Alzheimer’s Disease (AD)

Alzheimer’s Dis eas e (AD) P HAR 8 3 5 : F ALL 2 0 2 4 N A D I A KH A R TAB I L , P H A R MD , B C G P , A P H , MA S 1 Alzheimer’s Dis eas e (AD) • It is an age- related neurodegenerative dis eas e. It is a gradually progres s ive dementia affecting cognition, behavior and functional s tatus . in • AD is the mos t common form of dementia, accounts for 60- 80% of dementias . • AD is the 6 th leading caus e of death in the US. • Exact pathophys iologic mechanis ms are not entirely known, and no cure exis ts . • Drugs may reduce s ymptoms , but AD is eventually fatal and have a profound effect on patient and family. 4 Epidemiology , Ris k factors • Ris k factors : Known Ris k Factors • Age • Genetics • Pres enilin 1 &2 Genetic mutation (in EOAD) earning a • Apolipoprotein E*4 allele (2- 3- fold onset higher ris k of LOAD, and EOAD) • Familial Alzheimer Dis eas e Potential Contributing Factors • Ons et can be as early as 30 years of age • Early ons et (before 65 yrs .) : EOAD • Late ons et ( after 65 yrs .) : LOAD © 2023 Alzheimer's Association® • • • • • • waeas e Cardiovas cular Dis Type 2 Diabetes Oxidative Damage Inflammation Traumatic Brain Injury Female Gender 6 Pathophys iology: atlowacetylcholine • Signature les ions in AD : goy beMutdorst • Amyloid plaques • Neurofibrillary tangles (NFTs ) • Accumulation of beta amyloid plaques and intraneuronal hyperphos phorylated tau tangles : 1) Leads to neurodegeneration with s ynaptic and neuronal los s with cortical atrophy • Several hypothes es were dis cus s ed regarding AD: • Amyloid Cas cade Hypothes is : • Extracellular les ions in brain and cerebral vas culature. • Imbalance between production and clearance of A B peptides caus ing accumulation. • Neurofibrillary Tangles : • Abnormal hyperphos phorylated tau protein affecting cell’s trans portation and s keletal s upport s ys tem. • Dens ity of tangles correlates to s everity of AD. • Inflammatory Mediators : • Due to amyloid depos ition • As s ociated with releas e of cytokines , nitrous oxide, injuring neurons . 2) NMDA receptor s ynaptic depres s ion • Cholinergic Hypothes is : 3) Synaptic failure and cholinergic s ys tem failure • Neuronal damage leads to neurotrans mitter deficits (mos t prominent cholinergic) • May be s econdary to AD cons equence. 8 Symptoms of AD Symptoms can be categorized into three categories : Cognitive • As Memory los s (poor recall and los ing items ), aphas ia (circumlocution and anomia), apraxia, agnos ia, dis orientation (impaired perception of time and unable to recognize familiar people) • Impaired executive function Neurops ychiatric ( Behavioral) • Depres s ion, ps ychotic s ymptoms (hallucinations and delus ions ), behavioral dis turbances (phys ical and verbal aggres s ion, motor hyperactivity, uncooperativenes s , wandering, repetitive manneris ms and activities , and combativenes s ) I Functional • Inability to care for s elf (dres s ing, bathing, toileting, and eating) 10 Clinical Features and Stages •According to NIA and AA*, AD is now s een as a progres s ion of a s pectrum of 3 phas es : • An early preclinical s tage with no s ymptoms ( 3 s tages ) • A middle s tage of mild cognitive impairment (MCI) • A final s tage marked by s ymptoms of dementia. • Mild AD: MMSE s core 26- 21 • Moderate AD : MMSE s core 20- 10 • Severe AD : MMSE s core 9- 0 Mid 2621 M 26 10 S 90 11 *NIA : National Ins titute on Aging. AA : Alzheimer’s As s ociation. Major Neurocognitive Dis order (NCD) A. Evidence of s ignificant cognitive decline from a previous level of performance in 1 cognitive domains bas ed on: IT oh 1. Concern of patient, informant, or clinician, and 2. Subs tantial impairment in cognitive performance (preferably documented by s tandard neurops ychological tes ting) was B. Deficits interfere with independence in everyday activities C. Deficits do not occur exclus ively in the context of a delirium I D. Deficits are not better explained by another mental dis order American Ps ychiatric As s ociation. (2013). Diagnos tic and s tatis tical manual of mental dis orders : DSM- 5. 