1. ALZHEIMER’S DISEASE DIAGNOSIS and TREATMENT J. Wesson Ashford, M.D., Ph.D. Stanford / VA Alzheimer’s Center VAMC, Palo Alto, California Calabasas, California October 14, 2004 Slides at: www.medafile.com (Dr. Ashford’s lectures) www.medafile.com

2. Diagnostic Criteria For Dementia Of The Alzheimer Type (DSM-IV, APA, 1994) A.Multiple Cognitive Deficits 1. Memory Impairment 2. Other Cognitive Impairment B. Deficits Impair Social/Occupational C.Course Shows Gradual Onset And Decline D.Deficits Are Not Due to: 1. Other CNS Conditions 2. Substance Induced Conditions E. Do Not Occur Exclusively during Delirium F. Not Due to Another Psychiatric Disorder

3. PREVALENCE of AD Estimated 4 million cases in US (2000) Estimated 4 million cases in US (2000) (2000 - 46 million individuals over 60 y/o) (2000 - 46 million individuals over 60 y/o) Estimated 500,000 new cases per year Estimated 500,000 new cases per year Increase with age (prevalence) Increase with age (prevalence) 1% of 60 - 65 (10.7m) = 107,000 1% of 60 - 65 (10.7m) = 107,000 2% of 65 - 70 ( 9.4m) = 188,000 2% of 65 - 70 ( 9.4m) = 188,000 4% of 70 - 75 ( 8.7m) = 350,000 4% of 70 - 75 ( 8.7m) = 350,000 8% of 75 - 80 ( 7.4m) = 595,000 8% of 75 - 80 ( 7.4m) = 595,000 16% of 80 - 85 ( 5.0m) = 800,000 16% of 80 - 85 ( 5.0m) = 800,000

4. Assessment History Of The Development Of The Dementia Ask the Patient What Problem Has Brought Him to See You Ask the Patient What Problem Has Brought Him to See You Ask the Family, Companion about the Problem Ask the Family, Companion about the Problem Specifically Ask about Memory Problems Specifically Ask about Memory Problems Ask about the First Symptoms Ask about the First Symptoms Enquire about Time of Onset Enquire about Time of Onset Ask about Any Unusual Events Around the Time of Onset, e.g., stress, trauma, surgery Ask about Any Unusual Events Around the Time of Onset, e.g., stress, trauma, surgery Ask about Nature and Rate of Progression, Activities of Daily Living Ask about Nature and Rate of Progression, Activities of Daily Living Physical Examination Physical Examination Neurological Examination Neurological Examination Neuropsychological Assessment Neuropsychological Assessment Routine Laboratory Tests Routine Laboratory Tests Brain Scan Brain Scan

5. Why Diagnose AD Early? Safety (driving, compliance, cooking, etc.) Safety (driving, compliance, cooking, etc.) Family stress and misunderstanding (blame, denial) Family stress and misunderstanding (blame, denial) Early education of caregivers of how to handle patient (choices, getting started) Early education of caregivers of how to handle patient (choices, getting started) Advance planning while patient is competent (will, proxy, power of attorney, advance directives) Advance planning while patient is competent (will, proxy, power of attorney, advance directives) Patient’s and Family’s right to know Patient’s and Family’s right to know Promotes advocacy for research and treatment development Promotes advocacy for research and treatment development Specific treatments now available Specific treatments now available May slow underlying disease process, the sooner the better May slow underlying disease process, the sooner the better May delay nursing home placement longer if started earlier May delay nursing home placement longer if started earlier May prevent conversion from Mild Cognitive Impairment to AD May prevent conversion from Mild Cognitive Impairment to AD

6. Dementia Screening Test Need to get elderly, clinicians interested in screening for dementia Need to get elderly, clinicians interested in screening for dementia Need test to screen patients for Alzheimer’s disease Need test to screen patients for Alzheimer’s disease Test needs to be on multiple platforms: Test needs to be on multiple platforms: Doctor’s offices Doctor’s offices Best if computerized for rapid, objective assessment Best if computerized for rapid, objective assessment World-Wide Web – based testing, World-Wide Web – based testing, CD-distribution CD-distribution KIOSK administration – drug stores, shopping malls KIOSK administration – drug stores, shopping malls Test needs to be very brief (about 1-minute) Test needs to be very brief (about 1-minute) Multiple test forms needed so it can be repeated often (quarterly) Multiple test forms needed so it can be repeated often (quarterly) Screening should be done yearly after age 50, and repeated every 3 months for individuals over 65 years of age or with concerns Screening should be done yearly after age 50, and repeated every 3 months for individuals over 65 years of age or with concerns Any change over time needs to be detected Any change over time needs to be detected The test should be free The test should be free Need program to handle positive screens sensitively and efficiently Need program to handle positive screens sensitively and efficiently Doctors have been reluctant to diagnose Alzheimer’s disease because of the time required to explain the problem to the family and to coordinate treatment. Doctors have been reluctant to diagnose Alzheimer’s disease because of the time required to explain the problem to the family and to coordinate treatment.

