Alzheimers disease

Pharmacotherapy of Alzheimers disease

1. Pharmacotherapy of alzheimer’s disease Presenter: Dr. Roohana Hasan Moderator : Dr. Ali Ahmad

2. Overview Introduction History Epidemiology Etiology and Risk Factors Pathogenesis Amyloid Cascade Hypothesis Tau Hypothesis Cholinergic Hypothesis Genetic Mutations Diagnostic Evaluation Current Pharmacotherapy Recent Advances

3. introduction Alzheimer's disease (AD) is the most common neurodegenerative disease which has features of progressive impairments in memory, behaviour and cognition and can lead to death. In addition to the financial burden of AD on health care system, the disease has powerful emotional impact on caregivers and families of those afflicted.

4. history Alois Alzheimer, a German physician, is credited with being the first to describe AD. In 1901, Alzheimer observed a patient at the Frankfurt Asylum named  Auguste Deter. The 51-year-old patient had strange behavioral symptoms, including a loss of short-term memory; she became his obsession over the coming years. On 8 April 1906, Deter died, and Alzheimer had her medical records and brain brought to Munich where he was working in Kraepelin's laboratory. With two Italian physicians, he used the staining techniques of Bielschowsky to identify  amyloid  plaques and  neurofibrillary tangles. These brain anomalies would become identifiers of what later became known as Alzheimer's disease.

5. epidemiology Most common cause of dementia amongst people aged 65 and older Starting with 0.5% prevalence at 55 yrs, it goes on doubling every five years (60yrs-1%; 65yrs-2%; 70yrs- 4%; 75yrs- 8% and so on) Average prevalence of dementia in india : 3.7% At present nearly 47.5 million people worldwide with dementia. It is expected to be 74.7 million by 2030 and 131.5 million by 2050. A new case detected in every 3 seconds somewhere in world. (WHO) Neurol India. 2012 Nov-Dec;60(6):625-30. doi: 10.4103/0028-3886.105198.

6. Etiology and Risk factors Strong genetic component Gender – women, ? Estrogen Tobacco Head injury Obesity Hypertension diabetes Elevated serum cholesterol Elevated serum homocysteine Depression Lack of intellectual stimulation/education

7. THE STAGES OF ALZHEIMER’S DISEASE Mild Moderate Severe Memory Loss Language Problems Mood and Personality Changes Diminished Judgement Behavioral Personality Changes Unable to Learn or Recall New Information Long-Term Memory Affected Wandering Agitation Aggression Confusion Require Assistance with ADLs Unstable Gait Incontinence Motor Disturbances Bedridden Dysphagia Mute Poor/No ADLs

8. PATHOGENESIS AND PATHOPHYSIOLOGY Alzheimer’s disease is characterized by the loss of neurons and synapses in the cerebral cortex and certain subcortical regions. This loss results in gross atrophy of the affected regions , including degeneration in the temporal lobe and parietal lobe and parts of frontal cortex and cingulated gyrus .

9. The main pathological hallmarks of Alzheimer’s disease includes: extracellular deposition of ß- amyloid ( Aß ) plaques, intraneuronal neurofibrillary tangles. Loss of cortical cholinergic neurones in AD probably accounts for memory impairment.

10. Amyloid Cascade theory Alzheimer’s disease begins with the abnormal build-up of an amyloid protein in the brain from APP ( amyloid precursor protein). APP is normally found in the cell membranes of neurons and normally metabolised by a protease enzyme α- secretase . In AD, the metabolism of APP is altered by two other enzymes β and gamma- secretase and the product formed is called β amyloid ( Aβ ). Alzheimer’s disease begins with the abnormal build-up of an amyloid protein in the brain from APP ( amyloid precursor protein). APP is normally found in the cell membranes of neurons and normally metabolised by a protease enzyme α- secretase . In AD, the metabolism of APP is altered by two other enzymes β and gamma- secretase and the product formed is called β amyloid ( Aβ ).

11. A β1-42 is more prone to form insoluble aggregates (and therefore more toxic) than A β1-40. Once A β is formed, it accumulates into insoluble sheets (called β- pleated sheets). Ageing, seems to affect the balance between production and clearance of toxic Aβ peptides. Journal of Alzheimer’s Disease 33 (2013) S185 -S194 DOI 10.3233/JAD-2012-129028

12. These deposits are neurotoxic and activate inflammatory reaction resulting in the formation of senile or neuritic plaque. This is accompanied by hyperphosphorylation of tau protein, supporting the microtubules. Tau Hypothesis

13. Neurofibrillary tangles Neurons have an internal support structure partly made of Microtubules. A protein called Tau helps stabilizing microtubules. In AD, Tau changes causing microtubules collapse, and formation of paired helical filaments and then tau proteins clumps together to form Neurofibrillary Tangles.

