Alzheimer Disease: US Eastern Zone

Wright JF, Doherty ME, Dumas LG. · Norwell Visiting Nurse Association and Hospice, 91 Longwater Circle, Norwell, MA 02061, USA. · Nurs Clin North Am. · Pubmed #19463677 No free full text.

Abstract: Just as the voices of people with Alzheimer's disease are driving changes, the voices of caregivers can also facilitate change, which is vital now and for the future. Caregivers play an important role in the educational process.

Koren J, Jinwal UK, Lee DC, Jones JR, Shults CL, Johnson AG, Anderson LJ, Dickey CA. · Johnnie B. Byrd Sr. Alzheimer's Center and Research Institute, Department of Molecular Medicine, University of South Florida, Tampa, USA. · J Cell Mol Med. · Pubmed #19449461 No free full text.

Abstract: Molecular chaperones and heat shock proteins (Hsp) have emerged as critical regulators of proteins associated with neurodegenerative disease pathologies. The very nature of the chaperone system, which is to maintain protein quality control, means that most nascent proteins come in contact with chaperone proteins. Thus, amyloid precursor protein (APP), members of the gamma-secretase complex (presenilin 1 [PS1] collectively), the microtubule-associated protein tau (MAPT) as well as a number of neuroinflammatory components are all in contact with chaperones from the moment of their production. Chaperones are often grouped together as one machine presenting abnormal or mutant proteins to the proteasome for degradation, but this is not at all the case. In fact, the chaperone family consists of more than 100 proteins in mammalian cells, and the primary role for most of these proteins is to protect clients following synthesis and during stress; only as a last resort do they facilitate protein degradation. To the best of our current knowledge, the chaperone system in eukaryotic cells revolves around the ATPase activities of Hsp70 and Hsp90, the two primary chaperone scaffolds. Other chaperones and co-chaperones manipulate the ATPase activities of Hsp70 and Hsp90, facilitating either folding of the client or its degradation. In the case of Alzheimer's disease (AD), a number of studies have recently emerged describing the impact that these chaperones have on the proteotoxic effects of tau and amyloid- beta accumulation. Here, we present the current understandings of chaperone biology and examine the literature investigating these proteins in the context of AD.

Wang X, Su B, Zheng L, Perry G, Smith MA, Zhu X. · Department of Pathology, Case Western Reserve University, Cleveland, Ohio 44106, USA. · J Neurochem. · Pubmed #19393022 links to  free full text

Abstract: Mitochondria play critical roles in neuronal function and almost all aspects of mitochondrial function are altered in Alzheimer neurons. Emerging evidence shows that mitochondria are dynamic organelles that undergo continuous fission and fusion, the balance of which not only controls mitochondrial morphology and number, but also regulates mitochondrial function and distribution. In this review, after a brief overview of the basic mechanisms involved in the regulation of mitochondrial fission and fusion and how mitochondrial dynamics affects mitochondrial function, we will discuss in detail our and others' recent work demonstrating abnormal mitochondrial morphology and distribution in Alzheimer's disease (AD) models and how these abnormalities may contribute to mitochondrial and synaptic dysfunction in AD. We propose that abnormal mitochondrial dynamics plays a key role in causing the dysfunction of mitochondria that ultimately damage AD neurons.

Yan SD, Bierhaus A, Nawroth PP, Stern DM. · Department of Pathology, College of Physicians & Surgeons of Columbia University, New York City, NY, USA. · J Alzheimers Dis. · Pubmed #19387116 No free full text.

Abstract: Receptor for Advanced Glycation Endproducts (RAGE) is a multiligand member of the immunoglobulin superfamily of cell surface molecules which serves as a receptor for amyloid-beta peptide (Abeta) on neurons, microglia, astrocytes, and cells of vessel wall. Increased expression of RAGE is observed in regions of the brain affected by Alzheimer's disease (AD), and Abeta-RAGE interaction in vitro leads to cell stress with the generation of reactive oxygen species and activation of downstream signaling mechanisms including the MAP kinase pathway. RAGE-mediated activation of p38 MAP kinase in neurons causes Abeta-induced inhibition of long-term potentiation in slices of entorhinal cortex. Increased expression of RAGE in an Abeta-rich environment, using transgenic mouse models, accelerates and accentuates pathologic, biochemical, and behavioral abnormalities compared with mice overexpressing only mutant amyloid-beta protein precursor. Interception of Abeta interaction with RAGE, by infusion of soluble RAGE, decreases Abeta content and amyloid load, as well as improving learning/memory and synaptic function, in a murine transgenic model of Abeta accumulation. These data suggest that RAGE may be a therapeutic target for AD.

