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Screening for Mild Cognitive Impairment and
Alzheimer's Disease: Relevance of Age and APOE genotype
Memory & Aging Center TeamUniversity of California, San Francisco
May 21, 2004
J. Wesson Ashford, M.D., Ph.D.Stanford / VA Alzheimer’s Center
VAMC, Palo Alto, California
Slides at: www.medafile.com/MCIscra.ppt
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
DIAGNOSTIC CRITERIA FOR DEMENTIA OF THE ALZHEIMER TYPE
(DSM-IV, APA, 1994)
A. DEVELOPMENT OF MULTIPLE COGNITIVE DEFICITS
1. MEMORY IMPAIRMENT
2, OTHER COGNITIVE IMPAIRMENT
B. THESE IMPAIRMENTS CAUSE DYSFUNCTION IN
IN SOCIAL OR OCCUPATIONAL ACTIVITIES
C. COURSE SHOWS GRADUAL ONSET AND DECLINE
D. DEFICITS ARE NOT DUE TO:
1. OTHER CNS CONDITIONS
2. SUBSTANCE INDUCED CONDITIONS
F. DO NOT OCCUR EXCLUSIVELY DURING DELIRIUM
G. ARE NOT DUE TO OTHER PSYCHIATRIC DISORDER
BIOPSYCHOSOCIAL SYSTEMS AFFECTED BY ADNEUROPLASTIC MECHANISMS AFFECTED AT ALL LEVELS
(Ashford, Mattson, Kumar, 1998; Teter, Ashford, 2002)
• SOCIAL SYSTEMS• INSTRUMENTAL ADLs - EARLY• BASIC ADLs - LATE
• PSYCHOLOGICAL SYSTEMS• PRIMARY LOSS OF SHORT-TERM MEMORY
– LEARNING PROCESSES – CLASSICAL, OPERANT • LATER LOSS OF LEARNED SKILLS
• NEURONAL MEMORY SYSTEMS • CORTICAL GLUTAMATERGIC STORAGE• SUBCORTICAL
– (acetylcholine, norepinephrine, serotonin) • CELLULAR PLASTIC PROCESSES
– APP metabolism – early, broad cortical distribution– TAU hyperphosphorylation – late, focal effect,
dementia related
NEUROPATHOLOGY OF AD
• Senile plaques• beta-amyloid protein (? Primary problem)
• Neurofibrillary tangles• hyper-phosphorylated tau (loss of
synapses, dementia)
• Neurotransmitter losses• Acetylcholine (Ach) – major loss of
nicotinic receptors• Norepinephrine, serotonin, glutamate,
GABAss
• Inflammatory responses
New Neuropath Mechanisms
• Amyloid PreProtein (APP - ch21) (early changes)– metabolism occurs on cholesterol “rafts”
• Cholesterol transport by APOE (ch 19), provides, removes
– alpha-secretase vs beta/gamma secretase metabolism
– influence toward alpha-secretase by Acetylcholine– gamma-secretase (PreSenilin genes, ch14,1)– break down - Insulin Degrading Enzyme (ch10), etc.– prevention of fibril formation by melatonin
• Tau hyperphosphorylation (relation to dementia)– glycogen-synthase-kinase (GSK) 3-beta– inhibition by Ach, lithium, valproic acid
Differential Diagnosis: Top Ten
(commonly used mnemonic device: AVDEMENTIA)1. Alzheimer Disease (pure ~40%, + mixed~70%)2. Vascular Disease, MID (5-20%)3. Drugs, Depression, Delirium4. Ethanol (5-15%)5. Medical / Metabolic Systems6. Endocrine (thyroid, diabetes), Ears, Eyes, Environ.7. Neurologic (other primary degenerations, etc.)8. Tumor, Toxin, Trauma9. Infection, Idiopathic, Immunologic10. Amnesia, Autoimmune, Apnea, AAMI11. VA – consider PTSD, Gulf War Syndrome
Alzheimer’s Diseaseversus
Dementia– 50 - 70% of dementias are due to AD– Probable AD - 30% of cases, 90% neuropath - correct