7. MEMTRAX - Memory Test (to detect AD onset) New test to screen patients for AD: New test to screen patients for AD: World-Wide Web – based testing, World-Wide Web – based testing, CD-distribution CD-distribution KIOSK administration KIOSK administration Determine level of ability / impairment Determine level of ability / impairment Test takes about 1-minute Test takes about 1-minute Test can be repeated often (e.g., quarterly) Test can be repeated often (e.g., quarterly) Any change over time can be detected Any change over time can be detected Free test is at: www.medafile.com Free test is at: www.medafile.comwww.medafile.com

8. FIRST SUCCESSFUL TREATMENT: CHOLINESTERASE INHIBITION CHOLINESTERASE INHIBITION (1st double blind study - Ashford et al., 1981) (1st double blind study - Ashford et al., 1981) Presumably increases acetylcholine at synapses Presumably increases acetylcholine at synapses Improvement in cognition (? 6-12 months better) Improvement in cognition (? 6-12 months better) Improvement in function (ADLs, variable) Improvement in function (ADLs, variable) Improvement in behavior (stabilization? basal ganglia) Improvement in behavior (stabilization? basal ganglia) Slowing of disease course Slowing of disease course Treatment delays nursing home placement Treatment delays nursing home placement Loss of benefit with delay of treatment Loss of benefit with delay of treatment Need to consider early intervention Need to consider early intervention Prevent conversion from Mild Cognitive Impairment to AD Prevent conversion from Mild Cognitive Impairment to AD

9. Need to divide effects of drug treatment into 2 groups Acute effects of treatment Acute effects of treatment e.g., 3 months e.g., 3 months are the acute effects related to severity? are the acute effects related to severity? e.g., do AChEases may work very well in mild patients, e.g., do AChEases may work very well in mild patients, and in nursing home patients? and in nursing home patients? do these medications work in very early phases of the disease? do these medications work in very early phases of the disease? Chronic effects of treatment Chronic effects of treatment rate of change, after acute effects rate of change, after acute effects are the effects on rate of change related to severity are the effects on rate of change related to severity are very mild patients improved over time by AChEases? are very mild patients improved over time by AChEases? are new AChEase molecules created which require dose increases? are new AChEase molecules created which require dose increases? does sudden discontinuation lead to catastrophic decline? does sudden discontinuation lead to catastrophic decline? do early, chronic benefits suggest prevention? do early, chronic benefits suggest prevention?

10. Benefits of Treatment of AD With Acetylcholinesterase Inhibitors AChEIs may improve, maintain, or slow the decline of cognitive, behavioral, and functional performance in patients with mild-to-moderate AD AChEIs may improve, maintain, or slow the decline of cognitive, behavioral, and functional performance in patients with mild-to-moderate AD Delay of treatment leads to loss of potential benefit Delay of treatment leads to loss of potential benefit AChEIs may delay nursing home placement over 20 months, and potentially much more when started early. AChEIs may delay nursing home placement over 20 months, and potentially much more when started early. AChEIs have demonstrated consistent efficacy and safety in maintaining cognitive function, as measured by ADAS-cog in patients with mild-to-moderate AD for up to 1 year – relative to placebo!! AChEIs have demonstrated consistent efficacy and safety in maintaining cognitive function, as measured by ADAS-cog in patients with mild-to-moderate AD for up to 1 year – relative to placebo!! Donepezil 1 38 weeks Donepezil 1 38 weeks Rivastigmine 2 38–42 weeks Rivastigmine 2 38–42 weeks Galantamine 3 52 weeks (25-30% better) Galantamine 3 52 weeks (25-30% better) 1. Rogers SL et al. Eur Neuropsychopharmacol. 2000;10:195-203. 2. Farlow M et al. Eur Neurol. 2000;44:236-241. 3. Raskind MA et al. Neurology. 2000;54:2261-2268.

11. Reminyl ® (galantamine HBr): Proposed Mechanisms of Action Increases amount of acetylcholine available in synaptic cleft by inhibiting breakdown of acetylcholine Increases amount of acetylcholine available in synaptic cleft by inhibiting breakdown of acetylcholine By modulating activity at nicotinic receptors, it may increase release of acetylcholine from surviving presynaptic nerve terminals By modulating activity at nicotinic receptors, it may increase release of acetylcholine from surviving presynaptic nerve terminals Combination action may diminish cholinesterase supersensitivity from developing, prolonging the benefit. Combination action may diminish cholinesterase supersensitivity from developing, prolonging the benefit. May provide greatest delay of illness progression May provide greatest delay of illness progression May require increase of dose after patient declines below initial baseline, to maintain benefit for longer term. May require increase of dose after patient declines below initial baseline, to maintain benefit for longer term. Maelicke A, Albuquerque EX. Eur J Pharmacol. 2000;393:165-170.

12. Reminyl ® (galantamine HBr): Dosing Available in 4-mg, 8-mg, and 12-mg tablets and oral solution (4 mg/mL) Available in 4-mg, 8-mg, and 12-mg tablets and oral solution (4 mg/mL) Dose escalation Dose escalation 8 mg/day starting dose 8 mg/day starting dose for 4 weeks (4 mg bid) for 4 weeks (4 mg bid) 16 mg/day maintenance dose 16 mg/day maintenance dose for at least 4 weeks (8 mg bid) for at least 4 weeks (8 mg bid) The flexibility to increase to 24 mg/day The flexibility to increase to 24 mg/day (12 mg bid) – can try after 12 weeks if further benefit sought (12 mg bid) – can try after 12 weeks if further benefit sought Increase from 8 to 12 mg bid in moderate dementia Increase from 8 to 12 mg bid in moderate dementia Take initially with morning and evening meals Take initially with morning and evening meals Later, better with morning meal, mid-afternoon snack. Later, better with morning meal, mid-afternoon snack. (Avoid nocturnal cholinergic activation which may hasten the progression of Alzheimer’s disease!! – advantage over donepezil) (Avoid nocturnal cholinergic activation which may hasten the progression of Alzheimer’s disease!! – advantage over donepezil)