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Perspective

Discontinued disease-modifying therapies for Alzheimer’s disease: status and future perspectives

, , & ORCID Icon
Pages 919-933 | Received 18 May 2020, Accepted 09 Jul 2020, Published online: 26 Jul 2020

References

  • Brookmeyer R , Corrada MM , Curriero FC , et al. Survival following a diagnosis of Alzheimer disease. Arch Neurol. 2002;59:1764–1767.
  • Lucca U , Tettamanti M , Tiraboschi P , et al. Incidence of dementia in the oldest-old and its relationship with age: the Monzino 80-plus population-based study. Alzheimers Dement. 2020;16:472–481.
  • Jansen IE , Savage JE , Watanabe K , et al. Genome-wide meta-analysis identifies new loci and functional pathways influencing Alzheimer’s disease risk. Nat Genet. 2019;51:404–413.
  • Alzheimer’s Disease International . World Alzheimer report 2019: attitudes to dementia. London: Alzheimer’s Disease International; 2019.
  • Fink HA , Linskens EJ , MacDonald R , et al. Benefits and harms of prescription drugs and supplements for treatment of clinical Alzheimer-type dementia: a systematic review and meta-analysis. Ann Intern Med. 2020;172:656–668.
  • Quiroz YT , Sperling RA , Norton DJ , et al. association between amyloid and tau accumulation in young adults with autosomal dominant Alzheimer disease. JAMA Neurol. 2018;75:548–556.
  • Brothers HM , Gosztyla ML , Robinson SR. The physiological roles of amyloid-β peptide hint at new ways to treat Alzheimer’s disease. Front Aging Neurosci. 2018;10:118.
  • Eftekharzadeh B , Daigle JG , Kapinos LE , et al. Tau protein disrupts nucleocytoplasmic transport in Alzheimer’s disease. Neuron. 2018;99:925–940.
  • Hampel H , Caraci F,A , Cuello C , et al. A Path toward precision medicine for neuroinflammatory mechanisms in Alzheimer’s disease. Front Immunol. 2020;11:456.
  • Jonsson T , Atwal JK , Steinberg S , et al. A mutation in APP protects against Alzheimer’s disease and age-related cognitive decline. Nature. 2012;488:96–99.
  • Yamazaki Y , Zhao N , Caulfield TR , et al. Apolipoprotein E and Alzheimer disease: pathobiology and targeting strategies. Nat Rev Neurol. 2019;15:501–518.
  • Goedert M , Eisenberg DS , Crowther RA. Propagation of tau aggregates and neurodegeneration. Annu Rev Neurosci. 2017;40:189–210.
  • Braak H , Braak E. Neuropathological stageing of Alzheimer-related changes. Acta Neuropathol. 1991;82:239–259.
  • de Calignon A , Polydoro M , Suárez-Calvet M , et al. Propagation of tau pathology in a model of early Alzheimer’s disease. Neuron. 2012;73:685–697.
  • Guo JL , Narasimhan S , Changolkar L , et al. Unique pathological tau conformers from Alzheimer’s brains transmit tau pathology in nontransgenic mice. J Exp Med. 2016;213:2635–2654.
  • Cummings J , Blennow K , Johnson K , et al. Anti-tau trials for Alzheimer’s disease: a report from the EU/US/CTAD task force. J Prev Alzheimers Dis. 2019;6:157–163.
  • Deczkowska A , Weiner A , Amit I . The physiology, pathology, and potential therapeutic applications of the TREM2 signaling pathway. Cell. 2020;181:1207–1217.
  • Gratuze M , Eg Leyns C , Sauerbeck AD , et al. Impact of TREM2R47H variant on tau pathology-induced gliosis and neurodegeneration. J Clin Invest. 2020;138179. [Online ahead of print]. DOI:10.1172/JCI138179
  • Imbimbo BP , Solfrizzi V , Panza F . Are NSAIDs useful to treat Alzheimer’s disease or mild cognitive impairment? Front Aging Neurosci. 2010;2:pii: 19.
  • Hampel H , Vassar R , De Strooper B , et al. The β-secretase BACE1 in Alzheimer’s disease. Biol Psychiatry. 2020;S0006-3223(20)30063–9. [Online ahead of print]. DOI:10.1016/j.biopsych.2020.02.001
  • Deane R , Du Yan S , Submamaryan RK , et al. RAGE mediates amyloid-β peptide transport across the blood-brain barrier and accumulation in brain. Nat Med. 2003;9:907–913.