14. Cholinergic hypothesis Cell loss in the nucleus basalis of Meynert results in a deficit in the production of choline acetyltransferase , leading to subsequent inability to synthesize acetylcholine at the synaptic endings. In response to the reduced AChE activity, the activity of another cholinesterase enzyme, butyrylcholinesterase ( BuChE ), increases and the disease progresses. it becomes the main metabolising enzyme for acetylcholine, until the neurone is completely destroyed.

15. Genetic mutations Further research, particularly in the genetic domain, led to identification of APP and Presenilin genes (APP, PSEN1, and PSEN2) and mutations in these genes as cause of rare forms of early-onset familial AD. On other hand, e2 and ε4 allele of apolipoprotein E gene (APOE) has been recognized as a major risk factor for late-onset AD. Chromosome 21, which codes for APP, was first evaluated for an association with AD when Down's syndrome patients with the trisomy 21 aberration were observed to develop dementia in the fourth decade.

16. excitotoxicity Glutamate is found in the neural pathways associated with learning and memory. Abnormal levels of glutamate may be responsible for neuronal cell dysfunction and the eventual cell death and subsequent cognitive impairment observed in AD. Excessive influx of calcium into the cells leading to cell death called excitotoxicity . Also lead to excessive production of Aβ and tau phosphorylation .

17. there is growing evidence for the role of additional factors in the pathogenesis of AD. Oxidative stress Neuroinflammation Mitochondrial dysfunction

18. The main goals of treatment Symptomatic improvement, consist of enhanced cognition, more autonomy & improvement in neuropsychiatric & behavioural dysfunction Disease modification with slowing or arrest of symptom progression of the dementing process Primary prevention of disease by intervention in key pathogenic mechanisms at a pre-symptomatic stage

19. Current Treatment

20. Tacrine Tacrine was first synthesised in Melbourne in 1949 and has been used after anaesthesia and in combination with morphine because of its analeptic properties. An influential study published in 1994 led to tacrine's approval in the U.S.A. for use in mild to moderate Alzheimer's disease. Tacrine is a cholinesterase inhibitor that increases the availability of acetylcholine in muscarinic neurons.

21. Mechanism of Action   the drug is an anticholinesterase agent which reversibly binds with and inactivates cholinesterases . This inhibits the hydrolysis of acetylcholine released from functioning cholinergic neurons, thus leading to an accumulation of acetylcholine at cholinergic synapses. The result is a prolonged effect of acetylcholine.

22. Absorption- Tacrine is rapidly absorbed. Absolute bioavailability of tacrine is approximately 17%. Volume of distribution- 349 ± 193 L Protein binding-55% Metabolism-Hepatic. Cytochrome P450 1A2 is the principal isozyme involved in tacrine metabolism. The major metabolite, 1-hydroxy-tacrine ( velnacrine ), has central cholinergic activity. Half life- 2 to 4 hours Pharmacokinetics

23. Side Effects Nausea and/or vomiting   Diarrhoea Dizziness Anorexia Myalgia Dyspepsia Rhinitis Abdominal pain Rash Less common adverse effects include: Weight loss  Flatulence Constipation  Fatigue,  Ataxia Insomnia Tremor  Anxiety  Blood dyscrasias (very rare)

24. donepezil Donepezil (Aricept), a piperidine -based AchE inhibitor, was released on the market in 1996. This is a cerebroselective and reversible anti- AChE drug. Mechanism of action Donepezil binds and reversibly inactivates the cholinesterases , thus inhibiting hydrolysis of acetylcholine. This results in an increased acetylcholine concentrations at cholinergic synapses. In addition to its actions as an acetylcholinesterase inhibitor, donepezil has been found to act as a potent agonist of the σ 1  receptor ( K i  = 14.6 nM ), and has been shown to produce specific  antiamnestic  effects in animals mainly via this action.