– 20% have other contributing diagnoses
– Possible AD - 40% of cases, 70% are AD at neuropath– 40% have other contributing diagnoses
– Unlikely AD - 30% of cases, 30% are AD at neuropath– 80% have other contributing diagnoses
– Alzheimer’s disease is a pathological condition– Dementia is a clinical condition frequently caused by AD
• The AD dementia has some characteristics and some heterogeneity
UNDERLYING CONTINUUM OF ALZHEIMER SEVERITY
(unidimensional)
• CROSS-SECTIONAL MEASURES– DEMENTIA SEVERITY (cognitive, ADL)
• COGNITIVE SCALE SCORE• Z-SCORE• PRINCIPAL COMPONENT ANALYSIS
– BRAIN ATROPHY, DYSFUNCTION– AUTOPSY MEASURES: plaques, tangles– TIME TO DEATH
• LONGITUDINAL MEASUREMENT– TIME INTO THE DISEASE PROCESS
• CONSIDERABLE HETEROGENEITY IN DISEASE PRESENTATION AND BRAIN DISTRIBUTION
MILD COGNITIVE IMPAIRMENT CRITERIA (Amer. Acad. Neurology)
(Petersen et al., 2001 – Neurology 56:1133)
1. Memory complaint, preferably corroborated by an informant
2. Objective memory impairment3. Normal general cognitive function4. Intact activities of daily living5. Not demented
- Earlier descriptions by: Jonker, Hooyer, 1990 Flicker, Ferris, Reisberg, 1991 Zaudig, 1992
MILD COGNITIVE IMPAIRMENT ISSUES IN DEFINITION
(Petersen et al., 2001 – Neurology 56:1133)
Study Mean Age
Criteria Annual conversion rate to AD %
Mayo 81 MCI 12
Toronto 74 Memory Impairment 14
Columbia
66 Questionable dementia
15
MGH 72 CDR 0.5 6
Seattle 74 Isolated memory loss 12
NYU 71 GDS 3 25
Estimate MMSE as a function of time
0
5
10
15
20
25
30
-10 -8 -6 -4 -2 0 2 4 6 8 10
Estimated years into illness
MM
SE
scor
e
AAMI / MCI DEMENTIA
ALZHEIMER’S DISEASE
Ashford et al., 1995
Age-Associated Memory Impairmentvs
Mild Cognitive Impairment
• Memory declines with age – need to consider relative to APOE genotype!
• Age - related memory decline corresponds with atrophy of the hippocampus
• Older individuals remember more complex items and relationships
• Older individuals are slower to respond• Memory problems predispose to development of
Alzheimer’s disease• Thus --- screening for MCI / early AD must consider age!
– And should consider APOE genotype!
Early Recognition of AD: Consensus Statement(AAGP, AGS, Alzheimer’s Association)
• AD continues to be missed as diagnosis
• AD is unrecognized and under-reported– patients do not realized– families tend to compensate
• Effective treatment and management techniques are available – (AChEIs FDA approved)– Several other approaches are beneficial
Small et al., JAMA, 1997
AD is Underdiagnosed• Early Alzheimer’s disease is subtle – it is easy for
family members and physicians 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
• Undiagnosed AD patients often face avoidable social, financial, and medical problems
• Early diagnosis and appropriate intervention may lessen disease burden
• No definitive laboratory test for diagnosing AD exists
Evans DA. Milbank Quarterly. 1990; 68:267-289
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.