  • Shinohara M , Tachibana M , Kanekiyo T , et al. Role of LRP1 in the pathogenesis of Alzheimer’s disease: evidence from clinical and preclinical studies. J Lipid Res. 2017;58:1267–1281.
  • Burstein A , Sabbagh M , Andrews R , et al. Development of Azeliragon, an oral small molecule antagonist of the receptor for advanced glycation endproducts, for the potential slowing of loss of cognition in mild Alzheimer’s disease. J Prev Alzheimer’s Dis. 2018;5:149–154.
  • Panza F , Lozupone M , Logroscino G , et al. A critical appraisal of amyloid-β-targeting therapies for Alzheimer disease. Nat Rev Neurol. 2019;15:73–88.
  • Gilman S , Koller M , Black RS , et al. Clinical effects of Abeta immunization (AN1792) in patients with AD in an interrupted trial. Neurology. 2005;64:1553–1562.
  • Aisen PS , Gauthier S , Ferris SH , 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. 2011;7:102–111.
  • Green RC , Schneider LS , Amato DA , et al. Effect of tarenflurbil on cognitive decline and activities of daily living in patients with mild Alzheimer disease: a randomized controlled trial. JAMA. 2009;302:2557–2564.
  • Salloway S , Sperling R , Keren R , et al. A phase 2 randomized trial of ELND005, scyllo-inositol, in mild to moderate Alzheimer disease. Neurology. 2011;77:1253–1262.
  • Landen JW , Cohen S , Billing CB Jr , et al. Multiple-dose ponezumab for mild-to-moderate Alzheimer’s disease: safety and efficacy. Alzheimers Dement (N Y). 2017;3:339–347.
  • Doody RS , Raman R , Farlow M , et al. A phase 3 trial of semagacestat for treatment of Alzheimer’s disease. N Engl J Med. 2013;369:341–350.
  • Salloway S , Sperling R , Fox NC , et al. Two phase 3 trials of bapineuzumab in mild-to-moderate Alzheimer’s disease. N Engl J Med. 2014;370:322–333.
  • Coric V , van Dyck CH , Salloway S , et al. Safety and tolerability of the γ-secretase inhibitor avagacestat in a phase 2 study of mild to moderate Alzheimer disease. Arch Neurol. 2012;69:1430–1440.
  • Doody RS , Thomas RG , Farlow M , et al. Phase 3 trials of solanezumab for mild-to-moderate Alzheimer’s disease. N Engl J Med. 2014;370:311–321.
  • Pasquier F , Sadowsky C , Holstein A , 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. 2016;51:1131–1143.
  • Relkin NR , Thomas RG , Rissman RA , et al. A phase 3 trial of IV immunoglobulin for Alzheimer disease. Neurology. 2017;88:1768–1775.
  • May PC , Willis BA , Lowe SL , et al. The potent BACE1 inhibitor LY2886721 elicits robust central Aβ pharmacodynamic responses in mice, dogs, and humans. J Neurosci. 2015;35:1199–1210.
  • Schneeberger A , Hendrix S , Mandler M , 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. 2015;2:103–114.
  • Vandenberghe R , Riviere ME , Caputo A , et al. Active Aβ immunotherapy CAD106 in Alzheimer’s disease: A phase 2b study. Alzheimers Dement (N Y). 2016;3:10–22.
  • Villemagne VL , Rowe CC , Barnham KJ , 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 (N Y). 2017;3:622–635.
  • Cummings JL , Cohen S , van Dyck CH , et al. ABBY: A phase 2 randomized trial of crenezumab in mild to moderate Alzheimer disease. Neurology. 2018;90:e1889–e1897.
  • Salloway S , Honigberg LA , Cho W , 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. 2018;10:96.
  • Ostrowitzki S , Lasser RA , Dorflinger E , et al. A phase III randomized trial of gantenerumab in prodromal Alzheimer’s disease [published correction appears in Alzheimers Res Ther. 2018 Sep 27;10(1):99]. Alzheimers Res Ther. 2017;9:95.
  • Abi-Saab D , Andjelkovic M , Delmar P , et al. The effect of 6-month dosing on the rate of amyloid-related imaging abnormalities (ARIA) in the Marguerite RoAD study. Alzheimers Dement. 2017;13(Suppl.):P252–P253.
