive decline. Nature 488, 96–99 (2012).
Mawuenyega, K. G. et al. Decreased clearance of CNS β-amyloid in Alzheimer’s disease. Science 330, 1774 (2010).
Yang, L. B. et al. Elevated β-secretase expression and enzymatic activity detected in sporadic Alzheimer disease. Nat. Med. 9, 3–4 (2003).
Liu, C. C., Kanekiyo, T., Xu, H. & Bu, G. Apolipoprotein E and Alzheimer disease: risk, mechanisms and therapy. Nat. Rev. Neurol. 9, 106–118 (2013).
Lim, Y. Y. & Mormino, E. C. APOE genotype and early β-amyloid accumulation in older adults without dementia. Neurology 89, 1028–1034 (2017).
Jack, C. R. Jr et al. Tracking pathophysiological processes in Alzheimer’s disease: an updated hypothetical model of dynamic biomarkers. Lancet Neurol. 12, 207–216 (2013).
Bennett, D. A. et al. Neuropathology of older persons without cognitive impairment from two community-based studies. Neurology 66, 1837–1844 (2006).
Jansen, W. J. et al. Prevalence of cerebral amyloid pathology in persons without dementia: a meta-analysis. JAMA 313, 1924–1938 (2015).
Vos, S. J. et al. Preclinical Alzheimer’s disease and its outcome: a longitudinal cohort study. Lancet Neurol. 12, 957–965 (2013).
Villemagne, V. L. et al. Amyloid β deposition, neurodegeneration, and cognitive decline in sporadic Alzheimer’s disease: a prospective cohort study. Lancet Neurol. 12, 357–367 (2013).
Burnham, S. C. et al. Clinical and cognitive trajectories in cognitively healthy elderly individuals with suspected non-Alzheimer’s disease pathophysiology (SNAP) or Alzheimer’s disease pathology: a longitudinal study. Lancet Neurol. 15, 1044–1053 (2016).
Petersen, R. C. et al. Association of elevated amyloid levels with cognition and biomarkers in cognitively normal people from the community. JAMA Neurol. 73, 85–92 (2016).
Donohue, M. C. et al. Association between elevated brain amyloid and subsequent cognitive decline among cognitively normal persons. JAMA 317, 2305–2316 (2017).
Gomez-Isla, T. et al. Neuronal loss correlates with but exceeds neurofibrillary tangles in Alzheimer’s disease. Ann. Neurol. 41, 17–24 (1997).
Arriagada, P. V., Growdon, J. H., Hedley-Whyte, E. T. & Hyman, B. T. Neurofibrillary tangles but not senile plaques parallel duration and severity of Alzheimer’s disease. Neurology 42, 631–639 (1992).
Bierer, L. M. et al. Neocortical neurofibrillary tangles correlate with dementia severity in Alzheimer’s disease. Arch. Neurol. 52, 81–88 (1995).
Bennett, D. A., Schneider, J. A., Wilson, R. S., Bienias, J. L. & Arnold, S. E. Neurofibrillary tangles mediate the association of amyloid load with clinical Alzheimer disease and level of cognitive function. Arch. Neurol. 61, 378–384 (2004).
Buckley, R. F. et al. Region-specific association of subjective cognitive decline with tauopathy independent of global β-amyloid burden. JAMA Neurol. 74, 1455–1463 (2017).
Wang, L. et al. Evaluation of tau imaging in staging Alzheimer disease and revealing interactions between β-amyloid and tauopathy. JAMA Neurol. 73, 1070–1077 (2016).
Sutphen, C. L. et al. Longitudinal decreases in multiple cerebrospinal fluid biomarkers of neuronal injury in symptomatic late onset Alzheimer’s disease. Alzheimers Dement. 14, 869–879 (2018).
McDade, E. et al. Longitudinal cognitive and biomarker changes in dominantly inherited Alzheimer disease. Neurology 91, e1295–e1306 (2018).
Sato, C. et al. Tau kinetics in neurons and the human central nervous system. Neuron 97, 1284–1298 (2018).
He, Z. et al. Amyloid-β plaques enhance Alzheimer’s brain tau-seeded pathologies by facilitating neuritic plaque tau aggregation. Nat. Med. 24, 29–38 (2018).
Hansson, O. et al. Association between CSF biomarkers and incipient Alzheimer’s disease in patients with mild cognitive impairment: a follow-up study. Lancet Neurol. 5, 228–234 (2006).
Jack, C. R. Jr et al. Age-specific and sex-specific prevalence of cerebral β-amyloidosis, tauopathy, and neurodegeneration in cognitively unimpaired individuals aged 50–95 years: a cross-sectional study. Lancet Neurol. 16, 435–444 (2017).
Jones, D. T. et al. Tau, amyloid, and cascading network failure across the Alzheimer’s disease spectrum. Cortex 97, 143–159 (2017).
Holmes, C. et al. Long-term effects of Aβ42 immunisation in Alzheimer’s disease: follow-up of a randomised, placebo-controlled phase I trial. Lancet 372, 216–223 (2008).
Gilman, S. et al. Clinical effects of Aβ immunization (AN1792) in patients with AD in an interrupted trial. Neurology 64, 1553–1562 (2005).
