Beyond immunotherapy: new approaches for disease modifying treatments for early Alzheimer’s disease

References

• World Alzheimer Report. 2015: The Global Impact of Dementia - An Analysis of Prevalence, Incidence, Cost and Trends; 2015.
   Google Scholar
• Jentoft ME, Erickson LA. Alzheimer disease. Mayo Clin Proc. 2016 Aug;91(8):e117–e118.
   Google Scholar
• Perl DP. Neuropathology of Alzheimer’s disease. Mt Sinai J Med. 2010 Jan-Feb;77(1):32–42.
   PubMedGoogle Scholar
• Serrano-Pozo A, Frosch MP, Masliah E, et al. Neuropathological alterations in Alzheimer disease. Cold Spring Harb Perspect Med. 2011 Sep;1(1):a006189.
   PubMed Web of Science ®Google Scholar
• Hardy J, Selkoe DJ. The amyloid hypothesis of Alzheimer’s disease: progress and problems on the road to therapeutics. Science. 2002 Jul 19;297(5580):353–356.
   PubMed Web of Science ®Google Scholar
• Wang JZ, Xia YY, Grundke-Iqbal I, et al. Abnormal hyperphosphorylation of tau: sites, regulation, and molecular mechanism of neurofibrillary degeneration. J Alzheimers Dis. 2013;33(Suppl 1):S123–S139.
   PubMed Web of Science ®Google Scholar
• Iqbal K, Liu F, Gong C-X, et al. Tau in Alzheimer disease and related tauopathies. Curr Alzheimer Res. 2010 Dec;7(8):656–664.
   PubMed Web of Science ®Google Scholar
• Landau SM, Mintun MA, Joshi AD, et al. Amyloid deposition, hypometabolism, and longitudinal cognitive decline. Ann Neurol. 2012 Oct;72(4):578–586.
   PubMed Web of Science ®Google Scholar
• Herrmann N, Lanctot KL, Hogan DB. Pharmacological recommendations for the symptomatic treatment of dementia: the Canadian Consensus Conference on the Diagnosis and Treatment of Dementia 2012. Alzheimers Res Ther. 2013 Jul 8;5(Suppl 1):S5.
   PubMed Web of Science ®Google Scholar
• Lanctôt KL, Herrmann N, Yau KK, et al. Efficacy and safety of cholinesterase inhibitors in Alzheimer’s disease: a meta-analysis. CMAJ. 2003 Sep 16;169(6):557–564.
   PubMed Web of Science ®Google Scholar
• Birks J. Cholinesterase inhibitors for Alzheimer’s disease. Cochrane Database Syst Rev. 2006;1:CD005593.
   PubMed Web of Science ®Google Scholar
• Frisoni GB. Alzheimer disease: biomarker trajectories across stages of Alzheimer disease. Nat Rev Neurol. 2012 May 8;8(6):299–300.
   PubMed Web of Science ®Google Scholar
• Zemek F, Drtinova L, Nepovimova E, et al. Outcomes of Alzheimer’s disease therapy with acetylcholinesterase inhibitors and memantine. Expert Opin Drug Saf. 2014 Jun;13(6):759–774.
   PubMed Web of Science ®Google Scholar
• Changing the Trajectory of Alzheimer’s disease; 2015.
   Google Scholar
• Humpel C. Identifying and validating biomarkers for Alzheimer’s disease. Trends Biotechnol. 2011 Jan;29(1):26–32.
   PubMed Web of Science ®Google Scholar
• Cummings JL. Defining and labeling disease-modifying treatments for Alzheimer’s disease. Alzheimers Dement. 2009 Sep;5(5):406–418.
   PubMed Web of Science ®Google Scholar
• Cummings JL, Dubois B, Molinuevo JL, et al. International Work Group criteria for the diagnosis of Alzheimer disease. Med Clin North Am. 2013 May;97(3):363–368.
   PubMed Web of Science ®Google Scholar
• Citron M. Alzheimer’s disease: strategies for disease modification. Nat Rev Drug Discov. 2010 May;9(5):387–398.
   PubMed Web of Science ®Google Scholar
• Nigam SM, Xu S, Ackermann F, et al. Endogenous APP accumulates in synapses after BACE1 inhibition. Neurosci Res. 2016;109:9–15.
   PubMed Web of Science ®Google Scholar
• Ghosh AK, Tang J. Prospects of β-secretase inhibitors for the treatment of Alzheimer’s disease. ChemMedChem. 2015 Sep;10(9):1463–1466.
