Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress 2023 EHA Congress 2023 ASCO Annual Meeting
Clinical Collections
Advances in Alzheimer’s

ACC 2024 Congress

Catch up on all the top stories and latest evidence in cardiology research with our ACC 2024 Congress hub page.
ADVANCED SEARCH
Log in
Top
Molecular Neurodegeneration
Published in: Molecular Neurodegeneration 1/2018

Open Access 01-12-2018 | Review

Advances in developing novel therapeutic strategies for Alzheimer’s disease

Authors: Jiqing Cao, Jianwei Hou, Jing Ping, Dongming Cai

Published in: Molecular Neurodegeneration | Issue 1/2018

Login to get access

Abstract

Alzheimer’s Disease (AD), the most prevalent neurodegenerative disease of aging, affects one in eight older Americans. Nearly all drug treatments tested for AD today have failed to show any efficacy. There is a great need for therapies to prevent and/or slow the progression of AD. The major challenge in AD drug development is lack of clarity about the mechanisms underlying AD pathogenesis and pathophysiology. Several studies support the notion that AD is a multifactorial disease. While there is abundant evidence that amyloid plays a role in AD pathogenesis, other mechanisms have been implicated in AD such as tangle formation and spread, dysregulated protein degradation pathways, neuroinflammation, and loss of support by neurotrophic factors. Therefore, current paradigms of AD drug design have been shifted from single target approach (primarily amyloid-centric) to developing drugs targeted at multiple disease aspects, and from treating AD at later stages of disease progression to focusing on preventive strategies at early stages of disease development. Here, we summarize current strategies and new trends of AD drug development, including pre-clinical and clinical trials that target different aspects of disease (mechanism-based versus non-mechanism based, e.g. symptomatic treatments, lifestyle modifications and risk factor management).
Literature
1.
Alzheimer's Association. 2012 Alzheimer's disease facts and figures. Alzheimers Dement. 2012;8:131–68.CrossRef
2.
Minino AM, Murphy SL, Xu J, Kochanek KD. Deaths: final data for 2008. Natl Vital Stat Rep. 2011;59:1–126.PubMed
3.
Thies W, Bleiler L. Alzheimer's disease facts and figures. Alzheimers Dement. 2013;2013(9):208–45.
4.
Freudenberg-Hua Y, Li W, Davies P. The role of genetics in advancing precision medicine for Alzheimer's disease-a narrative review. Front Med. 2018;5:108.CrossRef
5.
Van Cauwenberghe C, Van Broeckhoven C, Sleegers K. The genetic landscape of Alzheimer disease: clinical implications and perspectives. Genet Med. 2016;18:421–30.PubMedCrossRef
6.
Verheijen J, Sleegers K. Understanding Alzheimer disease at the Interface between genetics and transcriptomics. Trends Genet. 2018;34:434–47.PubMedCrossRef
7.
Sorbi S. Molecular genetics of Alzheimer's disease. Aging (Milano). 1993;5:417–25.
8.
Scheltens P, Blennow K, Breteler MM, de Strooper B, Frisoni GB, Salloway S, Van der Flier WM. Alzheimer's disease. Lancet. 2016;388:505–17.PubMedCrossRef
9.
10.
11.
Morris JC. Early-stage and preclinical Alzheimer disease. Alzheimer Dis Assoc Disord. 2005;19:163–5.PubMedCrossRef
12.
Kennedy ME, Stamford AW, Chen X, Cox K, Cumming JN, Dockendorf MF, Egan M, Ereshefsky L, Hodgson RA, Hyde LA, et al. The BACE1 inhibitor verubecestat (MK-8931) reduces CNS beta-amyloid in animal models and in Alzheimer's disease patients. Sci Transl Med. 2016;8:363ra150.PubMedCrossRef
13.
May PC, Willis BA, Lowe SL, Dean RA, Monk SA, Cocke PJ, Audia JE, Boggs LN, Borders AR, Brier RA, et al. The potent BACE1 inhibitor LY2886721 elicits robust central Abeta pharmacodynamic responses in mice, dogs, and humans. J Neurosci. 2015;35:1199–210.PubMedCrossRefPubMedCentral
14.
May PC, Dean RA, Lowe SL, Martenyi F, Sheehan SM, Boggs LN, Monk SA, Mathes BM, Mergott DJ, Watson BM, et al. Robust central reduction of amyloid-beta in humans with an orally available, non-peptidic beta-secretase inhibitor. J Neurosci. 2011;31:16507–16.PubMedCrossRefPubMedCentral
15.
16.
Moussa CE. Beta-secretase inhibitors in phase I and phase II clinical trials for Alzheimer's disease. Expert Opin Investig Drugs. 2017;26:1131–6.PubMedCrossRef
17.
Hu X, Das B, Hou H, He W, Yan R. BACE1 deletion in the adult mouse reverses preformed amyloid deposition and improves cognitive functions. J Exp Med. 2018;215(3):927–40.PubMedPubMedCentralCrossRef
18.
De Strooper B, Iwatsubo T, Wolfe MS. Presenilins and gamma-secretase: structure, function, and role in Alzheimer disease. Cold Spring Harb Perspect Med. 2012;2:a006304.PubMedPubMedCentralCrossRef
19.
Zhang X, Li Y, Xu H, Zhang YW. The gamma-secretase complex: from structure to function. Front Cell Neurosci. 2014;8:427.PubMedPubMedCentral
20.
Barton AJ, Crook BW, Karran EH, Brown F, Dewar D, Mann DM, Pearson RC, Graham DI, Hardy J, Hutton M, et al. Alteration in brain presenilin 1 mRNA expression in early onset familial Alzheimer's disease. Neurodegeneration. 1996;5:213–8.PubMedCrossRef
21.
Borchelt DR, Thinakaran G, Eckman CB, Lee MK, Davenport F, Ratovitsky T, Prada CM, Kim G, Seekins S, Yager D, et al. Familial Alzheimer's disease-linked presenilin 1 variants elevate Abeta1-42/1-40 ratio in vitro and in vivo. Neuron. 1996;17:1005–13.PubMedCrossRef
22.
De Strooper B, Saftig P, Craessaerts K, Vanderstichele H, Guhde G, Annaert W, Von Figura K, Van Leuven F. Deficiency of presenilin-1 inhibits the normal cleavage of amyloid precursor protein. Nature. 1998;391:387–90.PubMedCrossRef
23.
Herreman A, Serneels L, Annaert W, Collen D, Schoonjans L, De Strooper B. Total inactivation of gamma-secretase activity in presenilin-deficient embryonic stem cells. Nat Cell Biol. 2000;2:461–2.PubMedCrossRef
24.
Li YM, Lai MT, Xu M, Huang Q, DiMuzio-Mower J, Sardana MK, Shi XP, Yin KC, Shafer JA, Gardell SJ. Presenilin 1 is linked with gamma-secretase activity in the detergent solubilized state. Proc Natl Acad Sci U S A. 2000;97:6138–43.PubMedPubMedCentralCrossRef
25.
Li YM, Xu M, Lai MT, Huang Q, Castro JL, DiMuzio-Mower J, Harrison T, Lellis C, Nadin A, Neduvelil JG, et al. Photoactivated gamma-secretase inhibitors directed to the active site covalently label presenilin 1. Nature. 2000;405:689–94.PubMedCrossRef
26.
Naruse S, Thinakaran G, Luo JJ, Kusiak JW, Tomita T, Iwatsubo T, Qian X, Ginty DD, Price DL, Borchelt DR, et al. Effects of PS1 deficiency on membrane protein trafficking in neurons. Neuron. 1998;21:1213–21.PubMedCrossRef
27.
Scheuner D, Eckman C, Jensen M, Song X, Citron M, Suzuki N, Bird TD, Hardy J, Hutton M, Kukull W, et al. Secreted amyloid beta-protein similar to that in the senile plaques of Alzheimer's disease is increased in vivo by the presenilin 1 and 2 and APP mutations linked to familial Alzheimer's disease. Nat Med. 1996;2:864–70.PubMedCrossRef
28.
Zhang Z, Nadeau P, Song W, Donoviel D, Yuan M, Bernstein A, Yankner BA. Presenilins are required for gamma-secretase cleavage of beta-APP and transmembrane cleavage of Notch-1. Nat Cell Biol. 2000;2:463–5.PubMedCrossRef
29.
30.
Dovey HF, John V, Anderson JP, Chen LZ, de Saint AP, Fang LY, Freedman SB, Folmer B, Goldbach E, Holsztynska EJ, et al. Functional gamma-secretase inhibitors reduce beta-amyloid peptide levels in brain. J Neurochem. 2001;76:173–81.PubMedCrossRef
31.
Lanz TA, Wood KM, Richter KE, Nolan CE, Becker SL, Pozdnyakov N, Martin BA, Du P, Oborski CE, Wood DE, et al. Pharmacodynamics and pharmacokinetics of the gamma-secretase inhibitor PF-3084014. J Pharmacol Exp Ther. 2010;334:269–77.PubMedCrossRef
32.
Searfoss GH, Jordan WH, Calligaro DO, Galbreath EJ, Schirtzinger LM, Berridge BR, Gao H, Higgins MA, May PC, Ryan TP. Adipsin, a biomarker of gastrointestinal toxicity mediated by a functional gamma-secretase inhibitor. J Biol Chem. 2003;278:46107–16.PubMedCrossRef
33.
Wong GT, Manfra D, Poulet FM, Zhang Q, Josien H, Bara T, Engstrom L, Pinzon-Ortiz M, Fine JS, Lee HJ, et al. Chronic treatment with the gamma-secretase inhibitor LY-411,575 inhibits beta-amyloid peptide production and alters lymphopoiesis and intestinal cell differentiation. J Biol Chem. 2004;279:12876–82.PubMedCrossRef
34.
Albright CF, Dockens RC, Meredith JE Jr, Olson RE, Slemmon R, Lentz KA, Wang JS, Denton RR, Pilcher G, Rhyne PW, et al. Pharmacodynamics of selective inhibition of gamma-secretase by avagacestat. J Pharmacol Exp Ther. 2013;344:686–95.PubMedCrossRef
35.