Tezapsidis N, Johnston JM, Smith MA, Ashford JW, Casadesus G, Robakis NK, Wolozin B, Perry G, Zhu X, Greco SJ, Sarkar S. · Neurotez, Inc., Bridgewater, New Jersey 08807, USA. · J Alzheimers Dis. · Pubmed #19387109 No free full text.

Abstract: Adipocyte-derived leptin appears to regulate a number of features defining Alzheimer's disease (AD) at the molecular and physiological level. Leptin has been shown to reduce the amount of extracellular amyloid beta, both in cell culture and animal models, as well as to reduce tau phosphorylation in neuronal cells. Importantly, chronic administration of leptin resulted in a significant improvement in the cognitive performance of transgenic animal models. In AD, weight loss often precedes the onset of dementia and the level of circulating leptin is inversely proportional to the severity of cognitive decline. It is speculated that a deficiency in leptin levels or function may contribute to systemic and CNS abnormalities leading to disease progression. Furthermore, a leptin deficiency may aggravate insulin-controlled pathways, known to be aberrant in AD. These observations suggest that a leptin replacement therapy may be beneficial for these patients.

Luchsinger JA, Gustafson DR. · Gertrude H. Sergievsky Center, New York, NY 10032, USA. · J Alzheimers Dis. · Pubmed #19387106 links to  free full text

Abstract: This manuscript provides a comprehensive review of the epidemiologic evidence linking the continuum of adiposity and type 2 diabetes (T2D) with Alzheimer's disease (AD). The mechanisms relating adiposity and T2D to AD may include hyperinsulinemia, advanced products of glycosylation, cerebrovascular disease, and products of adipose tissue metabolism. Elevated adiposity in middle age is related to a higher risk of AD but the data on this association in old age is conflicting. Several studies have shown that hyperinsulinemia, a consequence of higher adiposity and insulin resistance, is also related to a higher risk of AD. Hyperinsulinemia is a risk factor for T2D, and numerous studies have shown a relation of T2D with higher AD risk. The implication of these associations is that a large proportion of the world population may be at increased risk of AD given the trends for increasing prevalence of overweight, obesity, hyperinsulinemia, and T2D. However these associations may present a unique opportunity for prevention and treatment of AD. Several studies in the prevention and treatment of T2D are currently conducting, or have planned, cognition ancillary studies. In addition, clinical trials using insulin sensitizers in the treatment or prevention of AD are under way.

Chen JY, Youn E, Mooney SD. · Informatics and Technology Complex (IT), Indiana University School of Informatics, IUPUI, Indianapolis, IN, USA. · Methods Mol Biol. · Pubmed #19381537 No free full text.

Abstract: Understanding how mutations lead to changes in protein function and/or protein interaction is critical to understanding the molecular causes of clinical phenotypes. In this method, we present a path toward integration of protein interaction data and mutation data and then demonstrate the identification of a subset of proteins and interactions that are important to a particular disease. We then build a statistical model of disease mutations in this disease-associated subset of proteins, and visualize these results. Using Alzheimer's disease (AD) as case implementation, we find that we are able to identify a subset of proteins involved in AD and discriminate disease-associated mutations from SNPs in these proteins with 83% accuracy. As the molecular causes of disease become more understood, models such as these will be useful for identifying candidate variants most likely to be causative.

Wisniewski T. · New York University School of Medicine, Millhauser Laboratory, New York, NY 10016, USA. · CNS Neurol Disord Drug Targets. · Pubmed #19355935 No free full text.

This publication has no abstract.

Perry DP. · Chairman, ACT-AD Coalition, Washington, DC, USA. · Alzheimers Dement. · Pubmed #19328455 No free full text.

Abstract: The aging of the baby boom generation continues to put more Americans at increased risk for Alzheimer's disease (AD). The need for meaningful treatment options to fight the destruction caused by AD has never been greater. This article highlights the pivotal role that the U.S. Food and Drug Administration will play in making the review of emerging AD therapies a national priority and ways that various stakeholders are engaging with regulators to meet the challenges posed by the growing AD epidemic.

Petanceska S, Ryan L, Silverberg N, Buckholtz N. · Division of Neuroscience, National Institute on Aging, National Institutes of Health, Bethesda, MD, USA. · Alzheimers Dement. · Pubmed #19328442 No free full text.

This publication has no abstract.