Pasquier, F. et al. Two phase 2 multiple ascending-dose studies of vanutide cridificar (ACC-001) and QS-21 adjuvant in mild-to-moderate Alzheimer’s disease. J. Alzheimers Dis. 51, 1131–1143 (2016).
Wiessner, C. et al. The second-generation active Aβ immunotherapy CAD106 reduces amyloid accumulation in APP transgenic mice while minimizing potential side effects. J. Neurosci. 31, 9323–9331 (2011).
Winblad, B. et al. Safety, tolerability, and antibody response of active Aβ immunotherapy with CAD106 in patients with Alzheimer’s disease: randomised, double-blind, placebo-controlled, first-in-human study. Lancet Neurol. 11, 597–604 (2012).
Farlow, M. R. et al. Long-term treatment with active Aβ immunotherapy with CAD106 in mild Alzheimer’s disease. Alzheimers Res. Ther. 7, 23 (2015).
Vandenberghe, R. et al. Active Aβ immunotherapy CAD106 in Alzheimer’s disease: a phase 2b study. Alzheimers Dement. 3, 10–22 (2016).
Langbaum, J. B. et al. Establishing composite cognitive endpoints for use in preclinical Alzheimer’s disease trials. J. Prev. Alzheimers Dis. 2, 2–3 (2015).
Bouter, Y. et al. Aβ targets of the biosimilar antibodies of bapineuzumab, crenezumab, solanezumab in comparison to an antibody against N-truncated Aβ in sporadic Alzheimer disease cases and mouse models. Acta Neuropathol. 130, 713–729 (2015).
Dodart, J. C. et al. Immunization reverses memory deficits without reducing brain Aβ burden in Alzheimer’s disease model. Nat. Neurosci. 5, 452–457 (2002).
DeMattos, R. B. et al. Peripheral anti-Aβ antibody alters CNS and plasma Aβ clearance and decreases brain Aβ burden in a mouse model of Alzheimer’s disease. Proc. Natl Acad. Sci. USA 98, 8850–8855 (2001).
Mably, A. J. et al. Anti-Aβ antibodies incapable of reducing cerebral Aβ oligomers fail to attenuate spatial reference memory deficits in J20 mice. Neurobiol. Dis. 82, 372–384 (2015).
Siemers, E. R. et al. Safety and changes in plasma and cerebrospinal fluid amyloid-β after a single administration of an amyloid-β monoclonal antibody in subjects with Alzheimer disease. Clin. Neuropharmacol. 33, 67–73 (2010).
Uenaka, K. et al. Comparison of pharmacokinetics, pharmacodynamics, safety, and tolerability of the amyloid β monoclonal antibody solanezumab in Japanese and white patients with mild to moderate alzheimer disease. Clin. Neuropharmacol. 35, 25–29 (2012).
Farlow, M. et al. Safety and biomarker effects of solanezumab in patients with Alzheimer’s disease. Alzheimers Dement. 8, 261–271 (2012).
Doody, R. S. et al. Phase 3 trials of solanezumab for mild-to-moderate Alzheimer’s disease. N. Engl. J. Med. 370, 311–321 (2014).
Honig, L. S. et al. Trial of solanezumab for mild dementia due to Alzheimer’s disease. N. Engl. J. Med. 378, 321–330 (2018).
Sperling, R. A. et al. The A4 study: stopping AD before symptoms begin? Sci. Transl Med. 6, 228fs13 (2014).
Donohue, M. C. et al. The preclinical Alzheimer cognitive composite: measuring amyloid-related decline. JAMA Neurol. 71, 961–970 (2014).
Bohrmann, B. et al. Gantenerumab: a novel human anti-Aβ antibody demonstrates sustained cerebral amyloid-β binding and elicits cell-mediated removal of human amyloid-β. J. Alzheimers Dis. 28, 49–69 (2012).
Jacobsen, H. et al. Combined treatment with a BACE inhibitor and anti-Aβ antibody gantenerumab enhances amyloid reduction in APPLondon mice. J. Neurosci. 34, 11621–11630 (2014).
Barrow, P. et al. Reproductive and developmental toxicology studies with gantenerumab in PS2APP transgenic mice. Reprod. Toxicol. 73, 362–371 (2017).
Ostrowitzki, S. et al. Mechanism of amyloid removal in patients with Alzheimer disease treated with gantenerumab. Arch. Neurol. 69, 198–207 (2012).
Ostrowitzki, S. et al. A phase III randomized trial of gantenerumab in prodromal Alzheimer’s disease. Alzheimers Res. Ther. 9, 95 (2017).
Nikolcheva, T. et al. CSF and amyloid pet biomarker data from the phase 3 SCarlet RoAD trial, a study of gantenerumab in patients with prodromal AD. Neurobiol. Aging 39(Suppl.), S28–S29 (2016).
Abi-Saab, D. et al. The effect of 6-month dosing on the rate of amyloid-related imaging abnormalities (ARIA) in the Marguerite RoAD study. Alzheimers Dement. 13(Suppl.), P252–P253 (2017).
Abi-Saab, D. et al. MRI findings in the open label extension of the Marguerite RoAD study in patients with mild Alzheimer’s disease [abstract P36]. Presented at the 10th Clinical Trials on Alzheimer’s Disease, Boston, MA, USA (2017).
Adolfsson, O. et al. An effector-reduced anti-β-amyloid (Aβ) antibody with unique Aβ binding properties promotes neuroprotection and glial engulfment of Aβ. J. Neurosci. 32, 9677–9789 (2012).