Coric V, van Dyck CH, Salloway S, Andreasen N, Brody M, Richter RW, Soininen H, Thein S, Shiovitz T, Pilcher G, et al. Safety and tolerability of the gamma-secretase inhibitor avagacestat in a phase 2 study of mild to moderate Alzheimer disease. Arch Neurol. 2012;69:1430–40.PubMedCrossRef
36.
Doody RS, Aisen PS, Iwatsubo T. Semagacestat for treatment of Alzheimer's disease. N Engl J Med. 2013;369:1661.PubMedCrossRef
37.
Doody RS, Raman R, Farlow M, Iwatsubo T, Vellas B, Joffe S, Kieburtz K, He F, Sun X, Thomas RG, et al. A phase 3 trial of semagacestat for treatment of Alzheimer's disease. N Engl J Med. 2013;369:341–50.PubMedCrossRef
38.
Netzer WJ, Dou F, Cai D, Veach D, Jean S, Li Y, Bornmann WG, Clarkson B, Xu H, Greengard P. Gleevec inhibits beta-amyloid production but not notch cleavage. Proc Natl Acad Sci U S A. 2003;100:12444–9.PubMedPubMedCentralCrossRef
39.
Gillman KW, Starrett JE Jr, Parker MF, Xie K, Bronson JJ, Marcin LR, McElhone KE, Bergstrom CP, Mate RA, Williams R, et al. Discovery and evaluation of BMS-708163, a potent, selective and orally bioavailable gamma-secretase inhibitor. ACS Med Chem Lett. 2010;1:120–4.PubMedPubMedCentralCrossRef
40.
Folch J, Petrov D, Ettcheto M, Abad S, Sanchez-Lopez E, Garcia ML, Olloquequi J, Beas-Zarate C, Auladell C, Camins A. Current research therapeutic strategies for Alzheimer's disease treatment. Neural Plast. 2016;2016:8501693.PubMedPubMedCentralCrossRef
41.
Weggen S, Eriksen JL, Das P, Sagi SA, Wang R, Pietrzik CU, Findlay KA, Smith TE, Murphy MP, Bulter T, et al. A subset of NSAIDs lower amyloidogenic Abeta42 independently of cyclooxygenase activity. Nature. 2001;414:212–6.PubMedCrossRef
42.
Green RC, Schneider LS, Amato DA, Beelen AP, Wilcock G, Swabb EA, Zavitz KH, Tarenflurbil Phase 3 Study G. Effect of tarenflurbil on cognitive decline and activities of daily living in patients with mild Alzheimer disease: a randomized controlled trial. JAMA. 2009;302:2557–64.PubMedPubMedCentralCrossRef
43.
Bachurin SO, Bovina EV, Ustyugov AA. Drugs in clinical trials for Alzheimer's disease: the major trends. Med Res Rev. 2017;37:1186–225.PubMedCrossRef
44.
45.
Pasquier F, Sadowsky C, Holstein A, Leterme Gle P, Peng Y, Jackson N, Fox NC, Ketter N, Liu E, Ryan JM, Team ACCS. 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;51:1131–43.PubMedCrossRef
46.
47.
Davtyan H, Bacon A, Petrushina I, Zagorski K, Cribbs DH, Ghochikyan A, Agadjanyan MG. Immunogenicity of DNA- and recombinant protein-based Alzheimer disease epitope vaccines. Hum Vaccin Immunother. 2014;10:1248–55.PubMedPubMedCentralCrossRef
48.
Abushouk AI, Elmaraezy A, Aglan A, Salama R, Fouda S, Fouda R, AlSafadi AM. Bapineuzumab for mild to moderate Alzheimer's disease: a meta-analysis of randomized controlled trials. BMC Neurol. 2017;17:66.PubMedPubMedCentralCrossRef
49.
Laske C. Phase 3 trials of solanezumab and bapineuzumab for Alzheimer's disease. N Engl J Med. 2014;370:1459.PubMedCrossRef
50.
Tucker S, Moller C, Tegerstedt K, Lord A, Laudon H, Sjodahl J, Soderberg L, Spens E, Sahlin C, Waara ER, et al. The murine version of BAN2401 (mAb158) selectively reduces amyloid-beta protofibrils in brain and cerebrospinal fluid of tg-ArcSwe mice. J Alzheimers Dis. 2015;43:575–88.PubMedCrossRef
51.
Sevigny J, Chiao P, Bussiere T, Weinreb PH, Williams L, Maier M, Dunstan R, Salloway S, Chen T, Ling Y, et al. The antibody aducanumab reduces Abeta plaques in Alzheimer's disease. Nature. 2016;537:50–6.PubMedCrossRef
52.
Maccecchini ML, Chang MY, Pan C, John V, Zetterberg H, Greig NH. Posiphen as a candidate drug to lower CSF amyloid precursor protein, amyloid-beta peptide and tau levels: target engagement, tolerability and pharmacokinetics in humans. J Neurol Neurosurg Psychiatry. 2012;83:894–902.PubMedCrossRef
53.
Sinha S, Du Z, Maiti P, Klarner FG, Schrader T, Wang C, Bitan G. Comparison of three amyloid assembly inhibitors: the sugar scyllo-inositol, the polyphenol epigallocatechin gallate, and the molecular tweezer CLR01. ACS Chem Neurosci. 2012;3:451–8.PubMedPubMedCentralCrossRef
54.
Buee L, Bussiere T, Buee-Scherrer V, Delacourte A, Hof PR. Tau protein isoforms, phosphorylation and role in neurodegenerative disorders. Brain Res Brain Res Rev. 2000;33:95–130.PubMedCrossRef
55.
Drechsel DN, Hyman AA, Cobb MH, Kirschner MW. Modulation of the dynamic instability of tubulin assembly by the microtubule-associated protein tau. Mol Biol Cell. 1992;3:1141–54.PubMedPubMedCentralCrossRef
56.
Nelson PT, Alafuzoff I, Bigio EH, Bouras C, Braak H, Cairns NJ, Castellani RJ, Crain BJ, Davies P, Del Tredici K, et al. Correlation of Alzheimer disease neuropathologic changes with cognitive status: a review of the literature. J Neuropathol Exp Neurol. 2012;71:362–81.PubMedCrossRef
57.
Fath T, Eidenmuller J, Brandt R. Tau-mediated cytotoxicity in a pseudohyperphosphorylation model of Alzheimer's disease. J Neurosci. 2002;22:9733–41.PubMedCrossRefPubMedCentral
58.
Leschik J, Welzel A, Weissmann C, Eckert A, Brandt R. Inverse and distinct modulation of tau-dependent neurodegeneration by presenilin 1 and amyloid-beta in cultured cortical neurons: evidence that tau phosphorylation is the limiting factor in amyloid-beta-induced cell death. J Neurochem. 2007;101:1303–15.PubMedCrossRef
59.
Shahani N, Subramaniam S, Wolf T, Tackenberg C, Brandt R. Tau aggregation and progressive neuronal degeneration in the absence of changes in spine density and morphology after targeted expression of Alzheimer's disease-relevant tau constructs in organotypic hippocampal slices. J Neurosci. 2006;26:6103–14.PubMedCrossRefPubMedCentral
60.
Tackenberg C, Brandt R. Divergent pathways mediate spine alterations and cell death induced by amyloid-beta, wild-type tau, and R406W tau. J Neurosci. 2009;29:14439–50.PubMedCrossRefPubMedCentral
61.
Panza F, Solfrizzi V, Seripa D, Imbimbo BP, Lozupone M, Santamato A, Zecca C, Barulli MR, Bellomo A, Pilotto A, et al. Tau-centric targets and drugs in clinical development for the treatment of Alzheimer's disease. Biomed Res Int. 2016;2016:3245935.PubMedPubMedCentralCrossRef
62.
Baddeley TC, McCaffrey J, Storey JM, Cheung JK, Melis V, Horsley D, Harrington CR, Wischik CM. Complex disposition of methylthioninium redox forms determines efficacy in tau aggregation inhibitor therapy for Alzheimer's disease. J Pharmacol Exp Ther. 2015;352:110–8.PubMedCrossRef
63.
Wischik CM, Staff RT, Wischik DJ, Bentham P, Murray AD, Storey JM, Kook KA, Harrington CR. Tau aggregation inhibitor therapy: an exploratory phase 2 study in mild or moderate Alzheimer's disease. J Alzheimers Dis. 2015;44:705–20.PubMedCrossRef
64.
65.
Pei JJ, Bjorkdahl C, Zhang H, Zhou X, Winblad B. p70 S6 kinase and tau in Alzheimer's disease. J Alzheimers Dis. 2008;14:385–92.PubMedCrossRef
66.
Jia Q, Deng Y, Qing H. Potential therapeutic strategies for Alzheimer's disease targeting or beyond beta-amyloid: insights from clinical trials. Biomed Res Int. 2014;2014:837157.PubMedPubMedCentral
67.
Hampel H, Ewers M, Burger K, Annas P, Mortberg A, Bogstedt A, Frolich L, Schroder J, Schonknecht P, Riepe MW, et al. Lithium trial in Alzheimer's disease: a randomized, single-blind, placebo-controlled, multicenter 10-week study. J Clin Psychiatry. 2009;70:922–31.PubMedCrossRef
68.
Tariot PN, Aisen PS. Can lithium or valproate untie tangles in Alzheimer's disease? J Clin Psychiatry. 2009;70:919–21.PubMedCrossRef
69.
del Ser T, Steinwachs KC, Gertz HJ, Andres MV, Gomez-Carrillo B, Medina M, Vericat JA, Redondo P, Fleet D, Leon T. Treatment of Alzheimer's disease with the GSK-3 inhibitor tideglusib: a pilot study. J Alzheimers Dis. 2013;33:205–15.PubMed
70.
Martinez A. Preclinical efficacy on GSK-3 inhibitors: towards a future generation of powerful drugs. Med Res Rev. 2008;28:773–96.PubMedCrossRef
71.
Sereno L, Coma M, Rodriguez M, Sanchez-Ferrer P, Sanchez MB, Gich I, Agullo JM, Perez M, Avila J, Guardia-Laguarta C, et al. A novel GSK-3beta inhibitor reduces Alzheimer's pathology and rescues neuronal loss in vivo. Neurobiol Dis. 2009;35:359–67.CrossRefPubMed
72.
Natarajan P, Priyadarshini V, Pradhan D, Manne M, Swargam S, Kanipakam H, Bhuma V, Amineni U. E-pharmacophore-based virtual screening to identify GSK-3beta inhibitors. J Recept Signal Transduct Res. 2016;36:445–58.PubMedCrossRef
73.
74.
Mushtaq G, Greig NH, Anwar F, Al-Abbasi FA, Zamzami MA, Al-Talhi HA, Kamal MA. Neuroprotective mechanisms mediated by CDK5 inhibition. Curr Pharm Des. 2016;22:527–34.PubMedPubMedCentralCrossRef
75.
Wen Y, Yu WH, Maloney B, Bailey J, Ma J, Marie I, Maurin T, Wang L, Figueroa H, Herman M, et al. Transcriptional regulation of beta-secretase by p25/cdk5 leads to enhanced amyloidogenic processing. Neuron. 2008;57:680–90.PubMedPubMedCentralCrossRef