25. pharmacokinetics Absorption- Donepezil is well absorbed with a relative oral bioavailability of 100% and reaches peak plasma concentrations in 3 to 4 hours. Volume of distribution-12 L/kg Protein binding-96% Metabolism- Donepezil is metabolized by CYP 450 isoenzymes 2D6 and 3A4 in the liver and also undergoes glucuronidation . Route of elimination- Renal Half life-70 hours

26. Side effects Nausea Vomiting Dirrhoea Fatigue Headache Insomnia Cramping Hallucination syncope Postmarketing reports Abdominal pain, agitation, aggression, cholecystitis , convulsions, heart block (all types), hemolytic anemia, hepatitis, hyponatremia , neuroleptic malignant syndrome, pancreatitis, rash, rhabdomyolysis , QTc prolongation, Stevens Johnson syndrome toxic epidermal necrolysis and torsade de pointes

27. rivastigmine Rivastigmine is a parasympathomimetic or cholinergic agent for the treatment of mild to moderate dementia of the Alzheimer's type. Rivastigmine is a cholinesterase inhibitor that inhibits both butyrylcholinesterase and acetylcholinesterase . The carbamyl residue introduced by rivastigmine into AChE molecule dissociates slowly resulting in inhibition of cerebral AChE for upto 10 hours despite the 2 hr plasma t½ of the drug.

28. pharmacokinetics Volume of distribution-1.8 to 2.7 L/kg Protein binding-40% Metabolism- Rivastigmine is rapidly metabolized by cholinesterase-mediated hydrolysis. Route of elimination- Rivastigmine is extensively metabolized primarily via cholinesterase-mediated hydrolysis to the decarbamylated metabolite NAP226-90. Renal excretion of the metabolites is the major route of elimination. Less than 1% of the administered dose is excreted in the feces. Half life-1.5 hours

29. Side effects Nausea Vomiting Dizziness Diarrhea Headache Anorexia Abdominal pain Decreased weight Insomnia Anxiety Asthenia Vertigo Fatigue Postmarketing Reports Cardiac Disorders: Tachycardia Hepatobiliary Disorders: Abnormal liver function tests, hepatitis Nervous System Disorders: Seizure Psychiatric Disorders: Aggression, nightmares Skin and Subcutaneous Tissue Disorders: Allergic dermatitis, application site hypersensitivity (patch), blister, disseminated allergic dermatitis, Stevens-Johnson syndrome, urticaria

30. galantamine A benzazepine derived from norbelladine . It is found in galanthus and other amaryllidaceae . Reversible selective inhibitor cerebral AChE which prevents hydrolysis of acetylcholine leading to increased concentration of acetylcholine at cholinergic synapses. Galantamine also binds allosterically with nicotinic acetylcholine receptors and may possibly potentiate the action of agonists (such as acetylcholine) at these receptors.

31. Pharmacokinetics Half-Life: 7 hr Peak Plasma Time: 1 hr Bioavailability: 90% Protein Bound: 18% Vd : 175 L Metabolism: CYP2D6 & CYP3A4 Excretion: Urine

32. Side effects Nausea Diarrhea Vomiting Abdominal pain Anorexia Muscle cramp Fatigue Dizziness Headache Weight loss Depression Insomnia UTI Somnolence Anemia Syncope Bradycardia Complete atrioventricular block

33. Huperzine A Alkaloid isolated from the Chinese herb Huperzia serrata AChE inhibitor used since 1994 in China. A recent meta-analysis found that huperzine A 300–500 g daily for 8–24 weeks in Alzheimer’s disease led to significant improvements in MMSE and ADL. Wang BS et al. J Neural Transm 2009; 116:457–465.

34. Dimbolin

35. Piracetam This cyclic GABA derivative has no GABAlike activity and has been called ‘ nootropic ’ meaning a drug that selectively improves efficiency of higher telencephalic integrative activities. Piracetam is not a vasodilator, does not affect total/regional CBF, but may reduce blood viscosity. In India and some other countries it has been promoted for cognitive impairment and dementia in the elderly as well as for mental retardation in children for over 30 years. Side effects are minor: gastric discomfort, nervousness, excitement, insomnia, dizziness and skin rash.

36. Pyritinol ( Pyrithioxine ) - Pyritinol consists of two pyridoxine molecules joined through a disulfide bridge, but has no vit B6 activity. It is claimed to activate cerebral metabolism by selectively increasing glucose transport across blood-brain barrier and improving regional blood flow in ischaemic brain areas. It has been promoted for: Sequelae of cerebrovascular accidents, head injury, prolonged anaesthesia . Infants and children with developmental disorders of CNS, delayed milestones. Concentration and memory defects, senility, organic brain syndromes.

