This document provides an overview of the pharmacotherapy of Alzheimer's disease. It discusses the history and pathogenesis of the disease, focusing on the amyloid cascade hypothesis, tau hypothesis, and cholinergic hypothesis. It describes the stages of the disease and current understanding of risk factors and genetic factors. It then summarizes the current pharmacotherapy approaches, including cholinesterase inhibitors like tacrine, donepezil, and rivastigmine, which work by increasing acetylcholine levels in the brain. It discusses their mechanisms of action, pharmacokinetics, efficacy, and side effect profiles.

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.

10. 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.

11. • 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).

12. • AΒ1-42 IS MORE PRONE TO FORM
INSOLUBLE AGGREGATES (AND
THEREFORE MORE TOXIC) THAN AΒ1-
40.
• ONCE AΒ 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

13. • 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

14. 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.

16. 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.

17. 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.

18. 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.

19. THERE IS GROWING EVIDENCE FOR THE ROLE OF
ADDITIONAL FACTORS IN THE PATHOGENESIS OF AD.
 OXIDATIVE STRESS
 NEUROINFLAMMATION
 MITOCHONDRIAL DYSFUNCTION

25. • 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

27. Current Treatment

28. • 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.

29. • 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.

30. • 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

31. 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)

32. • 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 Σ1 RECEPTOR (KI = 14.6 NM), AND HAS
BEEN SHOWN TO PRODUCE SPECIFIC ANTIAMNESTIC EFFECTS IN ANIMALS MAINLY VIA THIS
ACTION.

33. 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

34. • 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

35. 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.

36. • 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

37. • 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

38. 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.

39. • HALF-LIFE: 7 HR
• PEAK PLASMA TIME: 1 HR
• BIOAVAILABILITY: 90%
• PROTEIN BOUND: 18%
• VD: 175 L
• METABOLISM: CYP2D6 & CYP3A4
• EXCRETION: URINE

40. • NAUSEA
• DIARRHEA
• VOMITING
• ABDOMINAL PAIN
• ANOREXIA
• MUSCLE CRAMP
• FATIGUE
• DIZZINESS
• HEADACHE
• WEIGHT LOSS
• DEPRESSION
• INSOMNIA
• UTI
• SOMNOLENCE
• ANEMIA
• SYNCOPE
• BRADYCARDIA
• COMPLETE ATRIOVENTRICULAR BLOCK

41. 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.

43. Dimbolin

44. 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.

45. • 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.

46. • 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.

47. • 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.

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

52. GAMMA-SECRETASE INHIBITORS/ MODULATORS
• BMS-299897
• MRK-560.
• LY450139 DEHYDRATE
AΒ-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

53. • 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

54. • 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

55. • 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

56. 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.

57. 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.

58. 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.

59. APOLIPOPROTEIN E (APOE)
 APOLIPOPROTEIN E (APOE) PROMOTES AΒ CLEARANCE
 THE APOE ACTIVATES MICROGLIA AND/OR ASTROCYTE TO DEGRADE AΒ.
 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.

60. 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.

61. • 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

62. • 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.

63. • 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-AAND -B INHIBITOR IN VIVO WHICH WAS SHOWN TO
ANTAGONIZE SCOPOLAMINE-INDUCED IMPAIRMENT IN SPATIAL MEMORY

64. • 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

65. • 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.

66. 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.

67. • 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

68. 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.

69. 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

70. 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.

71. 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.

72. 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.

73. 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

74. 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)

75. • 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 .