13 Common Rating Scales – Diagnos tic Tools Tes t Items / Score Domains Mini- Mental Status Exam (MMSE) 19 items - 30 points 21- 26: Mild 10- 20: Moderate <10: Severe Multidimens ional Montreal Cognitive As s es s ment (MoCA) 11 items - 30 points 18- 25: Mild 10- 17: Moderate <10: Severe Multidimens ional St. Louis Univers ity Mental Status 3 (SLUMS) 11 items - 30 points 21- 26: Mild 0- 20: Dementia Orientation, memory, attention, executive function • Definitive diagnos is of AD is through direct examination of brain tis s ue at autops y or biops y. • AD biomarkers , CSF tes ting and brain imaging are becoming increas ingly available for definitive diagnos is . 14 AD Diagnos is A. Criteria met for major or mild NCD B. Ins idious ons et & gradual progres s ion of impairment in C. 2 cognitive domains Criteria met for either probable or pos s ible Alzheimer’s dis eas e: • Probable Alzheimer’s if either of following is pres ent, otherwis e pos s ible Alzheimer’s 1. Evidence of caus ative AD genetic mutation from FH or genetic tes ting 2. All 3 of the following are pres ent Clear e/ o decline in memory & learning + 1 other cognitive domain ii. Steadily progres s ive, gradual decline in cognition, w/ o extended plateaus iii. No e/ o mixed etiology i. D. Not better explained by cerebrovas cular dis eas e, another neurodegenerative dis eas e, s ubs tances , or another mental, neurological, or s ys temic dis order 15 American Ps ychiatric As s ociation. (2013). Diagnos tic and s tatis tical manual of mental dis orders : DSM- 5. Workup ( PPCP- collect) Laboratory Tes ts Other Diagnos tic Tes ts Rule out vitamin B12 and folate deficiency Computed tomography (CT) or magnetic res onance imaging (MRI) s cans may aid diagnos is Rule out hypothyroidis m with thyroid function tes ts Blood cell counts , s erum electrolytes , liver function tes ts 16 Can it be a drug related problem? Key drugs to look for that may wors en dementia* CNS depres s ants : ropioids , s edatives cogentin Central anticholinergic medications (benztropine) 3 Barbiturates phenobarbital'inembatall Anti- his tamine ( firs t generation as diphenhydramine) Antiemeticss(promethazine) uphenergen Eta Famotidinea (not renally adjus ted in older adults ) gotAnticholinergics a(oxybutynin, IBS drugs ) addBenzodiazepines 8 Antips ychotics *Rxprep. Chapter 70. 17 Goals of Treatment: Maximize functional s tatus Pres erve cognition Improve QOL Delay time to ins titutionalization Reduce caregiver burden In addition to goals in mild dis eas e, goal is to s everity and impact of behavioral and ps ychological s ymptoms of dementia (BPSD) 19 General Treatment Approach • Prior to initiation therapy, thorough medication review is neces s ary. • Many drugs can contribute to cognitive impairment that can caus e delirium and can be revers ible. Drugs that can contribute to cognitive impairment Anticholinergics (benztropine) Antihis tamines (diphenhydramine, doxylamine) Antiemetics (as promethazine) Antips ychotics (as chlorpromazine, aripiprazole) Barbiturates (phenobarbital, butalbital) Benzodiazepines and s edative hypnotics Other CNS depres s ants as opioids 20 A Pharmacotherapy for Cognitive Symptoms Clas s r Cholines teras e inhibitors Achinthebrain 2 NMDA receptor Name Donepezil (Aricept®) FDA indications Mild- moderate e Moderate- s evere Rivas tigmine (Exelon®) Galantamine (Razadyne®) Mild- moderate Mild- moderate Memantine (Namenda®) Moderate- s evere antagonis t Inhibitglutamate 3 Monoclonal Aducanumab (Aduhelm®) Mild antibody • Other medications with limited evidence: Vitamin E, gingko biloba, NSAIDs , Statins , Es trogen. 