  • Honig LS , Vellas B , Woodward M , et al. Trial of Solanezumab for mild dementia due to Alzheimer’s disease. N Engl J Med. 2018;378:321–330.
  • Egan MF , Kost J , Tariot PN , et al. Randomized trial of verubecestat for mild-to-moderate Alzheimer’s disease. N Engl J Med. 2018;378:1691–1703.
  • Abbasi J . Promising results in 18-month analysis of Alzheimer drug candidate. JAMA. 2018;320:965.
  • Egan MF , Kost J , Voss T , et al. Randomized trial of verubecestat for prodromal Alzheimer’s disease. N Engl J Med. 2019;380:1408–1420.
  • Wessels AM , Tariot PN , Zimmer JA , et al. Efficacy and safety of lanabecestat for treatment of early and mild Alzheimer disease: the AMARANTH and DAYBREAK-ALZ randomized clinical trials [published online ahead of print, 2019 Nov 25]. JAMA Neurol. 2019;77:199–209.
  • Roche to discontinue Phase III CREAD 1 and 2 clinical studies of crenezumab in early Alzheimer’s disease (AD) - other company programmes in AD continue; [cited 2020 Jul 5 ]. Available from: https://www.roche.com/media/releases/med-cor-2019-01-30.htm.
  • Biogen and Eisai to discontinue phase 3 ENGAGE and EMERGE trials of aducanumab in Alzheimer’s disease; [cited 2020 Jul 5 ]. Available from: https://www.eisai.com/news/2019/news201917.html.
  • Howard R , Zubko O , Bradley R , et al. Minocycline at 2 different dosages vs placebo for patients with mild Alzheimer disease: a randomized clinical trial. JAMA Neurol. 2019;77:164–174.
  • Imbimbo BP , Watling M . Investigational BACE inhibitors for the treatment of Alzheimer’s disease. Expert Opin Investig Drugs. 2019;28:967–975.
  • Axon presented positive phase II trial results of AADvac1 at AAT-AD/PD 2020; [cited 2020 Jul 5 ]. Available from: https://aat-adpd.kenes.com/aat-ad-pd-in-the-news/.
  • Lyketsos CG , Breitner JC ; ADAPT Research Group, et al. Naproxen and celecoxib do not prevent AD in early results from a randomized controlled trial. Neurology. 2007;68:1800–1808.
  • Alexander R , Burns DK , Welsh-Bohmer KA , et al. TOMMORROW: A trial of delay the onset of MCI due to AD and qualify a genetic biomarker algorithm: topline results. J Prev Alzheimers Dis. 2018;5(Suppl 1):S37–S38.
  • Brown MH , Dustin ML . Retraction: steering CAR T cells into solid tumors. N Engl J Med. 2019;380:289–291. [retraction of: N Engl J Med 2019;380:289-291].N Engl J Med 2019;380:1286.
  • Lopez Lopez C , Tariot PN , Caputo A , et al. The Alzheimer’s prevention initiative generation program: study design of two randomized controlled trials for individuals at risk for clinical onset of Alzheimer’s disease. Alzheimers Dement (N Y). 2019;5:216–227.
  • Meyer PF , Tremblay-Mercier J , Leoutsakos J , et al. INTREPAD: A randomized trial of naproxen to slow progress of presymptomatic Alzheimer disease [published correction appears in Neurology 2019;93:371]. Neurology. 2019;92:e2070–e2080.
  • Lilly announces topline results for solanezumab from the dominantly inherited alzheimer network trials unit (DIAN-TU) study; [cited 2020 Jul 5 ]. Available from: https://investor.lilly.com/news-releases/news-release-details/lilly-announces-topline-results-solanezumab-dominantly-inherited.
  • AC immune/roche drop crenezumab after phase III CREAD Alzheimer’s failure; [cited 2020 Jul 5 ]. Available from: https://scrip.pharmaintelligence.informa.com/SC124573/AC-ImmuneRoche-Drop-Crenezumab-After-Phase-III-CREAD-Alzheimers-Failure. .
  • Ryan J , Storey E , Murray AM , et al. Randomized placebo-controlled trial of the effects of aspirin on dementia and cognitive decline. Neurology. 2020. [Online ahead of print]. DOI:10.1212/WNL.0000000000009277.