Zhao, J., Nussinov, R. & Ma, B. Mechanisms of recognition of amyloid-β (Aβ) monomer, oligomer, and fibril by homologous antibodies. J. Biol. Chem. 292, 18325–18343 (2017).
Ultsch, M. et al. Structure of crenezumab complex with Aβ shows loss of β-hairpin. Sci. Rep. 6, 39374 (2016).
Fuller, J. P. et al. Comparing the efficacy and neuroinflammatory potential of three anti-Aβ antibodies. Acta Neuropathol. 130, 699–711 (2015).
Cummings, J. L. et al. ABBY: a phase 2 randomized trial of crenezumab in mild to moderate Alzheimer disease. Neurology 90, e1889–e1897 (2018).
Salloway, S. et al. Amyloid positron emission tomography and cerebrospinal fluid results from a crenezumab anti-amyloid-beta antibody double-blind, placebo-controlled, randomized phase II study in mild-to-moderate Alzheimer’s disease (BLAZE). Alzheimers Res. Ther. 10, 96 (2018).
Asnaghi, V. et al. Safety and tolerability of crenezumab in mild-to-moderate AD patients treated with escalating doses for up to 25 months. Alzheimers Dement. 13(Suppl.), 602 (2017).
Blaettler, T. Clinical trial design of CREAD: a randomized, double-blind, placebo-controlled, parallel-group phase-3 study to evaluate crenezumab treatment in patients with prodromal-to-mild Alzheimer’s disease. Alzheimers Dement. 12 (Suppl.), 609 (2016).
Tariot, P. N. et al. The Alzheimer’s Prevention Initiative Autosomal-Dominant Alzheimer’s Disease Trial: a study of crenezumab versus placebo in preclinical PSEN1 E280A mutation carriers to evaluate efficacy and safety in the treatment of autosomal-dominant Alzheimer’s disease, including a placebo-treated noncarrier cohort. Alzheimers Dement. 4, 150–160 (2018).
Arndt, J. W. et al. Structural and kinetic basis for the selectivity of aducanumab for aggregated forms of amyloid-β. Sci. Rep. 8, 6412 (2018).
Sevigny, J. et al. The antibody aducanumab reduces Aβ plaques in Alzheimer’s disease. Nature 537, 50–56 (2016).
Kastanenka, K. V. et al. Immunotherapy with aducanumab restores calcium homeostasis in Tg2576 mice. J. Neurosci. 36, 12549–12558 (2016).
Ferrero, J. et al. First-in-human, double-blind, placebo-controlled, single-dose escalation study of aducanumab (BIIB037) in mild-to-moderate Alzheimer’s disease. Alzheimers Dement. 2, 169–176 (2016).
Budd Haeberlein, S. et al. Clinical development of aducanumab, an anti-Aβ human monoclonal antibody being investigated for the treatment of early Alzheimer’s disease. J. Prev. Alzheimers Dis. 4, 255–263 (2017).
Vassar, R. et al. Function, therapeutic potential and cell biology of BACE proteases: current status and future prospects. J. Neurochem. 130, 4–28 (2014).
Filser, S. et al. Pharmacological inhibition of BACE1 impairs synaptic plasticity and cognitive functions. Biol. Psychiatry 77, 729–739 (2015).
Zhu, K. et al. β-Site amyloid precursor protein cleaving enzyme 1 inhibition impairs synaptic plasticity via seizure protein 6. Biol. Psychiatry 83, 428–437 (2018).
Kennedy, M. E. et al. The BACE1 inhibitor verubecestat (MK-8931) reduces CNS β-amyloid in animal models and in Alzheimer’s disease patients. Sci. Transl Med. 8, 363ra150 (2016).
Villarreal, S. et al. Chronic verubecestat treatment suppresses amyloid accumulation in advanced aged Tg2576-AβPPswe mice without inducing microhemorrhage. J. Alzheimers Dis. 59, 1393–1413 (2017).
Egan, M. F. et al. Randomized trial of verubecestat for mild-to-moderate Alzheimer’s disease. N. Engl. J. Med. 378, 1691–1703 (2018).
Sur, C. et al. BACE inhibition by verubecestat produces a rapid, non-progressive reduction in brain and hippocampal volume in Alzheimer’s disease [abstract OC13]. Presented at the 11th Clinical Trials on Alzheimer’s Disease, Barcelona, Spain (2018).
Business Wire. Merck announces discontinuation of APECS study evaluating verubecestat (MK-8931) for the treatment of people with prodromal Alzheimer’s disease. Business Wire https://www.businesswire.com/news/home/20180213006582/en/ (2018).
Eketjäll, S. et al. AZD3293: a novel, orally active BACE1 inhibitor with high potency and permeability and markedly slow off-rate kinetics. J. Alzheimers Dis. 50, 1109–1123 (2016).
Cebers, G. et al. Reversible and species-specific depigmentation effects of AZD3293, a BACE inhibitor for the treatment of Alzheimer’s disease, are related to BACE2 inhibition and confined to epidermis and hair. J. Prev. Alzheimers Dis. 3, 202–218 (2016).
Cebers, G. et al. AZD3293: pharmacokinetic and pharmacodynamic effects in healthy subjects and patients with Alzheimer’s disease. J. Alzheimers Dis. 55, 1039–1053 (2017).