21 ATTE N DAN CE C ODE : 7 9 8 9 8 8 Cholines teras e Inhibitors • Cholinergic deficiency hypothes is . • Acetylcholines teras e (AChE) and butyrylcholines teras e enzymes convert ACh into choline. • Late- s tage dis eas e may not res pond as well due to neuron degeneration. • • • • AChEIs are the mains tay of treatment. • Three approved AChE Is by the FDA for AD : Donepezil, Rivas tigmine, Glantamine. • DOMINO- AD trial : higher mean dos e of AChEIs had delayed nurs ing home placement compared to lower mean dos e AchEIs patients . • • Monitor for both improvement and s ide effects . If there is no improvement or s ide effects are intolerable, drug can be d/ c. Mos t frequent advers e reactions : • Naus ea, vomiting, diarrhea, anorexia, weight los s ( Gradual dos e titration improve tolerability) • Peptic ulcer, GI bleed • Nightmares , ins omnia • Mus cle cramps Improvement : decline in MMSE < 2 points / year. Reas onable to change the AChEIs if decline is > 2- 4 points after 1 year of treatment. 23 Donepezil ( Aricept®) Indication Dos ing Mild, moderate, or s evere dementia Initial Dos e: 5mg PO Daily After 4- 6wks : to 10mg PO Daily After 3mo: to 23mg Patch: Once- weekly (Adlarity®) (s tore in fridge) Special Dos ing Cons iderations t 1/ 2: 70 hrs Metabolis m Precautions Gyo CYP2D6, CYP3A4, QTc prolongation glucuronidation drugs Tablets , ODT, s olution, and patch are interchangeable Strong CYP3A4 inhibitors 23mg tab cannot be s plit, crus hed, chewed Patients with HR <50 beats / min Take with or without food Patients < 55kg can have more naus ea and weight los s (adminis ter at night) Bradycardia is potential dos e- limiting AE Therapy interruption requires re- titration 24 2 Rivas tigmine (Exelon®) Indication Mild or moderate dementia Mild or moderate Parkins on’s dementia Dos ing Special Dos ing Cons iderations Initial Dos e: t 1/ 2: 1- 2 hrs Oral: 1.5mg PO BID Patch: 4.6mg/24hr Trans dermal Patch: Apply to clean, dry, hairles s s kin. Rotate After 4wks : Oral: may by 3mg s ites daily. Can us e while bathing but avoid daily to max exces s ive s unlight or 12mg/day external heat. Patch: may to Patch has les s GI SE. 13.3 mg/24hr Take with food, titrate s lowly due to GI s ide effects Metabolis m Renal/hepatic impairment, LBW (<50 kg): may only tolerate low dos es Precautions Hepatic impairment: max patch dos e =4.6 mg/24 hrs Interruption of therapy requires re- titration. If s kin reaction s us pected to drug, don’t res ume (ris k of SJ S reported) 25 3 Galantamine ( Razadyne, Razadyne ER) Indication Mild or moderate dementia Dos ing Special Dos ing Cons iderations Initial Dos e: - IR tab or s olution: 4mg PO BID - ER caps ule: 8mg PO daily t 1/ 2: 7 hrs Titrate: by 8mg/day q4weeks to max 24mg/day Take with food Benefit of 24mg/day vs . 16mg/day not obs erved in clinical trials Metabolis m/ Precautions CYP2D6, CYP3A4, Renal excretion Max dos e = 16 mg in moderate renal or hepatic impairment. 