   PubMed Web of Science ®Google Scholar
• Li R, Lindholm K, Yang LB, et al. Amyloid beta peptide load is correlated with increased beta-secretase activity in sporadic Alzheimer’s disease patients. Proc Natl Acad Sci U S A. 2004 Mar 9;101(10):3632–3637.
   PubMed Web of Science ®Google Scholar
• Yang LB, Lindholm K, Yan R, et al. Elevated beta-secretase expression and enzymatic activity detected in sporadic Alzheimer disease. Nat Med. 2003 Jan;9(1):3–4.
   PubMed Web of Science ®Google Scholar
• Vassar R. BACE1 inhibitor drugs in clinical trials for Alzheimer’s disease. Alzheimers Res Ther. 2014;6(9):89.
   PubMedGoogle Scholar
• Roberds SL, Anderson J, Basi G, et al. BACE knockout mice are healthy despite lacking the primary beta-secretase activity in brain: implications for Alzheimer’s disease therapeutics. Hum Mol Genet. 2001 Jun 1;10(12):1317–1324.
   PubMed Web of Science ®Google Scholar
• Mandal M, Wu Y, Misiaszek J, et al. Structure-based design of an iminoheterocyclic beta-site amyloid precursor protein cleaving enzyme (BACE) inhibitor that lowers central abeta in nonhuman primates. J Med Chem. 2016 Apr 14;59(7):3231–3248.
   PubMed Web of Science ®Google Scholar
• Hyde L, Chen X, Stahl L, et al. Chronic bace inhibition dramatically slows the rate of abeta accumulation and the development of amyloid plaques in young tgcrnd8 mice. Alzheimer’s Dement: J Alzheimer’s Assoc. 2012;8(4):P188.
   Google Scholar
• Ogu CC, Maxa JL. Drug interactions due to cytochrome P450. Proc (Bayl Univ Med Cent). 2000 Oct;13(4):421–423.
   PubMedGoogle Scholar
• Evin G. Future therapeutics in Alzheimer’s disease: development status of BACE inhibitors. BioDrugs. 2016 Jun;30(3):173–194.
   PubMed Web of Science ®Google Scholar
• Forman M, Palcza J, Tseng J, et al. The novel bace inhibitor mk-8931 dramatically lowers cerebrospinal fluid abeta; peptides in healthy subjects following single- and multiple-dose administration. Alzheimer’s Dement: J Alzheimer’s Assoc. 2012;8(4):P704.
   Google Scholar
• Forman M, Kleijn H-J, Dockendorf M, et al. The novel BACE inhibitor MK-8931 dramatically lowers CSF beta-amyloid in patients with mild-to-moderate Alzheimer’s disease. Alzheimer’s Dement: J Alzheimer’s Assoc. 2013;9(4):P139.
   Google Scholar
• Eketjäll S, Janson J, Kaspersson K, et al. AZD3293: A novel, orally active BACE1 inhibitor with high potency and permeability and markedly slow off-rate kinetics. J Alzheimers Dis. 2016;50(4):1109–1123.
   PubMed Web of Science ®Google Scholar
• Höglund K, Salter H, Zetterberg H, et al. Monitoring the soluble amyloid precursor protein alpha (sappa) and beta (sappb) fragments in plasma and CSF from healthy individuals treated with BACE inhibitor AZD3293 in a multiple ascending dose study: pharmacokinetic and pharmacodynamic correlate. Alzheimer’s Dement: J Alzheimer’s Assoc. 2014;10(4):P447
   Google Scholar
• Alexander R, Budd S, Russell M, et al. AZD3293 A novel BACE1 inhibitor: safety, tolerability, and effects on plasma and CSF Abeta; peptides following single- and multiple-dose administration. Neurobiol Aging. 2014;35:S2.
   Google Scholar
• Fukushima T, Osada Y, Ishibashi A, et al. Novel BACE1 inhibitor, E2609, lowers Abeta; levels in the brain, cerebrospinal fluid and plasma in rats and guinea pigs. Alzheimer’s Dement: J Alzheimer’s Assoc. 2012;8(4):P223–P224
   Google Scholar
• Timmers M, Van Broeck BJS Ramael, S, et al. Profiling the dynamics of CSF and plasma amyloid beta reduction with JNJ-54861911, an oral BACE inhibitor. 12th international conference on Alzheimer’s and Parkinson’s diseases and related neurological disorders; 2015 Mar 18-22; Nice (France).