Fick DM, Kolanowski A, Beattie E, McCrow J. · School of Nursing, The Pennsylvania State University, University Park, PA 16802, USA. · J Gerontol Nurs. · Pubmed #19326827 No free full text.

Abstract: Delirium is a disorder of acute onset with fluctuating symptoms and is character ized by inattention, disorganized thinking and altered levels of consciousness. The risk for delirium is greatest in individual with dementia, and the incidence of both is increasing worldwide because of the aging of our population. Although s clinical trials have tested interventions f delirium prevention in individuals without dementia, little is known about the m anisms for the prevention of delirium i early-stage Alzheimer's disease (AD). Th purpose of this article is to explore ways o preventing delirium and slowing the ra of cognitive decline in early-stage AD enhancing cognitive reserve. An agenda for future research on interventions to prevent delirium in individuals with early-stage AD is also presented.

Ghosh AK. · Departments of Chemistry and Medicinal Chemistry, Purdue University, West Lafayette, Indiana 47907, USA. · J Med Chem. · Pubmed #19323561 No free full text.

This publication has no abstract.

Abernethy AP, Farrell TW. · Duke Cancer Care Research Program, Duke University, Durham, North Carolina, USA. · J Pain Palliat Care Pharmacother. · Pubmed #19296357 No free full text.

Abstract: Timely and important studies are reviewed and commentaries provided by leading palliative care clinicians. Symptoms, interventions, and treatment-related adverse events addressed in this issue are management of Alzheimer's agitation with donepezil; needle-free lidocaine powder for minor painful procedures; psychostimulants in depression; anticoagulation for cancer-related venous thromboembolism; effect of waiting for acute pain treatment on risk of chronic pain; and an update on severe cutaneous reactions associated with medications.

Li H, Wolfe MS, Selkoe DJ. · Biology Department, Brookhaven National Laboratory, Upton, NY 11973-5000, USA. · Structure. · Pubmed #19278647 No free full text.

Abstract: Gamma-Secretase is an intramembrane protease complex that mediates the Notch signaling pathway and the production of amyloid beta-proteins. As such, this enzyme has emerged as an important target for development of novel therapeutics for Alzheimer disease and cancer. Great progress has been made in the identification and characterization of the membrane complex and its biological functions. One major challenge now is to illuminate the structure of this fascinating and important protease at atomic resolution. Here, we review recent progress on biochemical and biophysical probing of the structure of the four-component complex and discuss obstacles and potential pathways toward elucidating its detailed structure.

Williamson J, Goldman J, Marder KS. · Taub Institute for Research on Alzheimer Disease and the Aging Brain and the Gertrude H. Sergievsky Center, College of Physicians and Surgeons, Columbia University, Department of Neurology, New York, NY 10032, USA. · Neurologist. · Pubmed #19276785 No free full text.

Abstract: BACKGROUND: Alzheimer disease (AD) is a genetically complex disorder. Mutations in 3 genes, presenilin 1, amyloid precursor protein, and presenilin 2, lead to early-onset familial AD in rare families with onset of disease occurring prior to age 65. Specific polymorphisms in apolipoprotein E are associated with the more common, late-onset AD occurring after age 65. In this review, we discuss current advances in AD genetics, the implications of the known AD genes, presenilin 1, presenilin 2, amyloid precursor protein, and apolipoprotein E, and other possible genes on the clinical diagnosis, treatment, and genetic counseling of patients and families with early- and late-onset AD. REVIEW SUMMARY: In addition to the mutations in 4 known genes associated with AD, mutations in other genes may be implicated in the pathogenesis of the disease. Most recently, 2 different research groups have reported genetic association between 2 genes, sortilin-related receptor and GAB2, and AD. These associations have not changed the diagnostic and medical management of AD. CONCLUSIONS: New research in the genetics of AD have implicated novel genes as having a role in the disease, but these findings have not been replicated nor have specific disease causing mutations been identified. To date, clinical genetic testing is limited to familial early-onset disease for symptomatic individuals and asymptomatic relatives and, although not recommended, amyloid precursor protein apolipoprotein E testing as an adjunct to diagnosis of symptomatic individuals.

Tan ZS, Vasan RS. · Division of Aging, Brigham and Women's Hospital, Boston, MA 02160, USA. · J Alzheimers Dis. · Pubmed #19276542 No free full text.