  • Gauthier S , Feldman HH , Schneider LS , et al. Efficacy and safety of tau-aggregation inhibitor therapy in patients with mild or moderate Alzheimer’s disease: a randomised, controlled, double-blind, parallel-arm, phase 3 trial. Lancet. 2016;388:2873–2884.
  • Hoskin JL , Sabbagh MN , Al-Hasan Y , et al. Tau immunotherapies for Alzheimer’s disease. Expert Opin Investig Drugs. 2019;28:545–554.
  • Novak P , Schmidt R , Kontsekova E , et al. Safety and immunogenicity of the tau vaccine AADvac1 in patients with Alzheimer’s disease: a randomised, double-blind, placebo-controlled, phase 1 trial. Lancet Neurol. 2017;16:123–134.
  • Bowman Rogers M . Active tau vaccine: hints of slowing neurodegeneration. AAT-AD/ PD 2020 conference: Advances in Alzheimer’s and Parkinson’s Therapies. Alzheimer Research Forum; [cited 2020 July 5] .
  • Boxer AL , Qureshi I , Ahlijanian M , et al. Safety of the tau-directed monoclonal antibody BIIB092 in progressive supranuclear palsy: a randomised, placebo-controlled, multiple ascending dose phase 1b trial. Lancet Neurol. 2019;18:549–558.
  • Jackson M . Biogen’s tau antibody fails in PSP, but Alzheimer’s studies continue. Scrip. 2019 December 13.
  • Carroll J . AbbVie scraps an anti-tau study, and that may foretell more big trouble for a beleaguered Biogen. Endpoint News. 2019 July 26.
  • Roche provides topline results from investigator-led Phase II/III trial with gantenerumab in rare inherited form of Alzheimer’s disease; [cited 2020 Jul 5 ]. Available from: https://www.roche.com/media/releases/med-cor-2020-02-10.htm.
  • DeVos SL , Miller RL , Schoch KM , et al. Tau reduction prevents neuronal loss and reverses pathological tau deposition and seeding in mice with tauopathy. Sci Transl Med. 2017;9:pii: eaag0481.
  • Rauch JN , Luna G , Guzman E , et al. LRP1 is a master regulator of tau uptake and spread. Nature. 2020;580:381–385.
  • Griciuc A , Patel S , Federico AN , et al. TREM2 acts downstream of CD33 in modulating microglial pathology in Alzheimer’s disease. Neuron. 2019;103:820–835.
  • Miles LA , Hermans SJ , Crespi GAN , et al. Small molecule binding to alzheimer risk factor CD33 promotes Aβ phagocytosis. iScience. 2019;19:110–118.
  • Pase MP , Himali JJ , Beiser AS , et al. Association of CD14 with incident dementia and markers of brain aging and injury. Neurology. 2020;94:e254–e266.
  • O’Bryant SE , Zhang F , Johnson LA , et al. A Precision medicine model for targeted NSAID therapy in Alzheimer’s disease. J Alzheimers Dis. 2018;66:97–104.
  • Bowman Rogers M . Antibodies against microglial receptors TREM2 and CD33 head to trials. International conference on Alzheimer’s and Parkinson’s Disease 2019. Alzheimer Research Forum; [cited 2020 July 5 ].
  • Chetty A , Sharda A , Warburton R , et al. A purinergic P2Y6 receptor agonist prodrug modulates airway inflammation, remodeling, and hyperreactivity in a mouse model of asthma. J Asthma Allergy. 2018;11:159–171.
  • Sama DM , Mohmmad Abdul H , Furman JL , et al. Inhibition of soluble tumor necrosis factor ameliorates synaptic alterations and Ca2+ dysregulation in aged rats. PLoS One. 2012;7:e38170.
  • Fisher TL , Reilly CA , Winter LA , et al. Generation and preclinical characterization of an antibody specific for SEMA4D. MAbs. 2016;8:150–162.
  • Smith ES , Jonason A , Reilly C , et al. SEMA4D compromises blood-brain barrier, activates microglia, and inhibits remyelination in neurodegenerative disease. Neurobiol Dis. 2015;73:254–268.
  • Swanson KV , Deng M , Ting JP . The NLRP3 inflammasome: molecular activation and regulation to therapeutics. Nat Rev Immunol. 2019;19:477–489.
  • Kelley N , Jeltema D , Duan Y , et al. The NLRP3 inflammasome: an overview of mechanisms of activation and regulation. Int J Mol Sci. 2019;20:pii: E3328.
