Existing drugs for Alzheimer's disease provide symptomatic benefit for up to 12 months, but there are no approved disease-modifying therapies. Given the recent failures of various novel disease-modifying therapies in clinical trials, a complementary strategy based on repositioning drugs that are approved for other indications could be attractive. Indeed, a substantial body of preclinical work indicates that several classes of such drugs have potentially beneficial effects on Alzheimer's-like brain pathology, and for some drugs the evidence is also supported by epidemiological data or preliminary clinical trials. Here, we present a formal consensus evaluation of these opportunities, based on a systematic review of published literature. We highlight several compounds for which sufficient evidence is available to encourage further investigation to clarify an optimal dose and consider progression to clinical trials in patients with Alzheimer's disease.
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Wimo, A. & Prince, M. World Alzheimer Report 2010: The Global Economic Impact of Dementia (Alzheimer's Disease International, 2011).
Karran, E., Mercken, M. & De Strooper, B. The amyloid cascade hypothesis for Alzheimer's disease: an appraisal for the development of therapeutics. Nature Rev. Drug Discov. 10, 698–712 (2011).
Ittner, L. M. et al. Dendritic function of tau mediates amyloid-β toxicity in Alzheimer's disease mouse models. Cell 142, 387–397 (2010).
Ballard, C. et al. Alzheimer's disease. Lancet 377, 1019–1031 (2011).
Ballard, C., Corbett, A. & Sharp, S. Aligning the evidence with practice: NICE guidelines for drug treatment of Alzheimer's disease. Expert Rev. Neurother. 11, 327–329 (2011).
Wilcock, G. K. et al. Efficacy and safety of tarenflurbil in mild to moderate Alzheimer's disease: a randomised phase II trial. Lancet Neurol. 7, 483–493 (2008).
Green, R. C. et al. Effect of tarenflurbil on cognitive decline and activities of daily living in patients with mild Alzheimer disease: a randomized controlled trial. JAMA 302, 2557–2564 (2009).
Zhang, S. T., Hedskog, L., Petersen, C. A. H., Winblad, B. & Ankarcrona, M. Dimebon (latrepirdine) enhances mitochondrial function and protects neuronal cells from death. J. Alzheimers Dis. 21, 389–402 (2010).
D'Onofrio, G. et al. Advances in the identification of γ-secretase inhibitors for the treatment of Alzheimer's disease. Expert Opin. Drug Discov. 7, 19–37 (2012).
Schenk, D. et al. Immunization with amyloid-β attenuates Alzheimer-disease-like pathology in the PDAPP mouse. Nature 400, 173–177 (1999).
Holmes, C. et al. Long-term effects of Aβ42 immunisation in Alzheimer's disease: follow-up of a randomised, placebo-controlled phase I trial. Lancet 372, 216–223 (2008).
Thakker, D. R. et al. Intracerebroventricular amyloid-β antibodies reduce cerebral amyloid angiopathy and associated micro-hemorrhages in aged Tg2576 mice. Proc. Natl Acad. Sci. USA 106, 4501–4506 (2009).
Salloway, S. et al. A phase 2 multiple ascending dose trial of bapineuzumab in mild to moderate Alzheimer disease. Neurology 73, 2061–2070 (2009).
Dubois, B. et al. Research criteria for the diagnosis of Alzheimer's disease: revising the NINCDS-ADRDA criteria. Lancet Neurol. 6, 734–746 (2007).
Mangialasche, F., Solomon, A., Winblad, B., Mecocci, P. & Kivipelto, M. Alzheimer's disease: clinical trials and drug development. Lancet Neurol. 9, 702–716 (2010).
Sirota, M. et al. Discovery and preclinical validation of drug indications using compendia of public gene expression data. Sci. Transl. Med. 3, 96ra77 (2011).
Ashburn, T. T. & Thor, K. B. Drug repositioning: Identifying and developing new uses for existing drugs. Nature Rev. Drug Discov. 3, 673–683 (2004).
Hubsher, G., Haider, M. & Okun, M. S. Amantadine: the journey from fighting flu to treating Parkinson disease. Neurology 78, 1096–1099 (2012).