Abstract: Thyroid dysfunction has been implicated as a cause of reversible cognitive impairment and as such, the thyroid stimulating hormone has long been part of the screening laboratory test for dementia. Recently, several population-based studies demonstrated an association between hypo- or hyperthyroidism and Alzheimer's disease. This review discusses the role of thyroid hormone in the normal development and regulation of central nervous system functions and summarizes the studies that have linked thyroid function and dementia risk. Finally, it explores possible biological mechanisms to explain this association, including the direct effects of thyroid hormone on cerebral amyloid processing, neurodegeneration and thyrotropin-mediated mechanisms and vascular mediated enhancement of Alzheimer's disease risk.

Lovell MA. · Department of Chemistry and Sanders-Brown Center on Aging, University of Kentucky, Lexington, KY, USA. · J Alzheimers Dis. · Pubmed #19276540 No free full text.

Abstract: Although multiple studies have suggested a role for alterations of zinc (Zn) and zinc transport (ZnT) proteins in the pathogenesis of Alzheimer's disease, the exact role of this essential trace element in the progression of the disease remains unclear. The following review discusses the normal role of Zn and ZnT proteins in brain and the potential effects of their alteration in the pathogenesis of Alzheimer's disease, particularly in the processing of the amyloid-beta protein precursor and amyloid-beta peptide generation and aggregation.

Wilcock DM, Colton CA. · Duke University Medical Center, Division of Neurology, Research Dr, Durham, NC 27710, USA. · CNS Neurol Disord Drug Targets. · Pubmed #19275636 links to  free full text

Abstract: Alzheimer's disease (AD) is a progressive, neurodegenerative disorder that results in severe cognitive decline. Amyloid plaques are a principal pathology found in AD and are composed of aggregated amyloid-beta (Abeta) peptides. According to the amyloid hypothesis, Abeta peptides initiate the other pathologies characteristic for AD including cognitive deficits. Immunotherapy against Abeta is a potential therapeutic for the treatment of humans with AD. While anti-Abeta immunotherapy has been shown to reduce amyloid burden in both mouse models and in humans, immunotherapy also exacerbates vascular pathologies. Cerebral amyloid angiopathy (CAA), that is, the accumulation of amyloid in the cerebrovasculature, is increased with immunotherapy in humans with AD and in mouse models of amyloid deposition. CAA persists in the brains of clinical trial patients that show removal of parenchymal amyloid. Mouse model studies also show that immunotherapy results in multiple small bleeds in the brain, termed microhemorrhages. The neurovascular unit is a term used to describe the cerebrovasculature and its associated cells-astrocytes, neurons, pericytes and microglia. CAA affects brain perfusion and there is now evidence that the neurovascular unit is affected in AD when CAA is present. Understanding the type of damage to the neurovascular unit caused by CAA in AD and the underlying cause of microhemorrhage after immunotherapy is essential to the success of therapeutic vaccines as a treatment for AD.

Golde TE, Das P, Levites Y. · Mayo Clinic, College of Medicine, Department of Neuroscience, Mayo Clinic Florida, 4500 San Pablo Rd., Jacksonville, FL 32224, USA. · CNS Neurol Disord Drug Targets. · Pubmed #19275635 No free full text.

Abstract: There is substantial and compelling evidence that aggregation and accumulation of amyloid beta protein (Abeta) plays a pivotal role in the development of Alzheimer's disease (AD); thus, numerous strategies to prevent Abeta aggregation and accumulation or to facilitate removal of preexisting deposits of Abeta are being evaluated as ways to treat or prevent AD. Pre-clinical studies in mice demonstrate the therapeutic potential of altering Abeta deposition by inducing a humoral immune response to fibrillar Abeta42 (fAbeta42) or passively administering anti-Abeta antibodies (Abs), and both passive and active anti-Abeta immunotherapeutic approaches are now being tested in humans. Although a variety of mechanisms have been postulated regarding how Abeta immunotherapy might work to attenuate or in some circumstances clear Abeta from the brain, no mechanism has been definitively proven or disproven. Herein, we will review the various mechanisms that have been postulated. In addition we will discuss how a more thorough understanding of the pharmacokinetics of anti-Abeta Abs and their effects on Abeta levels and turnover provides insight into both the therapeutic potential and limitation of Abeta immunotherapy. We will conclude with a discussion of additional experimentation required to better understand the mechanism of action of anti-Abeta Abs in AD and optimize antibody (Ab) mediated therapy for AD.

Deane R, Bell RD, Sagare A, Zlokovic BV. · Center for Neurodegenerative and Vascular Brain Disorders, University of Rochester Medical Center, 601 Elmwood Avenue, Rochester, NY 14642, USA. · CNS Neurol Disord Drug Targets. · Pubmed #19275634 No free full text.