76.
Min SW, Chen X, Tracy TE, Li Y, Zhou Y, Wang C, Shirakawa K, Minami SS, Defensor E, Mok SA, et al. Critical role of acetylation in tau-mediated neurodegeneration and cognitive deficits. Nat Med. 2015;21:1154–62.PubMedPubMedCentralCrossRef
77.
Sohn PD, Tracy TE, Son HI, Zhou Y, Leite RE, Miller BL, Seeley WW, Grinberg LT, Gan L. Acetylated tau destabilizes the cytoskeleton in the axon initial segment and is mislocalized to the somatodendritic compartment. Mol Neurodegener. 2016;11:47.PubMedPubMedCentralCrossRef
78.
Tracy TE, Sohn PD, Minami SS, Wang C, Min SW, Li Y, Zhou Y, Le D, Lo I, Ponnusamy R, et al. Acetylated tau obstructs KIBRA-mediated signaling in synaptic plasticity and promotes Tauopathy-related memory loss. Neuron. 2016;90:245–60.PubMedPubMedCentralCrossRef
79.
Trzeciakiewicz H, Tseng JH, Wander CM, Madden V, Tripathy A, Yuan CX, Cohen TJ. A dual pathogenic mechanism links tau acetylation to sporadic Tauopathy. Sci Rep. 2017;7:44102.PubMedPubMedCentralCrossRef
80.
Min SW, Sohn PD, Li Y, Devidze N, Johnson JR, Krogan NJ, Masliah E, Mok SA, Gestwicki JE, Gan L. SIRT1 deacetylates tau and reduces pathogenic tau spread in a mouse model of Tauopathy. J Neurosci. 2018;38:3680–8.PubMedPubMedCentralCrossRef
81.
Albayram O, Kondo A, Mannix R, Smith C, Tsai CY, Li C, Herbert MK, Qiu J, Monuteaux M, Driver J, et al. Cis P-tau is induced in clinical and preclinical brain injury and contributes to post-injury sequelae. Nat Commun. 2017;8:1000.PubMedPubMedCentralCrossRef
82.
Kondo A, Shahpasand K, Mannix R, Qiu J, Moncaster J, Chen CH, Yao Y, Lin YM, Driver JA, Sun Y, et al. Antibody against early driver of neurodegeneration cis P-tau blocks brain injury and tauopathy. Nature. 2015;523:431–6.PubMedPubMedCentralCrossRef
83.
Lu KP, Kondo A, Albayram O, Herbert MK, Liu H, Zhou XZ. Potential of the antibody against cis-phosphorylated tau in the early diagnosis, treatment, and prevention of Alzheimer disease and brain injury. JAMA Neurol. 2016;73:1356–62.PubMedCrossRef
84.
Hart GW, Slawson C, Ramirez-Correa G, Lagerlof O. Cross talk between O-GlcNAcylation and phosphorylation: roles in signaling, transcription, and chronic disease. Annu Rev Biochem. 2011;80:825–58.PubMedPubMedCentralCrossRef
85.
Liu F, Shi J, Tanimukai H, Gu J, Gu J, Grundke-Iqbal I, Iqbal K, Gong CX. Reduced O-GlcNAcylation links lower brain glucose metabolism and tau pathology in Alzheimer's disease. Brain. 2009;132:1820–32.PubMedPubMedCentralCrossRef
86.
Flight MH. Neurodegenerative disease: tau immunotherapy targets transcellular propagation. Nat Rev Drug Discov. 2013;12:904.PubMedCrossRef
87.
Goedert M, Eisenberg DS, Crowther RA. Propagation of tau aggregates and neurodegeneration. Annu Rev Neurosci. 2017;40:189–210.PubMedCrossRef
88.
89.
Kfoury N, Holmes BB, Jiang H, Holtzman DM, Diamond MI. Trans-cellular propagation of tau aggregation by fibrillar species. J Biol Chem. 2012;287:19440–51.PubMedPubMedCentralCrossRef
90.
Yanamandra K, Kfoury N, Jiang H, Mahan TE, Ma S, Maloney SE, Wozniak DF, Diamond MI, Holtzman DM. Anti-tau antibodies that block tau aggregate seeding in vitro markedly decrease pathology and improve cognition in vivo. Neuron. 2013;80:402–14.PubMedPubMedCentralCrossRef
91.
Yanamandra K, Jiang H, Mahan TE, Maloney SE, Wozniak DF, Diamond MI, Holtzman DM. Anti-tau antibody reduces insoluble tau and decreases brain atrophy. Ann Clin Transl Neurol. 2015;2:278–88.PubMedPubMedCentralCrossRef
92.
Chukwu JE, Pedersen JT, Pedersen LO, Volbracht C, Sigurdsson EM, Kong XP. Tau antibody structure reveals a molecular switch defining a pathological conformation of the tau protein. Sci Rep. 2018;8:6209.PubMedPubMedCentralCrossRef
93.
Rajamohamedsait H, Rasool S, Rajamohamedsait W, Lin Y, Sigurdsson EM. Prophylactic active tau immunization leads to sustained reduction in both tau and amyloid-beta pathologies in 3xTg mice. Sci Rep. 2017;7:17034.PubMedPubMedCentralCrossRef
94.
Gruninger F. Invited review: drug development for tauopathies. Neuropathol Appl Neurobiol. 2015;41:81–96.PubMedCrossRef
95.
Dai CL, Chen X, Kazim SF, Liu F, Gong CX, Grundke-Iqbal I, Iqbal K. Passive immunization targeting the N-terminal projection domain of tau decreases tau pathology and improves cognition in a transgenic mouse model of Alzheimer disease and tauopathies. J Neural Transm. 2015;122:607–17.PubMedCrossRef
96.
Dai CL, Hu W, Tung YC, Liu F, Gong CX, Iqbal K. Tau passive immunization blocks seeding and spread of Alzheimer hyperphosphorylated tau-induced pathology in 3 × Tg-AD mice. Alzheimers Res Ther. 2018;10:13.PubMedPubMedCentralCrossRef
97.
98.
Malia TJ, Teplyakov A, Ernst R, Wu SJ, Lacy ER, Liu X, Vandermeeren M, Mercken M, Luo J, Sweet RW, Gilliland GL. Epitope mapping and structural basis for the recognition of phosphorylated tau by the anti-tau antibody AT8. Proteins. 2016;84:427–34.PubMedPubMedCentralCrossRef
99.
100.
Castellano JM, Kim J, Stewart FR, Jiang H, DeMattos RB, Patterson BW, Fagan AM, Morris JC, Mawuenyega KG, Cruchaga C, et al. Human apoE isoforms differentially regulate brain amyloid-beta peptide clearance. Sci Transl Med. 2011;3:89ra57.PubMedPubMedCentralCrossRef
101.
Cataldo AM, Peterhoff CM, Troncoso JC, Gomez-Isla T, Hyman BT, Nixon RA. Endocytic pathway abnormalities precede amyloid beta deposition in sporadic Alzheimer's disease and Down syndrome: differential effects of APOE genotype and presenilin mutations. Am J Pathol. 2000;157:277–86.PubMedPubMedCentralCrossRef
102.
Li J, Kanekiyo T, Shinohara M, Zhang Y, LaDu MJ, Xu H, Bu G. Differential regulation of amyloid-beta endocytic trafficking and lysosomal degradation by apolipoprotein E isoforms. J Biol Chem. 2012;287:44593–601.PubMedPubMedCentralCrossRef
103.
Holtzman DM, Herz J, Bu G. Apolipoprotein E and apolipoprotein E receptors: normal biology and roles in Alzheimer disease. Cold Spring Harb Perspect Med. 2012;2:a006312.PubMedPubMedCentral
104.
105.
Kuszczyk MA, Sanchez S, Pankiewicz J, Kim J, Duszczyk M, Guridi M, Asuni AA, Sullivan PM, Holtzman DM, Sadowski MJ. Blocking the interaction between apolipoprotein E and Abeta reduces intraneuronal accumulation of Abeta and inhibits synaptic degeneration. Am J Pathol. 2013;182:1750–68.PubMedPubMedCentralCrossRef
106.
Liu Q, Wu WH, Fang CL, Li RW, Liu P, Lei P, Hu J, Sun X, Zheng YZ, Zhao YF, Li YM. Mapping ApoE/Abeta binding regions to guide inhibitor discovery. Mol BioSyst. 2011;7:1693–700.PubMedCrossRef
107.
Sadowski MJ, Pankiewicz J, Scholtzova H, Mehta PD, Prelli F, Quartermain D, Wisniewski T. Blocking the apolipoprotein E/amyloid-beta interaction as a potential therapeutic approach for Alzheimer's disease. Proc Natl Acad Sci U S A. 2006;103:18787–92.PubMedPubMedCentralCrossRef
108.
Yang J, Ji Y, Mehta P, Bates KA, Sun Y, Wisniewski T. Blocking the apolipoprotein E/amyloid-beta interaction reduces fibrillar vascular amyloid deposition and cerebral microhemorrhages in TgSwDI mice. J Alzheimers Dis. 2011;24:269–85.PubMedPubMedCentralCrossRef
109.
Cramer PE, Cirrito JR, Wesson DW, Lee CY, Karlo JC, Zinn AE, Casali BT, Restivo JL, Goebel WD, James MJ, et al. ApoE-directed therapeutics rapidly clear beta-amyloid and reverse deficits in AD mouse models. Science. 2012;335:1503–6.PubMedPubMedCentralCrossRef
110.
Kim J, Castellano JM, Jiang H, Basak JM, Parsadanian M, Pham V, Mason SM, Paul SM, Holtzman DM. Overexpression of low-density lipoprotein receptor in the brain markedly inhibits amyloid deposition and increases extracellular a beta clearance. Neuron. 2009;64:632–44.PubMedPubMedCentralCrossRef
111.
Dodart JC, Marr RA, Koistinaho M, Gregersen BM, Malkani S, Verma IM, Paul SM. Gene delivery of human apolipoprotein E alters brain Abeta burden in a mouse model of Alzheimer's disease. Proc Natl Acad Sci U S A. 2005;102:1211–6.PubMedPubMedCentralCrossRef
112.
Hudry E, Dashkoff J, Roe AD, Takeda S, Koffie RM, Hashimoto T, Scheel M, Spires-Jones T, Arbel-Ornath M, Betensky R, et al. Gene transfer of human Apoe isoforms results in differential modulation of amyloid deposition and neurotoxicity in mouse brain. Sci Transl Med. 2013;5:212ra161.PubMedPubMedCentralCrossRef
113.
Kim J, Eltorai AE, Jiang H, Liao F, Verghese PB, Kim J, Stewart FR, Basak JM, Holtzman DM. Anti-apoE immunotherapy inhibits amyloid accumulation in a transgenic mouse model of Abeta amyloidosis. J Exp Med. 2012;209:2149–56.PubMedPubMedCentralCrossRef
114.