Yoshitake, T. et al. Incidence and risk-factors of vascular dementia and Alzheimers-disease in a defined elderly japanese population — the Hisayama study. Neurology 45, 1161–1168 (1995).
Skoog, I. et al. 15-year longitudinal study of blood pressure and dementia. Lancet 347, 1141–1145 (1996).
Launer, L. J. et al. Midlife blood pressure and dementia: the Honolulu-Asia aging study. Neurobiol. Aging 21, 49–55 (2000).
Posner, H. B. et al. The relationship of hypertension in the elderly to AD, vascular dementia, and cognitive function. Neurology 58, 1175–1181 (2002).
Qiu, C., Winblad, B. & Fratiglioni, L. The age-dependent relation of blood pressure to cognitive function and dementia. Lancet Neurol. 4, 487–499 (2005).
Dickstein, D. L. et al. Role of vascular risk factors and vascular dysfunction in Alzheimer's disease. Mt Sinai J. Med. 77, 82–102 (2010).
Snowdon, D. A. et al. Brain infarction and the clinical expression of Alzheimer disease — the nun study. JAMA 277, 813–817 (1997).
Kehoe, P. G., Miners, J. S. & Love, S. Angiotensins in Alzheimer's disease — friend or foe? Trends Neurosci. 32, 619–628 (1997).
Kehoe, P. G. & Passmore, P. A. The renin–angiotensin system and antihypertensive drugs in Alzheimer's disease: current standing of the angiotensin hypothesis? J. Alzheimers Dis. 30, S251–S269 (2012).
Wright, J. W. & Harding, J. W. Brain renin-angiotensin — a new look at an old system. Prog. Neurobiol. 95, 49–67 (2011).
Culman, J., Blume, A., Gohlke, P. & Unger, T. The renin-angiotensin system in the brain: possible therapeutic implications for AT1-receptor blockers. J. Hum. Hypertens. 16, S64–S70 (2002).
Wang, J. et al. Valsartan lowers brain β-amyloid protein levels and improves spatial learning in a mouse model of Alzheimer disease. J. Clin. Invest. 117, 3393–3402 (2007).
Ferrington, L. et al. Angiotensin II-inhibiting drugs have no effect on intraneuronal Aβ or oligomeric Aβ levels in a triple transgenic mouse model of Alzheimer's disease. Am. J. Transl. Res. 3, 197–208 (2011).
Hemming, M. L., Selkoe, D. J. & Farris, W. Effects of prolonged angiotensin-converting enzyme inhibitor treatment on amyloid β-protein metabolism in mouse models of Alzheimer disease. Neurobiol. Dis. 26, 273–281 (2007).
Takeda, S. et al. Angiotensin receptor blocker prevented β-amyloid-induced cognitive impairment associated with recovery of neurovascular coupling. Hypertension 54, 1345–1352 (2009).
Mogi, M. et al. Telmisartan prevented cognitive decline partly due to PPAR-γ activation. Biochem. Biophys. Res. Commun. 375, 446–449 (2008).
Danielyan, L. et al. Protective effects of intranasal losartan in the APP/PS1 transgenic mouse model of Alzheimer disease. Rejuven. Res. 13, 195–201 (2010).
Li, N.-C. et al. Use of angiotensin receptor blockers and risk of dementia in a predominantly male population: prospective cohort analysis. BMJ 340, b5465 (2010).
Davies, N. M., Kehoe, P. G., Ben-Shlomo, Y. & Martin, R. M. Associations of anti-hypertensive treatments with Alzheimer's disease, vascular dementia, and other dementias. J. Alzheimers Dis. 26, 699–708 (2011).
Anderson, C. et al. Renin-angiotensin system blockade and cognitive function in patients at high risk of cardiovascular disease: analysis of data from the ONTARGET and TRANSCEND studies. Lancet Neurol. 10, 43–53 (2011).
Lithell, H. et al. The study on cognition and prognosis in the elderly (SCOPE): principal results of a randomized double-blind intervention trial. J. Hypertens. 21, 875–886 (2003).
Skoog, I. et al. Effect of baseline cognitive function and anti hypertensive treatment on cognitive and cardiovascular outcomes: study on cognition and prognosis in the elderly (SCOPE). Am. J. Hypertens. 18, 1052–1059 (2005).