   Google Scholar
• Lai R, Albala B, Kaplow JM, et al. First-in-human study of E2609, a novel BACE1 inhibitor, demonstrates prolonged reductions in plasma beta-amyloid levels after single dosing. Alzheimer’s Dement: J Alzheimer’s Assoc. 2012;8(4):P96.
   Google Scholar
• Albala B, Kaplow JM, Lai R, et al. CSF amyloid lowering in human volunteers after 14 days’; oral administration of the novel BACE1 inhibitor E2609. Alzheimer’s Dement: J Alzheimer’s Assoc. 2012;8(4):S743
   Google Scholar
• Bernier F, Sato Y, Matijevic M, et al. Clinical study of E2609, a novel BACE1 inhibitor, demonstrates target engagement and inhibition of BACE1 activity in CSF. Alzheimer’s Dement: J Alzheimer’s Assoc. 2013;9(4):P886
   Google Scholar
• Krishnaswamy S, Verdile G, Groth D, et al. The structure and function of Alzheimer’s gamma secretase enzyme complex. Crit Rev Clin Lab Sci. 2009;46(5–6):282–301.
   PubMed Web of Science ®Google Scholar
• De Strooper B. Lessons from a failed gamma-secretase Alzheimer trial. Cell. 2014 Nov 6;159(4):721–726.
   PubMed Web of Science ®Google Scholar
• 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 Jul 25;369(4):341–350.
   PubMed Web of Science ®Google Scholar
• Coric V, Van Dyck CH, Salloway S, 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 Nov;69(11):1430–1440.
   PubMed Web of Science ®Google Scholar
• Gijsen HJM, Mercken M. Gamma-secretase modulators: can we combine potency with safety? Int J Alzheimer’s Dis. 2012;2012:10.
   Google Scholar
• Weggen S, Eriksen JL, Sagi SA, et al. Evidence that nonsteroidal anti-inflammatory drugs decrease amyloid beta 42 production by direct modulation of gamma-secretase activity. J Biol Chem. 2003 Aug 22;278(34):31831–31837.
   PubMed Web of Science ®Google Scholar
• Eriksen JL, Sagi SA, Smith TE, et al. NSAIDs and enantiomers of flurbiprofen target gamma-secretase and lower Abeta 42 in vivo. J Clin Invest. 2003 Aug;112(3):440–449.
   PubMed Web of Science ®Google Scholar
• Sivilia S, Lorenzini L, Giuliani A, et al. Multi-target action of the novel anti-Alzheimer compound CHF5074: in vivo study of long term treatment in Tg2576 mice. BMC Neurosci. 2013;14:44.
   PubMed Web of Science ®Google Scholar
• Balducci C, Mehdawy B, Mare L, et al. The gamma-secretase modulator CHF5074 restores memory and hippocampal synaptic plasticity in plaque-free Tg2576 mice. J Alzheimers Dis. 2011;24(4):799–816.
   PubMed Web of Science ®Google Scholar
• Lichtenstein MP, Carriba P, Baltrons MA, et al. Secretase-independent and RhoGTPase/PAK/ERK-dependent regulation of cytoskeleton dynamics in astrocytes by NSAIDs and derivatives. J Alzheimers Dis. 2010;22(4):1135–1155.
   PubMed Web of Science ®Google Scholar
• Ross J, Sharma S, Winston J, et al. CHF5074 reduces biomarkers of neuroinflammation in patients with mild cognitive impairment: a 12-week, double-blind, placebo-controlled study. Curr Alzheimer Res. 2013 Sep;10(7):742–753.
   PubMed Web of Science ®Google Scholar
• Rogers K, Felsenstein KM, Hrdlicka L, et al. Modulation of gamma-secretase by EVP-0015962 reduces amyloid deposition and behavioral deficits in Tg2576 mice. Mol Neurodegener. 2012;7:61.
   PubMed Web of Science ®Google Scholar
• Chapman PF, Kairiss EW, Keenan CL, et al. Long-term synaptic potentiation in the amygdala. Synapse. 1990;6(3):271–278.
   PubMed Web of Science ®Google Scholar
• Corbett A, Pickett J, Burns A, et al. Drug repositioning for Alzheimer’s disease. Nat Rev Drug Discov. 2012 Nov;11(11):833–846.
