Jeffrey L. Cummings|Richard Isaacson|Frederick A. Schmitt|Drew M. Velting
A practical algorithm for managing Alzheimer's disease: what, when, and why?
Lou Ruvo Brain Institute|Cleveland Clinic|Cornell University|University of Kentucky|Novartis (United States)
annals clinical translational neurologyvolume 2 issue 3 p 307323 reviewopen access practical algorithm managing alzheimers disease jeffrey l cummings corresponding author jeffrey l cummings cleveland clinic lou ruvo center brain health las vegas nevada cleveland ohio correspondence jeffrey l cummings cleveland clinic lou ruvo center brain health 888 w bonneville las vegas nevada 89106 tel 1 702 483 6029 fax 1 702 483 6028 email cumminjccforgsearch papers authorrichard isaacson richard isaacson weill cornell medical college new york new yorksearch papers authorfrederick schmitt frederick schmitt sandersbrown center aging university kentucky medical center lexington kentuckysearch papers authordrew velting drew velting novartis pharmaceuticals corporation east hanover new jerseysearch papers author jeffrey l cummings corresponding author jeffrey l cummings cleveland clinic lou ruvo center brain health las vegas nevada cleveland ohio correspondence jeffrey l cummings cleveland clinic lou ruvo center brain health 888 w bonneville las vegas nevada 89106 tel 1 702 483 6029 fax 1 702 483 6028 email cumminjccforgsearch papers authorrichard isaacson richard isaacson weill cornell medical college new york new yorksearch papers authorfrederick schmitt frederick schmitt sandersbrown center aging university kentucky medical center lexington kentuckysearch papers authordrew velting drew velting novartis pharmaceuticals corporation east hanover new jerseysearch papers author first published 23 january 2015 httpsdoiorg101002acn3166citations 47aboutsectionspdf toolsrequest permissionexport citationadd favoritestrack citation shareshare give accessshare full text accessshare fulltext accessplease review terms conditions use check box share fulltext version articlei read accept wiley online library terms conditions useshareable linkuse link share fulltext version article friends colleagues learn morecopy url share linkshare onfacebooktwitterlinked inredditwechat abstract alzheimers disease ad common form dementia prevalence increasing recent developments ad management provide improved ways supporting patients caregivers throughout disease continuum managing cardiovascular risk factors maintaining active lifestyle regular physical mental social activity following mediterranean diet appear reduce ad risk may slow cognitive decline pharmacologic therapy ad initiated upon diagnosis currently available cholinesterase inhibitors cheis donepezil galantamine rivastigmine indicated mildtomoderate ad donepezil 10 23 mgday rivastigmine transdermal patch 133 mg24 h indicated moderatetosevere ad memantine nmethyldaspartate receptor antagonist approved moderatetosevere ad cheis shown improve cognitive function global clinical status patients ability perform activities daily living also evidence reduction emergence behavioral symptoms chei therapy treatment choice eg oral vs transdermal based patient caregiver preference ease use tolerability cost treatment individualized patients switched one chei another initial agent poorly tolerated ineffective memantine may introduced moderatetosevere disease stages clinicians regularly monitor symptoms behaviors manage comorbidities assess function educate help caregivers access information support evaluate patients fitness drive firearms provide advice need legal financial planning review caregiver wellbeing prompt referral support vital introduction alzheimers disease ad common form dementia accounting 6080 cases1 united states one nine people aged 65 years ad twothirds women one person develops ad every 67 sec1 alzheimers disease international estimates prevalence ad increase 225 2050 affecting 115 million people globally2 138 million people united states1 ad associated initial memory loss followed impairments cognitive function language visuospatial skills executive function coupled behavioral changes3 terminally patients may become bedridden incontinent unable communicate4 ad imposes intolerable burden healthcare systems society patients families one leading contributors disability among elderly people5 patients require assistance activities daily living adl many eventually require fulltime care supervision2 4 caring patient ad stressful especially patient displays neuropsychiatric symptoms irritability dysphoria delusions6 clinicians play key role medical management ad provide recommendations advice patients familiescaregivers broad range issues including psychosocial problems legal