Landmark, K. et al. Nitrendipine and mefruside in elderly hypertensives — effects on blood-pressure, cardiac-output, cerebral blood-flow and metabolic parameters. J. Hum. Hypertens. 9, 281–285 (1995).
Hanyu, H. et al. Favourable effects of nilvadipine on cognitive function and regional cerebral blood flow on SPECT in hypertensive patients with mild cognitive impairment. Nuclear Med. Commun. 28, 281–287 (2007).
Forsman, M., Olsnes, B. T., Semb, G. & Steen, P. A. Effects of nimodipine on cerebral blood flow and neuropsychological outcome after cardiac surgery. Br. J. Anaesth. 65, 514–520 (1990).
Zhao, W. et al. Identification of antihypertensive drugs which inhibit amyloid-β protein oligomerization. J. Alzheimers Dis. 16, 49–57 (2009).
Bachmeier, C., Beaulieu-Abdelahad, D., Mullan, M. & Paris, D. Selective dihydropyiridine compounds facilitate the clearance of β-amyloid across the blood–brain barrier. Eur. J. Pharmacol. 659, 124–129 (2011).
Anekonda, T. S. et al. L-type voltage-gated calcium channel blockade with isradipine as a therapeutic strategy for Alzheimer's disease. Neurobiol. Dis. 41, 62–70 (2011).
Li, N., Liu, B., Dluzen, D. E. & Jin, Y. Protective effects of ginsenoside Rg2 against glutamate-induced neurotoxicity in PC12 cells. J. Ethnopharmacol. 111, 458–463 (2007).
Paris, D. et al. Selective antihypertensive dihydropyridines lower Aβ accumulation by targeting both the production and the clearance of Aβ across the blood–brain barrier. Mol. Med. 17, 149–162 (2011).
Iwasaki, K. et al. Nilvadipine prevents the impairment of spatial memory induced by cerebral ischemia combined with β-amyloid in rats. Biol. Pharm. Bull. 30, 698–701 (2007).
Copenhaver, P. F. et al. A translational continuum of model systems for evaluating treatment strategies in Alzheimer's disease: isradipine as a candidate drug. Dis. Model. Mech. 4, 634–648 (2011).
Lopez-Arrieta, J. M. & Birks, J. Nimodipine for primary degenerative, mixed and vascular dementia. Cochrane Database Syst. Rev. 2002, CD000147 (2002).
Branconnier, R. J., Branconnier, M. E., Walshe, T. M., McCarthy, C. & Morse, P. A. Blocking the Ca2+-activated cytotoxic mechanisms of cholinergic neuronal death: a novel treatment strategy for Alzheimer's disease. Psychopharmacol. Bull. 28, 175–181 (1992).
Morich, F. J. et al. Nimodipine in the treatment of probable Alzheimer's disease — results of two multicentre trials. Clin. Drug Invest. 11, 185–195 (1996).
Kennelly, S. P. et al. Demonstration of safety in Alzheimer's patients for intervention with an anti-hypertensive drug nilvadipine: results from a 6-week open label study. Int. J. Geriatr. Psychiatry 26, 1038–1045 (2011).
Kennelly, S. 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 27, 415–422 (2012).
Khachaturian, A. S. et al. Antihypertensive medication use and incident Alzheimer disease — the Cache County study. Arch. Neurol. 63, 686–692 (2006).
Forette, F. et al. The prevention of dementia with antihypertensive treatment. Arch. Intern. Med. 162, 2046–2052 (2002).
Schrijvers, E. M. C. et al. Insulin metabolism and the risk of Alzheimer disease — the Rotterdam study. Neurology 75, 1982–1987 (2010).
Moloney, A. M. et al. Defects in IGF-1 receptor, insulin receptor and IRS-1/2 in Alzheimer's disease indicate possible resistance to IGF-1 and insulin signalling. Neurobiol. Aging 31, 224–243 (2010).
Stockhorst, U., de Fries, D., Steingrueber, H. J. & Scherbaum, W. A. Insulin and the CNS: effects on food intake, memory, and endocrine parameters and the role of intranasal insulin administration in humans. Physiol. Behav. 83, 47–54 (2004).
