Neuroprotective therapeutics for Alzheimer's disease: progress and prospects.

The number of people with Alzheimer's disease (AD) has never been greater and is set to increase substantially in the decades ahead as the proportion of the population aged 65 years or more rises sharply. There is therefore an urgent need for safe and effective pharmacotherapy to help combat the corresponding and substantial increase in disease burden. Increased understanding of disease aetiology and pathophysiology, particularly in relation to the loss of vulnerable neurons and the formation of plaques and tangles, has increased hope for medications that can slow (or perhaps even halt) the course of the disease. In this article I review the neurobiological basis of AD, current progress towards neuroprotective therapeutics, and prospects for the future.

[1]  S. Pimplikar,et al.  Reassessing the amyloid cascade hypothesis of Alzheimer's disease. , 2009, The international journal of biochemistry & cell biology.

[2]  D. Avramopoulos Genetics of Alzheimer's disease: recent advances , 2009, Genome Medicine.

[3]  Kathryn Ziegler-Graham,et al.  Forecasting the global burden of Alzheimer’s disease , 2007, Alzheimer's & Dementia.

[4]  Bradley T. Hyman,et al.  Neurofibrillary tangles but not senile plaques parallel duration and severity of Alzheimer's disease , 1992, Neurology.

[5]  K. Davis,et al.  Effects of rofecoxib or naproxen vs placebo on Alzheimer disease progression: a randomized controlled trial. , 2003, JAMA.

[6]  F. Panza,et al.  Towards disease-modifying treatment of Alzheimer's disease: drugs targeting beta-amyloid. , 2010, Current Alzheimer research.

[7]  Jeffrey L. Cummings,et al.  The spectrum of behavioral changes in Alzheimer's disease , 1996, Neurology.

[8]  M. Goedert,et al.  The value of incomplete mouse models of Alzheimer’s disease , 2008, European Journal of Nuclear Medicine and Molecular Imaging.

[9]  M. Tabaton,et al.  Neuropil threads of Alzheimer's disease show a marked alteration of the normal cytoskeleton , 1991, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[10]  Xiuzhen Zhang,et al.  Valproic acid as a promising agent to combat Alzheimer's disease , 2010, Brain Research Bulletin.

[11]  P. Bosco,et al.  The CALHM1 P86L polymorphism is a genetic modifier of age at onset in Alzheimer's disease: a meta-analysis study. , 2010, Journal of Alzheimer's disease : JAD.

[12]  Šimon Scharf,et al.  A double-blind, placebo-controlled trial of diclofenac/misoprostol in Alzheimer’s disease , 1999, Neurology.

[13]  M. Albert,et al.  Prevalence of Alzheimer's disease in a community population of older persons. Higher than previously reported. , 1989, JAMA.

[14]  J. Cummings,et al.  Disease-modifying therapies in Alzheimer’s disease ⁎ ⁎ EDITOR’S NOTE: The Journal intended to include this article in the January 2008 supplement, “Leon Thal Symposium on Prevention of Dementia.” , 2008, Alzheimer's & Dementia.

[15]  L. Thal,et al.  A Randomized, Double-Blind, Study of Rofecoxib in Patients with Mild Cognitive Impairment , 2005, Neuropsychopharmacology.

[16]  G. Logroscino,et al.  REVIEW: γ‐Secretase Inhibitors for the Treatment of Alzheimer's Disease: The Current State , 2010, CNS neuroscience & therapeutics.

[17]  Robert C Green,et al.  Effect of tarenflurbil on cognitive decline and activities of daily living in patients with mild Alzheimer disease: a randomized controlled trial. , 2009, JAMA.

[18]  T. Comery,et al.  Begacestat (GSI-953): A Novel, Selective Thiophene Sulfonamide Inhibitor of Amyloid Precursor Protein γ-Secretase for the Treatment of Alzheimer's Disease , 2009, Journal of Pharmacology and Experimental Therapeutics.

