Pathophysiology and management of alzheimer's disease

Definition, epidemiology, etiology, risk factors, pathophysiology, diagnosis and management of Alzheimer's disease

1. ALZHEIMER’S DISEASE
T.SOUJANYA
16DC1T0021
PHARM.D

2. DEFINITION:
Alzheimer’sdisease(AD)isaneurodegenerativedisorder,characterizedby
cognitive&behaviouralimpairmentthatsignificantlyinterfereswithsocial&
occupationalfunctioning.
Alzheimer’sdiseaseisalsoknownasseniledementiaoftheAlzheimertype
(SDAT)orsimplyAlzheimer’s,themostcommonformofdementia.Itisanincurable,
degenerative,terminaldisease.
ADresultsfromanincreaseintheproductionoraccumulationofspecificprotein
(β-amyloidprotein)inthebrainthatleadstonervecelldeath.

3. EPIDEMIOLOGY:
➢Accordingto2015report,ADaffects5.3millionpeopleinUS.
➢ADwasthe6
th
leadingcauseofdeathin2015.
➢ADandotherdementiasaremorelikelycommoninAfricanAmericans,thanin
whites.
➢AccordingtotheWHO’sreviewin2000,onthe“globalburdenofdementia”:
approximateratesofdementiaareunder1%inpersonsaged60-69yearsand39%
inpersonsaged90-95years,prevalencedoubleswithevery5yearsofage(within
theaboveranges).

4. ETIOLOGY:
TheexactetiologyofAlzheimer’sdiseaseisnotknownandassociatedwithrisk
factors.Butstatedthatthereareseveralgeneticalandenvironmentalfactorshave
beenexploredaspotentialcausesoftheAlzheimer’sdisease.
Otherfactorsinclude:
1.Advancingage
2.Familyhistory
3.Trauma
4.Education
5.Vasculardiseaselikestrokeetc.

5. RISK FACTORS:
Thecommon riskfactorsfor
developingAlzheimer’sdiseaseare:
➢Increasedage(over65yearsofage)
➢Hypertension(highbloodpressure)
➢Increasedcholesterollevels
➢Coronaryarterydisease
➢Diabetes
Otherriskfactorsare:
➢Genetics
➢Smokingandalcoholuse
➢Plasmahomocysteine
➢Downsyndrome
➢Mildcognitiveimpairment

6. PATHOPHYSIOLOGY:
Thebrainhasbillionsofneurons,eachwithanaxonandmanydendrites.Tostay
healthy,neuronsmustcommunicatewitheachother,carryoutmetabolismand
repairthemselves.ADdisruptsallthreeoftheseessentialjobs.
TherearetwosignaturelesionsinAlzheimer’sdisease.Theyare:
1.Neuriticplaques/β-amyloidplaques,whicharedensedepositsofproteinand
cellularmaterialthataccumulateoutsideandaroundnervecells.
2.Neurofibrillarytangles(NFT’s),whicharetwistedfibersthatbuildupinsidethe
nervecell.

7. 1. NEURITIC PLAQUES:
Depositsofaproteinfragmentcalledβ-amyloid,thataccumulatesinthespaces
betweenthenervecells(neurons).
APP(amyloidprecursorprotein)istheprecursorofamyloidplaque.
a)APPsticksthroughtheneuronmembrane.
b)Enzymeslikeβ-secretaseandα-secretasecuttheAPPintofragmentsofprotein
(neurotoxicAβ
42fragment),includingβ-amyloid.
c)β-amyloidfragmentscometogetherinclumpstoformplaques.
InAD,manyoftheseclumpsform,disruptingtheworkofneurons.Thisaffectsthe
hippocampusandotherareasofthecerebralcortex.