financial resources7 specialists involved ad diagnosis management include neurologists geriatricians geriatric psychiatrists therapeutic nihilism disbelief efficacy clinical value therapy key issue dementia management particularly among clinicians due negative associations stigma associated progressive illness8 perceptions overcome may delay diagnosis referral treatment8 review provides recommendations managing ad based current knowledge available pharmacologic agents support patients families caregivers also discussed early recognition difficult decisions around endstage care goal approach maximize quality life throughout course complex disease data sources include pivotal clinical studies donepezil galantamine rivastigmine memantine medical foods identified using pubmed 2014 relevant united states prescribing information englishlanguage articles considered relevance primary care physicians relation ad diagnosis management included previous guidelines management recommendations reviewed recent metaanalysis brain health activities alzheimers disease international key document9 general brain health wellness modifying risk factors cognitive dysfunction potential risk factors protective factors cognitive dysfunction reasonable recommend modifying based available evidence recommendations maintaining brain health adults without ad summarized box 1 box 1 recommendations maintaining brain health elderly patients without ad consider following mediterraneanstyle diet fish vegetables legumes fruit cereals unsaturated fatty acids eg olive oil limited amount meat dairy products consider taking supplements containing omega3 particularly docosahexaenoic acid bcomplex vitamins including b12 b6 folic acid vitamin e keep alcohol intake lowtomoderate level eg one glass wine per day dinner engage regular physical activity maintain leisure social activities keep socially engaged continue take activities help stimulate brain eg tai chi dancing puzzles become educated ad seek support others ad eg alzheimers association alzheimers foundation america keep memory alive community groups include music daily life listening music playing instrument singing maintain regular sleep patterns manage stress stop things becoming stressful eg volunteer work answering telephone keep regular daily schedule include relaxing activities eg playing pets massage aromatherapy observational studies point protective role certain nutrients dietary patterns mediterranean diet however data randomized controlled trials inconsistent whether factors cooking processes dietary components explain inconsistencies uncertain potential mechanisms certain nutrients may protect brain health also remain established10 longterm studies relationship physical activity incidence noncommunicable diseases general limited however available studies indicate physical activity healthy people important factor preventing development cognitive impairment ad11 depression associated cognitive decline12 supporting management depressive symptoms elderly clinical rationale actively manage hyperlipidemia diabetes13 untreated hypertension associated rapid decline cognitive function vulnerable individuals14 family history ad risk factor disorder family members encouraged adopt brainhealthy lifestyle lifestyle considerations patients ad despite evidence omega3 fatty acids slow cognitive decline elderly findings patients ad inconsistent1517 one trial reported benefits omega3 fatty acid lipoic acid treatment cognition adl performance16 however due small sample sizes studies required16 folic acid vitamin b supplements may help preserve brain function18 small doubleblind randomized controlled trial reported folic acid supplementation may improve response cholinesterase inhibitor chei therapy19 time institutionalization daily living functioning improved following vitamin e supplementation20 21 interventions benefitrisk ratio supplements considered recent metaanalysis concluded high blood levels docosahexaenoic acid eicosapentaenoic acid possibly associated increased risks highgrade prostate cancer22 findings interpreted caution due multifactorial etiology prostate cancer complex metabolism longchain omega3 fatty acids22 dementia symptoms stressful patients caregivers families2326 patients believe nothing done illness likely experience depression27 clinicians educate patients steps take preserve function box 1 learning ad seeking support early disease course help reduce stress improve coping healthrelated behaviors28 artistic pursuits may help maintain sense identity selfexpression improve aspects behavior enhance communication2931 music therapy reportedly improves language functions patients dementia32 symptoms anxiety depression patients