Sakamoto, K. et al. BACE1 inhibitor lanabecestat (AZD3293) in a phase 1 study of healthy japanese subjects: pharmacokinetics and effects on plasma and cerebrospinal fluid Aβ peptides. J. Clin. Pharmacol. 57, 1460–1471 (2017).
Sims, J. R. et al. Development review of the BACE1 inhibitor lanabecestat (AZD3293/LY3314814). J. Prev. Alzheimers Dis. 4, 247–254 (2017).
Malone, E. Lilly/AstraZeneca’s lanabecestat becomes latest BACE inhibitor casualty. Scrip https://scrip.pharmaintelligence.informa.com/SC123243/LillyAstraZenecas-Lanabecestat-Becomes-Latest-BACE-Inhibitor-Casualty (2018).
Lai, R. et al. First-in-human study of E2609, a novel BACE1 inhibitor, demonstrates prolonged reductions in plasma beta-amyloid levels after single dosing. Alzheimers Dement. 8(Suppl.), 96 (2012).
Albala, B. et al. CSF amyloid lowering in human volunteers after 14 days’ oral administration of the novel BACE1 inhibitor E2609. Alzheimers Dement. 8 (Suppl.), S743 (2012).
Oneeb, M. et al. Dose-related reductions of CSF amyloid β(1-x) by E2609, a novel BACE inhibitor in patients with mild cognitive impairment due to Alzheimer’s disease (AD and mild-moderate AD dementia [abstract P3-28]. Presented at the 9th Clinical Trials on Alzheimer’s Disease, 2016, San Diego, CA, USA (2016).
Wang, J. et al. ADCOMS: a composite clinical outcome for prodromal Alzheimer’s disease trials. J. Neurol. Neurosurg. Psychiatry 87, 993–999 (2016).
Ito, H. et al. Preclinical multi-species pharmacokinetic/pharmacodynamic analysis of the oral BACE inhibitor JNJ-54861911. Alzheimers Dement. 13(Suppl.), P266–P267 (2017).
Timmers, M. et al. Profiling the dynamics of CSF and plasma Aβ reduction after treatment with JNJ-54861911, a potent oral BACE inhibitor. Alzheimers Dement. 2, 202–212 (2016).
Streffer, J. et al. Pharmacodynamics of the oral BACE inhibitor JNJ-54861911 in early Alzheimer’s disease. Alzheimers Dement. 12 (Suppl.), P199–P200 (2016).
Janssen. Update on Janssen’s BACE inhibitor program. Janssen https://www.janssen.com/update-janssens-bace-inhibitor-program (2018).
Neumann, U. et al. The BACE-1 inhibitor CNP520 for prevention trials in Alzheimer’s disease. EMBO Mol. Med. 10, e9316 (2018).
Ufer, M. et al. Results from a first-in-man study with the BACE inhibitor CNP520. Alzheimers Dement. 12(Suppl.), 200 (2016).
Lopez Lopez, C. et al. Alzheimer’s Prevention Initiative Generation Program: evaluating CNP520 efficacy in the prevention of Alzheimer’s disease. J. Prev. Alzheimers Dis. 4, 242–246 (2017).
Selkoe, D. J. & Hardy, J. The amyloid hypothesis of Alzheimer’s disease at 25 years. EMBO Mol. Med. 8, 595–608 (2016).
Giannakopoulos, P. et al. Tangle and neuron numbers, but not amyloid load, predict cognitive status in Alzheimer’s disease. Neurology 60, 1495–1500 (2003).
Kuo, Y. M. et al. Water-soluble Aβ (N-40, N-42) oligomers in normal and Alzheimer disease brains. J. Biol. Chem. 271, 4077–4081 (1996).
Funato, H., Enya, M., Yoshimura, M., Morishima-Kawashima, M. & Ihara, Y. Presence of sodium dodecyl sulfate-stable amyloid β-protein dimers in the hippocampus CA1 not exhibiting neurofibrillary tangle formation. Am. J. Pathol. 155, 23–28 (1999).
Yang, T., Li, S., Xu, H., Walsh, D. M. & Selkoe, D. J. Large soluble oligomers of amyloid β-protein from Alzheimer brain are far less neuroactive than the smaller oligomers to which they dissociate. J. Neurosci. 37, 152–163 (2017).
Wang, Z. X., Tan, L., Liu, J. & Yu, J. T. The essential role of soluble Aβ oligomers in Alzheimer’s disease. Mol. Neurobiol. 53, 1905–1924 (2016).
Polanco, J. C. et al. Amyloid-β and tau complexity — towards improved biomarkers and targeted therapies. Nat. Rev. Neurol. 14, 22–39 (2018).
Zhao, Y. et al. Amyloid β peptides block new synapse assembly by Nogo receptor-mediated inhibition of T-type calcium channels. Neuron 96, 355–372 (2017).
Lesné, S. E. et al. Brain amyloid-β oligomers in ageing and Alzheimer’s disease. Brain 136, 1383–1398 (2013).
Amar, F. et al. The amyloid-β oligomer Aβ*56 induces specific alterations in neuronal signaling that lead to tau phosphorylation and aggregation. Sci. Signal. 10, eaal2021 (2017).