8. APP (amyloid precursor protein)
Cleaved by β-secretase and α-secretase
Mutation of amyloid precursor protein on chromosome no. 21
Increased production of amyloid precursor protein
Produces of amyloid protein
Accumulation of β-amyloid protein
(due to increased production of APP)
Directly neurotoxin
Alzheimer’s disease

9. 2. NEUROFIBRILLARY TANGLES (NFT’S):
Neuronshaveaninternalsupportstructure
partlymadeupofmicrotubules.Aproteincalled
“tau”helpstostabilizemicrotubules.InAD,“tau”
changes,causingmicrotubulestocollapseand
“tau”proteinsclumptogethertoform
neurofibrillarytangles.

10. CONTD…
Although autopsy studies show that most people develop
some plaques & tangles as they age
Those with AD tend to develop them far more & in a predictable pattern
They develop in the areas important for memory
before spreading to other regions
Plaques & tangles disable/block communication among neurons
Gradually spread to other areas of brain
Causes symptoms of Alzheimer’s disease

11. SYMPTOMS:
ThesymptomsofADareclassifiedas:
1.Cognitivesymptoms
2.Noncognitivesymptoms
3.Functionalsymptoms

12. CONTD…
1.Cognitivesymptoms:
▪Memoryloss(poorrecallandlosing
items)
▪Aphasia(circumlocutionandanomia)
▪Apraxia,agnosia,
▪Disorientation(impairedperceptionof
timeandunabletorecognizefamiliar
people)
▪Impairedexecutivefunction.
2.Noncognitivesymptoms:
▪Depression, psychotic symptoms
(hallucinationanddelusions).
▪Behaviouraldisturbances(physicaland
verbalaggression,motorhyperactivity,
uncooperativeness,wandering,repetitive
mannerisms and activitiesand
combativeness).
3.Functionalsymptoms:
▪Inabilitytocareforself(dressing,bathing,
eatingetc.)

13. CLINICAL MANIFESTATIONS/STAGES OF
ALZHEIMER’S DISEASE (AD):
ADcanbedividedinto5stages:
1.Pre-clinicalAD
2.MildAD
3.ModerateAD
4.SevereAD
5.End-stageAD

14. CONTD…
1.Pre-clinicalAD:
▪Patientmayappearnormalonphysicalexamination&mentalstatustesting.
▪Specificregionsofbrain(entorhinalcortex,hippocampus)arelikelytobeaffected,
decadesbeforeantsigns/symptomsappear.
2.MildAD:Signsinclude:
▪Memoryloss,confusionaboutlocationoffamiliarplaces,takinglongertimeto
accomplishnormal,dailytasks(troubleinhandlingmoney&payingbills).
▪Compromisedjudgement,oftenleadingtobaddecisions.
▪Lossofspontaneity&senseofinitiative.
▪Mood&personalitychanges(increasedanxiety).

15. CONTD…
3.ModerateAD:Signsinclude:
▪Increasedmemoryloss,increasedconfusion,shortenedattentionspan.
▪Problemsrecognizingfriends&familymembers,difficultyinlanguage,problems
withreading,writing,workingwithnumbers.
▪Difficultyorganizingthoughtsandinlogicalthinking.
▪Inabilitytolearnnewthings/tocopewithnew/unexpectedsituations.
▪Restlessness,agitation,anxiety,tearfulness,hallucinations,delusions,irritability.
▪Lossofimpulsecontrol.
▪Perceptual-motorproblems(e.g.troublegettingoutofachair/settingthetable).

16. CONTD…
4.SevereAD:Signsinclude:
▪PatientwithsevereADcan’trecognizethefamily/lovedones.
▪Can’tcommunicateeffectively,completelydependonothersforcare.
▪Allsenseofselfseemstovanish.
▪Othersymptomsincludeweightloss,seizures,skininfections,dysphagia,groaning,
moaning/grunting,increasedsleepinglackofbladder&bowelcontrol.
5.End-stageAD:
▪Duringend-stageAD,patientsareinbedallofthetime.
▪Deathusuallyoccursdoetootherillness,notablyaspirationpneumonia.