Liao F, Hori Y, Hudry E, Bauer AQ, Jiang H, Mahan TE, Lefton KB, Zhang TJ, Dearborn JT, Kim J, et al. Anti-ApoE antibody given after plaque onset decreases Abeta accumulation and improves brain function in a mouse model of Abeta amyloidosis. J Neurosci. 2014;34:7281–92.PubMedPubMedCentralCrossRef
115.
Brodbeck J, McGuire J, Liu Z, Meyer-Franke A, Balestra ME, Jeong DE, Pleiss M, McComas C, Hess F, Witter D, et al. Structure-dependent impairment of intracellular apolipoprotein E4 trafficking and its detrimental effects are rescued by small-molecule structure correctors. J Biol Chem. 2011;286:17217–26.PubMedPubMedCentralCrossRef
116.
Chen HK, Liu Z, Meyer-Franke A, Brodbeck J, Miranda RD, McGuire JG, Pleiss MA, Ji ZS, Balestra ME, Walker DW, et al. Small molecule structure correctors abolish detrimental effects of apolipoprotein E4 in cultured neurons. J Biol Chem. 2012;287:5253–66.PubMedCrossRef
117.
Wang C, Najm R, Xu Q, Jeong DE, Walker D, Balestra ME, Yoon SY, Yuan H, Li G, Miller ZA, et al. Gain of toxic apolipoprotein E4 effects in human iPSC-derived neurons is ameliorated by a small-molecule structure corrector. Nat Med. 2018;24:647–57.PubMedPubMedCentralCrossRef
118.
Donkin JJ, Stukas S, Hirsch-Reinshagen V, Namjoshi D, Wilkinson A, May S, Chan J, Fan J, Collins J, Wellington CL. ATP-binding cassette transporter A1 mediates the beneficial effects of the liver X receptor agonist GW3965 on object recognition memory and amyloid burden in amyloid precursor protein/presenilin 1 mice. J Biol Chem. 2010;285:34144–54.PubMedPubMedCentralCrossRef
119.
Fitz NF, Cronican A, Pham T, Fogg A, Fauq AH, Chapman R, Lefterov I, Koldamova R. Liver X receptor agonist treatment ameliorates amyloid pathology and memory deficits caused by high-fat diet in APP23 mice. J Neurosci. 2010;30:6862–72.PubMedPubMedCentralCrossRef
120.
Koldamova RP, Lefterov IM, Staufenbiel M, Wolfe D, Huang S, Glorioso JC, Walter M, Roth MG, Lazo JS. The liver X receptor ligand T0901317 decreases amyloid beta production in vitro and in a mouse model of Alzheimer's disease. J Biol Chem. 2005;280:4079–88.PubMedCrossRef
121.
Riddell DR, Zhou H, Comery TA, Kouranova E, Lo CF, Warwick HK, Ring RH, Kirksey Y, Aschmies S, Xu J, et al. The LXR agonist TO901317 selectively lowers hippocampal Abeta42 and improves memory in the Tg2576 mouse model of Alzheimer's disease. Mol Cell Neurosci. 2007;34:621–8.PubMedCrossRef
122.
Laskowitz DT, Lei B, Dawson HN, Wang H, Bellows ST, Christensen DJ, Vitek MP, James ML. The apoE-mimetic peptide, COG1410, improves functional recovery in a murine model of intracerebral hemorrhage. Neurocrit Care. 2012;16:316–26.PubMedCrossRef
123.
Laskowitz DT, McKenna SE, Song P, Wang H, Durham L, Yeung N, Christensen D, Vitek MP. COG1410, a novel apolipoprotein E-based peptide, improves functional recovery in a murine model of traumatic brain injury. J Neurotrauma. 2007;24:1093–107.PubMedCrossRef
124.
Vitek MP, Christensen DJ, Wilcock D, Davis J, Van Nostrand WE, Li FQ, Colton CA. APOE-mimetic peptides reduce behavioral deficits, plaques and tangles in Alzheimer's disease transgenics. Neurodegener Dis. 2012;10:122–6.PubMedPubMedCentralCrossRef
125.
Wang H, Durham L, Dawson H, Song P, Warner DS, Sullivan PM, Vitek MP, Laskowitz DT. An apolipoprotein E-based therapeutic improves outcome and reduces Alzheimer's disease pathology following closed head injury: evidence of pharmacogenomic interaction. Neuroscience. 2007;144:1324–33.PubMedCrossRef
126.
Liu S, Breitbart A, Sun Y, Mehta PD, Boutajangout A, Scholtzova H, Wisniewski T. Blocking the apolipoprotein E/amyloid beta interaction in triple transgenic mice ameliorates Alzheimer's disease related amyloid beta and tau pathology. J Neurochem. 2014;128:577–91.PubMedCrossRef
127.
Mak AC, Pullinger CR, Tang LF, Wong JS, Deo RC, Schwarz JM, Gugliucci A, Movsesyan I, Ishida BY, Chu C, et al. Effects of the absence of apolipoprotein e on lipoproteins, neurocognitive function, and retinal function. JAMA Neurol. 2014;71:1228–36.PubMedPubMedCentralCrossRef
128.
Heywood WE, Galimberti D, Bliss E, Sirka E, Paterson RW, Magdalinou NK, Carecchio M, Reid E, Heslegrave A, Fenoglio C, et al. Identification of novel CSF biomarkers for neurodegeneration and their validation by a high-throughput multiplexed targeted proteomic assay. Mol Neurodegener. 2015;10:64.PubMedPubMedCentralCrossRef
129.
Martinez-Morillo E, Hansson O, Atagi Y, Bu G, Minthon L, Diamandis EP, Nielsen HM. Total apolipoprotein E levels and specific isoform composition in cerebrospinal fluid and plasma from Alzheimer's disease patients and controls. Acta Neuropathol. 2014;127:633–43.PubMedCrossRef
130.
Simon R, Girod M, Fonbonne C, Salvador A, Clement Y, Lanteri P, Amouyel P, Lambert JC, Lemoine J. Total ApoE and ApoE4 isoform assays in an Alzheimer's disease case-control study by targeted mass spectrometry (n=669): a pilot assay for methionine-containing proteotypic peptides. Mol Cell Proteomics. 2012;11:1389–403.PubMedPubMedCentralCrossRef
131.
Talwar P, Sinha J, Grover S, Agarwal R, Kushwaha S, Srivastava MV, Kukreti R. Meta-analysis of apolipoprotein E levels in the cerebrospinal fluid of patients with Alzheimer's disease. J Neurol Sci. 2016;360:179–87.PubMedCrossRef
132.
133.
Burns MP, Vardanian L, Pajoohesh-Ganji A, Wang L, Cooper M, Harris DC, Duff K, Rebeck GW. The effects of ABCA1 on cholesterol efflux and Abeta levels in vitro and in vivo. J Neurochem. 2006;98:792–800.PubMedCrossRef
134.
Casali BT, Corona AW, Mariani MM, Karlo JC, Ghosal K, Landreth GE. Omega-3 fatty acids augment the actions of nuclear receptor agonists in a mouse model of Alzheimer's disease. J Neurosci. 2015;35:9173–81.PubMedPubMedCentralCrossRef
135.
Escribano L, Simon AM, Gimeno E, Cuadrado-Tejedor M, Lopez de Maturana R, Garcia-Osta A, Ricobaraza A, Perez-Mediavilla A, Del Rio J, Frechilla D. Rosiglitazone rescues memory impairment in Alzheimer's transgenic mice: mechanisms involving a reduced amyloid and tau pathology. Neuropsychopharmacology. 2010;35:1593–604.PubMedPubMedCentralCrossRef
136.
Jiang Q, Lee CY, Mandrekar S, Wilkinson B, Cramer P, Zelcer N, Mann K, Lamb B, Willson TM, Collins JL, et al. ApoE promotes the proteolytic degradation of Abeta. Neuron. 2008;58:681–93.PubMedPubMedCentralCrossRef
137.
LaClair KD, Manaye KF, Lee DL, Allard JS, Savonenko AV, Troncoso JC, Wong PC. Treatment with bexarotene, a compound that increases apolipoprotein-E, provides no cognitive benefit in mutant APP/PS1 mice. Mol Neurodegener. 2013;8:18.PubMedPubMedCentralCrossRef
138.
Skerrett R, Pellegrino MP, Casali BT, Taraboanta L, Landreth GE. Combined liver X receptor/peroxisome proliferator-activated receptor gamma agonist treatment reduces amyloid beta levels and improves behavior in amyloid precursor protein/Presenilin 1 mice. J Biol Chem. 2015;290:21591–602.PubMedPubMedCentralCrossRef
139.
Tachibana M, Shinohara M, Yamazaki Y, Liu CC, Rogers J, Bu G, Kanekiyo T. Rescuing effects of RXR agonist bexarotene on aging-related synapse loss depend on neuronal LRP1. Exp Neurol. 2016;277:1–9.PubMedCrossRef
140.
Tai LM, Koster KP, Luo J, Lee SH, Wang YT, Collins NC, Ben Aissa M, Thatcher GR, LaDu MJ. Amyloid-beta pathology and APOE genotype modulate retinoid X receptor agonist activity in vivo. J Biol Chem. 2014;289:30538–55.PubMedPubMedCentralCrossRef
141.
Vanmierlo T, Rutten K, Dederen J, Bloks VW, van Vark-van der Zee LC, Kuipers F, Kiliaan A, Blokland A, Sijbrands EJ, Steinbusch H, et al. Liver X receptor activation restores memory in aged AD mice without reducing amyloid. Neurobiol Aging. 2011;32:1262–72.PubMedCrossRef
142.
Cummings JL, Zhong K, Kinney JW, Heaney C, Moll-Tudla J, Joshi A, Pontecorvo M, Devous M, Tang A, Bena J. Double-blind, placebo-controlled, proof-of-concept trial of bexarotene Xin moderate Alzheimer's disease. Alzheimers Res Ther. 2016;8:4.PubMedPubMedCentralCrossRef
143.
Hu J, Liu CC, Chen XF, Zhang YW, Xu H, Bu G. Opposing effects of viral mediated brain expression of apolipoprotein E2 (apoE2) and apoE4 on apoE lipidation and Abeta metabolism in apoE4-targeted replacement mice. Mol Neurodegener. 2015;10:6.PubMedPubMedCentralCrossRef
144.
Yamazaki Y, Painter MM, Bu G, Kanekiyo T. Apolipoprotein E as a therapeutic target in Alzheimer's disease: a review of basic research and clinical evidence. CNS Drugs. 2016;30:773–89.PubMedPubMedCentralCrossRef
145.
Zhong N, Scearce-Levie K, Ramaswamy G, Weisgraber KH. Apolipoprotein E4 domain interaction: synaptic and cognitive deficits in mice. Alzheimers Dement. 2008;4:179–92.PubMedPubMedCentralCrossRef
146.