   PubMed Web of Science ®Google Scholar
• Paris D, Bachmeier C, Patel N, et al. Selective antihypertensive dihydropyridines lower Abeta accumulation by targeting both the production and the clearance of Abeta across the blood-brain barrier. Mol Med. 2011 Mar-Apr;17(3–4):149–162.
   PubMed Web of Science ®Google Scholar
• Hanyu H, Hirao K, Shimizu S, et al. Nilvadipine prevents cognitive decline of patients with mild cognitive impairment. Int J Geriatr Psychiatry. 2007 Dec;22(12):1264–1266.
   PubMed Web of Science ®Google Scholar
• Kennelly S, Abdullah L, Kenny RA, et al. Apolipoprotein E genotype-specific short-term cognitive benefits of treatment with the antihypertensive nilvadipine in Alzheimer’s patients–an open-label trial. Int J Geriatr Psychiatry. 2012 Apr;27(4):415–422.
   PubMed Web of Science ®Google Scholar
• Sills GJ, Leach JP, Fraser CM, et al. Neurochemical studies with the novel anticonvulsant levetiracetam in mouse brain. Eur J Pharmacol. 1997 Apr 23;325(1):35–40.
   PubMed Web of Science ®Google Scholar
• Celone KA, Calhoun VD, Dickerson BC, et al. Alterations in memory networks in mild cognitive impairment and Alzheimer’s disease: an independent component analysis. J Neurosci. 2006 Oct 4;26(40):10222–10231.
   PubMed Web of Science ®Google Scholar
• Ewers M, Insel P, Jagust WJ, et al. CSF biomarker and PIB-PET-derived beta-amyloid signature predicts metabolic, gray matter, and cognitive changes in nondemented subjects. Cereb Cortex. 2012 Sep;22(9):1993–2004.
   PubMed Web of Science ®Google Scholar
• Quiroz YT, Budson AE, Celone K, et al. Hippocampal hyperactivation in presymptomatic familial Alzheimer’s disease. Ann Neurol. 2010 Dec;68(6):865–875.
   PubMed Web of Science ®Google Scholar
• Dickerson BC, Salat DH, Bates JF, et al. Medial temporal lobe function and structure in mild cognitive impairment. Ann Neurol. 2004 Jul;56(1):27–35.
   PubMed Web of Science ®Google Scholar
• Dickerson BC, Salat DH, Greve DN, et al. Increased hippocampal activation in mild cognitive impairment compared to normal aging and AD. Neurology. 2005 Aug 9;65(3):404–411.
   PubMed Web of Science ®Google Scholar
• Hämäläinen A, Pihlajamäki M, Tanila H, et al. Increased fMRI responses during encoding in mild cognitive impairment. Neurobiol Aging. 2007 Dec;28(12):1889–1903.
   PubMed Web of Science ®Google Scholar
• Yassa MA, Stark SM, Bakker A, et al. High-resolution structural and functional MRI of hippocampal CA3 and dentate gyrus in patients with amnestic Mild Cognitive Impairment. Neuroimage. 2010 Jul 1;51(3):1242–1252.
   PubMed Web of Science ®Google Scholar
• Koh MT, Haberman RP, Foti S, et al. Treatment strategies targeting excess hippocampal activity benefit aged rats with cognitive impairment. Neuropsychopharmacology. 2010 Mar;35(4):1016–1025.
   PubMed Web of Science ®Google Scholar
• Sanchez PE, Zhu L, Verret L, et al. Levetiracetam suppresses neuronal network dysfunction and reverses synaptic and cognitive deficits in an Alzheimer’s disease model. Proc Natl Acad Sci U S A. 2012 Oct 16;109(42):E2895–E903.
   PubMed Web of Science ®Google Scholar
• Bakker A, Krauss GL, Albert MS, et al. Reduction of hippocampal hyperactivity improves cognition in amnestic mild cognitive impairment. Neuron. 2012 May 10;74(3):467–474.
   PubMed Web of Science ®Google Scholar
• Bakker A, Albert MS, Krauss G, et al. Response of the medial temporal lobe network in amnestic mild cognitive impairment to therapeutic intervention assessed by fMRI and memory task performance. Neuroimage Clin. 2015;7:688–698.
   PubMed Web of Science ®Google Scholar
• Bierhaus A, Humpert PM, Morcos M, et al. Understanding RAGE, the receptor for advanced glycation end products. J Mol Med (Berl). 2005 Nov;83(11):876–886.