Holscher, C. Development of β-amyloid-induced neurodegeneration in Alzheimer's disease and novel neuroprotective strategies. Rev. Neurosci. 16, 181–212 (2005).
Hoyer, S. Glucose metabolism and insulin receptor signal transduction in Alzheimer disease. Eur. J. Pharmacol. 490, 115–125 (2004).
Li, L. & Hölscher, C. Common pathological processes in Alzheimer disease and type 2 diabetes: a review. Brain Res. Rev. 56, 384–402 (2007).
Cohen, A. C., Tong, M., Wands, J. R. & de la Monte, S. M. Insulin and insulin-like growth factor resistance with neurodegeneration in an adult chronic ethanol exposure model. Alcohol Clin. Exp. Res. 31, 1558–1573 (2007).
van Dam, P. & Aleman, A. Insulin-like growth factor-I, cognition and brain aging. Eur. J. Pharmacol. 490, 87–95 (2004).
Li, Z. G., Zhang, W. & Sima, A. A. Alzheimer-like changes in rat models of spontaneous diabetes. Diabetes 56, 1817–1824 (2007).
Carro, E. & Torres, A. I. The role of insulin and insulin-like growth factor I in the molecular and cellular mechanisms underlying the pathology of Alzheimer's disease. Eur. J. Pharmacol. 490, 127–133 (2004).
Watson, G. S. & Craft, S. Modulation of memory by insulin and glucose: neuropsychological observations in Alzheimer's disease. Eur. J. Pharmacol. 490, 97–113 (2004).
Zhao, W. Q. Chen, H., Quon, M. J. & Alkon, D. L. Insulin and the insulin receptor in experimental models of learning and memory. Eur. J. Pharmacol. 490, 71–81 (2004).
Reger, M. A. et al. Intranasal insulin administration dose-dependently modulates verbal memory and plasma amyloid-β in memory-impaired older adults. J. Alzheimers Dis. 13, 323–331 (2008).
Okereke, O. I. et al. A profile of impaired insulin degradation in relation to late-life cognitive decline: a preliminary investigation. Int. J. Geriatr. Psychiatry 24, 177–182 (2008).
Reger, M. A. et al. Intranasal insulin improves cognition and modulates β-amyloid in early AD. Neurology 70, 440–448 (2008).
Baker, L. D. et al. Insulin resistance and Alzheimer-like reductions in regional cerebral glucose metabolism for cognitively normal adults with prediabetes or early type 2 diabetes. Arch. Neurol. 68, 51–57 (2010).
Craft, S. et al. Intranasal insulin therapy for Alzheimer disease and amnestic mild cognitive impairment: a pilot clinical trial. Arch. Neurol. 69, 29–38 (2012).
Holscher, C. in Vitamins and Hormones: Incretins and Insulin Secretion (ed. Litwack, G.) 331–354 (Academic Press, 2010).
Perry, T. et al. Glucagon-like peptide-1 decreases endogenous amyloid-β peptide (Aβ) levels and protects hippocampal neurons from death induced by Aβ and iron. J. Neurosci. Res. 72, 603–612 (2003).
Li, L. et al. (Val8) glucagon-like peptide-1 prevents tau hyperphosphorylation, impairment of spatial learning and ultra-structural cellular damage induced by streptozotocin in rat brains. Eur. J. Pharmacol. 674, 280–286 (2012).
Perry, T. et al. A novel neutrotrophic property of glucagon-like peptide 1: a promoter of nerve growth factor-mediated differentiation in PC12 cells. J. Pharmacol. Exp. Ther. 300, 958–966 (2002).
Wang, X. H. et al. Val8-glucagon-like peptide-1 protects against Aβ1–40-induced impairment of hippocampal late-phase long-term potentiation and spatial learning in rats. Neuroscience 170, 1239–1248 (2010).
Radde, R. et al. Aβ42-driven cerebral amyloidosis in transgenic mice reveals early and robust pathology. EMBO Rep. 7, 940–946 (2006).