Busche, M. A. et al. Decreased amyloid-β and increased neuronal hyperactivity by immunotherapy in Alzheimer’s models. Nat. Neurosci. 18, 1725–1727 (2015).
Abbott, A. & Dolgin, E. Failed Alzheimer’s trial does not kill leading theory of disease. Nature 540, 15–16 (2016).
Maarouf, C. L. et al. The biochemical aftermath of anti-amyloid immunotherapy. Mol. Neurodegener. 5, 39 (2010).
Hara, H. et al. An oral Aβ vaccine using a recombinant adeno-associated virus vector in aged monkeys: reduction of amyloid plaques and increase of Aβ oligomers. J. Alzheimers Dis. 54, 1047–1059 (2016).
Townsend, M. et al. Orally available compound prevents deficits in memory caused by the Alzheimer amyloid-β oligomers. Ann. Neurol. 60, 668–676 (2006).
Yamada, J. et al. Aβ immunotherapy: intracerebral sequestration of Aβ by an anti Aβ monoclonal antibody 266 with high affinity to soluble Aβ. J. Neurosci. 29, 11393–11398 (2009).
Watts, R. J. et al. Selection of an anti-Aβ antibody that binds various forms of Aβ and blocks toxicity both in vitro and in vivo. Alzheimers Dement. 5 (Suppl.), 426 (2009).
Relkin, R. N. Natural human antibodies targeting amyloid aggregates in intravenous immunoglobulin. Alzheimers Dement. 4 (Suppl.), T101 (2008).
Du, Y. et al. Human anti-β-amyloid antibodies block β-amyloid fibril formation and prevent β-amyloid-induced neurotoxicity. Brain 26, 1935–1939 (2003).
Ma, Q. L. et al. Antibodies against β-amyloid reduce Aβ oligomers, glycogen synthase kinase-3β activation and τ phosphorylation in vivo and in vitro. J. Neurosci. Res. 83, 374–384 (2006).
Logovinsky, V. et al. Safety and tolerability of BAN2401 — a clinical study in Alzheimer’s disease with a protofibril selective Aβ antibody. Alzheimers Res. Ther. 8, 14 (2016).
Astrén Eriksson, C. et al. BioArctic announces positive topline results of BAN2401 phase 2b at 18 months in early Alzheimer’s disease. BioArctic https://www.bioarctic.se/en/bioarctic-announces-positive-topline-results-of-ban2401-phase-2b-at-18-months-in-early-alzheimers-disease-3600/ (2018).
Kim, J. et al. Normal cognition in transgenic BRI2-Aβ mice. Mol. Neurodegener. 8, 15 (2013).
Chételat, G. Alzheimer disease: Aβ-independent processes-rethinking preclinical AD. Nat. Rev. Neurol. 9, 123–124 (2013).
Morris, G. P., Clark, I. A. & Vissel, B. Inconsistencies and controversies surrounding the amyloid hypothesis of Alzheimer’s disease. Acta Neuropathol. Commun. 2, 135 (2014).
Musiek, E. S. & Holtzman, D. M. Three dimensions of the amyloid hypothesis: time, space and ‘wingmen’. Nat. Neurosci. 18, 800–806 (2015).
Braak, H. & Del Tredici, K. The pathological process underlying Alzheimer’s disease in individuals under thirty. Acta Neuropathol. 121, 171–181 (2011).
Knopman, D. S. et al. Brain injury biomarkers are not dependent on β-amyloid in normal elderly. Ann. Neurol. 73, 472–480 (2013).
Knopman, D. S. et al. Short-term clinical outcomes for stages of NIA-AA preclinical Alzheimer disease. Neurology 78, 1576–1582 (2012).
Jagust, W. J. & Landau, S. M. Apolipoprotein E, not fibrillar β-amyloid, reduces cerebral glucose metabolism in normal aging. J. Neurosci. 32, 18227–18233 (2012).
Gordon, B. A. et al. Spatial patterns of neuroimaging biomarker change in individuals from families with autosomal dominant Alzheimer’s disease: a longitudinal study. Lancet Neurol. 17, 241–250 (2018).
Jack, C. R. Jr et al. Hypothetical model of dynamic biomarkers of the Alzheimer’s pathological cascade. Lancet Neurol. 9, 119–128 (2010).
Sperling, R. A. et al. Toward defining the preclinical stages of Alzheimer’s disease: recommendations from the National Institute on Aging–Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s disease. Alzheimers Dement. 7, 280–292 (2011).
Jansen, W. J. et al. Association of cerebral amyloid-β aggregation with cognitive functioning in persons without dementia. JAMA Psychiatry 75, 84–95 (2018).
Dubois, B. et al. Cognitive and neuroimaging features and brain β-amyloidosis in individuals at risk of Alzheimer’s disease (INSIGHT-preAD): a longitudinal observational study. Lancet Neurol. 17, 335–346 (2018).
Herrup, K. The case for rejecting the amyloid cascade hypothesis. Nat. Neurosci. 18, 794–799 (2015).
Bishop, G. M. & Robinson, S. R. Physiological roles of amyloid-β and implications for its removal in Alzheimer’s disease. Drugs Aging 21, 621–630 (2004).
Puzzo, D., Gulisano, W., Arancio, O. & Palmeri, A. The keystone of Alzheimer pathogenesis might be sought in Aβ physiology. Neuroscience 307, 26–36 (2015).