   PubMed Web of Science ®Google Scholar
• Galasko D, Bell J, Mancuso JY, et al. Clinical trial of an inhibitor of RAGE-Abeta interactions in Alzheimer disease. Neurology. 2014 Apr 29;82(17):1536–1542.
   PubMed Web of Science ®Google Scholar
• Sabbagh MN, Agro A, Bell J, et al. PF-04494700, an oral inhibitor of receptor for advanced glycation end products (RAGE), in Alzheimer disease. Alzheimer Dis Assoc Disord. 2011 Jul-Sep;25(3):206–212.
   PubMed Web of Science ®Google Scholar
• Wang Q, Yu X, Li L, et al. Inhibition of amyloid-beta aggregation in Alzheimer’s disease. Curr Pharm Des. 2014;20(8):1223–1243.
   PubMed Web of Science ®Google Scholar
• Walsh DM, Selkoe DJ. A beta oligomers - a decade of discovery. J Neurochem. 2007 Jun;101(5):1172–1184.
   PubMed Web of Science ®Google Scholar
• Sun XJ, Zhao L, Zhao N, et al. Benfotiamine prevents increased beta-amyloid production in HEK cells induced by high glucose. Neurosci Bull. 2012 Oct;28(5):561–566.
   PubMed Web of Science ®Google Scholar
• Pan X, Gong N, Zhao J, et al. Powerful beneficial effects of benfotiamine on cognitive impairment and beta-amyloid deposition in amyloid precursor protein/presenilin-1 transgenic mice. Brain. 2010 May;133(Pt 5):1342–1351.
   PubMed Web of Science ®Google Scholar
• McLaurin J, Golomb R, Jurewicz A, et al. Inositol stereoisomers stabilize an oligomeric aggregate of Alzheimer amyloid beta peptide and inhibit abeta -induced toxicity. J Biol Chem. 2000 Jun 16;275(24):18495–18502.
   PubMed Web of Science ®Google Scholar
• Lyketsos C, Abushakra S, Liang E, et al. Effects of oral ELND005 (scyllo-inositol) on neuropsychiatric symptoms in a 78-week phase 2 study in mild/moderate Alzheimer’s disease (AD): Potential role of myo-inositol reduction. Alzheimer’s Dement: J Alzheimer’s Assoc. 2012;8(4):S771–S72.
   Google Scholar
• ELND005 for Agitation and Aggression in Alzheimer’s Disease (HARMONY-AD Study). Phase 2/3 design and clinical outcomes. Barcelona: Clinical Trials in Alzheimer’s disease (CTAD); 2015.
   Google Scholar
• Hasegawa M. Molecular Mechanisms in the Pathogenesis of Alzheimer’s disease and Tauopathies-Prion-Like Seeded Aggregation and Phosphorylation. Biomolecules. 2016 Apr;6(2). doi:10.3390/biom6020024.
   PubMed Web of Science ®Google Scholar
• Braak H, Braak E. Staging of Alzheimer’s disease-related neurofibrillary changes. Neurobiol Aging. 1995 May-Jun;16(3):271–278. discussion 78-84
   PubMed Web of Science ®Google Scholar
• Panza F, Solfrizzi V, Seripa D, et al. Tau-centric targets and drugs in clinical development for the treatment of Alzheimer’s disease. Biomed Res Int. 2016;2016:3245935.
   PubMed Web of Science ®Google Scholar
• Rapoport M, Dawson HN, Binder LI, et al. Tau is essential to beta -amyloid-induced neurotoxicity. Proc Natl Acad Sci U S A. 2002 Apr 30;99(9):6364–6369.
   PubMed Web of Science ®Google Scholar
• Terwel D, Muyllaert D, Dewachter I, et al. Amyloid activates GSK-3beta to aggravate neuronal tauopathy in bigenic mice. Am J Pathol. 2008 Mar;172(3):786–798.
   PubMed Web of Science ®Google Scholar
• Divinski I, Mittelman L, Gozes I. A femtomolar acting octapeptide interacts with tubulin and protects astrocytes against zinc intoxication. J Biol Chem. 2004 Jul 2;279(27):28531–28538.
   PubMed Web of Science ®Google Scholar
• Gozes I, Divinski I. The femtomolar-acting NAP interacts with microtubules: novel aspects of astrocyte protection. J Alzheimers Dis. 2004 Dec;6(6 Suppl):S37–S41.