Gengler, S., McClean, P., McCurtin, R., Gault, V. & Holscher, C. Val(8)GLP-1 rescues synaptic plasticity and reduces dense core plaques in APP/PS1 mice. Neurobiol. Aging 33, 265–276 (2012).
McClean, P. L., Parthsarathy, V., Faivre, E. & Holscher, C. The diabetes drug liraglutide prevents degenerative processes in a mouse model of Alzheimer's disease. J. Neurosci. 31, 6587–6594 (2011).
Hamilton, A., Patterson, S., Porter, D., Gault, V. A. & Holscher, C. Novel GLP-1 mimetics developed to treat type 2 diabetes promote progenitor cell proliferation in the brain. J. Neurosci. Res. 89, 481–489 (2011).
Kastin, A. J., Akerstrom, V. & Pan, W. Interactions of glucagon-like peptide-1 (GLP-1) with the blood–brain barrier. J. Mol. Neurosci. 18, 7–14 (2002).
Kastin, A. J. & Akerstrom, V. Entry of exendin-4 into brain is rapid but may be limited at high doses. Int. J. Obes. Relat. Metab. Disord. 27, 313–318 (2003).
McClean, P., Pathasarthy, V., Faivre, E. & Hölscher, C. Liraglutide, a novel GLP-1 analogue, prevents the impairment of learning and LTP in an APP/PS-1 mouse model of Alzheimer's disease. Session 556.11, Poster K20 (Society for Neuroscience 40th Annual Meeting, San Diego, California; 2010).
Astrup, A. et al. Effects of liraglutide in the treatment of obesity: a randomised, double-blind, placebo-controlled study. Lancet 374, 1606–1616 (2009).
Forloni, G., Colombo, L., Girola, L., Tagliavini, F. & Salmona, M. Anti-amyloidogenic activity of tetracyclines: studies in vitro. FEBS Lett. 487, 404–407 (2001).
Ryu, J. K., Franciosi, S., Sattayaprasert, P., Kim, S. U. & McLarnon, J. G. Minocycline inhibits neuronal death and glial activation induced by β-amyloid peptide in rat hippocampus. Glia 48, 85–90 (2004).
Fan, R. et al. Minocycline reduces microglial activation and improves behavioral deficits in a transgenic model of cerebral microvascular amyloid. J. Neurosci. 27, 3057–3063 (2007).
Garcia-Alloza, M. et al. Matrix metalloproteinase inhibition reduces oxidative stress associated with cerebral amyloid angiopathy in vivo in transgenic mice. J. Neurochem. 109, 1636–1647 (2009).
Noble, W., Garwood, C. J. & Hanger, D. P. Minocycline as a potential therapeutic agent in neurodegenerative disorders characterised by protein misfolding. Prion 3, 78–83 (2009).
Parachikova, A., Vasilevko, V., Cribbs, D. H., LaFerla, F. M. & Green, K. N. Reductions in amyloid-β-derived neuroinflammation, with minocycline, restore cognition but do not significantly affect tau hyperphosphorylation. J. Alzheimers Dis. 21, 527–542 (2010).
Cai, Z. Y., Zhao, Y., Yao, S. T. & Zhao, B. Increases in β-amyloid protein in the hippocampus caused by diabetic metabolic disorder are blocked by minocycline through inhibition of NF-κB pathway activation. Pharmacol. Rep. 63, 381–391 (2011).
Cuello, A. C. et al. Early-stage inflammation and experimental therapy in transgenic models of the Alzheimer-like amyloid pathology. Neurodegener. Dis. 7, 96–98 (2010).
Seabrook, T. J., Jiang, L. Y., Maier, M. & Lemere, C. A. Minocycline affects microglia activation, Aβ deposition, and behavior in APP-tg mice. Glia 53, 776–782 (2006).
Malm, T. M. et al. Minocycline reduces engraftment and activation of bone marrow-derived cells but sustains their phagocytic activity in a mouse model of Alzheimer's disease. Glia 56, 1767–1779 (2008).
Reagan-Shaw, S., Nihal, M. & Ahmad, N. Dose translation from animal to human studies revisited. FASEB J. 22, 659–661 (2008).