mildtomoderate ad33 interactions pets may reduce agitation anxiety patients dementia34 patients caregivers also reduce stress adjusting activities suit patients abilities keeping regular daily routine includes relaxing activities35 clinicians urge patients ad participate leisure activities possible preserving function quality life23 25 36 cognitive training may improve function patients encouraged learn new skills hobbies undertake activities stimulate mental activity12 37 social interactions may difficult patients ad may withdraw due selfconsciousness depression apathy23 25 participation specialized adult day programs patients dementia may enhance benefits drug therapy improve sleep quality keeping patient engaged reducing inactivity38 specialized memory rehabilitation programs patients ad also proven valuable39 widely available diagnosis clinical trials diagnostic statistical manual mental disorders 4th edition dsmiv criteria commonly used diagnose dementia alzheimers type40 recently updated version dsm5 published key updates change dementia newly named entity major neurocognitive disorder ncd recognition less severe level cognitive impairment termed mild ncd41 recent diagnostic guidelines national institute aging alzheimers association define three stages ad42 preclinical phase neuropathologic changes occur overt subtle symptoms phase mild cognitive impairment symptoms become apparent adl preserved patient dementia dementia phase adl impaired may preclinical neurologic changes form cerebrospinal fluid amyloid imaging biomarkers43 however ad diagnosis principally based clinical criteria fig 144 45 biomarkers used define ad probable underlying cause cognitive impairment strictly necessary diagnosis42 45 accuracy diagnosis enhanced integration biomarkers table 1 outlines recommended diagnostic steps46 table 1 steps diagnosis assessment patient suspected ad primary care46 step purpose toolsinformation required step 1 prediagnostic tests identify risks neurocognitive disorders risk factor assessment medical history laboratory tests identify risk factors define comorbidities early warning signs preclinical dementia step 2 assess performance cognitive assessment cognitive tests eg mmse126 minicog127 moca128 sib8129 informantrated tools eg ad8130 step 3 assess daily functioning determine level independence degree disability daily function assessment tool eg adcsadl131 step 4 assess behavioral symptoms determine presence degree behavioral symptoms behavioral assessment tool eg npiq132 assess potential causes behaviors eg drug toxicity medical psychiatric comorbidity step 5 identify caregiver assess needs identify primary caregiver assess adequacy family support systems identify caregivers establish collaboration assess health primary caregiver refer psychologist social worker healthcare resources needed considerations identify cultural differences language literacy level patient caregiver recognize differences illness interpretations caregiving patterns cultures aware preferred language recognize paperandpencil tests forms may work well patient caregiver literacylanguage barriers ad alzheimers disease ad8 8item ascertain dementia tool adcsadl alzheimers disease cooperative studyactivities daily living scale minicog mini cognitive assessment instrument mmse minimental state examination moca montreal cognitive assessment npiq neuropsychiatric inventory questionnaire sib8 severe impairment battery 8item reproduced permission american board family medicine figure 1open figure viewerpowerpoint diagnostic criteria ad45 permission reproduce text used figure kindly provided elsevier limited ad alzheimers disease csf cerebrospinal fluid mri magnetic resonance imaging pet positron emission tomography pharmacotherapy number food drug administration fdaapproved pharmacotherapies ad table 2 may improve symptoms delay decline none impact underlying neurodegenerative process47 important patients caregivers understand make informed treatment decisions realistic expectations regarding impact treatment48 table 2 food drug administrationapproved ad therapies b medical foods mechanism approvedintended indication administration route dosing frequency pharmacologic agents donepezil aricept49 chei mildtomoderate ad moderatetosevere ad po tablet titration initiate 5 mgday may increase 10 mgday 46 weeks severe ad may increase 23 mgday additional 3 months minimum maintenance mildtomoderate ad 5 10 mgday moderatetosevere ad 10 23 mgday daily galantamine razadyne50 chei mildtomoderate ad po tabletoral solution titration initiate 8 mgday increase 16 mgday 4 weeks minimum may increase 24 mgday additional 4 weeks minimum maintenance 16 24 mgday twice daily food galantamine er razadyne er50 chei