[19]  B. Strooper,et al.  The secretases: enzymes with therapeutic potential in Alzheimer disease , 2010, Nature Reviews Neurology.

[20]  Fei Liu,et al.  Tau in Alzheimer disease and related tauopathies. , 2010, Current Alzheimer research.

[21]  G. Jicha,et al.  Omega-3 fatty acids: potential role in the management of early Alzheimer’s disease , 2010, Clinical interventions in aging.

[22]  H. Braak,et al.  Evolution of Alzheimer's disease related cortical lesions. , 1998, Journal of neural transmission. Supplementum.

[23]  John Hardy,et al.  The amyloid hypothesis for Alzheimer’s disease: a critical reappraisal , 2009, Journal of neurochemistry.

[24]  R. Green,et al.  Naproxen and celecoxib do not prevent AD in early results from a randomized controlled trial , 2007, Neurology.

[25]  D. Price,et al.  The neuropathology of aminergic nuclei in Alzheimer's disease , 1988, Progress in clinical and biological research.

[26]  P. Passmore,et al.  Can statins prevent or help treat Alzheimer's disease? , 2010, Journal of Alzheimer's disease : JAD.

[27]  M. Sabbagh Drug development for Alzheimer's disease: where are we now and where are we headed? , 2009, The American journal of geriatric pharmacotherapy.

[28]  R. Motter,et al.  Immunization with amyloid-β attenuates Alzheimer-disease-like pathology in the PDAPP mouse , 1999, Nature.

[29]  G. Grosveld γ-secretase inhibitors: Notch so bad , 2009, Nature Medicine.

[30]  R. Green,et al.  Cognitive function over time in the Alzheimer's Disease Anti-inflammatory Prevention Trial (ADAPT): results of a randomized, controlled trial of naproxen and celecoxib. , 2008, Archives of neurology.

[31]  S. J. Martin,et al.  New life in an old idea: The synaptic plasticity and memory hypothesis revisited , 2002, Hippocampus.

[32]  F. LaFerla,et al.  Alzheimer's disease. , 2010, The New England journal of medicine.

[33]  J. Rusted,et al.  Vitamin E for Alzheimer's dementia and mild cognitive impairment. , 2012, The Cochrane database of systematic reviews.

[34]  H. Braak,et al.  Neuropathological stageing of Alzheimer-related changes , 2004, Acta Neuropathologica.

[35]  Statins for the treatment of dementia , 2010, Alzheimer's & Dementia.

[36]  N. Tabet,et al.  Vitamin E for Alzheimer's disease and mild cognitive impairment. , 2008, The Cochrane database of systematic reviews.

[37]  A. Kaszniak,et al.  Clinical trial of indomethacin in Alzheimer's disease , 1993, Neurology.

[38]  G. Koch,et al.  Beyond the Cholinergic Hypothesis: Do Current Drugs Work in Alzheimer's Disease? , 2010, CNS neuroscience & therapeutics.

[39]  D. Neary,et al.  Alzheimer's disease: a correlative study. , 1986, Journal of neurology, neurosurgery, and psychiatry.

[40]  J. Dungan Ginkgo biloba for Preventing Cognitive Decline in Older Adults: A Randomized Trial , 2010 .

[41]  I. Grundke‐Iqbal,et al.  Targeting Tau Protein in Alzheimer’s Disease , 2010, Drugs & aging.

[42]  J. Morris,et al.  Profound Loss of Layer II Entorhinal Cortex Neurons Occurs in Very Mild Alzheimer’s Disease , 1996, The Journal of Neuroscience.

[43]  M. Sarter,et al.  Cholinergic Mediation of Attention , 2008, Annals of the New York Academy of Sciences.

[44]  R. Pearson,et al.  Cortical connections and the pathology of Alzheimer's disease. , 1996, Neurodegeneration : a journal for neurodegenerative disorders, neuroprotection, and neuroregeneration.