Abstract: The main receptors for amyloid-beta peptide (Abeta) transport across the blood-brain barrier (BBB) from brain to blood and blood to brain are low-density lipoprotein receptor related protein-1 (LRP1) and receptor for advanced glycation end products (RAGE), respectively. In normal human plasma a soluble form of LRP1 (sLRP1) is a major endogenous brain Abeta 'sinker' that sequesters some 70 to 90 % of plasma Abeta peptides. In Alzheimer's disease (AD), the levels of sLRP1 and its capacity to bind Abeta are reduced which increases free Abeta fraction in plasma. This in turn may increase brain Abeta burden through decreased Abeta efflux and/or increased Abeta influx across the BBB. In Abeta immunotherapy, anti-Abeta antibody sequestration of plasma Abeta enhances the peripheral Abeta 'sink action'. However, in contrast to endogenous sLRP1 which does not penetrate the BBB, some anti-Abeta antibodies may slowly enter the brain which reduces the effectiveness of their sink action and may contribute to neuroinflammation and intracerebral hemorrhage. Anti-Abeta antibody/Abeta immune complexes are rapidly cleared from brain to blood via FcRn (neonatal Fc receptor) across the BBB. In a mouse model of AD, restoring plasma sLRP1 with recombinant LRP-IV cluster reduces brain Abeta burden and improves functional changes in cerebral blood flow (CBF) and behavioral responses, without causing neuroinflammation and/or hemorrhage. The C-terminal sequence of Abeta is required for its direct interaction with sLRP and LRP-IV cluster which is completely blocked by the receptor-associated protein (RAP) that does not directly bind Abeta. Therapies to increase LRP1 expression or reduce RAGE activity at the BBB and/or restore the peripheral Abeta 'sink' action, hold potential to reduce brain Abeta and inflammation, and improve CBF and functional recovery in AD models, and by extension in AD patients.

Morgan D. · Department of Molecular Pharmacology and Physiology, University of South Florida, Tampa, FL 33612, USA. · CNS Neurol Disord Drug Targets. · Pubmed #19275633 No free full text.

Abstract: Immunotherapy has emerged as a leading new approach to the reduction of amyloid deposits in the brains of Alzheimer patients. At least 4 distinct actions of anti-Abeta antibodies have been proposed as contributing to the inhibition of amyloid deposition and its clearance. Critically, each of these proposed mechanisms may be acting simultaneously, and it is feasible that different antibodies may utilize each mechanism to a different extent. One of these proposed mechanisms involves the activation of microglia and the phagocytosis of Abeta peptide. In general this is assumed to proceed through the Fcgamma-receptor binding by antibody opsonized Abeta aggregates, however modifying the microglial phenotype into one with a greater propensity for phagocytosing Abeta is also feasible, as microglia avidly phagocytose Abeta in vitro without antibody present. Evidence is presented supporting arguments that microglial activation does play a role in amyloid removal, particularly compacted amyloid deposits, under certain conditions. In addition to the specific antibody used, other considerations in comparing different reports of antibody action in APP mice include the age of the mice, the extent of pre-existing amyloid when therapy is initiated, the time point when the effects of the therapy are examined and the route of antibody administration. Future questions will consider the source of the activated microglia near the plaques after antibody administration (resident or peripheral) and the extent to which shifts in the microglial phenotype mediate some of the amyloid lowering actions of immunotherapy.

Henry RG, Smith BJ. · Department of Dental Services (160), Veterans Affairs Medical Center, Cooper Dr. Division, Lexington, KY 40502, USA. · Dent Clin North Am. · Pubmed #19269397 No free full text.

Abstract: Neurologic diseases represent some of the most common disabling and costly conditions in older age. Alzheimer disease and cerebrovascular accidents (strokes) are two of the most common neurologic conditions, and represent the leading causes of nursing home placement. Dental professionals will be caring for older patients who have age-associated neurologic diseases, including Alzheimer disease and stroke because of the increased longevity of the United States population coupled with improved survivorship of these conditions as a result of advanced medical diagnosis and treatment. Understanding the clinical manifestations of these two common, but distinctly different, neurologic conditions will enable dental professionals to provide safe and rational dental care.

Fotuhi M, Mohassel P, Yaffe K. · Center for Memory and Brain Health, LifeBridge Health Brain & Spine Institute, Sinai Hospital of Baltimore, Baltimore, MD 21209, USA. · Nat Clin Pract Neurol. · Pubmed #19262590 No free full text.