mildtomoderate ad po capsule titration initiate 8 mgday increase 16 mgday 4 weeks minimum may increase 24 mgday additional 4 weeks minimum maintenance 16 24 mgday daily morning food rivastigmine exelon51 chei mildtomoderate ad mildtomoderate pdd po capsulesoral solution titration initiate 3 mgday tolerated may increase 6 mgday 9 12 mgday 2 weeks minimum previous dose 4 weeks pdd maintenance mildtomoderate ad 612 mgday mildtomoderate pdd 312 mgday twice daily rivastigmine patch exelon patch52 chei mildtomoderate ad severe ad mildtomoderate pdd td patch titration initiate 46 mg24 h 4 weeks minimum tolerated increase 95 mg24 h may increase 133 mg24 h additional 4 weeks minimum maintenance mildtomoderate ad 95 133 mg24 h severe ad 133 mg24 h mildtomoderate pdd 95 133 mg24 h apply new patch every 24 h memantine namenda66 nmda receptor antagonist moderatetosevere ad po tabletoral solution titration initiate 5 mgday increase 10 mgday 15 20 mgday 1 week minimum previous dose maintenance 20 mgday twice daily memantine namenda xr67 nmda receptor antagonist moderatetosevere ad po capsules titration initiate 7 mgday increase dose 14 21 28 mgday 1 week minimum previous dose maintenance 28 mgday daily b medical foods caprylidene axona72 medical food nutritionally supports brain metabolism mildtomoderate ad po powder added 48 oz liquid titration 810 gday 2 days increase dose 810 g every day tolerated maximum 40 gday maintenance 40 gday daily food lmethylfolatemethylcobalaminnacetylcysteine cerefolinnac triveencf nac73 medical food supports brains metabolic balance mild moderate cognitive impairment po caplet 1 capletday daily phosphatidylserinedocosahexaenoic acideicosapentaenoic acid vayacog medical food supports management lipid imbalances early memory impairment po capsule 1 capsuleday daily omega3 fatty acids uridine choline vitamins c e b6 b12 selenium folic acid souvenaid medical food supports synaptic integrity early ad po liquid 1 bottle 125 ml per day daily contrast fdaapproved drugs premarket review process exists medical foods data supporting effectiveness data exist undergone rigorous scientific scrutiny approved drugs ad alzheimers disease chei cholinesterase inhibitor er extended release nmda nmethyldaspartate pdd parkinsons disease dementia po per os oral administration td transdermal cheis three cheis donepezil aricept eisai inc woodcliff lake new jersey galantamine razadyne janssen pharmaceuticals inc titusville new jersey rivastigmine exelon capsules exelon patch novartis pharmaceuticals corporation east hanover new jersey indicated mildtomoderate ad united states donepezil rivastigmine transdermal patch also indicated severe ad4952 three cheis approved oral formulations4951 rivastigmine chei also approved delivery via transdermal patch52 approval highdose 23 mgday donepezil moderatetosevere ad based randomized clinical trial demonstrated greater cognitive efficacy versus standard dose 10 mgday53 highdose 133 mg24 h rivastigmine patch approved mildtomoderate severe ad based positive findings optima optimising transdermal exelon mildtomoderate alzheimers disease action activities daily living cognition studies respectively54 55 three cheis demonstrated clinical benefits cognitive function global clinical status5457 performance adl5456 58 proven clinically meaningful differences agents terms efficacy56 57 59 efficacy tolerability associated cheis dose dependent60 high doses may efficacious adverse events aes dose limiting agents similar tolerability profiles nausea vomiting diarrhea common aes56 gastrointestinal gi aes typically arise due peaks plasma drug concentrations61 strategies reduce dosing frequency lower peak plasma concentrations reduce rate peak concentrations reached may improve tolerability62 sustainedrelease formulation donepezil developed provide access high therapeutic doses avoiding rapid rises peak drug plasma concentrations53 donepezil 23 mgday associated greater cognitive benefits moderatetosevere ad donepezil 10 mgday ir however doserelated increase aes53 pharmacokinetic analysis predicted lower peaks plasma drug concentrations similar area curve extendedrelease er galantamine compared ir formulation63 clinical study oncedaily galantamine er twicedaily galantamine ir flexible dosing 16 24 mgday demonstrated superiority placebo cognition patients mildtomoderate ad similar incidence aes observed three groups64 providing sustained delivery 24h period transdermal delivery may improve gi tolerability permit easier access highdose efficacy compared oral dosing62 relative 6 mg twicedaily oral rivastigmine 95 mg24 h rivastigmine transdermal patch associated comparable efficacy twothirds fewer gi aes65 rivastigmine patch treatment initiated 