  • Kirkland JL , Tchkonia T , Zhu Y , et al. The clinical potential of senolytic drugs. J Am Geriatr Soc. 2017;65:2297–2301.
  • Wissler GEO , Zhu Y , Tchkonia T , et al. Discovery, development, and future application of senolytics: theories and predictions. Febs J. 2020;287:2418–2427. [ Epub ahead of print].
  • Biber K , Moller T , Boddeke E , et al. Central nervous system myeloid cells as drug targets: current status and translational challenges. Nat Rev Drug Discov. 2016;15:110–124.
  • Brennan FH , Lee JD , Ruitenberg MJ , et al. Therapeutic targeting of complement to modify disease course and improve outcomes in neurological conditions. Semin Immunol. 2016;28:292–308.
  • Montagne A , Nation DA , Sagare AP , et al. APOE4 leads to blood–brain barrier dysfunction predicting cognitive decline. Nature. 2020;581:71–76.
  • Therriault J , Benedet AL , Pascoal TA , et al. Association of apolipoprotein E ε4 with medial temporal tau independent of amyloid-β. JAMA Neurol. 2019;77:470–479.
  • Reiman EM , Arboleda-Velasquez JF , Quiroz YT , et al. Exceptionally low likelihood of Alzheimer’s dementia in APOE2 homozygotes from a 5,000-person neuropathological study. Nat Commun. 2020;11:667.
  • Arboleda-Velasquez JF , Lopera F , O’Hare M , et al. Resistance to autosomal dominant Alzheimer’s disease in an APOE3 Christchurch homozygote: a case report. Nat Med. 2019;25:1680–1683.
  • Huynh TV , Liao F , Francis CM , et al. Age-dependent effects of apoE reduction using antisense oligonucleotides in a model of β-amyloidosis. Neuron. 2017;96:1013–1023.
  • Kim J , Eltorai AE , Jiang H , et al. Anti-apoE immunotherapy inhibits amyloid accumulation in a transgenic mouse model of Aβ amyloidosis. J Exp Med. 2012;209:2149–2156.
  • Liao F , Li A , Xiong M , et al. Targeting of nonlipidated, aggregated apoE with antibodies inhibits amyloid accumulation. J Clin Invest. 2018;128:2144–2155.
  • Rosenberg JB , Kaplitt MG , De BP , et al. AAVrh.10-mediated APOE2 central nervous system gene therapy for APOE4-associated Alzheimer’s disease. Hum Gene Ther Clin Dev. 2018;29:24–47.
  • Cattaneo A , Cattane N , Galluzzi S , et al. Association of brain amyloidosis with pro-inflammatory gut bacterial taxa and peripheral inflammation markers in cognitively impaired elderly. Neurobiol Aging. 2017;49:60–68.
  • Jiang C , Li G , Huang P , et al. The Gut microbiota and Alzheimer’s disease. J Alzheimers Dis. 2017;58:1–15.
  • Panza F , Lozupone M , Solfrizzi V , et al. Time to test antibacterial therapy in Alzheimer’s disease. Brain. 2019;142:2905–2929.
  • Minter MR , Zhang C , Leone V , et al. Antibiotic-induced perturbations in gut microbial diversity influences neuro-inflammation and amyloidosis in a murine model of Alzheimer’s disease. Sci Rep. 2016;6:30028.
  • Dodiya HB , Kuntz T , Shaik SM , et al. Sex-specific effects of microbiome perturbations on cerebral Aβ amyloidosis and microglia phenotypes. J Exp Med. 2019;216:1542–1560.
  • Devanand DP , Andrews H , Kreisl WC , et al. Antiviral therapy: valacyclovir treatment of Alzheimer’s disease (VALAD) Trial: protocol for a randomised, double-blind,placebo-controlled, treatment trial. BMJ Open. 2020;10:e032112.
  • Loeb MB , Molloy DW , Smieja M , et al. A randomized, controlled trial of doxycycline and rifampin for patients with Alzheimer’s disease. J Am Geriatr Soc. 2004;52:381–387.
  • Arastu-Kapur S , Nguyen M , Raha D , et al. Treatment of Porphyromonas gulae infection and downstream pathology in the aged dog by lysine-gingipain inhibitor COR388. Pharmacol Res Perspect. 2020;8:e00562.
  • Wang X , Sun G , Feng T , et al. Sodium oligomannate therapeutically remodels gut microbiota and suppresses gut bacterial amino acids-shaped neuroinflammation to inhibit Alzheimer’s disease progression. Cell Res. 2019;29:787–803.