[45]  Z. Qin,et al.  Molecular mechanisms of excitotoxicity and their relevance to pathogenesis of neurodegenerative diseases , 2009, Acta Pharmacologica Sinica.

[46]  A. Palmer,et al.  A comparative assessment of the efficacy and side-effect liability of neuroprotective compounds in experimental stroke , 2001, Brain Research.

[47]  Jonathan D. Cohen,et al.  An integrative theory of locus coeruleus-norepinephrine function: adaptive gain and optimal performance. , 2005, Annual review of neuroscience.

[48]  M. Mesulam,et al.  Cholinergic nucleus basalis tauopathy emerges early in the aging‐MCI‐AD continuum , 2004, Annals of neurology.

[49]  K. Jain Neuroprotection in traumatic brain injury. , 2008, Drug discovery today.

[50]  F. Panza,et al.  Towards Disease-Modifying Treatment of Alzheimers Disease: Drugs Targeting β -Amyloid , 2009 .

[51]  A. Palmer Pharmacotherapy for Alzheimer's disease: progress and prospects. , 2002, Trends in pharmacological sciences.

[52]  D. Praticò Oxidative stress hypothesis in Alzheimer's disease: a reappraisal. , 2008, Trends in pharmacological sciences.

[53]  D. Neary,et al.  THE PROGRESSION OF THE PATHOLOGICAL CHANGES OF ALZHEIMER'S DISEASE IN FRONTAL AND TEMPORAL NEOCORTEX EXAMINED BOTH AT BIOPSY AND AT AUTOPSY , 1988, Neuropathology and applied neurobiology.

[54]  Seth Love,et al.  Long-term effects of Aβ42 immunisation in Alzheimer's disease: follow-up of a randomised, placebo-controlled phase I trial , 2008, The Lancet.

[55]  I. Gozes Tau pathology and future therapeutics. , 2010, Current Alzheimer research.

[56]  B. Winblad,et al.  Alzheimer's disease: clinical trials and drug development , 2010, The Lancet Neurology.

[57]  Myron D. Ginsberg,et al.  Neuroprotection for ischemic stroke: Past, present and future , 2008, Neuropharmacology.

[58]  T. Robbins,et al.  Behavioural pharmacology: 40+ years of progress, with a focus on glutamate receptors and cognition , 2006, Trends in pharmacological sciences.

[59]  N. Sims Energy metabolism, oxidative stress and neuronal degeneration in Alzheimer's disease. , 1996, Neurodegeneration : a journal for neurodegenerative disorders, neuroprotection, and neuroregeneration.

[60]  B. Dubois,et al.  Subacute meningoencephalitis in a subset of patients with AD after Aβ42 immunization , 2003, Neurology.

[61]  P. Dayan,et al.  Serotonin in affective control. , 2009, Annual review of neuroscience.

[62]  A. Palmer Neurochemical studies of Alzheimer's disease. , 1996, Neurodegeneration : a journal for neurodegenerative disorders, neuroprotection, and neuroregeneration.

[63]  L. Cork Neuropathology of Down syndrome and Alzheimer disease. , 2005, American journal of medical genetics. Supplement.

[64]  M. Hasselmo,et al.  Modes and Models of Forebrain Cholinergic Neuromodulation of Cognition , 2011, Neuropsychopharmacology.

[65]  A. Palmer,et al.  Drug metabolism and pharmacokinetics, the blood-brain barrier, and central nervous system drug discovery , 2005, NeuroRx.

[66]  H. Shill,et al.  Latrepirdine, a potential novel treatment for Alzheimer's disease and Huntington's chorea. , 2010, Current opinion in investigational drugs.

[67]  H. Möller,et al.  Lithium trial in Alzheimer's disease: a randomized, single-blind, placebo-controlled, multicenter 10-week study. , 2009, The Journal of clinical psychiatry.