37. Dihydroergotoxine ( Codergocrine ): It is a semisynthetic ergot alkaloid having α adrenergic blocking property; claimed to increase cerebral blood flow selectively. It is believed to act by protecting altered brain metabolism. Side effects: flushing, headache, nasal congestion, postural hypotension, g.i . disturbances and rashes. Piribedil : It is a dopaminergic agonist claimed to improve memory, concentration, vigilance, giddiness and tinnitus in the elderly due to circulatory insufficiency, but benefit is unsubstantiated. Minor efficacy in parkinsonism has also been reported. Side effects are mild g.i . complaints.

38. Citicoline -It is a compound derived from choline and cytidine , that is involved in biosynthesis of lecithin. Citicoline is believed to improve cerebral function by increasing blood flow to the brain and enhancing cerebral metabolism. Ginkgo biloba - The dried extract of this Chinese plant contains a mixture of ginkgoflavon glycosides (e.g. ginkgolide B) which have PAF antagonistic action. Since PAF has been implicated in cerebral thrombosis and infarcts, it is professed that G. biloba will prevent cerebral impairment in cerebrovascular insufficiency. It has been promoted for a variety of cognitive and behavioural disorders in the elderly.

39. Formation of plaques and neurofibrillary tangles in Alzheimer’s disease, and sites of action of future drug treatments

40. Gamma - SECRETASE INHIBITORS/ modulators BMS-299897 MRK-560. LY450139 dehydrate A β- aggregation inhibitors The neurotoxic effect of Aβ has been documented on numerous occasions and thus decreasing its neurotoxicity or inhibiting its aggregation may have therapeutic potentials. The first drug was a β-sheet breaker iAβ5p , which showed that intrahippocampal injection of it resulted in improved spatial memory and decreased amyloid plaque deposits. Tramiprosate (3APS, Alzhemed ) is a compound that binds to soluble Aβ and inhibits the formation of neurotoxic aggregates that lead to amyloid plaque deposition in the brain. Semagacestat Avagacestat

41. Since α- secretase and β- secretase compete for the same substrate of APP, upregulation of α- secretase activity may decrease the amount of APP available for β- secretase , and thus decrease Aβ secretion and have therapeutic potential. Many studies had indicated that members of the adamalysin family of proteins, mainly ADAM 10, ADAM 17 and ADAM 9, fulfill some of the criteria required of α- secretase . Deprenyl , a neuroprotective agent used to slow AD progress, was shown to increase α- secretase activity by promoting ADAM10 and PKCα /ε translocation. α- secretase activators/modulators

42. Ab Degarading Enzymes Recent studies have indicated that Aβ peptide could be degraded by a kind of protease called Aβ degrading enzyme, rather than being cleared from the vascular system by the so-called “vascular pathway”. There is a kinetic equilibrium between Aβ production, degradation and transportation within the brain and transport out of the brain. The following proteinases have the abilities of degradating Aβ peptide: neprilysin (NEP), insulin degrading enzyme (IDE), plasmin , endothelin converting enzyme (ECE) 1 and 2 and angiotensin -converting enzyme (ACE). All these proteinase can degrade the Aβ peptide at different amino acid residues within the Aβ sequence

43. Imatinib , a tyrosine kinase inhibitor, was shown to elevate AICD in H4 human neuroglioma cells, and this was accompanied by concomitant increases of NEP protein, mRNA levels, and activity. Valproic acid: Valproic acid is a histone deacetylase (HDAC) inhibitor. A widely used drug in the treatment of epilepsy, was capable of up-regulating NEP expression, seen in experimental rats. Estrogen and green tea - could increase NEP activity and suggest their potential in AD treatment but there is a long way before their final clinical application. Hong-Qi et al. Translational Neurodegeneration 2012, 1:21

44. M1 muscarinic agonists M1 muscarinic receptors play a role in an apparent linkage of three major hallmarks of AD: Aβ peptide; tau hyperphosphorylation and loss of cholinergic function conductive to cognitive impairments . It can regulate secretase activities. Activation of M1 mAChRs with these agonists leads to enhanced secretion of sAPPα , (via α- secretase activation), to decreased Aβ (via γ- secretase inhibition), and the inhibition of Aβ - and/or oxidative stress-induced cell death. Talsaclidine is a functionally selective muscarinic M1 agonist that stimulates non- amyloidogenic α- secretase processing in vitro.