  • Syed YY . Sodium oligomannate: first approval. Drugs. 2020;80:441–444.
  • Imbimbo BP , Ippati S , Ceravolo F , et al. Is therapeutic plasma exchange a viable option for treating Alzheimer’s disease? Alzheimers Dement. 2020;6:e12004.
  • Middeldorp J , Lehallier B , Villeda SA , et al. Preclinical assessment of young blood plasma for Alzheimer disease. JAMA Neurol. 2016;73:1325–1333.
  • Sha SJ , Deutsch GK , Tian L , et al. Safety, tolerability, and feasibility of young plasma infusion in the plasma for Alzheimer symptom amelioration study: a randomized clinical trial. JAMA Neurol. 2019;76:35–40.
  • Lopez OL . AMBAR(Alzheimer’s management by albumin replacement) phase IIb/III results. J Prevent Alzheimers Dis. 2018;5(Suppl 1):S8.
  • Morrison JH , Baxter MG . The ageing cortical synapse: hallmarks and implications for cognitive decline. Nat Rev Neurosci. 2012;13:240–250.
  • Scheff SW , Price DA , Schmitt FA , et al. Hippocampal synaptic loss in early Alzheimer’s disease and mild cognitive impairment. Neurobiol Aging. 2006;27:1372–1384.
  • James ML , Belichenko NP , Shuhendler AJ , et al. [(18)F]GE-180 PET detects reduced microglia activation after LM11A-31 therapy in a mouse model of Alzheimer’s disease. Theranostics. 2017;7:1422–1436.
  • Simmons DA , Knowles JK , Belichenko NP , et al. A small molecule p75NTR ligand, LM11A-31, reverses cholinergic neurite dystrophy in Alzheimer’s disease mouse models with mid- to late-stage disease progression. PLoS One. 2014;9:e102136.
  • van Deijk AF , Broersen LM , Verkuyl JM , et al. High content analysis of hippocampal neuron-astrocyte co-cultures shows a positive effect of fortasyn connect on neuronal survival and postsynaptic maturation. Front Neurosci. 2017;11:440.
  • Soininen H , Solomon A , Visser PJ , et al. 24-month intervention with a specific multinutrient in people with prodromal Alzheimer’s disease (LipiDiDiet): a randomised, double-blind, controlled trial. Lancet Neurol. 2017;16:965–975.
  • Bowman Rogers M . Non-Aβ, non-tau drugs tweak markers, cognition in Alzheimer’s, Huntington’s. AAT-AD/PD 2020 conference: Advances in Alzheimer’s and Parkinson’s Therapies. Alzheimer Research Forum; [cited 2020 July 5 ].
  • Rubinsztein DC , Marino G , Kroemer G . Autophagy and aging. Cell. 2011;146:682–695.
  • Boyle PA , Yang J , Yu L , et al. Varied effects of age-related neuropathologies on the trajectory of late life cognitive decline. Brain. 2017;140:804–812.
  • Li Q , Liu Y , Sun M . Autophagy and Alzheimer’s disease. Cell Mol Neurobiol. 2017;37:377–388.
  • Lonskaya I , Hebron ML , Desforges NM , et al. Nilotinib-induced autophagic changes increase endogenous parkin level and ubiquitination, leading to amyloid clearance. J Mol Med. 2014;92:373–386.
  • Grimm A , Eckert A . Brain aging and neurodegeneration: from a mitochondrial point of view. J Neurochem. 2017;143:418–431.
  • Guo L , Tian J , Du H . Mitochondrial dysfunction and synaptic transmission failure in Alzheimer’s disease. J Alzheimers Dis. 2017;57:1071–1086.
  • Podlesniy P , Figueiro-Silva J , Llado A , et al. Low cerebrospinal fluid concentration of mitochondrial DNA in preclinical Alzheimer disease. Ann Neurol. 2013;74:655–668.
  • Swerdlow RH . Mitochondria and mitochondrial cascades in Alzheimer’s disease. J Alzheimers Dis. 2018;62:1403–1416.
  • Lanzillotta C , Di Domenico F , Perluigi M , et al. Targeting mitochondria in Alzheimer disease: rationale and perspectives. CNS Drugs. 2019;33:957–969.
