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ALZHEIMER’S DISEASE DIAGNOSIS and TREATMENT. J. Wesson Ashford, M.D., Ph.D. Stanford / VA Alzheimer’s Center VAMC, Palo Alto, California San Francisco, California October 5, 2004 Slides at: (Dr. Ashford’s lectures). Alzheimer Issues.

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alzheimer s disease diagnosis and treatment


J. Wesson Ashford, M.D., Ph.D.

Stanford / VA Alzheimer’s Center

VAMC, Palo Alto, California

San Francisco, California

October 5, 2004

Slides at: (Dr. Ashford’s lectures)

alzheimer issues
Alzheimer Issues
  • Definition of dementia, differential diagnosis
  • Epidemiology (why diagnosis is important)
  • Diagnosis of Alzheimer’s disease (how to)
  • Treatment options
    • The need to treat
    • The benefits of cholinesterase inhibitors
    • The advantage of galantamine (Reminyl)
dementia definition
Dementia Definition
  • Multiple Cognitive Deficits:
    • Memory dysfunction
      • especially new learning, a prominent early symptom
    • At least one additional cognitive deficit
      • aphasia, apraxia, agnosia, or executive dysfunction
  • Cognitive Disturbances:
    • Sufficiently severe to cause impairment of occupational or social functioning and
    • Must represent a decline from a previous level of functioning
differential diagnosis top ten commonly used mnemonic device avdementia
Differential Diagnosis: Top Ten (commonly used mnemonic device: AVDEMENTIA)

1. Alzheimer Disease (pure ~40%, + mixed~70%, ? dLbd)

2. Vascular Disease, MID (5-20%)

3. Drugs, Depression, Delirium

4. Ethanol (5-15%)

5. Medical / Metabolic Systems

6. Endocrine (thyroid, diabetes), Ears, Eyes, Environ.

  • Neurologic (other primary degenerations, fronto-temporal

- Consider diffuse Lewy body dementia, Parkinson component)

8. Tumor, Toxin, Trauma

9. Infection, Idiopathic, Immunologic

10. Amnesia, Autoimmune, Apnea, AAMI

Adapted from Yesavage, 1979

diagnostic criteria for dementia of the alzheimer type dsm iv apa 1994
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

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

Total = 281,421,906

>60 = 45,809,291

>65 = 35,003,844

>85 = 4,251,678

>100= 62,545

JW Ashford, MD PhD, 2003


JW Ashford, MD PhD, 2003

Mortality Equationst = age in yearsTd = time for mortality rate to doubleRo = mortality rate at time zeroalpha = ln(2) / Td
  • Mortality rate u(t)

R = Ro x exp (alpha x t)

  • Survival curve s(t)

S = exp ( - Ro/alpha x (exp (alpha x t) –1 ))

  • Number of deaths per year d(t)

D = -ds/dt = ( Ro + alpha x ln (1/s(t) )) x s(t)

= u(t) x s(t)

genes and alzheimer s disease 60 80 of causation
Genes and Alzheimer’s disease(60% - 80 % of causation)
  • Familial AD (onset < 60 y/o) (<5%)
      • all known autosomal dominant genes relate to b-amyloid
    • Presenilin I, II (ch 14, 1)
    • APP (ch 21)
  • Non-familial (late onset)
    • APOE
      • Clinical studies suggest 40 – 50% due to e4
      • If e2 is considered, may be 95% of causation
      • Population studies suggest 10 – 20% cause
      • Evolution over last 300,000 to 200,000 years
    • At least 20 other genes suspected of relating to AD

Ashford & Mortimer, 2002, J. Alz. Dis. 4:1-9.

