1. ALZHEIMER’S DISEASEDIAGNOSIS 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)

2. Diagnostic Criteria For Dementia Of The Alzheimer Type(DSM-IV, APA, 1994) • Multiple Cognitive Deficits 1. Memory Impairment 2. Other Cognitive Impairment B. Deficits Impair Social/Occupational • Course Shows Gradual Onset And Decline • 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) • (2000 - 46 million individuals over 60 y/o) • Estimated 500,000 new cases per year • Increase with age (prevalence) • 1% of 60 - 65 (10.7m) = 107,000 • 2% of 65 - 70 ( 9.4m) = 188,000 • 4% of 70 - 75 ( 8.7m) = 350,000 • 8% of 75 - 80 ( 7.4m) = 595,000 • 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 Family, Companion about the Problem • Specifically Ask about Memory Problems • Ask about the First Symptoms • Enquire about Time of Onset • 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 • Physical Examination • Neurological Examination • Neuropsychological Assessment • Routine Laboratory Tests • Brain Scan

5. Why Diagnose AD Early? • Safety (driving, compliance, cooking, etc.) • Family stress and misunderstanding (blame, denial) • 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) • Patient’s and Family’s right to know • Promotes advocacy for research and treatment development • Specific treatments now available • May slow underlying disease process, the sooner the better • May delay nursing home placement longer if started earlier • May prevent conversion from Mild Cognitive Impairment to AD

6. Dementia Screening Test • Need to get elderly, clinicians interested in screening for dementia • Need test to screen patients for Alzheimer’s disease • Test needs to be on multiple platforms: • Doctor’s offices • Best if computerized for rapid, objective assessment • World-Wide Web – based testing, • CD-distribution • KIOSK administration – drug stores, shopping malls • Test needs to be very brief (about 1-minute) • 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 • Any change over time needs to be detected • The test should be free • 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.

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

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

9. Need to divide effects of drug treatment into 2 groups • Acute effects of treatment • e.g., 3 months • are the acute effects related to severity? • e.g., do AChEases may work very well in mild patients, and in nursing home patients? • do these medications work in very early phases of the disease? • Chronic effects of treatment • rate of change, after acute effects • are the effects on rate of change related to severity • are very mild patients improved over time by AChEases? • are new AChEase molecules created which require dose increases? • does sudden discontinuation lead to catastrophic decline? • 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 • 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 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!! • Donepezil1 38 weeks • Rivastigmine2 38–42 weeks • Galantamine3 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 • 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. • May provide greatest delay of illness progression • 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) • Dose escalation • 8 mg/day starting dose • for 4 weeks (4 mg bid) • 16 mg/day maintenance dose • for at least 4 weeks (8 mg bid) • The flexibility to increase to 24 mg/day • (12 mg bid) – can try after 12 weeks if further benefit sought • Increase from 8 to 12 mg bid in moderate dementia • Take initially with morning and evening meals • Later, better with morning meal, mid-afternoon snack. • (Avoid nocturnal cholinergic activation which may hasten the progression of Alzheimer’s disease!! – advantage over donepezil)