Zhong N, Weisgraber KH. Understanding the association of apolipoprotein E4 with Alzheimer disease: clues from its structure. J Biol Chem. 2009;284:6027–31.PubMedPubMedCentralCrossRef
147.
148.
Hanson AJ, Bayer-Carter JL, Green PS, Montine TJ, Wilkinson CW, Baker LD, Watson GS, Bonner LM, Callaghan M, Leverenz JB, et al. Effect of apolipoprotein E genotype and diet on apolipoprotein E lipidation and amyloid peptides: randomized clinical trial. JAMA Neurol. 2013;70:972–80.PubMedCrossRef
149.
Tai LM, Bilousova T, Jungbauer L, Roeske SK, Youmans KL, Yu C, Poon WW, Cornwell LB, Miller CA, Vinters HV, et al. Levels of soluble apolipoprotein E/amyloid-beta (Abeta) complex are reduced and oligomeric Abeta increased with APOE4 and Alzheimer disease in a transgenic mouse model and human samples. J Biol Chem. 2013;288:5914–26.PubMedPubMedCentralCrossRef
150.
Youmans KL, Tai LM, Nwabuisi-Heath E, Jungbauer L, Kanekiyo T, Gan M, Kim J, Eimer WA, Estus S, Rebeck GW, et al. APOE4-specific changes in Abeta accumulation in a new transgenic mouse model of Alzheimer disease. J Biol Chem. 2012;287:41774–86.PubMedPubMedCentralCrossRef
151.
Tai LM, Mehra S, Shete V, Estus S, Rebeck GW, Bu G, LaDu MJ. Soluble apoE/Abeta complex: mechanism and therapeutic target for APOE4-induced AD risk. Mol Neurodegener. 2014;9:2.PubMedPubMedCentralCrossRef
152.
Vance JE, Hayashi H. Formation and function of apolipoprotein E-containing lipoproteins in the nervous system. Biochim Biophys Acta. 1801;2010:806–18.
153.
Zhu L, Zhong M, Elder GA, Sano M, Holtzman DM, Gandy S, Cardozo C, Haroutunian V, Robakis NK, Cai D. Phospholipid dysregulation contributes to ApoE4-associated cognitive deficits in Alzheimer's disease pathogenesis. Proc Natl Acad Sci U S A. 2015;112:11965–70.PubMedPubMedCentralCrossRef
154.
Hanson AJ, Craft S, Banks WA. The APOE genotype: modification of therapeutic responses in Alzheimer's disease. Curr Pharm Des. 2015;21:114–20.PubMedCrossRef
155.
Salloway S, Sperling R, Fox NC, Blennow K, Klunk W, Raskind M, Sabbagh M, Honig LS, Porsteinsson AP, Ferris S, et al. Two phase 3 trials of bapineuzumab in mild-to-moderate Alzheimer's disease. N Engl J Med. 2014;370:322–33.PubMedPubMedCentralCrossRef
156.
Szekely CA, Breitner JC, Fitzpatrick AL, Rea TD, Psaty BM, Kuller LH, Zandi PP. NSAID use and dementia risk in the cardiovascular health study: role of APOE and NSAID type. Neurology. 2008;70:17–24.PubMedCrossRef
157.
Altmann A, Tian L, Henderson VW, Greicius MD, Alzheimer's Disease Neuroimaging Initiative I. Sex modifies the APOE-related risk of developing Alzheimer disease. Ann Neurol. 2014;75:563–73.PubMedPubMedCentralCrossRef
158.
Farrer LA, Cupples LA, Haines JL, Hyman B, Kukull WA, Mayeux R, Myers RH, Pericak-Vance MA, Risch N, van Duijn CM. Effects of age, sex, and ethnicity on the association between apolipoprotein E genotype and Alzheimer disease. A meta-analysis. APOE and Alzheimer disease Meta analysis consortium. JAMA. 1997;278:1349–56.PubMedCrossRef
159.
Nyarko JNK, Quartey MO, Pennington PR, Heistad RM, Dea D, Poirier J, Baker GB, Mousseau DD. Profiles of beta-amyloid peptides and key secretases in brain autopsy samples differ with sex and APOE epsilon4 status: impact for risk and progression of Alzheimer disease. Neuroscience. 2018;373:20–36.PubMedCrossRef
160.
Abram M, Wegmann M, Fokuhl V, Sonar S, Luger EO, Kerzel S, Radbruch A, Renz H, Zemlin M. Nerve growth factor and neurotrophin-3 mediate survival of pulmonary plasma cells during the allergic airway inflammation. J Immunol. 2009;182:4705–12.PubMedCrossRef
161.
Bergmann I, Reiter R, Toyka KV, Koltzenburg M. Nerve growth factor evokes hyperalgesia in mice lacking the low-affinity neurotrophin receptor p75. Neurosci Lett. 1998;255:87–90.PubMedCrossRef
162.
Dyck PJ, Peroutka S, Rask C, Burton E, Baker MK, Lehman KA, Gillen DA, Hokanson JL, O'Brien PC. Intradermal recombinant human nerve growth factor induces pressure allodynia and lowered heat-pain threshold in humans. Neurology. 1997;48:501–5.PubMedCrossRef
163.
Malcangio M, Lessmann V. A common thread for pain and memory synapses? Brain-derived neurotrophic factor and trkB receptors. Trends Pharmacol Sci. 2003;24:116–21.PubMedCrossRef
164.
Pezet S, Malcangio M, McMahon SB. BDNF: a neuromodulator in nociceptive pathways? Brain Res Brain Res Rev. 2002;40:240–9.PubMedCrossRef
165.
Sah DW, Ossipo MH, Porreca F. Neurotrophic factors as novel therapeutics for neuropathic pain. Nat Rev Drug Discov. 2003;2:460–72.PubMedCrossRef
166.
167.
Pardridge WM. Neurotrophins, neuroprotection and the blood-brain barrier. Curr Opin Investig Drugs. 2002;3:1753–7.PubMed
168.
Poduslo JF, Curran GL. Permeability at the blood-brain and blood-nerve barriers of the neurotrophic factors: NGF, CNTF, NT-3, BDNF. Brain Res Mol Brain Res. 1996;36:280–6.PubMedCrossRef
169.
Saltzman WM, Mak MW, Mahoney MJ, Duenas ET, Cleland JL. Intracranial delivery of recombinant nerve growth factor: release kinetics and protein distribution for three delivery systems. Pharm Res. 1999;16:232–40.PubMedCrossRef
170.
Tuszynski MH, Thal L, Pay M, Salmon DP, U HS, Bakay R, Patel P, Blesch A, Vahlsing HL, Ho G, et al. A phase 1 clinical trial of nerve growth factor gene therapy for Alzheimer disease. Nat Med. 2005;11:551–5.PubMedCrossRef
171.
Rafii MS, Baumann TL, Bakay RA, Ostrove JM, Siffert J, Fleisher AS, Herzog CD, Barba D, Pay M, Salmon DP, et al. A phase1 study of stereotactic gene delivery of AAV2-NGF for Alzheimer's disease. Alzheimers Dement. 2014;10:571–81.PubMedCrossRef
172.
Tuszynski MH, Yang JH, Barba D, U HS, Bakay RA, Pay MM, Masliah E, Conner JM, Kobalka P, Roy S, Nagahara AH. Nerve growth factor gene therapy: activation of neuronal responses in Alzheimer disease. JAMA Neurol. 2015;72:1139–47.PubMedPubMedCentralCrossRef
173.
Rafii MS, Tuszynski MH, Thomas RG, Barba D, Brewer JB, Rissman RA, Siffert J, Aisen PS, Team ANS. Adeno-associated viral vector (serotype 2)-nerve growth factor for patients with Alzheimer disease: a randomized clinical trial. JAMA Neurol. 2018;75(7):834–41.PubMedCrossRefPubMedCentral
174.
Longo FM, Massa SM. Small-molecule modulation of neurotrophin receptors: a strategy for the treatment of neurological disease. Nat Rev Drug Discov. 2013;12:507–25.PubMedCrossRef
175.
Massa SM, Xie Y, Yang T, Harrington AW, Kim ML, Yoon SO, Kraemer R, Moore LA, Hempstead BL, Longo FM. Small, nonpeptide p75NTR ligands induce survival signaling and inhibit proNGF-induced death. J Neurosci. 2006;26:5288–300.PubMedCrossRefPubMedCentral
176.
Tep C, Lim TH, Ko PO, Getahun S, Ryu JC, Goettl VM, Massa SM, Basso M, Longo FM, Yoon SO. Oral administration of a small molecule targeted to block proNGF binding to p75 promotes myelin sparing and functional recovery after spinal cord injury. J Neurosci. 2013;33:397–410.PubMedPubMedCentralCrossRef
177.
Knowles JK, Simmons DA, Nguyen TV, Vander Griend L, Xie Y, Zhang H, Yang T, Pollak J, Chang T, Arancio O, et al. Small molecule p75NTR ligand prevents cognitive deficits and neurite degeneration in an Alzheimer's mouse model. Neurobiol Aging. 2013;34:2052–63.PubMedCrossRefPubMedCentral
178.
Nguyen TV, Shen L, Vander Griend L, Quach LN, Belichenko NP, Saw N, Yang T, Shamloo M, Wyss-Coray T, Massa SM, Longo FM. Small molecule p75NTR ligands reduce pathological phosphorylation and misfolding of tau, inflammatory changes, cholinergic degeneration, and cognitive deficits in AbetaPP(L/S) transgenic mice. J Alzheimers Dis. 2014;42:459–83.PubMedPubMedCentralCrossRef
179.
Simmons DA, Knowles JK, Belichenko NP, Banerjee G, Finkle C, Massa SM, Longo FM. 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.PubMedPubMedCentralCrossRef
180.
Aboulkassim T, Tong XK, Tse YC, Wong TP, Woo SB, Neet KE, Brahimi F, Hamel E, Saragovi HU. Ligand-dependent TrkA activity in brain differentially affects spatial learning and long-term memory. Mol Pharmacol. 2011;80:498–508.PubMedCrossRef
181.
Scarpi D, Cirelli D, Matrone C, Castronovo G, Rosini P, Occhiato EG, Romano F, Bartali L, Clemente AM, Bottegoni G, et al. Low molecular weight, non-peptidic agonists of TrkA receptor with NGF-mimetic activity. Cell Death Dis. 2012;3:e389.PubMedPubMedCentralCrossRef
182.
Wang J, Hancock MK, Dudek JM, Bi K. Cellular assays for high-throughput screening for modulators of Trk receptor tyrosine kinases. Curr Chem Genomics. 2008;1:27–33.PubMedPubMedCentralCrossRef
183.
Zhang Q, Descamps O, Hart MJ, Poksay KS, Spilman P, Kane DJ, Gorostiza O, John V, Bredesen DE. Paradoxical effect of TrkA inhibition in Alzheimer's disease models. J Alzheimers Dis. 2014;40:605–17.PubMedPubMedCentralCrossRef
184.