APO-E genotype and AD risk46 Million in US > 60 y/o //// 4 Million have AD(data from Saunders et al., 1993; Farrer et al., 1997)

JW Ashford, MD PhD, 2003


Reprinted with permission from Brumback, RA, Leech RW, J. Ohio State Med Assoc. 1994: 87, 103-111

economic impact of ad
  • 2 million AD patients in nursing homes
    • Projection to California – 240,000
  • Nursing homes cost - $120 to $160 per day
  • Annualized cost of nursing homes ranges
    • from $40,000 to $70,000 per year
  • Nursing Home Care of AD patients costs $80 billion per year
    • for life-time cost – about $175,000 per patient
  • The majority of patients live at home and are cared for by family and friends
  • With lost wages of patients and families plus costs for non-nursing home patients:
    • Total costs: $120 billion annually (Am J Publ Hlth)
    • Projection to California – $14.5 billion annually!
ad can be readily diagnosed
AD Can Be Readily Diagnosed
  • A diagnosis of Alzheimer’s disease can be made with a high degree of certainty
  • Using NINCDS-ADRDA criteria, accuracy in autopsy-verified cases is approximately 90%
  • Diagnosis is a 2-step process:
    • Detection through screening
    • Confirmation through patient history and physical, caregiver interview, brain imaging, and appropriate laboratory studies

McKhann G et al. Neurology. 1984;34:939-944.

Kazee AM et al. Alzheimer Dis Assoc Disord. 1993;7:152-164.

Ashford JW et al, Psychiaric Annals, 1996;26:262-268.

ad is often misdiagnosed
Patient initially diagnosed with ADAD Is Often Misdiagnosed

Patient’s first diagnosis other than AD




No 72%




Yes 28%

Dementia (not AD)


No diagnosis


Normal aging


Source: Consumer Health Sciences, LLC. Alzheimer’s Caregiver Project. 1999.

ad is under diagnosed
AD is Under-diagnosed
  • Early Alzheimer’s disease is subtle, the diagnosis continues to be missed
    • it is easy for family members to avoid the problem and compensate for the patient
    • physicians tend to miss the initial signs and symptoms
  • Less than half of AD patients are diagnosed
    • Estimates are that 25% to 50% of cases remain undiagnosed
    • Diagnoses are missed at all levels of severity: mild, moderate, severe
  • Undiagnosed AD patients often face avoidable social, financial, and medical problems
  • Early diagnosis and appropriate intervention may lessen disease burden
    • Early treatment may improve overall course substantially
  • No definitive laboratory test for diagnosing AD exists
    • Efforts to develop biomarkers, early recognition by brain scan

Evans DA. Milbank Quarterly. 1990; 68:267-289


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
laboratory tests routine
    • electrolytes, liver, kidney function tests, glucose
    • thyroid function tests (T3, T4, FTI, TSH)
    • vitamin B12, folate
    • complete blood count, ESR
    • VDRL, HIV (if indicated)
  • EKG (if indicated)
  • CHEST X-RAY (if indicated)
special laboratory tests
  • FUNCTIONAL BRAIN IMAGING (SPECT, PET – Medicare will pay special cases)
  • EEG, Evoked Potentials (P300)
  • REACTION TIMES (slowed in the elderly, especially when complex response is required
    • ELEVATED TAU (future possible)
    • DECREASED AMYLOID (future possible)
  • HEAVY METAL SCREEN (24 hr urine)
    • APO-LIPOPROTEIN-E (for supporting dx)
    • AUTOSOMAL DOMINANT (young onset)
why diagnose ad early
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



Ashford et al., 1995

need to develop better screening and early assessment tools
Need to Develop Better Screening and Early Assessment Tools
  • Genetic vulnerability testing (trait risk)
  • Vulnerability factors (education, occupation, head injury)
  • Early recognition (10 warning signs)
  • Screening tools (6th vital sign in elderly)
  • Positive diagnostic tests
    • CSF – tau levels elevated, amyloid levels low
    • Brain scan – PET – DDNP, Congo-red derivatives
  • Mild Dementia severity assessments
  • Detecting early change over time
    • predicting progression, measuring rate
alzheimer warning signs top ten alzheimer association
Alzheimer Warning SignsTop TenAlzheimer Association