17. DIAGNOSIS:
Theseinclude;
1.Bloodstudies
2.BrainMRI/CT-scan
3.SPECT(SinglePositronEmissionComputerizedTomography)/PET(Positron
EmissionTomography)
4.Lumbarpuncture
5.Genotyping
6.Electroencephalography

18. MANAGEMENT OF AD:
Goalsoftherapy:
1.Tomaintainpatient’sbrainfunctionasfaraspossible.
2.Totreatpatient’spsychiatricandbehavioursequelae.
3.Todeceleratethelikelihoodofprogressionintocomplications.
4.Tofocusonemotional&supportivecarefortheconcernedpatient.
5.Toreducemorbidity&mortalityasfaraspossible.
6.Toimprovequalityoflife.

19. PHARMACOLOGICAL TREATMENT:
1.Cholinesteraseinhibitors:
MOA:
Thesedrugsselectivelyinhibitacetylcholinesterase,theenzymeresponsiblefor
thedestructionofacetylcholine.Thus,acetylcholinegetsaccumulated(improves
Achavailability)andproducescholinergiceffects.
Acetyl CoA + Choline
Choline acetyl transferase
Acetyl choline (Ach)
Acetyl cholinesterase
Choline + Acetate
Cholinesterase inhibitors
(e.g. donepezil, rivastigmine, galantamine)

20. CONTD…
ADRs:Adverseeffectsofanticholinesterasesincludeincreasedsweating,salivation,
nausea,vomiting,abdominalcramps,bradycardia,diarrhea,tremorsand
hypertension.
Uses:TheyaremainlyusedinthetreatmentofAlzheimer’sdisease,myasthenia
gravis,belladonnapoisoning,curarepoisoning,post-operativeurinaryretentionand
paralyticileus.
Dose:
▪Donepezil:5-10mgOD(formild-moderateAD),10-20mg(formoderate-severeAD)
▪Rivastigmine:1.5mgPO,BD(initialdose),12mg/dayPO(Max.dose)
▪Galantamine:16-24mg/day(maintenancedose)

21. CONTD…
2.NMDAreceptorantagonists(Memantine):
MOA:
TheN-methyl-D-aspartatereceptor(alsoknownasNMDAreceptor)isaglutamate
receptorandionchannelproteinfoundinnervecells.TheNMDAreceptorisvery
importantincontrollingsynapticplasticityandmemoryfunction.NMDAtype
glutamatereceptorsmaybeoveractivatedinAD(glutamatergicexcitotoxicity).
MemantinebindspreferentiallytoNMDAreceptorandblocksit.Blockingusually
occursonlyunderconditionsofexcessivestimulationandnotunder
neurotransmission.

22. CONTD…
Memantine
Blocks
NMDA receptor (blocks glutamate)
Prevents too much calcium from moving into the brain cells
Reduces excessive stimulation
Reduces the symptoms of Alzheimer’s disease
▪ADRs:Hypertension,cataract,CVA,thromboembolismetc.
▪Uses:Itiscommonlyusedformoderate-severedementiainpatientswithAD.
▪Dose:Memantine:5mgOD(initialdose);20mg/day(Max.dose)

23. Patient diagnosed with AD according to NINCDS-ADRDA criteria
Assess all comorbid medical disorders and drug therapies that
may affect cognition
Rule out comorbid depression
Evaluate for pharmacotherapy based on illness stage
Moderate-severe AD
Cholinesterase inhibitor, memantine or
combination of cholinesterase inhibitor
and memantine
+
Vitamin E
Mild AD
Cholinesterase inhibitor or memantine
+
Vitamin E
Stable MMSE
(<4-point decline over 1 year)
Continue regimen above
Deteriorating MMSE
(≥4-point decline over 1 year)
Alternate from above + vitamin E
Treatment algorithm for Alzheimer’s disease