26 Not nomengtin Dorgpail already Memantine (Namenda®, Namzaric®) Indication Moderate, or s evere dementia Dis continuation not as s ociation with s ignificant wors ening of cognitive decline Combination (Memantine + Donepezil) : Namzaric® Dos ing Initial Dos e: - IR tab: 5mg po daily Special Dos ing Cons iderations CauseonDonapTt t 1/ 2: 60- 80 hrs Renal adj: If CrCL 5- 29ml/ min Titrate: may by 5mg/ day Renal excretion qweek, target dos e 10mg PO BID IR 10mg BID = XR 28mg (max 5mg bid if CrCl daily <30ml/ min) 7 mg/ 10 mg, taken once a day in the evening only ifpthas Dos e tapering depends on: 1- If patient is already on Donepezil. 2- CrCl Notes / Precautions Blocks glutamatergic by antagonizing NMDA receptors (Mitigates excitotoxic neurotoxicity) ADR : Dizzines s , confus ion, headache, cons tipation. urine pH may lead to an accumulation of memantine. 27 Memantine: • Dis continuation of Memantine is not as s ociated with s ignificant wors ening of cognitive decline. • Monitoring of therapy : • Cognitive function • Functional outcomes 28 Anti- amyloid Monoclonal Antibody • Four humanized, immunoglobulin G1 monoclonal antibodies have been des ignated as AD breakthrough therapies : • Aducanumab If thing whole • Lecanemab Instagram • Donanemab • Gantenerumab • Aducanumab and lecanemab received the accelerated approval for treatment of mild AD. • Donanemab- azbt (Kis unla®) was approved on J uly 2,2024 Alzheimer’s Res earch UK. https :/ / www.alzheimers res earchuk.org/ blog/ new- alzheimers - drug- donanemab- what- is - it- and- how- does - it- work/ 29 30 Aducanumab (Aduhelm®) Monoclonal expensive Infus ion # Dos age Notes Mechanis m 1 &2 1mg/ kg Infus ions every 4 weeks , and >21 days apart 3 &4 3mg/ kg 5 &6 6mg/ kg 7+ 10mg/ kg • Recombinant human immunoglobulin gamma 1 (IgG1) monoclonal antibody agains t amyloid beta Monitoring: • MRI: bas eline (within 1 year), prior to 7 th infus ion, prior to 12 th infus ion Warning and Precautions Maintenance: 10mg/ kg IV • Amyloid Related Imaging Abnormalities infus ion over 60 minutes (ARIA): Enhanced clinical vigilance firs t 8 every 4 weeks dos es • Hypers ens itivity reactions with angioedema and urticaria Cos t: $4,312 per infus ion Annual cos t: $56,000 for high dos e 31 Lecanemab ( Leqembi®) Infus ion # Dos age 10 mg/ kg once every 2 weeks Notes Mechanis m Monitoring: • MRI: prior to 5 th, 7 th, and 14 th infus ions • Sugges ted: 52 week (prior to the 26th infus ion) MRI, es pecially in APOE4 carriers or thos e with evidence of ARIA on earlier MRIs • Recombinant human immunoglobulin gamma 1 (IgG1) monoclonal antibody agains t amyloid beta Warning and Precautions • Amyloid Related Imaging Abnormalities (ARIA) • Infus ion reactions : flu- like s ymptoms , N/ V, hypotens ion Annual cos t: $26,500 32 Monitoring and management of pharmacological therapy for AD cognitive s ymptoms Medication Advers e reaction Monitoring Comment AChEIs Dizzines s , s yncope, bradycardia, atrial arrhythmias , s inoatrial and atrioventricular block, myocardial infarction Report of dizzines s or falls , puls e, bl ood pres s ure, and pos tural blood pres s ure change • N/ V, Diarrhea, Anorexia, weight los s Weight, GI complaints • • • Take with food Dos e related GI AE Patients with Low body weight at higher ris k of GI AE, weight los s ( ++ rivas tigmine or 23mg donepezil) Peptic ulcer dis eas e, GI bleeding Signs or s ymptoms of active or occul t GI bleeding • concern + patient with his tory of ulcer or taking NSAIDs Ins omnia, vivid/abnormal dreams , nightmares Complaints of s leep dis turbances , da ytime drows ines s Donepezil can be taken in the morning to dec reas e ris k of s leep dis turbances . Galantamine Severe s kin reactions (SJ S) Skin ins pection • • D/c at firs t s ign of ras h, Cons ider alternative treatment Memantine Headache, hallucination, dizzines s Reports of falls , hallucinations • Confus ion us ually trans ient, + dos e titration Cons tipation GI complaints • Might mitigate GI AE + AChEIs • Dizzines s is us ually mild, trans ient, and n ot related to cardiovas cular problems . Routine puls e checks at bas eline, monthl y during dos e titration and every 6 months after. 