1. Recent memory loss affecting job

2. Difficulty performing familiar tasks

3. Problems with language

4. Disorientation to time or place

5. Poor or decreased judgment

6. Problems with abstract thinking

7. Misplacing things

8. Changes in mood or behavior

9. Changes in personality

10. Loss of initiative

need for a brief screening test for dementia alzheimer s disease
Need for a Brief Screening Test for Dementia, Alzheimer’s Disease
  • Recent evidence of benefits of anti-cholinesterase agents in the treatment of mild Alzheimer’s disease
    • Improvement of cognition
    • Slowing of progression
    • Delay of conversion to diagnosis
  • How to get elderly, clinicians interested in screening for dementia
  • How 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.
brief alzheimer screen bas
Brief Alzheimer Screen (BAS)
  • Repeat these three words: “apple, table, penny”.
  • So you will remember these words, repeat them again.
  • What is today’s date?
      • D = 1 if within 2 days.
  • Spell the word “WORLD” backwards
      • S = 1 point for each word in correct order
  • “Name as many animals as you can in 30 seconds, GO!”
      • A = number of animals
  • “What were the 3 words I asked you to repeat?” (no prompts)
      • R = 1 point for each word recalled

BAS = 3 x R + 2/3 x A + 5 x D + 2 x S

(Mendiondo et al., 2003)

dementia screening test
Dementia Screening Test
  • 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
memtrax memory test to detect ad onset
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:
first successful treatment
      • (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 (? basal ganglia)
    • Slowing of disease course
      • Treatment delays nursing home placement
      • There is loss of benefit with delay of treatment
    • Need to consider early intervention
treatment of alzheimer s disease



Treatment of Alzheimer’s Disease





Patients (millions)









with AChEIs

* Any drug treatment, not limited to acetylcholinesterase inhibitors.

Source: Decision Resources, March 2000.

cholinergic changes in ad
Cholinergic Changes in AD
  • The most prominent neurotransmitter abnormalities are cholinergic
    • Reduced activity of choline acetyltransferase (synthesis of acetylcholine)1
  • Reduced number of cholinergic neurons in late AD (particularly in basal forebrain)2
  • Selective loss of nicotinic receptor subtypes in hippocampus and cortex1,3

1. Bartus RT et al. Science. 1982;217:408-414. 2. Whitehouse PJ et al. Science. 1982;215:1237-1239. 3. Guan ZZ et al. J Neurochem. 2000;74:237-243.



extra cellular

Lipid raft

Formed by cholesterol

Transported by ApoE

From macroglia

Stimulated by acetylcholine

through muscarinic receptor

Favored when lipid raft too large


? To establish

new connections

? Free-radical generator

? To remove old synapses

JW Ashford, MD PhD, 2003

need to divide effects of drug treatment into 2 groups
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?
exelon improves cognitive function adas cog mean change from baseline
ExelonImproves Cognitive Function: ADAS-Cog mean change from baseline†


1–4 mg/day Exelon®

6–12 mg/day Exelon®













12 18 26



Mean change inADAS-Cog score



†B352 OC study analysis; *p<0.05 vs placebo


Corey-Bloom J et al, for the ENA 713 B352 Study Group. Int J Geriatr Psychopharmacol. 1998;1:55-65.

exelon longterm effects on cognition mean change in adas cog from baseline at week 52
Exelon Longterm Effects on Cognition:Mean Change in ADAS-Cog from Baseline at Week 52










All Patients

Taking Exelon

B352 Patients in B353 (OC) at Week 52

* p< 0.05 vs projected placebo

Sohn et al. In: Proceedings of the CPNP. April 2000.

reminyl galantamine hbr pooled analysis change in adas cog scores at 6 and 12 months
REMINYL® (galantamine HBr) Pooled Analysis: Change in ADAS-cog Scores at 6 and 12 Months

Advanced Moderate AD Patients With Baseline ADAS-cog Scores >30














* †

† ‡

Mean (SE) Change in

ADAS-cog From Baseline


REMINYL 24 mg/d

Placebo from RCTs

Historical placebo

Baseline 1 3 6 9 12

Time (mo)

*p<0.001 vs placebo.

