Treatment of Alzheimer’s disease: 2007 Update

1. Treatment of Alzheimer’s disease: 2007 Update Howard S. Kirshner, M.D. Vanderbilt University

2. Alzheimer’s diseaseDefinition: NINCDS/ADRDA ’84, DSM IV • Acquired syndrome of memory and 2 other cognitive functions (aphasia, apraxia, agnosia, executive function) • Progressive • Sufficient to affect daily life • No alteration of consciousness • Age of onset 40-90 • No other proved cause • Correlation with pathology 80-100%

3. Dementia comes to us all

4. AD Epidemiology • AD is the most common dementia (50-60% of dementia cases, another 15% mixed with vascular disease) • AD affects >4 million patients in U.S. • Estimated ~1 million on Rx • Projected: >14 million patients by 2050 • Costs: $90 to $100 billion/year • Average cost of care: $50,000 per patient/year

6. AD—History Timeline 7th century BCAge-related mental deterioration recognized 1907AD first described by Dr. Alois Alzheimer Early 1960sAwareness of AD as a single disease 1980Alzheimer’sAssociationestablished 1991APOE implicated 1993First cholinesterase inhibitor approved Research into treatments continues 700 BC 2000 AD ~200 ADGalen associates “morosis” (dementia) with old age 1978?Single entity established—senile dementia of the Alzheimer’s type (SDAT) 1983Cholinergic deficit identified 1992AHCPR develops screening guidelines for AD 1994Brain inflammatory response identified as pathogenetic

8. 10 Warning Signs of AD(AAN Practice Parameter ’01) • Memory loss that affects job skills • Difficulty performing familiar tasks • Problems with language • Disorientation to time and place • Decreased judgment • Problems with abstract thinking • Misplacing objects • Changes in mood or behavior • Changes in personality • Loss of initiative

9. Differential Diagnosis of AD • Delirium: (drugs, toxins, systemic dz) • Depression • Metabolic (thyroid) • Normal pressure hydrocephalus • Subdural hematoma • Tumor • Infections • Creutzfeldt Jakob Dz • Vascular dementia • Dementia due to Parkinson's disease • Dementia with Lewy bodies • Frontotemporal dementia

10. Dementia: Differential Dx Other dementias Frontal lobe dementia Creutzfeldt-Jakob disease Corticobasal degeneration Progressive supranuclear palsy, many others Vascular dementias Multi-infarct dementia Binswanger’s disease Lewy body dementias Parkinson’s disease Diffuse Lewy body disease Lewy body variant of AD Vascular dementias and Alzheimer’s disease (AD) AD and Lewybody dementias AD 10% 10% 60% 5% 7% 8% Adapted with permission from Zurad E. Drug Benefit Trends. 2001;13:27-40.

11. Mild Cognitive Impairment • Preclinical period termed MCI • Memory performance below normal • No significant loss of function • Clinical course shows gradual decline • Some patients have MCI for 10-15 yrs • Conversion to AD 12-16%/yr (Petersen) • Do all cases eventually develop AD?

12. Mild Cognitive Impairment -2- • Donepizil trial (Petersen, 2005): modest benefit at 1 year, none at 3 years • APOE subgroup: benefit at 3 years • Vitamin E: no effect • Galantamine trial stopped (13 deaths, 2 placebo)

13. Clinical Progression of AD and MCI Time (y) 0 y 10 y Time? MCIMMSE 24–30 Mild ADMMSE 20–23 • Mild subjective/objective memory loss • Normal function • Forgetfulness • Repetitive questions • Daily function impaired Moderate ADMMSE 10–19 • Progression of cognitive deficits • Short-term memory loss • Word-finding difficulties Cognitive function Severe ADMMSE 0–9 • Agitation • Altered sleep patterns • Total dependence: dressing, feeding, bathing

14. Keep appointments 25% 75% Telephone Obtain meal/snack Loss of optimal (independent) performance Travel alone Use home appliance Find belongings Select clothes Dress Activities of daily living (ADLs) Groom Maintain hobby Dispose of litter Clear table Walk Eat 25 20 15 10 5 0 MMSE score Progressive loss of function Adapted with permission from Galasko et al. Eur J Neurol. 1998;5(suppl 4):S9-S17. Functional Decline in AD

15. Motor cortex Primary somatic sensory cortex Central sulcus Parietal-temporal-occipital association cortex Parietal lobe Frontal lobe Prefrontalassociationcortex Occipital lobe Primary visual cortex Temp-parietal junction Temporal lobe AD Symptoms Correlate With Affected Areas of the Brain Cummings JL. Am J Psychiatry. 2000;157:4-15. Van Hoesen GW et al. Cereb Cortex. 2000;10:243-251.