Yu, Y., Jans, D. C., Winblad, B., Tjernberg, L. O. & Schedin-Weiss, S. Neuronal Aβ42 is enriched in small vesicles at the presynaptic side of synapses. Life Sci. Alliance 1, e201800028 (2018).
Livingston, G. et al. Dementia prevention, intervention, and care. Lancet 390, 2673–2734 (2017).
Butterfield, D. A., Di Domenico, F. & Barone, E. Elevated risk of type 2 diabetes for development of Alzheimer disease: a key role for oxidative stress in brain. Biochim. Biophys. Acta 1842, 1693–1706 (2014).
Arnold, S. E. et al. Brain insulin resistance in type 2 diabetes and Alzheimer disease: concepts and conundrums. Nat. Rev. Neurol. 14, 168–181 (2018).
Mielke, J. G. & Wang, Y. T. Insulin, synaptic function, and opportunities for neuroprotection. Prog. Mol. Biol. Transl Sci. 98, 133–186 (2011).
Chiu, S. L., Chen, C. M. & Cline, H. T. Insulin receptor signaling regulates synapse number, dendritic plasticity, and circuit function in vivo. Neuron 58, 708–719 (2008).
Bruehl, H. et al. Cognitive impairment in nondiabetic middle-aged and older adults isassociated with insulin resistance. J. Clin. Exp. Neuropsychol. 32, 487–493 (2010).
De Felice, F. G. & Ferreira, S. T. Inflammation, defective insulin signaling, and mitochondrial dysfunction as common molecular denominators connecting type 2 diabetes to Alzheimer disease. Diabetes 63, 2262–2272 (2014).
Yarchoan, M. & Arnold, S. E. Repurposing diabetes drugs for brain insulin resistance in Alzheimer disease. Diabetes 63, 2253–2261 (2014).
Benedict, C. & Grillo, C. A. Insulin resistance as a therapeutic target in the treatment of Alzheimer’s disease: a state-of-the-art. Front. Neurosci. 12, 215 (2018).
Batista, A. F. et al. The diabetes drug liraglutide reverses cognitive impairment in mice and attenuates insulin receptor and synaptic pathology in a non-human primate model of Alzheimer’s disease. J. Pathol. 245, 85–100 (2018).
Craft, S. et al. Effects of regular and long-acting insulin on cognition and Alzheimer’s disease biomarkers: a pilot clinical trial. J. Alzheimers Dis. 57, 1325–1334 (2017).
Abbott, A. Is ‘friendly fire’ in the brain provoking Alzheimer’s disease? Nature 556, 426–428 (2018).
Salter, M. W. & Stevens, B. Microglia emerge as central players in brain disease. Nat. Med. 23, 1018–1027 (2017).
Bu, X. L. et al. A study on the association between infectious burden and Alzheimer’s disease. Eur. J. Neurol. 22, 1519–1525 (2015).
Fani, L. et al. Helicobacter pylori and the risk of dementia: a population-based study. Alzheimers Dement. 14, 1377–1382 (2018).
Marsh, S. E. et al. The adaptive immune system restrains Alzheimer’s disease pathogenesis by modulating microglial function. Proc. Natl Acad. Sci. USA 113, E1316–E1325 (2016).
Congdon, E. E. & Sigurdsson, E. M. Tau-targeting therapies for Alzheimer disease. Nat. Rev. Neurol. 14, 399–415 (2018).
Kamenetz, F. et al. APP processing and synaptic function. Neuron 37, 925–937 (2003).
Esteban, J. A. Living with the enemy: a physiological role for the β-amyloid peptide. Trends Neurosci. 27, 1–3 (2004).
Parihar, M. S. & Brewer, G. J. Amyloid-β as a modulator of synaptic plasticity. J. Alzheimers Dis. 22, 741–763 (2010).
Lawrence, J. L. et al. Regulation of presynaptic Ca2+, synaptic plasticity and contextual fear conditioning by a N-terminal β-amyloid fragment. J. Neurosci. 34, 14210–14218 (2014).
Palmeri, A. et al. Amyloid-β peptide is needed for cGMP-induced long-term potentiation and memory. J. Neurosci. 37, 6926–6937 (2017).
Abramov, E. et al. Amyloid-β as a positive endogenous regulator of release probability at hippocampal synapses. Nat. Neurosci. 12, 1567–1576 (2009).
Morley, J. E. et al. A physiological role for amyloid-β protein: enhancement of learning and memory. J. Alzheimers Dis. 19, 441–449 (2010).
Puzzo, D. et al. Endogenous amyloid-β is necessary for hippocampal synaptic plasticity and memory. Ann. Neurol. 69, 819–830 (2011).
López-Toledano, M. A. & Shelanski, M. L. Neurogenic effect of β-amyloid peptide in the development of neural stem cells. J. Neurosci. 24, 5439–5444 (2004).
Plant, L. D., Boyle, J. P., Smith, I. F., Peers, C. & Pearson, H. A. The production of amyloid β peptide is a critical requirement for the viability of central neurons. J. Neurosci. 23, 5531–5535 (2003).
Marklund, N. et al. Monitoring of β-amyloid dynamics after human traumatic brain injury. J. Neurotrauma 31, 42–55 (2014).
Gatson, J. W. et al. Detection of β-amyloid oligomers as a predictor of neurological outcome after brain injury. J. Neurosurg. 118, 1336–1342 (2013).