  • Reddy PH , Manczak M , Kandimalla R . Mitochondria-targeted small molecule SS31: a potential candidate for the treatment of Alzheimer’s disease. Hum Mol Genet. 2017;26:1483–1496.
  • Chen Q , Prior M , Dargusch R , et al. A novel neurotrophic drug for cognitive enhancement and Alzheimer’s disease. PLoS One. 2011;6:e27865.
  • Prior M , Dargusch R , Ehren JL , et al. The neurotrophic compound J147 reverses cognitive impairment in aged Alzheimer’s disease mice. Alzheimers Res Ther. 2013;5:25.
  • Zhang L , Zhang S , Maezawa I , et al. Modulation of mitochondrial complex I activity averts cognitive decline in multiple animal models of familial Alzheimer’s Disease. EBioMedicine. 2015;2:294–305.
  • Maezawa I , Zou B , Di Lucente J , et al. Anti-amyloid-β and neuroprotective properties of a novel tricyclic pyrone molecule. J Alzheimers Dis. 2017;58:559–574.
  • Gudala K , Bansal D , Schifano F , et al. Diabetes mellitus and risk of dementia: a meta-analysis of prospective observational studies. J Diabetes Investig. 2013;4:640–650.
  • Sebastiao I , Candeias E , Santos MS , et al. Insulin as a bridge between type 2 diabetes and Alzheimer disease: how anti-diabetics could be a solution for dementia. Front Endocrinol. 2014;5:110.
  • Arnold SE , Arvanitakis Z , Macauley-Rambach SL , et al. Brain insulin resistance in type 2 diabetes and Alzheimer disease: concepts and conundrums. Nat Rev Neurol. 2018;14:168–181.
  • McIntosh EC , Nation DA . Alzheimer’s disease neuroimaging initiative. importance of treatment status in links between type 2 diabetes and Alzheimer’s disease. Diabetes Care. 2019;42:972–979.
  • Kuehn BM . In Alzheimer research, glucose metabolism moves to center stage. JAMA. 2020 Jan 8. Epub ahead of print. DOI:10.1001/jama.2019.20939
  • Cukierman-Yaffe T , Gerstein HC , Colhoun HM , et al. Effect of dulaglutide on cognitive impairment in type 2 diabetes: an exploratory analysis of the REWIND trial. Lancet Neurol. 2020;19:582–590.
  • Craft S , Raman R , Chow TW , et al. Safety, efficacy, and feasibility of intranasal insulin for the treatment of mild cognitive impairment and Alzheimer disease dementia: a randomized clinical trial. JAMA Neurol. 2020;e201840. [Online ahead of print]. doi:10.1001/jamaneurol.2020.1840
  • Femminella GD , Frangou E , Love SB , et al. Evaluating the effects of the novel GLP-1 analogue liraglutide in Alzheimer’s disease: study protocol for a randomised controlled trial (ELAD study). Trials. 2019;20:191.
  • Stovall S.  Will novo nordisk get lift from gut-brain axis? Scrip. [cited 2020 Jul 5 ].
  • Salas J , Morley JE , Scherrer JF , et al. Risk of incident dementia following metformin initiation compared with noninitiation or delay of antidiabetic medication therapy [published online ahead of print, 2020 May 3]. Pharmacoepidemiol Drug Saf. 2020. DOI:10.1002/pds.5014.
  • Toledo JB , Arnold SE , Raible K , et al. Contribution of cerebrovascular disease in autopsy confirmed neurodegenerative disease cases in the National Alzheimer’s coordinating centre. Brain. 2013;136:2697–2706.
  • Chu CS , Tseng PT , Stubbs B , et al. Use of statins and the risk of dementia and mild cognitive impairment: A systematic review and meta-analysis. Sci Rep. 2018;8:5804.
  • Walker VM , Kehoe PG , Martin RM , et al. Repurposing antihypertensive drugs for the prevention of Alzheimer’s disease: a Mendelian randomization study. Int J Epidemiol. 2019:pii: dyz155. [ Epub ahead of print]. DOI:10.1093/ije/dyz155
  • Hughes D , Judge C , Murphy R , et al. Association of blood pressure lowering with incident dementia or cognitive impairment: a systematic review and meta-analysis. JAMA. 2020;323:1934–1944.
  • van Middelaar T , van Vught LA , van Gool WA , et al. Blood pressure-lowering interventions to prevent dementia: a systematic review and meta-analysis. J Hypertens. 2018;36:1780–1787.