33 Monitoring and management of pharmacological therapy for AD cognitive s ymptoms Medication Advers e reaction Monitoring Comment Aducanumab Amyloid- related imaging abnormalities (ARIA) • MRI :at bas eline, and prior to 7 th, 1 2 th infus ion Or • If a patient experiences s ymptoms s ugges tive of ARIA to identify brain edema, microhemorrhage, s uperficial s ideros is • Symptoms of headache, confus ion, dizzines s , vis ual dis turbances and naus ea Vigilance for ARIA and foca l neurologic changes are recommended during the firs t 8 dos es , es pecially during dos e titration. Hypers ens itivity reactions Angioedema, urticaria (rare) D/ c infus ion at 1 s t s ign of hypers ens itivity Reaction. 34 Other Potential Treatment Options • Es trogen replacement • Evidence does not s upport us e of es trogen to treat/ prevent dementia • Anti- inflammatory agents • NSAIDs – no cognitive benefit in AD; ris ks exceed any benefit • Lipid lowering agents • More res earch needed to unders tand relations hip between choles terol, s tatins and cognitive function • Res erved for patients with compelling indication 35 Dietary Supplements • Vitamin E so • Polyphenols • Ins ufficient evidence to recommend vitamin E • Moderate inges tion of wine as s ociated with s upplementation lower incidence of AD • Res veratrol – propos ed benefits are • Ginkgo biloba prevention of oxidative s tres s and apoptos is • Clinical s ignificance of modes t benefits is mediated neurodegeneration unclear • Curcumin (turmeric) – may prevent/treat AD • No direct comparis ons to ChE- inhibitors or by decreas ing amyloid plaque formation, memantine clearing exis ting plaques and chelating • Huperazine A metal ions • Not adequately s tudied for us e in AD • Product potency and purity concerns • Omega- 3 fatty acids • Ins ufficient evidence to recommend 36 Treatment of Non- Cognitive Behavioral Symptoms • Patients with dementia ( =0- 40%) have s ignificant behavioral and ps ychiatric s ymptoms • Aggres s ion, agitation, anxiety, delus ions , depres s ion, hallucinations , s leep dis turbances , wandering, etc.. • Thes e neurops ychiatric s ymptoms can be categorized into 4 categories : 1. Ps ychotic 2. Hyperactive ( inappropriate or dis ruptive behavior) 3. Affective ( depres s ion) 4. Apathy 8 5 • There can be s o many factors contributing to the above s ymptoms , s o how can we manage them? 37 Treatment of Non- Cognitive Behavioral Symptoms : Behavioral and ps ychological s ymptoms of dementia (BPSD) As s es s • Rule out other caus es (medications , cons tipation, dehydration, infections ) Non- pharm • Eliminate caus ative factors ,(unmet phys ical, ps ychological needs ) provide ps ychos ocial interventions Pharm • Antips ychotics • Anticonvuls ants • Antidepres s ants Dis continuation 38 Step 1 : Rule out • DEMENTIA • D = drugs • Benzodiazepines , opioids , s edatives , anticholinergics • EME = endocrine/metabolic/exocrine • Diabetes (hypo/ hyperglycemia), electrolyte dis turbances , hypo/ hyperthyroidis m • N = nutrition/ neoplas m • Wernicke’s encephalopathy (B1) • CNS malignancy or metas tas es • T = trauma/toxin • Head trauma or toxic inges tion • I = infection/ictal (s eizure) • A = alcohol American Geriatrics Society, American Association for Geriatric Psychiatry. J Am Geriatr Soc. 2003;51:1287-1298. 