Gordon, P. H. et al. Efficacy of minocycline in patients with amyotrophic lateral sclerosis: a Phase III randomised trial. Lancet Neurol. 6, 1045–1053 (2007).
Bonelli, R. M., Heuberger, C. & Reisecker, F. Minocycline for Huntington's disease: an open label study. Neurology 60, 883–884 (2003).
Bonelli, R. M., Hodl, A. K., Hofmann, P. & Kapfhammer, H. P. Neuroprotection in Huntington's disease: a 2-year study on minocycline. Int. Clin. Psychopharmacol. 19, 337–342 (2004).
Thomas, M., Ashizawa, T. & Jankovic, J. Minocycline in Huntington's disease: a pilot study. Mov. Disord. 19, 692–695 (2004).
Schwarz, H. et al. A futility study of minocycline in Huntington's disease. Mov. Disord. 25, 2219–2224 (2010).
Kieburtz, K. et al. A pilot clinical trial of creatine and minocycline in early Parkinson disease: 18-month results. Clin. Neuropharmacol. 31, 141–150 (2008).
Goodman, A. B. & Pardee, A. B. Evidence for defective retinoid transport and function in late onset Alzheimer's disease. Proc. Natl Acad. Sci. USA 100, 2901–2905 (2003).
Corcoran, J. P. T., So, P. L. & Maden, M. Disruption of the retinoid signalling pathway causes a deposition of amyloid β in the adult rat brain. Eur. J. Neurosci. 20, 896–902 (2004).
Husson, M. et al. Retinoic acid normalizes nuclear receptor mediated hypo-expression of proteins involved in β-amyloid deposits in the cerebral cortex of vitamin A deprived rats. Neurobiol. Dis. 23, 1–10 (2006).
Ding, Y. et al. Retinoic acid attenuates β-amyloid deposition and rescues memory deficits in an Alzheimer's disease transgenic mouse model. J. Neurosci. 28, 11622–11634 (2008).
Tippmann, F., Hundt, J., Schneider, A., Endres, K. & Fahrenholz, F. Up-regulation of the α-secretase ADAM10 by retinoic acid receptors and acitretin. FASEB J. 23, 1643–1654 (2009).
Jarvis, C. I. et al. Retinoic acid receptor-α signalling antagonizes both intracellular and extracellular amyloid-β production and prevents neuronal cell death caused by amyloid-β. Eur. J. Neurosci. 32, 1246–1255 (2010).
Kawahara, K. et al. Oral administration of synthetic retinoid am80 (tamibarotene) decreases brain β-amyloid peptides in APP23 mice. Biol. Pharm. Bull. 32, 1307–1309 (2009).
Cramer, P. E. et al. ApoE-directed therapeutics rapidly clear β-amyloid and reverse deficits in AD mouse models. Science 335, 1503–1506 (2012).
Castellano, J. M. et al. Human apoE isoforms differentially regulate brain amyloid-β peptide clearance. Sci. Transl. Med. 3, 89ra57 (2011).
Melino, G. et al. Regulation by retinoic acid of insulin-degrading enzyme and of a related endoprotease in human neuroblastoma cell lines. Cell Growth Differ. 7, 787–796 (1996).
So, P. L. et al. Interactions between retinoic acid, nerve growth factor and sonic hedgehog signalling pathways in neurite outgrowth. Dev. Biol. 298, 167–175 (2006).
Goncalves, M. et al. Sequential RARβ and α signalling in vivo can induce adult forebrain neural progenitor cells to differentiate into neurons through Shh and FGF signalling pathways. Dev. Biol. 326, 305–313 (2009).
Lee, H. P. et al. All-trans retinoic acid as a novel therapeutic strategy for Alzheimer's disease. Expert Rev Neurother. 9, 1615–1621 (2009).
Shudo, K., Fukasawa, H., Nakagomi, M. & Yamagata, N. Towards retinoid therapy for Alzheimer's disease. Curr. Alzheimer Res. 6, 302–311 (2009).
Eisenhardt, E. U. & Bickel, M. H. Kinetics of tissue distribution and elimination of retinoid drugs in the rat. I. Acitretin. Drug Metab. Dispos. 22, 26–30 (1994).