Schmid DA, Yang T, Ogier M, Adams I, Mirakhur Y, Wang Q, Massa SM, Longo FM, Katz DM. A TrkB small molecule partial agonist rescues TrkB phosphorylation deficits and improves respiratory function in a mouse model of Rett syndrome. J Neurosci. 2012;32:1803–10.PubMedPubMedCentralCrossRef
185.
Simmons DA, Belichenko NP, Yang T, Condon C, Monbureau M, Shamloo M, Jing D, Massa SM, Longo FM. A small molecule TrkB ligand reduces motor impairment and neuropathology in R6/2 and BACHD mouse models of Huntington's disease. J Neurosci. 2013;33:18712–27.PubMedPubMedCentralCrossRef
186.
Devi L, Ohno M. 7,8-dihydroxyflavone, a small-molecule TrkB agonist, reverses memory deficits and BACE1 elevation in a mouse model of Alzheimer's disease. Neuropsychopharmacology. 2012;37:434–44.PubMedCrossRef
187.
Jang SW, Liu X, Yepes M, Shepherd KR, Miller GW, Liu Y, Wilson WD, Xiao G, Blanchi B, Sun YE, Ye K. A selective TrkB agonist with potent neurotrophic activities by 7,8-dihydroxyflavone. Proc Natl Acad Sci U S A. 2010;107:2687–92.PubMedPubMedCentralCrossRef
188.
Zhang Z, Liu X, Schroeder JP, Chan CB, Song M, Yu SP, Weinshenker D, Ye K. 7,8-dihydroxyflavone prevents synaptic loss and memory deficits in a mouse model of Alzheimer's disease. Neuropsychopharmacology. 2014;39:638–50.PubMedCrossRef
189.
Zhou W, Li X, Huang D, Zhou W, Li T, Song W. No significant effect of 7,8-dihydroxyflavone on APP processing and Alzheimer-associated phenotypes. Curr Alzheimer Res. 2015;12:47–52.PubMedCrossRef
190.
191.
Heneka MT, Kummer MP, Latz E. Innate immune activation in neurodegenerative disease. Nat Rev Immunol. 2014;14:463–77.PubMedCrossRef
192.
Perry VH, Holmes C. Microglial priming in neurodegenerative disease. Nat Rev Neurol. 2014;10:217–24.PubMedCrossRef
193.
Prokop S, Miller KR, Heppner FL. Microglia actions in Alzheimer's disease. Acta Neuropathol. 2013;126:461–77.PubMedCrossRef
194.
Zhang B, Gaiteri C, Bodea LG, Wang Z, McElwee J, Podtelezhnikov AA, Zhang C, Xie T, Tran L, Dobrin R, et al. Integrated systems approach identifies genetic nodes and networks in late-onset Alzheimer's disease. Cell. 2013;153:707–20.PubMedPubMedCentralCrossRef
195.
Mathur R, Ince PG, Minett T, Garwood CJ, Shaw PJ, Matthews FE, Brayne C, Simpson JE, Wharton SB, Function MRCC, Ageing Neuropathology Study G. A reduced astrocyte response to beta-amyloid plaques in the ageing brain associates with cognitive impairment. PLoS One. 2015;10:e0118463.PubMedPubMedCentralCrossRef
196.
Mrak RE, Griffinbc WS. The role of activated astrocytes and of the neurotrophic cytokine S100B in the pathogenesis of Alzheimer's disease. Neurobiol Aging. 2001;22:915–22.PubMedCrossRef
197.
Paradisi S, Sacchetti B, Balduzzi M, Gaudi S, Malchiodi-Albedi F. Astrocyte modulation of in vitro beta-amyloid neurotoxicity. Glia. 2004;46:252–60.PubMedCrossRef
198.
Thal DR. The role of astrocytes in amyloid beta-protein toxicity and clearance. Exp Neurol. 2012;236:1–5.PubMedCrossRef
199.
Tuppo EE, Arias HR. The role of inflammation in Alzheimer's disease. Int J Biochem Cell Biol. 2005;37:289–305.PubMedCrossRef
200.
Holmes C, Cunningham C, Zotova E, Woolford J, Dean C, Kerr S, Culliford D, Perry VH. Systemic inflammation and disease progression in Alzheimer disease. Neurology. 2009;73:768–74.PubMedPubMedCentralCrossRef
201.
Sudduth TL, Schmitt FA, Nelson PT, Wilcock DM. Neuroinflammatory phenotype in early Alzheimer's disease. Neurobiol Aging. 2013;34:1051–9.PubMedCrossRef
202.
von Bernhardi R, Cornejo F, Parada GE, Eugenin J. Role of TGFbeta signaling in the pathogenesis of Alzheimer's disease. Front Cell Neurosci. 2015;9:426.
203.
204.
Parachikova A, Vasilevko V, Cribbs DH, LaFerla FM, Green KN. Reductions in amyloid-beta-derived neuroinflammation, with minocycline, restore cognition but do not significantly affect tau hyperphosphorylation. J Alzheimers Dis. 2010;21:527–42.PubMedPubMedCentralCrossRef
205.
Green HF, Nolan YM. GSK-3 mediates the release of IL-1beta, TNF-alpha and IL-10 from cortical glia. Neurochem Int. 2012;61:666–71.PubMedCrossRef
206.
Hu J, Ferreira A, Van Eldik LJ. S100beta induces neuronal cell death through nitric oxide release from astrocytes. J Neurochem. 1997;69:2294–301.PubMedCrossRef
207.
Liu B, Hong JS. Role of microglia in inflammation-mediated neurodegenerative diseases: mechanisms and strategies for therapeutic intervention. J Pharmacol Exp Ther. 2003;304:1–7.PubMedCrossRef
208.
Malinski T. Nitric oxide and nitroxidative stress in Alzheimer's disease. J Alzheimers Dis. 2007;11:207–18.PubMedCrossRef
209.
Swerdlow RH, Burns JM, Khan SM. The Alzheimer's disease mitochondrial cascade hypothesis: progress and perspectives. Biochim Biophys Acta. 1842;2014:1219–31.
210.
Bharadwaj PR, Bates KA, Porter T, Teimouri E, Perry G, Steele JW, Gandy S, Groth D, Martins RN, Verdile G. Latrepirdine: molecular mechanisms underlying potential therapeutic roles in Alzheimer's and other neurodegenerative diseases. Transl Psychiatry. 2013;3:e332.PubMedPubMedCentralCrossRef
211.
Shevtsova EF, Vinogradova DV, Kireeva EG, Reddy VP, Aliev G, Bachurin SO. Dimebon attenuates the Abeta-induced mitochondrial permeabilization. Curr Alzheimer Res. 2014;11:422–9.PubMedCrossRef
212.
Condello C, Yuan P, Schain A, Grutzendler J. Microglia constitute a barrier that prevents neurotoxic protofibrillar Abeta42 hotspots around plaques. Nat Commun. 2015;6:6176.PubMedCrossRef
213.
Wang A, Das P, Switzer RC 3rd, Golde TE, Jankowsky JL. Robust amyloid clearance in a mouse model of Alzheimer's disease provides novel insights into the mechanism of amyloid-beta immunotherapy. J Neurosci. 2011;31:4124–36.PubMedPubMedCentralCrossRef
214.
Lee S, Varvel NH, Konerth ME, Xu G, Cardona AE, Ransohoff RM, Lamb BT. CX3CR1 deficiency alters microglial activation and reduces beta-amyloid deposition in two Alzheimer's disease mouse models. Am J Pathol. 2010;177:2549–62.PubMedPubMedCentralCrossRef
215.
Liu Z, Condello C, Schain A, Harb R, Grutzendler J. CX3CR1 in microglia regulates brain amyloid deposition through selective protofibrillar amyloid-beta phagocytosis. J Neurosci. 2010;30:17091–101.PubMedPubMedCentralCrossRef
216.
Cederblad L, Rosengren B, Ryberg E, Hermansson NO. AZD8797 is an allosteric non-competitive modulator of the human CX3CR1 receptor. Biochem J. 2016;473:641–9.PubMedCrossRef
217.
Bhaskar K, Konerth M, Kokiko-Cochran ON, Cardona A, Ransohoff RM, Lamb BT. Regulation of tau pathology by the microglial fractalkine receptor. Neuron. 2010;68:19–31.PubMedPubMedCentralCrossRef
218.
Lopez-Lopez A, Gelpi E, Lopategui DM, Vidal-Taboada JM. Association of the CX3CR1-V249I variant with neurofibrillary pathology progression in late-onset Alzheimer's disease. Mol Neurobiol. 2018;55:2340–9.PubMedCrossRef
219.
Niess JH, Brand S, Gu X, Landsman L, Jung S, McCormick BA, Vyas JM, Boes M, Ploegh HL, Fox JG, et al. CX3CR1-mediated dendritic cell access to the intestinal lumen and bacterial clearance. Science. 2005;307:254–8.PubMedCrossRef
220.
Condello C, Yuan P, Grutzendler J. Microglia-Mediated Neuroprotection, TREM2, and Alzheimer's Disease: Evidence From Optical Imaging. Biol Psychiatry. 2018;83:377–87.PubMedCrossRef
221.
Singer AC, Martorell AJ, Douglas JM, Abdurrob F, Attokaren MK, Tipton J, Mathys H, Adaikkan C, Tsai LH. Noninvasive 40-Hz light flicker to recruit microglia and reduce amyloid beta load. Nat Protoc. 2018;13:1850–68.PubMedCrossRef
222.
Iaccarino HF, Singer AC, Martorell AJ, Rudenko A, Gao F, Gillingham TZ, Mathys H, Seo J, Kritskiy O, Abdurrob F, et al. Gamma frequency entrainment attenuates amyloid load and modifies microglia. Nature. 2016;540:230–5.PubMedPubMedCentralCrossRef
223.
Iaccarino HF, Singer AC, Martorell AJ, Rudenko A, Gao F, Gillingham TZ, Mathys H, Seo J, Kritskiy O, Abdurrob F, et al. Author correction: gamma frequency entrainment attenuates amyloid load and modifies microglia. Nature. 2018;562:E1.PubMedCrossRef
224.
Eimer WA, Vijaya Kumar DK, Navalpur Shanmugam NK, Rodriguez AS, Mitchell T, Washicosky KJ, Gyorgy B, Breakefield XO, Tanzi RE, Moir RD. Alzheimer's disease-associated beta-amyloid is rapidly seeded by Herpesviridae to protect against brain infection. Neuron. 2018;99:56–63 e53.PubMedPubMedCentralCrossRef
225.
Kumar DK, Choi SH, Washicosky KJ, Eimer WA, Tucker S, Ghofrani J, Lefkowitz A, McColl G, Goldstein LE, Tanzi RE, Moir RD. Amyloid-beta peptide protects against microbial infection in mouse and worm models of Alzheimer's disease. Sci Transl Med. 2016;8:340ra372.CrossRef
226.