39 Step 2 : Non- Pharmacological therapy • Nonpharmacological interventions include • Sensory therapy • Activities therapy • Modification of activities of daily living care to meet individuals’ needs • Environmental modifications • Behavioral theory treatments • Social contact treatments 40 Step 3 : Pharmacological treatment of BPSD General Guidelines : • Pharmacotherapy is res erved to s ituations where nonpharmacological therapy fails . • Generally , us e reduced dos es . • Monitor clos ely • Minimal duration pos s ible • Attempt tapers Indications for medications • Significant dis tres s to patient or caregiver • Interference with function or caus ing dis ability • Impending delivery of neces s ary care • Pos ing a danger to s elf or others • Document carefully 41 Pharmacological Agents for Behavioral Control • Antips ychotics • Limited clinical data , treatment is empiric. • Choices bas ed on s ide effect profiles ( Avoid ps ychotropics with anti- cholinergic effects , mos t data on quetiapine , ris peridone, olanzapine, aripiprazole) • Black box warning: Increas ed mortality in older adults treated for dementia- related ps ychos is . ( Heart failure, pneumonia) • Anticonvuls ants • Valproic acid, carbamazepine, gabapentin • Mixed data; primarily cas e s tudies , open label s tudies • Antidepres s ants • Trazodone, others – poor data other than treatment of depres s ion • Conflicting res ults , mos t us ed SSIs : Sertraline and Citalopram. • Avoid Tricyclic antidepres s ants ( Anti- cholinergic effect) • Do not us e benzodiazepines • Leads to dementia, falls , fractures , confus ion 42 v8 antipsychol pBrexpiprazole – FDA approved Neurops ychiatric s ymptoms management of agitation in AD Renatti 65 • Rexulti: • It is not approved for dementia related ps ychos is • Dos age adjus tment is needed in: • Poor CYP 450 2D6 metabolizers • Concomitant CYP 3A4 inhibitors , inducers • Renal or hepatic dys function • Like other antips ychotics , there is the BBW of increas ed ris k of death in elderly with dementiarelated ps ychos is . 43 Ins omnia Treatment Firs t line = nonpharmacological • Sleep hygiene • CBT for ins omnia Pharmacological treatment • • • • Melatonin PR 2mg Trazodone 25mg Zaleplon or zolpidem IR 5mg Doxepin 3mg (low dos e only) I Benzodiazepines not recommended Diphenhydramine not recommended Antips ychotics s hould not be us ed s olely for s leep Tricyclic antidepres s ants generally not recommended 44 Brain Vas cular Health • There is a link between AD and cardiovas cular dis eas es (heart failure, atrial fibrillation, and coronary artery dis eas e) and is linked to dementia. • Management • Blood pres s ure • Choles terol • Homocys teine • Primary prevention • Smoking • Underactivity, obes ity • Hypertens ion • Diabetes 45 Patient and Family Education Progres s ive dis eas e with no cure, although medication treatments may help s low the progres s ion of the dis eas e. Meds will not REVERSE s ymptoms , but may s low decline and may prolong time to SNF placement Behavioral dis turbances are common in Alzheimer’s dis eas e; firs t- line treatment is non- pharmacologic (Educate family member on redirecting, other activities , etc. ) Side effects to watch for with cholines teras e inhibitors include N/ V, weight los s , and fainting (s yncope). Heart rate s hould be monitored while on thes e medications Evidence for alternative/ herbal treatments for Alzheimer’s dis eas e is limited and there may be s ide effects / drug interactions . Always dis cus s with MD/ pharmacis t prior to initiating Any s udden changes in s ymptoms or cognition s hould be worked up medically (delirium, rapid decline) ) 46