Nebes, R. D. et al. Persistence of cognitive impairment in geriatric patients following antidepressant treatment: a randomized, double-blind clinical trial with nortriptyline and paroxetine. J. Psychiatr. Res. 37, 99–108 (2003).
Scholey, A. B. et al. An extract of Salvia (sage) with anticholinesterase properties improves memory and attention in healthy older volunteers. Psychopharmacology 198, 127–139 (2008).
McGuinness, B., Todd, S., Passmore, P. & Bullock, R. Blood pressure lowering in patients without prior cerebrovascular disease for prevention of cognitive impairment and dementia. Cochrane Database Syst. Rev. 2009, CD004034 (2009).
Gorelick, P. B. Role of inflammation in cognitive impairment: results of observational epidemiological studies and clinical trials. Ann. NY Acad. Sci. 1207, 155–162 (2010).
Jaturapatporn, D., Isaac, M., McCleery, J. & Tabet, N. Aspirin, steroidal and non-steroidal anti-inflammatory drugs for the treatment of Alzheimer's disease. Cochrane Database Syst. Rev. 2012, CD006378 (2012).
Holmes, C. et al. Systemic inflammation and disease progression in Alzheimer disease. Neurology 73, 768–774 (2009).
Chen, Y. M., Chen, H. H., Lan, J. L. & Chen, D. Y. Improvement of cognition, a potential benefit of anti-TNF therapy in elderly patients with rheumatoid arthritis. Joint Bone Spine 77, 366–367 (2010).
Smith, A. D. et al. Homocysteine-lowering by B vitamins slows the rate of accelerated brain atrophy in mild cognitive impairment: a randomized controlled trial. PLoS ONE 5, e12244 (2010).
Krishnan, S., Cairns, R. & Howard, R. Cannabinoids for the treatment of dementia. Cochrane Database Syst. Rev. 2009, CD007204 (2009).
Wozniak, M. A., Mee, A. P. & Itzhaki, R. F. Herpes simplex virus type 1 DNA is located within Alzheimer's disease amyloid plaques. J. Pathol. 217, 131–138 (2009).
Itzhaki, R. F. & Wozniak, M. A. Herpes simplex virus type 1 in Alzheimer's disease: the enemy within. J. Alzheimers Dis. 13, 393–405 (2008).
Macdonald, A. et al. A feasibility and tolerability study of lithium in Alzheimer's disease. Int. J. Geriatr. Psychiatry 23, 704–711 (2008).
Hampel, H. et al. Lithium trial in Alzheimer's disease: a randomized, single-blind, placebo-controlled, multicenter 10-week study. J. Clin. Psychiatry 70, 922–931 (2009).
Brunden, K. R., Trojanowski, J. Q. & Lee, V. M. Y. Advances in tau-focused drug discovery for Alzheimer's disease and related tauopathies. Nature Rev. Drug Discov. 8, 783–793 (2009).
Gupta, A., Bisht, B. & Dey, C. S. Peripheral insulin-sensitizer drug metformin ameliorates neuronal insulin resistance and Alzheimer's-like changes. Neuropharmacology 60, 910–920 (2011).
Hsu, C. C., Wahlqvist, M. L., Lee, M. S. & Tsai, H. N. Incidence of dementia is increased in type 2 diabetes and reduced by the use of sulfonylureas and metformin. J. Alzheimers Dis. 24, 485–493 (2011).
Loeb, M. B. et al. A randomized, controlled trial of doxycycline and rifampin for patients with Alzheimer's disease. J. Am. Geriatr. Soc. 52, 381–387 (2004).
Fleisher, A. S. et al. Chronic divalproex sodium use and brain atrophy in Alzheimer disease. Neurology 77, 1263–1271 (2011).
Gold, M. et al. Rosiglitazone monotherapy in mild-to-moderate Alzheimer's disease: results from a randomized, double-blind, placebo-controlled Phase III study. Dementia Geriatr. Cognitive Disord. 30, 131–146 (2010).
Sato T. et al. Efficacy of PPAR-γ agonist pioglitazone in mild Alzheimer's disease. Neurobiol. Aging 32, 1626–1633 (2011).