  • Balachandar R , Soundararajan S , Bagepally BS . Docosahexaenoic acid supplementation in age-related cognitive decline: a systematic review and meta-analysis. Eur J Clin Pharmacol. 2020;76:639–648.
  • Zlokovic BV . Neurovascular pathways to neurodegeneration in Alzheimer’s disease and other disorders. Nat Rev Neurosci. 2011;12:723–738.
  • Maloney B , Lahiri DK . Epigenetics of dementia: understanding the disease as a transformation rather than a state. Lancet Neurol. 2016;15:760–774.
  • Esposito M , Sherr GL . Epigenetic modifications in Alzheimer’s neuropathology and therapeutics. Front Neurosci. 2019;13:476.
  • Li P , Marshall L , Oh G , et al. Epigenetic dysregulation of enhancers in neurons is associated with Alzheimer’s disease pathology and cognitive symptoms. Nat Commun. 2019;10:2246.
  • Nativio R , Donahue G , Berson A , et al. Dysregulation of the epigenetic landscape of normal aging in Alzheimer’s disease. Nat Neurosci. 2018;21:497–505.
  • Liu X , Jiao B , Shen L . The epigenetics of Alzheimer’s disease: factors and therapeutic implications. Front Genet. 2018;9:579.
  • Fang Y , Liao G , Yu B . LSD1/KDM1A inhibitors in clinical trials: advances and prospects. J Hematol Oncol. 2019;12:129.
  • Maes T , Molinero C , Antonijoan RM , et al. First-in-human phase I results show safety, tolerability and brain penetrance of ORY-2001, an epigenetic drug targeting LSD1 and MAO-B. Alzheimers Dement. 2017;13:P1573–P1574.
  • Morris JC . Editorial: is now the time for combination therapies for Alzheimer disease? J Prev Alzheimers Dis. 2019;6:153–154.
  • Kubota K , Niinuma Y , Kaneko M , et al. Suppressive effects of 4-phenylbutyrate on the aggregation of Pael receptors and endoplasmic reticulum stress. J Neurochem. 2006;97:1259–1268.
  • Cuadrado-Tejedor M , Ricobaraza AL , Torrijo R , et al. Phenylbutyrate is a multifaceted drug that exerts neuroprotective effects and reverses the Alzheimer s disease like phenotype of a commonly used mouse model. Curr Pharm Des. 2013;19:5076–5084.
  • Daruich A , Picard E , Boatright JH , et al. The bile acids urso- and tauroursodeoxycholic acid as neuroprotective therapies in retinal disease. Mol Vis. 2019;25:610–624.
  • Nunes AF , Amaral JD , Lo AC , et al. TUDCA, a bile acid, attenuates amyloid precursor protein processing and amyloid-β deposition in APP/PS1 mice. Mol Neurobiol. 2012;45:440–454.
  • Dionisio PA , Amaral JD , Ribeiro MF , et al. Amyloid β pathology is attenuated by tauroursodeoxycholic acid treatment in APP/PS1 mice after disease onset. Neurobiol Aging. 2015;36:228–240.
  • Osswald G , BioArctic announces positive topline results of BAN2401 Phase 2b at 18 months in early Alzheimer’s disease. BioArctic. press release [cited 2020 July 5 ].
  • Tucker S , Möller C , Tegerstedt K , et al. The murine version of BAN2401 (mAb158) selectively reduces amyloid-β protofibrils in brain and cerebrospinal fluid of tg-ArcSwe mice. J Alzheimers Dis. 2015;43:575–588.
  • Panza F , Lozupone M , Bellomo A , et al. Do anti-amyloid-β drugs affect neuropsychiatric status in Alzheimer’s disease patients? Ageing Res Rev. 2019;55:100948.
  • Jack CR , Bennett DA , Blennow K , et al. A/T/N: an unbiased descriptive classification scheme for Alzheimer disease biomarkers. Neurology. 2016;87:539–547.
  • Halaas NB , Henjum K , Blennow K , et al. CSF sTREM2 and tau work together in predicting increased temporal lobe atrophy in older adults. Cereb Cortex. 2020;30:2295–2306.
  • Zetterberg H , Bendlin BB . Biomarkers for Alzheimer’s disease-preparing for a new era of disease-modifying therapies. Mol Psychiatry. 2020. [ Epub ahead of print]. DOI:10.1038/s41380-020-0721-9

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