Johnson, V., Stewart, W. & Smith, D. H. Traumatic brain injury and amyloid-β pathology: a link to Alzheimer’s disease? Nat. Rev. Neurosci. 11, 361–370 (2010).
Abrahamson, E. E. et al. Simvastatin therapy prevents brain trauma-induced increases in β-amyloid peptide levels. Ann. Neurol. 66, 407–414 (2009).
Stein, T. D. et al. β-Amyloid deposition in chronic traumatic encephalopathy. Acta Neuropathol. 130, 21–34 (2015).
McKee, A. C., Stein, T. D., Kiernan, P. T. & Alvarez, V. E. The neuropathology of chronic traumatic encephalopathy. Brain Pathol. 25, 350–364 (2015).
Dong, Y. et al. The common inhalational anesthetic sevoflurane induces apoptosis and increases β-amyloid protein levels. Arch. Neurol. 66, 620–631 (2009).
Perucho, J. et al. Anesthesia with isoflurane increases amyloid pathology in mice models of Alzheimer’s disease. J. Alzheimers Dis. 19, 1245–1257 (2010).
Fodale, V., Santamaria, L. B., Schifilliti, D. & Mandal, P. K. Anaesthetics and postoperative cognitive dysfunction: a pathological mechanism mimicking Alzheimer’s disease. Anaesthesia 65, 388–395 (2010).
Jiang, J. & Jiang, H. Effect of the inhaled anesthetics isoflurane, sevoflurane and desflurane on the neuropathogenesis of Alzheimer’s disease (review). Mol. Med. Rep. 12, 3–12 (2015).
Yu, P., Wang, H., Mu, L., Ding, X. & Ding, W. Effect of general anesthesia on serum β-amyloid protein and regional cerebral oxygen saturation of elderly patients after subtotal gastrectomy. Exp. Ther. Med. 12, 3561–3566 (2016).
Mäkinen, S. et al. Coaccumulation of calcium and β-amyloid in the thalamus after transient middle cerebral artery occlusion in rats. J. Cereb. Blood Flow Metab. 28, 263–268 (2008).
Li, L. et al. Hypoxia increases Aβ generation by altering β- and γ-cleavage of APP. Neurobiol. Aging 30, 1091–1098 (2009).
Garcia-Alloza, M. et al. Cerebrovascular lesions induce transient β-amyloid deposition. Brain 134, 3697–3707 (2011).
Pluta, R., Furmaga-Jabłonska, W., Maciejewski, R., Ułamek-Kozioł, M. & Jabłonski, M. Brain ischemia activates β- and γ-secretase cleavage of amyloid precursor protein: significance in sporadic Alzheimer’s disease. Mol. Neurobiol. 47, 425–434 (2013).
ElAli, A., Thériault, P., Préfontaine, P. & Rivest, S. Mild chronic cerebral hypoperfusion induces neurovascular dysfunction, triggering peripheral β-amyloid brain entry and aggregation. Acta Neuropathol. Commun. 1, 75 (2013).
Pomara, N. et al. Lower CSF amyloid beta peptides and higher F2-isoprostanes in cognitively intact elderly individuals with major depressive disorder. Am. J. Psychiatry 169, 523–530 (2012).
Wu, K. Y. et al. Increased brain amyloid deposition in patients with a lifetime history of major depression: evidenced on 18F-florbetapir (AV-45/Amyvid) positron emission tomography. Eur. J. Nucl. Med. Mol. Imaging 41, 714–722 (2014).
Donovan, N. J. et al. Longitudinal association of amyloid β and anxious-depressive symptoms in cognitively normal older adults. Am. J. Psychiatry 175, 530–537 (2018).
Bryson, J. B. et al. Amyloid precursor protein (APP) contributes to pathology in the SOD1(G93A) mouse model of amyotrophic lateral sclerosis. Hum. Mol. Genet. 21, 3871–3882 (2012).
Coan, G. & Mitchell, C. S. An assessment of possible neuropathology and clinical relationships in 46 sporadic amyotrophic lateral sclerosis patient autopsies. Neurodegener. Dis. 15, 301–312 (2015).
Zetterberg, H. et al. Hypoxia due to cardiac arrest induces a time-dependent increase in serum amyloid β levels in humans. PLOS ONE 6, e28263 (2011).
Palotás, A. et al. Coronary artery bypass surgery provokes Alzheimer’s disease-like changes in the cerebrospinal fluid. J. Alzheimers Dis. 21, 1153–1164 (2010).
Reinsfelt, B., Westerlind, A., Blennow, K., Zetterberg, H. & Ricksten, S. E. Open-heart surgery increases cerebrospinal fluid levels of Alzheimer-associated amyloid β. Acta Anaesthesiol. Scand. 57, 82–88 (2013).
Hu, Y. et al. Effects of heart bypass surgery on plasma Aβ40 and Aβ42 levels in infants and young children. Medicine 95, e2684 (2016).
Ooms, S. et al. Effect of 1 night of total sleep deprivation on cerebrospinal fluid β-amyloid 42 in healthy middle-aged men: a randomized clinical trial. JAMA Neurol. 71, 971–977 (2014).
Lucey, B. P. et al. Effect of sleep on overnight cerebrospinal fluid amyloid β kinetics. Ann. Neurol. 83, 197–204 (2018).