Readhead B, Haure-Mirande JV, Funk CC, Richards MA, Shannon P, Haroutunian V, Sano M, Liang WS, Beckmann ND, Price ND, et al. Multiscale analysis of independent Alzheimer's cohorts finds disruption of molecular, genetic, and clinical networks by human herpesvirus. Neuron. 2018;99:64–82 e67.PubMedCrossRefPubMedCentral
227.
Buckley JS, Salpeter SR. A risk-benefit assessment of dementia medications: systematic review of the evidence. Drugs Aging. 2015;32:453–67.PubMedCrossRef
228.
229.
Olivares D, Deshpande VK, Shi Y, Lahiri DK, Greig NH, Rogers JT, Huang X. N-methyl D-aspartate (NMDA) receptor antagonists and memantine treatment for Alzheimer's disease, vascular dementia and Parkinson's disease. Curr Alzheimer Res. 2012;9:746–58.PubMedPubMedCentralCrossRef
230.
231.
Deardorff WJ, Shobassy A, Grossberg GT. Safety and clinical effects of EVP-6124 in subjects with Alzheimer's disease currently or previously receiving an acetylcholinesterase inhibitor medication. Expert Rev Neurother. 2015;15:7–17.PubMedCrossRef
232.
Thomsen MS, Hansen HH, Timmerman DB, Mikkelsen JD. Cognitive improvement by activation of alpha7 nicotinic acetylcholine receptors: from animal models to human pathophysiology. Curr Pharm Des. 2010;16:323–43.PubMedCrossRef
233.
Wilkinson D, Windfeld K, Colding-Jorgensen E. Safety and efficacy of idalopirdine, a 5-HT6 receptor antagonist, in patients with moderate Alzheimer's disease (LADDER): a randomised, double-blind, placebo-controlled phase 2 trial. Lancet Neurol. 2014;13:1092–9.PubMedCrossRef
234.
Atri A, Frolich L, Ballard C, Tariot PN, Molinuevo JL, Boneva N, Windfeld K, Raket LL, Cummings JL. Effect of Idalopirdine as adjunct to cholinesterase inhibitors on change in cognition in patients with Alzheimer disease: three randomized clinical trials. JAMA. 2018;319:130–42.PubMedPubMedCentralCrossRef
235.
Grove RA, Harrington CM, Mahler A, Beresford I, Maruff P, Lowy MT, Nicholls AP, Boardley RL, Berges AC, Nathan PJ, Horrigan JP. A randomized, double-blind, placebo-controlled, 16-week study of the H3 receptor antagonist, GSK239512 as a monotherapy in subjects with mild-to-moderate Alzheimer's disease. Curr Alzheimer Res. 2014;11:47–58.PubMedCrossRef
236.
Haig GM, Pritchett Y, Meier A, Othman AA, Hall C, Gault LM, Lenz RA. A randomized study of H3 antagonist ABT-288 in mild-to-moderate Alzheimer's dementia. J Alzheimers Dis. 2014;42:959–71.PubMedCrossRef
237.
Youdim MB. The path from anti Parkinson drug selegiline and rasagiline to multifunctional neuroprotective anti Alzheimer drugs ladostigil and m30. Curr Alzheimer Res. 2006;3:541–50.PubMedCrossRef
238.
Bansal Y, Silakari O. Multifunctional compounds: smart molecules for multifactorial diseases. Eur J Med Chem. 2014;76:31–42.PubMedCrossRef
239.
Weinreb O, Amit T, Bar-Am O, Yogev-Falach M, Youdim MB. The neuroprotective mechanism of action of the multimodal drug ladostigil. Front Biosci. 2008;13:5131–7.PubMedCrossRef
240.
Weinreb O, Amit T, Bar-Am O, Youdim MB. Ladostigil: a novel multimodal neuroprotective drug with cholinesterase and brain-selective monoamine oxidase inhibitory activities for Alzheimer's disease treatment. Curr Drug Targets. 2012;13:483–94.PubMedCrossRef
241.
Youdim MB. Multi target neuroprotective and neurorestorative anti-Parkinson and anti-Alzheimer drugs ladostigil and m30 derived from rasagiline. Exp Neurobiol. 2013;22:1–10.PubMedPubMedCentralCrossRef
242.
Hongpaisan J, Sun MK, Alkon DL. PKC epsilon activation prevents synaptic loss, Abeta elevation, and cognitive deficits in Alzheimer's disease transgenic mice. J Neurosci. 2011;31:630–43.PubMedCrossRefPubMedCentral
243.
Grant SG, O'Dell TJ, Karl KA, Stein PL, Soriano P, Kandel ER. Impaired long-term potentiation, spatial learning, and hippocampal development in fyn mutant mice. Science. 1992;258:1903–10.PubMedCrossRef
244.
Kojima N, Ishibashi H, Obata K, Kandel ER. Higher seizure susceptibility and enhanced tyrosine phosphorylation of N-methyl-D-aspartate receptor subunit 2B in fyn transgenic mice. Learn Mem. 1998;5:429–45.PubMedPubMedCentral
245.
Nakazawa T, Komai S, Tezuka T, Hisatsune C, Umemori H, Semba K, Mishina M, Manabe T, Yamamoto T. Characterization of Fyn-mediated tyrosine phosphorylation sites on GluR epsilon 2 (NR2B) subunit of the N-methyl-D-aspartate receptor. J Biol Chem. 2001;276:693–9.PubMedCrossRef
246.
Prybylowski K, Chang K, Sans N, Kan L, Vicini S, Wenthold RJ. The synaptic localization of NR2B-containing NMDA receptors is controlled by interactions with PDZ proteins and AP-2. Neuron. 2005;47:845–57.PubMedPubMedCentralCrossRef
247.
Isosaka T, Hattori K, Kida S, Kohno T, Nakazawa T, Yamamoto T, Yagi T, Yuasa S. Activation of Fyn tyrosine kinase in the mouse dorsal hippocampus is essential for contextual fear conditioning. Eur J Neurosci. 2008;28:973–81.PubMedCrossRef
248.
Kaufman AC, Salazar SV, Haas LT, Yang J, Kostylev MA, Jeng AT, Robinson SA, Gunther EC, van Dyck CH, Nygaard HB, Strittmatter SM. Fyn inhibition rescues established memory and synapse loss in Alzheimer mice. Ann Neurol. 2015;77:953–71.PubMedPubMedCentralCrossRef
249.
250.
251.
Ittner LM, Ke YD, Delerue F, Bi M, Gladbach A, van Eersel J, Wolfing H, Chieng BC, Christie MJ, Napier IA, et al. Dendritic function of tau mediates amyloid-beta toxicity in Alzheimer's disease mouse models. Cell. 2010;142:387–97.PubMedCrossRef
252.
Nygaard HB, Wagner AF, Bowen GS, Good SP, MacAvoy MG, Strittmatter KA, Kaufman AC, Rosenberg BJ, Sekine-Konno T, Varma P, et al. A phase Ib multiple ascending dose study of the safety, tolerability, and central nervous system availability of AZD0530 (saracatinib) in Alzheimer's disease. Alzheimers Res Ther. 2015;7:35.PubMedPubMedCentralCrossRef
253.
Prickaerts J, Heckman PRA, Blokland A. Investigational phosphodiesterase inhibitors in phase I and phase II clinical trials for Alzheimer's disease. Expert Opin Investig Drugs. 2017;26:1033–48.PubMedCrossRef
254.
Garcia-Osta A, Cuadrado-Tejedor M, Garcia-Barroso C, Oyarzabal J, Franco R. Phosphodiesterases as therapeutic targets for Alzheimer's disease. ACS Chem Neurosci. 2012;3:832–44.PubMedPubMedCentralCrossRef
255.
Arai H, Takahashi T. A combination therapy of donepezil and cilostazol for patients with moderate Alzheimer disease: pilot follow-up study. Am J Geriatr Psychiatry. 2009;17:353–4.PubMedCrossRef
256.
Ihara M, Nishino M, Taguchi A, Yamamoto Y, Hattori Y, Saito S, Takahashi Y, Tsuji M, Kasahara Y, Takata Y, Okada M. Cilostazol add-on therapy in patients with mild dementia receiving donepezil: a retrospective study. PLoS One. 2014;9:e89516.PubMedPubMedCentralCrossRef
257.
Taguchi A, Takata Y, Ihara M, Kasahara Y, Tsuji M, Nishino M, Stern D, Okada M. Cilostazol improves cognitive function in patients with mild cognitive impairment: a retrospective analysis. Psychogeriatrics. 2013;13:164–9.PubMedCrossRef
258.
Sperling RA, Jack CR Jr, Aisen PS. Testing the right target and right drug at the right stage. Sci Transl Med. 2011;3:111cm133.CrossRef
259.
Norton S, Matthews FE, Barnes DE, Yaffe K, Brayne C. Potential for primary prevention of Alzheimer's disease: an analysis of population-based data. Lancet Neurol. 2014;13:788–94.PubMedCrossRef
260.
Hsu D, Marshall GA. Primary and secondary prevention trials in Alzheimer disease: looking Back, Moving Forward. Curr Alzheimer Res. 2017;14:426–40.PubMedPubMedCentral
261.
Sperling RA, Jack CR Jr, Black SE, Frosch MP, Greenberg SM, Hyman BT, Scheltens P, Carrillo MC, Thies W, Bednar MM, et al. Amyloid-related imaging abnormalities in amyloid-modifying therapeutic trials: recommendations from the Alzheimer's Association research roundtable workgroup. Alzheimers Dement. 2011;7:367–85.PubMedPubMedCentralCrossRef
262.
Kozauer N, Katz R. Regulatory innovation and drug development for early-stage Alzheimer's disease. N Engl J Med. 2013;368:1169–71.PubMedCrossRef
263.
Forette F, Seux ML, Staessen JA, Thijs L, Birkenhager WH, Babarskiene MR, Babeanu S, Bossini A, Gil-Extremera B, Girerd X, et al. Prevention of dementia in randomised double-blind placebo-controlled systolic hypertension in Europe (Syst-Eur) trial. Lancet. 1998;352:1347–51.PubMedCrossRef
264.
Satizabal C, Beiser AS, Seshadri S. Incidence of dementia over three decades in the Framingham heart study. N Engl J Med. 2016;375:93–4.PubMedPubMedCentral
265.
266.
Heart Protection Study Collaborative G. MRC/BHF heart protection study of cholesterol lowering with simvastatin in 20,536 high-risk individuals: a randomised placebo-controlled trial. Lancet. 2002;360:7–22.CrossRef
267.