16. Cortical atrophy Normal AD

17. Amyloid Plaques and Microglial Activation This photo shows an Alzheimer amyloid plaque (white) surrounded by reactive astrocytes (brown) and a cluster of microglial cells (black) sitting on top Amyloid is made up of A-beta peptides of amyloid, 40-42 amino acids Source: www.interchg.ubc.ca/mcgeerpl/curres.html.

18. Neurofibrillary Tangles(tau filaments)

21. AD: Research on etiology • Genetics: Chromosome 21, APP gene, associated with early AD (also Down’s) • Chromosomes 1, 14 also associated with early onset AD; presenilins 1, 2 shown to be part of gamma secretase • APO E4 associated with sporadic, late onset AD; APO E4 is involved with assembly of A-beta peptides • Amyloid hypothesis: A-beta peptide is toxic to neurons • Inflammation in plaques: NSAIDS • Vascular risk factors: HTN, lipids

22. -amyloid precursor protein Extracellular space TM Cytoplasm A peptide COOH NH2 -secretase -secretase Proteolytic Cleavages of Amyloid Precursor Protein (APP) Produces A Peptide Selkoe DJ et al. JAMA. 2000;283:1615-1617.

23. Molecular biology of AD • Current emphasis on amyloid A-beta peptide • Aggregates of A-beta may modify kinases, causing overphosphorylation of tau, leading to formation of “twisted tubules” • Tau may be involved in microtubule transfer, disrupted in twisted tubules • Tau is a byproduct of A-beta in AD, may be genetically altered in other conditions such as frontotemporal dementia, PSP

24. Treatment of Dementia

25. Therapy for AD: Overview • Cholinesterase inhibitors • Other drug therapy - memantine • Antioxidants (Vitamins C, E) • Rx of behavioral disorders • NSAIDS: ineffective, risky • Estrogens: Harmful • Statins: ? • Nonpharmacologic approaches

26. Other AD Treatment Options Rx largely disproved • Chelation therapy • Lecithin, choline • Ergot mesylate (Hydergine) Other compounds under investigation • Vaccines: active on hold; passive, pending • Gamma secretase inhibitors • Inhibitors of plaque formation (Alzhemed, binds to A-beta)

27. Treatment of behavioral symptoms in AD • Antidepressants (SSRI’s) • Atypical antipsychotics (risperidone, olanzepine, quetiapine) * FDA warning • Avoid phenothiazines, haloperidol • Avoid benzodiazepines • Trazodone for sleep, valproate for agitation • Acetylcholinesterase inhibitors • Memantine (Cummings et al, Neurology ’06)

28. Antioxidants • Oxidative stress hypothesis: excess accumulation of amyloid beta-peptide generates free radicals, which induce neuronal death • Vitamin E: 2000 IU (Sano ’97) - ? Slowed disease progression - 2005 MCI study: no effect • Vit E & C: ? Reduced incidence (Cache Cy, Utah, Arch Neurology 1/04) • Ginkgo biloba: One + trial, one – trial, others pending Sano M, Ernesto C, Thomas RG, et al. N Engl J Med. 1997. Bastianetto S, Ramassamy C, Dore S, et al. Eur J Neurosci. 2000.

29. Memantine(Reisberg et al, NEJM 348:1333, ’03;Tariot et al, JAMA 291:317, ’04) • Memantine: glutamate receptor blocker • Reisberg: 181 pts, mod-severe AD (MMSE 3-14, x 8), memantine 20 mg vs placebo • Less deterioration with memantine, significant for ADL, borderline for CIBIC • Minimal side effects • Tariot: memantine + donepizil improved outcomes vs donepizil in mod-severe AD • No evidence yet in mild AD (AAN ’04 abstract, + monotherapy, FDA P) • Clinical use mostly combined with AChE-i

30. Results: Cognition—SIB

31. Memantine in Moderate to Severe AD—OLEX Results: Cognition—SIB* Patients Who Switched From Placebo to Memantine Improved Relative to the Projected Rate of Decline Double-Blind Phase Open-Label Extension 5 Improvement 0 P<.001† P=.002† Mean Change From Baseline in SIB Score (± SEM) -5 -10 Deterioration Memantine to Memantine -15 P=.049‡ Placebo to Memantine Placebo to Placebo (projected) -20 0 4 12 28 40 52 Week n = 95 95 74 66 94 n = 80 80 79 75 70 *OC analysis; †Memantine vs placebo; ‡Rate of decline between placebo group (weeks 1-28) and placebo-memantine group (weeks 28-52). Sources: Ferris S, et al. Presented at the 16th Annual Meeting of the American Association for Geriatric Psychiatry; March 1-4, 2003; Honolulu, Hawaii. Data on file, Forest Laboratories, Inc.