45. ACTIVE IMMUNIZATION Induces an IgM response to generate antibodies against pathogenic Aβ , which further mobilize microglia to clean plaques through phagocytosis AN 1792 – PHASE 2 - The trial was interrupted due to the occurrence of meningoencephalitis in 6% of subjects. CAD106 - PHASE 1 -Able to reduce Aβ accumulation in cortical and subcortical brain regions Bioorg Med Chem Lett 2011; 21 : 2655-8. S, Jacobson LH, et al.. J Neurosci 2011; 31 : 9323-31.

46. PASSIVE IMMUNISATION Intravenous administration of full monoclonal antibodies or antibody fragments which directly target Aβ . BAPINEUZUMAB Undergoing phase 3 studies. Researchers reported that it failed to protect against cognitive and functional decline of AD patients undergoing a phase 3 trial. SOLANEZUMAB Phase 3 trials failed to demonstrate clinical benefits. But In a study conducted in Japan with AD patients associated with increased clearance of Aβ from the brain. PONEZUMAB Targets the amino-terminal portion of Aβ1-40 Phase 2 studies did not confirm clinical efficacy. The European Federation of Neurological Societies annual 23. meeting, in Stokholm , Sweden; 2012. Clin Neuropharmacol 2013; 36 : 14-23.

47. Apolipoprotein E ( ApoE ) Apolipoprotein E ( ApoE ) promotes A β clearance The ApoE activates microglia and/or astrocyte to degrade A β. It decreased brain amyloid plaque burden and improved behaviour functions in AD transgenic mice. Bexarotene is a nuclear receptor modulator and ApoE activator, whether it is effective in AD prevention needs to be explored clinically.

48. Drugs influencing Aβ blood–brain barrier transport The receptor for advanced glycation end products (RAGE) resides in the blood vessel wall cells and transport Aβ across the blood brain barrier from systemic circulation to facilitate their accumulation in brain. In contrast to RAGE, low-density lipoprotein receptor-related protein-1 (LRP-1) mediates transport of Aβ peptide out of brain. In AD patients the RAGE is elevated while the LRP-1 is lowered. Inhibition of RAGE- ligand interaction suppresses accumulation of Aβ in brain parenchyma in a mouse transgenic model. Thus inhibition of RAGE and/or activation of LRP-1 may be a therapeutic target for AD, but there are no clinical data available at present.

49. Drugs development based on the metals hypothesis There is increasing evidence that metal (mainly Cu, Zn and Fe) metabolism is involved in the major phthophysiological events of AD: APP processing and tau hyperphosphorylation . Several chelators of Zn/Cu have been shown to inhibit Aβ aggregation in vitro and in vivo. A phase II clinical trial with clioquinol , a metal-protein-attenuating compound that inhibits zinc and copper ions from binding to Aβ , led to improved cognitive function, decreased plasma Aβ42 level and zinc concentration. Other metal chelators are XH1, DP-109, PBT2 , Aβ42 and PBT2

50. HMG- CoA reductase inhibitors (the “ statins ”) β- and γ- secretase enzymes found predominantly in the cholesterol rich micro domains of the cell membrane Risk factors for AD - dyslipidaemia , coronary artery and cerebrovascular disease. Statins are widely prescribed for their cholesterol lowering ability In experimental models of AD, statins reduce the production of Aβ by disrupting secretase enzyme function Epidemiological studies suggest that statins may reduce the incidence of AD. Clinical trial with atorvastatin provides some clinical benefit in AD patients. Treatment with lovastatin resulted in decreased plasma Aβ level.

51. Monoamine oxidase inhibitors MAO inhibitor deprenyl is an anti-Parkinson drug used to inhibit dopamine degradation in the brain. Also as a neuroprotective agent, deprenyl has been used to slow the progress of neurodegenerative diseases such as AD for many years. Another MAO-B inhibitor rasagiline is a bifunctional molecule which also has acetylcholinesterase inhibition activity. Ladostigil is a dual acetylcholinebutyrylcholineesterase and brain selective MAO-A and -B inhibitor in vivo which was shown to antagonize scopolamine-induced impairment in spatial memory

52. Tau is a microtubule-associated protein normally present in neurons. In AD, hyperphosphorylated tau forms the paired helical filaments (PHF). This process severely impairs axonal transport. Treatments based on tau pathology

53. Prevention of phosphorylation of tau Cyclin -dependent kinase-5 (CDK5) is a kinase suggested to phosphorylate tau in AD. Glycogen synthase kinase (GSK)-3β has also been suggested as a drug target to inhibit tangle formation. Lithium , a mood stabiliser or for augmenting antidepressive therapy; it inhibits tau phosphorylation with beneficial effects in animal models. The M1 muscarinic agonist AF267B has been shown to inhibit GSK-3β activity and reduce tau pathology in transgenic mice. Two additional inhibitors of tau hyperphosphorylation that have shown modest effect in transgenic mouse models are propentofylline (PPF) and SRN-003- 556.