The authors thank: the UK Alzheimer's Society for supporting this work; I. Testad and E. Perry for their contributions to the consensus process; and the UK National Institute for Health Research (NIHR) Biomedical Research Unit at South London and Maudsley UK National Health Service (NHS) Trust/King's College London for supporting the involvement of C.B. in this work.
Clive Holmes is in receipt of a grant from Pfizer to investigate peripherally administered etanercept. The UK Alzheimer's Society supported Anne Corbett, James Pickett, Emma Jones, Ian Kearns and Clive Ballard in the preparation of this manuscript. The other authors declare no competing financial interests.
- APP23 mice
Transgenic mice carrying the double Swedish mutation (K670N/M671L) of amyloid precursor protein (APP), which leads to familial Alzheimer's disease. These animals overexpress APP by about sevenfold and develop amyloid deposits and behavioural deficits as they age.
- APP/PSEN1 mice
A transgenic mouse model of Alzheimer's disease carrying both human amyloid precursor protein (APP) with the Swedish mutation (K670N/M671L) and the presenilin 1 (PSEN1) A246E mutation. These mice develop amyloid deposits and behavioural deficits at a younger age than the APP transgenic animals (K670N/M671L models alone).
- Delphi-type process
A structured technique to achieve consensus from a panel of experts using a systematic method, usually using two or more stages to share and discuss the emerging consensus in order to achieve the best overall consensus from the expert group.
- J20 mice
A transgenic mouse model of Alzheimer's disease. These mice express a mutant form of human amyloid precursor protein (APP) bearing both the Swedish (K670N/M671L) and the Indiana (V717F) mutations of familial Alzheimer's disease. These mice develop amyloid deposits and behavioural deficits as they age.
- Mini mental state examination
(MMSE). A brief and widely used 30-point neuropsychological assessment evaluating a number of cognitive domains. A score of 25 or less is indicative of a degree of cognitive deficit requiring further evaluation. In patients with Alzheimer's disease, an MMSE score <10 indicates severe dementia, 10–20 indicates moderate dementia and >20 indicates mild dementia.
- Non-APOE4 carriers
Individuals who do not carry the E4 allele of the gene encoding apolipoprotein E (APOE); APOE4 is a known risk factor for the development of late-onset Alzheimer's disease; 25% of the population and 50% of patients with Alzheimer's disease carry at least one E4 allele.
- 'Peripheral sink' hypothesis
A hypothesis stating that antibodies bind to amyloid-β in the bloodstream, shifting the distribution of amyloid-β between the brain and the peripheral circulatory system and thereby leading to a net efflux of amyloid-β from the central nervous system to plasma, where it is degraded.
- Standardized mean difference
(SMD). A statistical method for calculating a standardizing coefficient to quantify differences between treatment groups based on mean changes and standard deviation to enable comparison of outcomes across studies that have used different outcome measures.
- Tg2576 transgenic mice
Transgenic mice expressing abnormal variants of the human genes encoding amyloid precursor protein (APP) that are a rare cause of familial Alzheimer's disease. These mice exhibit a fivefold increase in APP levels in the brain and develop amyloid deposits and behavioural deficits as they age.
- Triple-transgenic mice
(3xTg-AD mice). A novel mouse model of Alzheimer's disease, incorporating human genes that lead to abnormal processing of amyloid-β and tau. This mouse model is the only model to exhibit both amyloid-β and tau pathology, and therefore mimics human Alzheimer's disease more closely than other mouse models.
- Weighted mean difference
(WMD). A statistical method for calculating a standardizing coefficient to quantify differences between treatment groups based on mean changes and standard deviation to enable comparison of outcomes across studies that have used different outcome measures to enable them to be combined in meta-analyses; this method makes the calculation based on the size of the individual studies.
- Wistar rat
A breed of non-transgenic rat that has been widely used for experimental studies.
An intramembrane protease complex that cleaves the transmembrane amyloid precursor protein to produce amyloid-β.
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Corbett, A., Pickett, J., Burns, A. et al. Drug repositioning for Alzheimer's disease. Nat Rev Drug Discov 11, 833–846 (2012). https://doi.org/10.1038/nrd3869
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