†p<0.001 vs historical placebo.

‡Not significant vs baseline.

Baseline ADAS-cog score: 37.3 (REMINYL 24 mg/d) vs 37.4 (placebo).

Adapted from Blesa R et al. Dement Geriatr Cogn Discord. 2003;15:79-87.

gal gbr 2 mmse change from baseline
GAL-GBR-2MMSE: Change From Baseline




Reminyl® (galantamine HBr)(n = 94)



Aricept® (n = 87)





Mean MMSE change

(± SE) from baseline














* p  0.0001 vs baseline; †p = 0.0006 vs baseline; #p = 0.0003 vs baseline. NS = p > 0.1.

Data on file, Janssen Pharmaceutica Products, L.P. Bullock R et al. Poster presented at the 41st Annual Meeting of the ACNP, San Juan, Puerto Rico, December 8–12, 2002.

benefits of treatment of ad with acetylcholinesterase inhibitors
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.

  • REMINYL® (galantamine HBr) is approved for the treatment of patients with mild-to-moderate dementia of the Alzheimer’s type
  • The most frequent adverse events associated with REMINYL included nausea, vomiting, diarrhea, anorexia, and weight loss; most were generally transient and mild to moderate in severity
  • REMINYL is available in 4-mg, 8-mg and 12-mg tablets and an oral solution (4 mg/mL) and is taken twice a day, preferably with morning and evening meals
  • May benefit very early cases, particular APOE-e4 carriers
reminyl galantamine hbr proposed mechanisms of action
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.

reminyl galantamine hbr gi tolerability
Reminyl® (galantamine HBr) GI Tolerability
  • Nausea and vomiting: typically transient and related to treatment initiation and dose escalation
    • Among patients experiencing nausea, median duration was 5 to 7 days
  • Weight loss: reported as an adverse event in  5% of patients, with none discontinuing treatment due to weight loss

REMINYL Full Prescribing Information, 2001. Data on file, Janssen Pharmaceutica Products, L.P.

reminyl galantamine hbr pharmacokinetics
Reminyl®(galantamine HBr) Pharmacokinetics
  • Linear pharmacokinetics
  • Bioavailability: 90%
  • Half-life: 7 hours
    • - can provide decrease inhibition at night!!
  • Low (18%) plasma protein binding
  • Hepatic metabolism via multiple pathways, primarily CYP2D6 and CYP3A4
  • Renal excretion
reminyl galantamine hbr dosing
Reminyl® (galantamine HBr): Dosing
  • Simple, one-step 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) – should try after 12 weeks if further benefit sought
  • Taken preferably with morning and evening meals
    • Later, better with morning meal, mid-afternoon snack.
    • (Avoid nocturnal cholinergic activation!!)
  • Available in 4-mg, 8-mg, and 12-mg tablets and oral solution (4 mg/mL)
switching guidelines cont
Switching Guidelines (cont)
  • Switching from Aricept® to Reminyl® (galantamine HBr)
    • No washout period of Aricept® should be undertaken before initiating REMINYL. The standard dose escalation should be undertaken the next day after the last Aricept® administration
  • Switching from Exelon® to REMINYL
    • No washout period of Exelon® should be undertaken before initiating REMINYL. The standard dose escalation should be undertaken the next day after the last Exelon® administration

Morris JC et al. Clin Ther. 2001;23(suppl A):A31-39.

switching guidelines cont60
Switching guidelines (cont)
  • Exceptions
    • For patients who are experiencing poor tolerability on Aricept® or Exelon®, a washout period of up to 7 days should be undertaken, or until symptoms resolve
    • The standard dose escalation of Reminyl® (galantamine HBr) should then be undertaken
  • Combined dosing
    • Combination therapy with AChEIs is not recommended by the manufacturing company
    • Galantamine may be combined with Namenda® (memantine)
      • Evidence suggests additional efficacy
      • Combination appears to be at least as effective as combination of donepezil and memantine

Morris JC et al. Clin Ther. 2001;23(suppl A):A31-39.