54. Prevention of the aggregation of tau Recent studies using cell models have demonstrated that certain drug inhibitors are able to prevent tau protein aggregation and even dissolve the developed aggregates, which include phenothiazines , anthraquinones , polyphenols , thiacarbocyanine dyes, N- phenylamines , thiazolyl-hydrazides , rhodanines , quinoxalines , aminothienopyridazines Although these initial findings are promising, studies in vivo are still needed to demonstrate efficacy and safety of tau aggregate inhibitors.

55. Prevent the misfolding of tau Increasing activation of molecular chaperones might prevent the misfolding of tau, which would then reduce the development of NFTs. Heat shock proteins have been shown to activate chaperones that prevent misfolding and even promote tau binding with microtubules

56. Non-steroidal anti-inflammatory drugs (NSAIDs) Many epidemiological studies, have suggested that the prolonged intake of NSAIDs may be associated with a reduced incidence of AD. Estrogens Estrogens are neuroprotective against oxidative stress, excitatory neurotoxicity, and ischemia in the brain. Studis shown that estradiol administration significantly ameliorates the neurodegeneration characteristic of AD in experimental rat model. This may be attributed to its powerful antioxidant, antiapoptotic , neurotrophic as well as its antiamyloidogenic activities. Merlo et al. reported that estrogen can activate matrix metalloproteinases-2 and −9 to increase beta amyloid degradation.

57. Nicotine Nicotine is a cholinergic agonist that acts both postsynaptically and pre- synaptically to release acetylcholine, which is an alkaloid derived from the leaves of tobacco plants ( Nicotiana tabacum and Nicotiana rustica ). Significant improvements were reported in several cognitive tasks such as free recall, visual attention and perception and in mood although not on memory

58. Melatonin Melatonin (N-acetyl-5-methoxytryptamine) is a tryptophan metabolite, synthesized mainly by the pineal gland. In AD patients, melatonin supplementation has been suggested to improve circadian rhythmicity , and to produce beneficial effects on memory. Melatonin also inhibits the aggregation of the amyloid beta protein into neurotoxic microaggregates . Recent report has indicated that melatonin can alter lipid levels of mitochondrial membranes induced by amyloid beta protein. Melatonin has been shown to prevent the hyperphosphorylation of the tau protein in rats.

59. Cell transplantation and gene therapy In AD rat model, transplantation of cholinergic-rich tissue or peripheral cholinergic neurons ameliorates abnormal behavior and cognitive function. But no clinical trials in AD patients have been initiated with this method. Lack of endogenous nerve growth factor (NGF) can lead to memory deficits, whereas NGF administration rescues neurons from injury-induced cell damage and leads to associated memory improvements and thus NGF is good for gene therapy.

60. Docosa-hexaenoic acid (DHA) Epidemiological studies suggest that increased intake of the omega-3(n-3) polyunsaturated fatty acid DHA is associated with a reduced risk for AD . DHA is the most abundant omega 3 fatty acid in the brain. Resveratrol Resveratrol , a red wine polyphenol , is known to protect against cardiovascular diseases and cancers, as well as to promote anti-aging effects in numerous organisms. Some recent studies on red wine bioactive compounds suggest that resveratrol modulates multiple mechanisms of AD pathology. It has been recently suggested that resveratrol can be effective in slowing down AD development.

61. β- Sheet Breakers Tjernberg's peptide (KLVFF) and Soto's peptide (LPFFD), also known as β- sheet breaker peptides. Vitamin E Cerebrolysin Omega 3 Fatty acid

62. Indian Medicinal Plants for Alzheimer’s disease / Memory improvements Brahmi ( Bacopa Monnieri ) Haldi ( Curcumin ) Amla ( Phyllanthus Emblica ) Guduchi ( Tinospora Cordifolia ) Tulsi ( Ocimum Sanctum) Ashwagandha ( Withania somnifera ) Shankhapushpi (Convolvulus pluricaulis ) Haritaki ( Terminalia chebula )

63. Conclusions Cholinergic agents initially improve and transiently maintain cognitive abilities in patients with mild-to-moderate AD. Cognitive abilities worsen over time, indicating treatment does not stop (but may delay) the progression of AD. New treatments that maintain cognitive ability and stop the progression of AD are needed .

64. ,mnbvc5