32. Results: Cognition—SIB

33. Cholinergic Hypothesis • Reduction in acetylcholine, choline acetyltransferase in cortex • Degeneration of nucleus of Meynert and its cholinergic projections to cortex • Cholinergic deficiency contributes to memory loss and ? behavioral changes • Anticholinesterase medications improve memory and behavior (symptomatic Rx) Cummings JL, Back C. Am J Geriatr Psychiatry. 1998.

34. PC FC BF OC H Cholinergic Pathways From theBasal Forebrain Cummings JL. Am J Psychiatry. 2000;157:4-15.

35. Acetic acid Choline Drug inhibits AChE* Anticholinesterase:Mechanism of Action Presynaptic nerve terminal Muscarinic receptor Postsynaptic nerve terminal ACh Acetylcholinesterase(AChE) Nicotinic receptor * Clinical significance of this mechanism is unknown. Maelicke A, Albuquerque EX. Eur J Pharmacol. 2000;393:165-170. Nordberg A, Svensson A-L. Drug Safety. 1998;19:465-480.

36. Anticholinesterase drugs • FDA-approved agents: • Tacrine (Cognex): 10, 20, 30, 40 mg qid • Donepezil (Aricept): 5 and 10 mg qd • Rivastigmine (Exelon): 1.5, 3, 4.5, 6 mg bid • Galantamine (Razadyne): 4, 8, 12 mg bid Razadyne ER: 8, 16, 24 mg qd • Efficacy in mild/moderate AD • Evidence for long-term treatment and use in late-stage disease • All have mainly GI side effects Krall WJ, Sramek JJ, Cutler NR. Ann Pharmacother. 1999.

37. Anticholinesterase drugsIs one better than another? • No non-industry sponsored head-to-head trials • One donepizil trial: better tolerated than rivastigmine • Rivastigmine trial: marginally superior to donepizil (Bullock et al, Curr Med Res Opinion 2005;21:1317-27) • Galantamine, ? Better % improvement at 1 year vs donepizil, but one donepizil trial found the opposite

40. Clinical improvement Clinical decline Endpoint Cognitive Benefits in More Advanced AD (MMSE: 5-17)(also Winblad et al, Lancet 2006;367:1057-65) (Donepizil is FDA approved in advanced AD) P=.0004 3 P<.0001 P=.0019 2 1 MMSE change from baseline 0 -1 Aricept (n=144) Placebo (n=146) -2 0 12 24 Study week Adapted with permission from Feldman et al. Neurology. 2001;57:613-620. See Appendix for study description and safety information (Moderate to Severe AD [MSAD]).

44. Rivastigmine and Cholinergic Function Acetyl CoA Glia Presynaptic neuron + Choline Choline BuChE ChAT ACh BuChE Synaptic cleft ACh Choline + AChE Acetate Postsynapticneuron AChE Cholinergic receptor ACh = acetylcholine; AChE = acetylcholinesterase; BuChE = butyrylcholinesterase; ChAT = choline acetyltransferase; CoA = coenzyme A. Adapted from Mycek M et al. In: Harvey RA, Champe PC, eds. Pharmacology: Lippincott’s Illustrated Reviews. Philadelphia, Pa: JB Lippincott Co; 1992:35-44.

45. Rivastigmine: Dose Response -2 -1 Improvement 0 Mean Change in ADAS-CogScore From Baseline 1 2 Decline 3 95% CI Predicted response(n=1923) 4 0 2 4 6 8 10 12 Last Prescribed Dosage (mg/day) Pooled study analysis involving approximately 2800 AD patients treated with either rivastigmine (1-12 mg/day) or placebo for 26 weeks in 4 phase III, randomized, double-blind, placebo-controlled trials.

46. LONG TERM EFFECTS OF EXELON ON COGNITION: MEAN CHANGE IN ADAS-COG FROM BASELINE THROUGH WEEK 52 * * * * * * * * * All Patients Taking Exelon Adapted from Proceedings, Satellite Symposium, IPA 9th Cong. Aug, 99, P11 * p < 0.05 v/s projected placebo

47. RAZADYNE™ ER (galantamine HBr): Cognition: ADAS-cog/11

48. RAZADYNE™ ER (galantamine HBr): ADCS-ADL

50. Investigational uses of acetylcholinesterase inhibitors • Vascular dementia: Phase III clinical trial with galantamine, donepizil • Diffuse Lewy Body Disease: also evidence from all drugs • Memory loss in Multiple Sclerosis, Traumatic Brain Injury, AIDS Dementia Complex, ADD: small series