Abstract: Long-chain omega-3 fatty acids could have neuroprotective properties against dementia, which is becoming a major global public health issue. We conducted a systematic review of the literature to establish the association between eating fish (a source of long-chain omega-3 fatty acids) or taking long-chain omega-3 fatty acid supplements and the risk of cognitive decline or Alzheimer disease (AD). We identified eleven observational studies and four clinical trials. All three observational studies that used cognitive decline as an outcome reported significant benefits, whereas only four of eight observational studies that used incidence of AD or dementia as an outcome reported positive findings. None of four small clinical trials provided convincing evidence for the use of this approach in the prevention or treatment of any form of dementia. In summary, the existing data favor a role for long-chain omega-3 fatty acids in slowing cognitive decline in elderly individuals without dementia, but not for the prevention or treatment of dementia (including AD). This apparent dichotomy might reflect differences in study designs with regard to participants, dosages, the ratio of long-chain omega-3 to omega-6 fatty acids, or the choice of outcome measurements. Large clinical trials of extended duration should help to provide definitive answers.

Zawia NH, Lahiri DK, Cardozo-Pelaez F. · Department of Biomedical and Pharmaceutical Sciences, University of Rhode Island, Kingston, RI 02881, USA. · Free Radic Biol Med. · Pubmed #19245828 No free full text.

Abstract: Alzheimer disease (AD) is a progressive neurodegenerative disorder whose clinical manifestations appear in old age. The sporadic nature of 90% of AD cases, the differential susceptibility to and course of the illness, as well as the late age onset of the disease suggest that epigenetic and environmental components play a role in the etiology of late-onset AD. Animal exposure studies demonstrated that AD may begin early in life and may involve an interplay between the environment, epigenetics, and oxidative stress. Early life exposure of rodents and primates to the xenobiotic metal lead (Pb) enhanced the expression of genes associated with AD, repressed the expression of others, and increased the burden of oxidative DNA damage in the aged brain. Epigenetic mechanisms that control gene expression and promote the accumulation of oxidative DNA damage are mediated through alterations in the methylation or oxidation of CpG dinucleotides. We found that environmental influences occurring during brain development inhibit DNA-methyltransferases, thus hypomethylating promoters of genes associated with AD such as the beta-amyloid precursor protein (APP). This early life imprint was sustained and triggered later in life to increase the levels of APP and amyloid-beta (Abeta). Increased Abeta levels promoted the production of reactive oxygen species, which damage DNA and accelerate neurodegenerative events. Whereas AD-associated genes were overexpressed late in life, others were repressed, suggesting that these early life perturbations result in hypomethylation as well as hypermethylation of genes. The hypermethylated genes are rendered susceptible to Abeta-enhanced oxidative DNA damage because methylcytosines restrict repair of adjacent hydroxyguanosines. Although the conditions leading to early life hypo- or hypermethylation of specific genes are not known, these changes can have an impact on gene expression and imprint susceptibility to oxidative DNA damage in the aged brain.

Desilets AR, Gickas JJ, Dunican KC. · Massachusetts College of Pharmacy and Health Sciences-Worcester/Manchester, MA, USA. · Ann Pharmacother. · Pubmed #19240260 No free full text.

Abstract: OBJECTIVE: To review the role of huperzine A in the treatment of Alzheimer's disease (AD). DATA SOURCES: A literature search was conducted through MEDLINE (1950-September week 2, 2008), EMBASE (all years), Google Scholar, International Pharmaceutical Abstracts, and a bibliographic review of relevant articles. Key words included huperzine, huperin, Huperzia serrata, and Alzheimer's disease. STUDY SELECTION AND DATA EXTRACTION: All clinical trials published in the English language that evaluated huperzine A in patients with AD were included in this review. Articles published in Chinese were included when English abstracts or electronic translation technology were available. DATA SYNTHESIS: AD is a progressive neurodegenerative brain disorder for which there is no cure; available therapies only decrease cognitive decline. Huperzine A, an alkaloid derived from Chinese club moss (H. serrata), acts as a selective inhibitor of acetylcholinesterase and may also display neuroprotective properties. Preliminary data suggest that huperzine A may improve cognition; studies ranging from 8 to 12 weeks have found improvements in the Mini-Mental State Examination score of 1-5 points. CONCLUSIONS: Although use of huperzine A has shown promising results in patients with AD, data supporting its use are limited by weak study design. Largescale, randomized, placebo-controlled trials are necessary to establish the role of huperzine A in the treatment of AD.