46 mg24 h dose uptitration minimum effective dose 95 mg24 h patch least 4 weeks assuming good tolerability52 additional 4 weeks welltolerated dose may increased 133 mg24 h patch52 continued use 46 mg24 h dose considered patients weighing less 50 kg tolerability concerns patients mildtomoderate hepatic impairment52 transdermal delivery may associated application site reactions patients occurrence minimized following recommendations rivastigmine patch united states prescribing information52 include rotating application site applying patch clean dry hairless skin free redness irritation cuts burns ensuring skin free creams lotions powders prior patch application52 initiating chei treatment patients assessed 24 weeks development aes7 36 months effects cognitive function behaviorsabilities7 chei doses uptitrated according prescribing information table 24952 regular followup appointments established assess disease progression patients switched another chei develop intolerable nontransient aes respond initial agent ie continued deterioration pretreatment rate7 caregiver patient preferences change principle switching transition patient one chei another attempt improve clinical outcomes switching follow recommendations outlined relevant prescribing information4952 nmda receptor antagonist memantine namenda forest pharmaceuticals inc st louis missouri nmethyldaspartate nmda receptor antagonist indicated moderatetosevere ad table 266 67 clinical studies demonstrated efficacy memantine 20 mgday versus placebo cognition global function adl performance68 69 highdose 28 mgday oncedaily er formulation demonstrated cognitive efficacy acceptable tolerability profile compared placebo patients moderatetosevere ad receiving cheis70 memantine used monotherapy71 combination chei7 47 combining two agents different mechanisms action may improve efficacy relative singleagent therapy use memantine oral cheis may ameliorate cheirelated gi aes47 medical foods several medical foods available united states management ad andor cognitive impairment including caprylidene axona accera inc broomfield california proprietary formulation mediumchain triglycerides intended dietary management mildtomoderate ad72 cerefolin nac pamlab llc covington louisiana combination folic acid vitamin b12 nacetylcysteine intended dietary management mild cognitive impairment73 vayacog vaya pharma inc greenville south carolina combination phosphatidylserine docosahexaenoic acid eicosapentaenoic acid intended dietary management lipid imbalances associated early memory impairment74 noncarriers apolipoprotein 4 allele shown significant improvements cognitive function caprylidene75 currently limited published evidence support using folic acid vitamin b12 nacetylcysteine76 except setting hyperhomocysteinemia however older adults receiving folic acid supplementation 3 years plasma homocysteine levels reduced memory function improved compared placebo77 15week randomized doubleblind study reported phosphatidylserinecontaining omega3 fatty acids improved cognitive performance elderly memory complaints without dementia although studies required confirm findings78 souvenaid nutricia advanced medical nutrition schiphol netherlands combination omega3 fatty acids uridine choline vitamins c e b6 b12 selenium folic acid yet available united states souvenaid available europe food special medical purpose dietary means supporting synaptic integrity clinical trials patients mild ad combination demonstrated significant improvement delayed verbal memory79 80 global cognition79 performance adl81 single agent combination suit every patient clinicians construct comprehensive integrated multifaceted treatment plan reflects preferences patient caregiver recent scientific guidance clinicians prepared reassess approach achieve optimal therapeutic benefitoutcomes optimal duration chei treatment established patients clinical trials shown benefit 4 years82 continuing treatment long patients tolerate medication families support treatment reasonable maintaining open discussions family disease progression treatment outcomes may guide clinician regarding whether maintain treatment help family prepare eventual need longterm residential placement managing comorbidities one study 679 patients ad united states 61 3 medical comorbidities number increased advancing dementia severity83 controlling variables higher medical comorbidity associated worse cognitive function poorer selfcare83 data show patients ad 55 likely admitted hospital people without ad84 common medical comorbidities patients ad include cardiovascular disease thyroid dysfunction sleep apnea osteoporosis glaucoma cancer falls depression infections anorexia rheumatoid conditions incontinen