   Google Scholar
• Divinski I, Holtser-Cochav M, Vulih-Schultzman I, et al. Peptide neuroprotection through specific interaction with brain tubulin. J Neurochem. 2006 Aug;98(3):973–984.
   PubMed Web of Science ®Google Scholar
• Vulih-Shultzman I, Pinhasov A, Mandel S, et al. Activity-dependent neuroprotective protein snippet NAP reduces tau hyperphosphorylation and enhances learning in a novel transgenic mouse model. J Pharmacol Exp Ther. 2007 Nov;323(2):438–449.
   PubMed Web of Science ®Google Scholar
• Matsuoka Y, Jouroukhin Y, Gray AJ, et al. A neuronal microtubule-interacting agent, NAPVSIPQ, reduces tau pathology and enhances cognitive function in a mouse model of Alzheimer’s disease. J Pharmacol Exp Ther. 2008 Apr;325(1):146–153.
   PubMed Web of Science ®Google Scholar
• Morimoto BH, Schmechel D, Hirman J, et al. A double-blind, placebo-controlled, ascending-dose, randomized study to evaluate the safety, tolerability and effects on cognition of AL-108 after 12 weeks of intranasal administration in subjects with mild cognitive impairment. Dement Geriatr Cogn Disord. 2013;35(5–6):325–336.
   PubMed Web of Science ®Google Scholar
• Brunden KR, Zhang B, Carroll J, et al. Epothilone D improves microtubule density, axonal integrity, and cognition in a transgenic mouse model of tauopathy. J Neurosci. 2010 Oct 13;30(41):13861–13866.
   PubMed Web of Science ®Google Scholar
• Crowe A, James MJ, Lee VM, et al. Aminothienopyridazines and methylene blue affect Tau fibrillization via cysteine oxidation. J Biol Chem. 2013 Apr 19;288(16):11024–11037.
   PubMed Web of Science ®Google Scholar
• Wen Y, Li W, Poteet EC, et al. Alternative mitochondrial electron transfer as a novel strategy for neuroprotection. J Biol Chem. 2011 May 6;286(18):16504–16515.
   PubMed Web of Science ®Google Scholar
• Wischik CM, Staff RT, Wischik DJ, et al. Tau aggregation inhibitor therapy: an exploratory phase 2 study in mild or moderate Alzheimer’s disease. J Alzheimers Dis. 2015;44(2):705–720.
   PubMed Web of Science ®Google Scholar
• Kaufman AC, Salazar SV, Haas LT, et al. Fyn inhibition rescues established memory and synapse loss in Alzheimer mice. Ann Neurol. 2015 Jun;77(6):953–971.
   PubMed Web of Science ®Google Scholar
• Sereno L, Coma M, Rodriguez M, et al. A novel GSK-3beta inhibitor reduces Alzheimer’s pathology and rescues neuronal loss in vivo. Neurobiol Dis. 2009 Sep;35(3):359–367.
   PubMed Web of Science ®Google Scholar
• Morales-Garcia JA, Luna-Medina R, Alonso-Gil S, et al. Glycogen synthase kinase 3 inhibition promotes adult hippocampal neurogenesis in vitro and in vivo. ACS Chem Neurosci. 2012 Nov 21;3(11):963–971.
   PubMed Web of Science ®Google Scholar
• Sheehan B. Assessment scales in dementia. Ther Adv Neurol Disord. 2012 Nov;5(6):349–358.
   PubMed Web of Science ®Google Scholar
• Thal LJ, Kantarci K, Reiman EM, et al. The role of biomarkers in clinical trials for Alzheimer disease. Alzheimer Dis Assoc Disord. 2006 Jan-Mar;20(1):6–15.
   PubMed Web of Science ®Google Scholar
• Sperling RA, Jack CR Jr., Aisen PS. Testing the right target and right drug at the right stage. Sci Transl Med. 2011 Nov 30;3(111):111cm33.
   PubMed Web of Science ®Google Scholar
• Sperling RA, Rentz DM, Johnson KA, et al. The A4 study: stopping AD before symptoms begin? Sci Transl Med. 2014 Mar 19;6(228):228fs13.
   PubMed Web of Science ®Google Scholar
• Guo LH, Alexopoulos P, Eisele T, et al. The National Institute on Aging-Alzheimer’s Association research criteria for mild cognitive impairment due to Alzheimer’s disease: predicting the outcome. Eur Arch Psychiatry Clin Neurosci. 2013 Jun;263(4):325–333.
   PubMed Web of Science ®Google Scholar