Shokri-Kojori, E. et al. β-Amyloid accumulation in the human brain after one night of sleep deprivation. Proc. Natl Acad. Sci. USA 115, 4483–4488 (2018).
Ju, Y. S. et al. Slow wave sleep disruption increases cerebrospinal fluid amyloid-β levels. Brain 140, 2104–2111 (2017).
Zhao, H. Y. et al. Chronic sleep restriction induces cognitive deficits and cortical β-amyloid deposition in mice via BACE1-antisense activation. CNS Neurosci. Ther. 23, 233–240 (2017).
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).
Lee, H. G. et al. Amyloid-β in Alzheimer disease: the null versus the alternate hypotheses. J. Pharmacol. Exp. Ther. 321, 823–829 (2007).
Kokjohn, T. A., Maarouf, C. L. & Roher, A. E. Is Alzheimer’s disease amyloidosis the result of a repair mechanism gone astray? Alzheimers Dement. 8, 574–583 (2012).
Krstic, D. & Knuesel, I. Deciphering the mechanism underlying late-onset Alzheimer disease. Nat. Rev. Neurol. 9, 25–34 (2013).
Struble, R. G. et al. Is brain amyloid production a cause or a result of dementia of the Alzheimer’s type? J. Alzheimers Dis. 22, 393–399 (2010).
Herrup, K. Reimagining Alzheimer’s disease — an age-based hypothesis. J. Neurosci. 30, 16755–16762 (2010).
Castellani, R. J., Lee., H. G., Zhu, X., Perry, G. & Smith, M. A. Alzheimer disease pathology as a host response. J. Neuropathol. Exp. Neurol. 67, 523–531 (2008).
Castello, M. A. & Soriano, S. Rational heterodoxy: cholesterol reformation of the amyloid doctrine. Ageing Res. Rev. 12, 282–288 (2013).
Aisen, P. S. et al. Tramiprosate in mild-to-moderate Alzheimer’s disease — a randomized, double-blind, placebo-controlled, multi-centre study (the Alphase Study). Arch. Med. Sci. 7, 102–111 (2011).
Green, R. C. et al. Effect of tarenflurbil on cognitive decline and activities of daily living in patients with mild Alzheimer disease: a randomized controlled trial. JAMA 302, 2557–2564 (2009).
Salloway, S. et al. A phase 2 randomized trial of ELND005, scyllo-inositol, in mild to moderate Alzheimer disease. Neurology 77, 1253–1262 (2011).
Kirk, R. Clinical trials in CNS — SMi’s eighth annual conference. IDrugs 13, 66–69 (2010).
Landen, J. W. et al. Multiple-dose ponezumab for mild-to-moderate Alzheimer’s disease: safety and efficacy. Alzheimers Dement. 3, 339–347 (2017).
Doody, R. S. et al. A phase 3 trial of semagacestat for treatment of Alzheimer’s disease. N. Engl. J. Med. 369, 341–350 (2013).
Salloway, S. et al. Two phase 3 trials of bapineuzumab in mild-to-moderate Alzheimer’s disease. N. Engl. J. Med. 370, 322–333 (2014).
Coric, V. et al. Safety and tolerability of the γ-secretase inhibitor avagacestat in a phase 2 study of mild to moderate Alzheimer disease. Arch. Neurol. 69, 1430–1440 (2012).
Coric, V. et al. Targeting prodromal Alzheimer disease with avagacestat: a randomized clinical trial. JAMA Neurol. 72, 1324–1333 (2015).
Relkin, N. R. et al. A phase 3 trial of IV immunoglobulin for Alzheimer disease. Neurology 88, 1768–1775 (2017).
Lahiri, D. K., Maloney, B., Long, J. M. & Greig, N. H. Lessons from a BACE1 inhibitor trial: off-site but not off base. Alzheimers Dement. 10(Suppl.), S411–S419 (2014).
Yan, R. Stepping closer to treating Alzheimer’s disease patients with BACE1 inhibitor drugs. Transl Neurodegener. 5, 13 (2016).
Schneeberger, A. et al. Results from a phase II study to assess the clinical and immunological activity of AFFITOPE® AD02 in patients with early Alzheimer’s disease. J. Prev. Alzheimers Dis. 2, 103–114 (2015).
Villemagne, V. L. et al. A randomized, exploratory molecular imaging study targeting amyloid β with a novel 8-OH quinoline in Alzheimer’s disease: the PBT2-204 IMAGINE study. Alzheimers Dement. 3, 622–635 (2017).
Carroll, J. Eli Lilly shutters the last PhIII sola study, certain of failure. Endpoints News https://endpts.com/eli-lilly-shutters-the-last-phiii-sola-study-certain-of-failure/ (2017).
Grifols. Grifols AMBAR results demonstrate a significant reduction in the progression of moderate Alzheimer’s disease. https://www.grifols.com/en/view-news/-/new/grifols-ambar-results-demonstrate-a-significant-reduction-in-the-progression-of-moderate-alzheimers-disease (2018).
Xiao, S. et al. Phase 3 clinical trial for a novel and multi-targeted oligosaccharide in patients with mild-moderate AD in China [abstract OC3]. Presented at the 11th Clinical Trials on Alzheimer’s Disease, Barcelona, Spain (2018).
About this article
Journal of Bioethical Inquiry (2019)