Shepherd J, Blauw GJ, Murphy MB, Bollen EL, Buckley BM, Cobbe SM, Ford I, Gaw A, Hyland M, Jukema JW, et al. Pravastatin in elderly individuals at risk of vascular disease (PROSPER): a randomised controlled trial. Lancet. 2002;360:1623–30.CrossRefPubMed
268.
Launer LJ, Miller ME, Williamson JD, Lazar RM, Gerstein HC, Murray AM, Sullivan M, Horowitz KR, Ding J, Marcovina S, et al. Effects of intensive glucose lowering on brain structure and function in people with type 2 diabetes (ACCORD MIND): a randomised open-label substudy. Lancet Neurol. 2011;10:969–77.PubMedPubMedCentralCrossRef
269.
Dineley KT, Jahrling JB, Denner L. Insulin resistance in Alzheimer's disease. Neurobiol Dis. 2014;72(Pt A):92–103.PubMedCrossRef
270.
Freiherr J, Hallschmid M, Frey WH 2nd, Brunner YF, Chapman CD, Holscher C, Craft S, De Felice FG, Benedict C. Intranasal insulin as a treatment for Alzheimer's disease: a review of basic research and clinical evidence. CNS Drugs. 2013;27:505–14.PubMedPubMedCentralCrossRef
271.
Craft S, Baker LD, Montine TJ, Minoshima S, Watson GS, Claxton A, Arbuckle M, Callaghan M, Tsai E, Plymate SR, et al. Intranasal insulin therapy for Alzheimer disease and amnestic mild cognitive impairment: a pilot clinical trial. Arch Neurol. 2012;69:29–38.PubMedCrossRef
272.
Reger MA, Watson GS, Green PS, Baker LD, Cholerton B, Fishel MA, Plymate SR, Cherrier MM, Schellenberg GD, Frey WH 2nd, Craft S. Intranasal insulin administration dose-dependently modulates verbal memory and plasma amyloid-beta in memory-impaired older adults. J Alzheimers Dis. 2008;13:323–31.PubMedPubMedCentralCrossRef
273.
Reger MA, Watson GS, Green PS, Wilkinson CW, Baker LD, Cholerton B, Fishel MA, Plymate SR, Breitner JC, DeGroodt W, et al. Intranasal insulin improves cognition and modulates beta-amyloid in early AD. Neurology. 2008;70:440–8.PubMedCrossRef
274.
275.
276.
Feart C, Samieri C, Rondeau V, Amieva H, Portet F, Dartigues JF, Scarmeas N, Barberger-Gateau P. Adherence to a Mediterranean diet, cognitive decline, and risk of dementia. JAMA. 2009;302:638–48.PubMedPubMedCentralCrossRef
277.
Morris MC, Tangney CC, Wang Y, Sacks FM, Barnes LL, Bennett DA, Aggarwal NT. MIND diet slows cognitive decline with aging. Alzheimers Dement. 2015;11:1015–22.PubMedPubMedCentralCrossRef
278.
Morris MC, Tangney CC, Wang Y, Sacks FM, Bennett DA, Aggarwal NT. MIND diet associated with reduced incidence of Alzheimer's disease. Alzheimers Dement. 2015;11:1007–14.PubMedPubMedCentralCrossRef
279.
Stephen R, Hongisto K, Solomon A, Lonnroos E. Physical activity and Alzheimer's disease: a systematic review. J Gerontol A Biol Sci Med Sci. 2017;72:733–9.PubMed
280.
Lautenschlager NT, Cox KL, Flicker L, Foster JK, van Bockxmeer FM, Xiao J, Greenop KR, Almeida OP. Effect of physical activity on cognitive function in older adults at risk for Alzheimer disease: a randomized trial. JAMA. 2008;300:1027–37.PubMedCrossRef
281.
Scarmeas N, Luchsinger JA, Schupf N, Brickman AM, Cosentino S, Tang MX, Stern Y. Physical activity, diet, and risk of Alzheimer disease. JAMA. 2009;302:627–37.PubMedPubMedCentralCrossRef
282.
Rebok GW, Ball K, Guey LT, Jones RN, Kim HY, King JW, Marsiske M, Morris JN, Tennstedt SL, Unverzagt FW, et al. Ten-year effects of the advanced cognitive training for independent and vital elderly cognitive training trial on cognition and everyday functioning in older adults. J Am Geriatr Soc. 2014;62:16–24.PubMedPubMedCentralCrossRef
283.
Farina N, Llewellyn D, Isaac MG, Tabet N. Vitamin E for Alzheimer's dementia and mild cognitive impairment. Cochrane Database Syst Rev. 2017;1:CD002854.PubMed
284.
Dysken MW, Guarino PD, Vertrees JE, Asthana S, Sano M, Llorente M, Pallaki M, Love S, Schellenberg GD, McCarten JR, et al. Vitamin E and memantine in Alzheimer's disease: clinical trial methods and baseline data. Alzheimers Dement. 2014;10:36–44.PubMedCrossRef
285.
Dysken MW, Sano M, Asthana S, Vertrees JE, Pallaki M, Llorente M, Love S, Schellenberg GD, McCarten JR, Malphurs J, et al. Effect of vitamin E and memantine on functional decline in Alzheimer disease: the TEAM-AD VA cooperative randomized trial. JAMA. 2014;311:33–44.PubMedPubMedCentralCrossRef
286.
DeKosky ST, Williamson JD, Fitzpatrick AL, Kronmal RA, Ives DG, Saxton JA, Lopez OL, Burke G, Carlson MC, Fried LP, et al. Ginkgo biloba for prevention of dementia: a randomized controlled trial. JAMA. 2008;300:2253–62.PubMedPubMedCentralCrossRef
287.
Williamson JD, Vellas B, Furberg C, Nahin R, Dekosky ST. Comparison of the design differences between the Ginkgo evaluation of memory study and the GuidAge study. J Nutr Health Aging. 2008;12:73S–9S.PubMedCrossRef
288.
Vellas B, Coley N, Ousset PJ, Berrut G, Dartigues JF, Dubois B, Grandjean H, Pasquier F, Piette F, Robert P, et al. Long-term use of standardised Ginkgo biloba extract for the prevention of Alzheimer's disease (GuidAge): a randomised placebo-controlled trial. Lancet Neurol. 2012;11:851–9.PubMedCrossRef
289.
Fotuhi M, Mohassel P, Yaffe K. Fish consumption, long-chain omega-3 fatty acids and risk of cognitive decline or Alzheimer disease: a complex association. Nat Clin Pract Neurol. 2009;5:140–52.PubMed
290.
Yurko-Mauro K, McCarthy D, Rom D, Nelson EB, Ryan AS, Blackwell A, Salem N Jr, Stedman M, Investigators M. Beneficial effects of docosahexaenoic acid on cognition in age-related cognitive decline. Alzheimers Dement. 2010;6:456–64.PubMedCrossRef
291.
Ngandu T, Lehtisalo J, Solomon A, Levalahti E, Ahtiluoto S, Antikainen R, Backman L, Hanninen T, Jula A, Laatikainen T, et al. A 2 year multidomain intervention of diet, exercise, cognitive training, and vascular risk monitoring versus control to prevent cognitive decline in at-risk elderly people (FINGER): a randomised controlled trial. Lancet. 2015;385:2255–63.PubMedCrossRef
292.
Bateman RJ, Xiong C, Benzinger TL, Fagan AM, Goate A, Fox NC, Marcus DS, Cairns NJ, Xie X, Blazey TM, et al. Clinical and biomarker changes in dominantly inherited Alzheimer's disease. N Engl J Med. 2012;367:795–804.PubMedPubMedCentralCrossRef
293.
Albert MS, DeKosky ST, Dickson D, Dubois B, Feldman HH, Fox NC, Gamst A, Holtzman DM, Jagust WJ, Petersen RC, et al. The diagnosis of mild cognitive impairment due to Alzheimer's disease: recommendations from the National Institute on Aging-Alzheimer's Association workgroups on diagnostic guidelines for Alzheimer's disease. Alzheimers Dement. 2011;7:270–9.PubMedPubMedCentralCrossRef
294.
McKhann GM, Knopman DS, Chertkow H, Hyman BT, Jack CR Jr, Kawas CH, Klunk WE, Koroshetz WJ, Manly JJ, Mayeux R, et al. The diagnosis of dementia due to Alzheimer's disease: recommendations from the National Institute on Aging-Alzheimer's Association workgroups on diagnostic guidelines for Alzheimer's disease. Alzheimers Dement. 2011;7:263–9.PubMedPubMedCentralCrossRef
295.
Panza F, Solfrizzi V, Imbimbo BP, Logroscino G. Amyloid-directed monoclonal antibodies for the treatment of Alzheimer's disease: the point of no return? Expert Opin Biol Ther. 2014;14:1465–76.PubMedCrossRef
296.
Hane FT, Robinson M, Lee BY, Bai O, Leonenko Z, Albert MS. Recent Progress in Alzheimer's disease research, part 3: diagnosis and treatment. J Alzheimers Dis. 2017;57:645–65.PubMedPubMedCentralCrossRef
Metadata
Title
Advances in developing novel therapeutic strategies for Alzheimer’s disease
Authors
Jiqing Cao
Jianwei Hou
Jing Ping
Dongming Cai
Publication date
01-12-2018
Publisher
BioMed Central
Published in
Molecular Neurodegeneration / Issue 1/2018
Electronic ISSN: 1750-1326
DOI
https://doi.org/10.1186/s13024-018-0299-8

Other articles of this Issue 1/2018

Molecular Neurodegeneration 1/2018 Go to the issue

Research article

BACE1 elevation engendered by GGA3 deletion increases β-amyloid pathology in association with APP elevation and decreased CHL1 processing in 5XFAD mice

Research article

Counteracting roles of MHCI and CD8+ T cells in the peripheral and central nervous system of ALS SOD1G93A mice

Review

2D versus 3D human induced pluripotent stem cell-derived cultures for neurodegenerative disease modelling

Research article

Deep proteomic network analysis of Alzheimer’s disease brain reveals alterations in RNA binding proteins and RNA splicing associated with disease

Research article

Alzheimer-associated cerebrospinal fluid fragments of neurogranin are generated by Calpain-1 and prolyl endopeptidase

Research article

Early long-term administration of the CSF1R inhibitor PLX3397 ablates microglia and reduces accumulation of intraneuronal amyloid, neuritic plaque deposition and pre-fibrillar oligomers in 5XFAD mouse model of Alzheimer’s disease