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
• Physical Examination• Neurological Examination• Laboratory Tests• Neuropsychological / Cognitive Assessment
RELATIVE RISK FACTORS FOR ALZHEIMER’S DISEASE
• Family history of dementia 3.5 (2.6 - 4.6)• Family history – Downs 2.7 (1.2 - 5.7)• Family history - Parkinson’s 2.4 (1.0 - 5.8)• Maternal age > 40 years 1.7 (1.0 - 2.9)• Head trauma (with LOC) 1.8 (1.3 - 2.7)• History of depression 1.8 (1.3 - 2.7)• History of hypothyroidism 2.3 (1.0 - 5.4)• History of severe headache 0.7 (0.5 - 1.0)• NSAID use or statin use 0.2 (0.05 – 0.83)
Roca, 1994, t’Veldt, 2002
NEUROPSYCHOLOGICAL TESTING (WAIS, WECHSLER)
• MEMORY: SHORT-TERM, REMOTE• VERBAL FUNCTION, FLUENCY• VISUO-SPATIAL FUNCTION• ATTENTION• EXECUTIVE FUNCTION• ABSTRACT THINKING• ACCOUNT FOR EDUCATION• ACCOUNT FOR PRIOR DISFUNCTIONS
BRIEF CLINICAL TOOLS FOR COGNITIVE
ASSESSMENT• MINI-MENTAL STATE EXAM• CLOCK DRAWING• ANIMAL NAMING (1 minute)• MATTIS DEMENTIA RATING SCALE• ALZHEIMER’S DISEASE
ASSESSEMENT SCALE (ADAS)• ACTIVITIES OF DAILY LIVING• GLOBAL CLINICAL SCALE• CLINICAL DEMENTIA RATING SCALE• GLOBAL DETERIORATION SCALE / FAST
Justification for Brain Scan in Dementia Diagnosis
• Differential Diagnosis: Tumor, Stroke, Subdural Hematoma, Normal Pressure Hydrocephalus, Encephalomalacia
• Confirmation of atrophy pattern• Estimation of severity of brain atrophy• MRI shows T2 white matter changes
– Periventricular, basal ganglia, focal vs confluent– These may indicate vascular pathology
• SPECT, PET - estimation of regions of physiologic dysfunction, areas of infarction
• Helps family to visualize problem
Etiology• Age (initial genesis vs response to stress)
– Bigger factor than for mortality (a = 5 yrs vs 7.5 or 8.2 yrs)– Degree of natural vulnerability of neuroplastic (memory)
systems– Stressor response (pathology - vulnerability during activity of
repair mechanisms): trauma (head injury), vascular (stroke), surgery, loss, grief, etc.
• Genetics (neuroplasticity related - amyloid and cell membrane)– Familial, early onset: APP (21), PS (14, 1) (less than 5%)– Late onset: APOE e4 (ch19) (?50% - 90% of AD)
• relation to brain cholesterol metabolism? – cell membranes• APOE e2 may be most protective
– many other candidate genes
• Relation to vascular factors, cholesterol, BP• Education (more reserve)
– (? design – larger brain vs better development vs protection – wiser choices)
• Environment - diet, exercise, smoking
Genes and Alzheimer’s disease(60% - 80 % of causation)
(all known genes relate to amyloid)
• Familial AD (onset < 60 y/o) (<5%)– Presenilin I, II (ch 14, 1)– APP (ch 21)
• Non-familial (late onset)– APOE
• Clinical studies suggest 40 – 50% due to 4• If 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
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)
GenT %pop %AD #pop #AD risk If all US
E2/2 1% 0.1% 0.5M .004M 0.8% .4 M
E2/3 12 % 4% 5.5M .18M 3.2% 1.5 M
E3/3 60% 35% 27.6M 1.4M 5.1% 2.3 M
E3/4 21% 42% 9.6M 1.7M 18% 8.2 M
E4/4 2% 16% .9M .6M 67% 30.7M
JW Ashford, MD PhD, 2003
Are we ready to do genetic testing to predict AD?
• The family members want it– They consider recommendations against genetic
testing to be “paternalistic”• Family members can make more powerful financial
decisions based on this knowledge than the relevance of insurance companies implementing changes in actuarial calculations
• Those at risk can seek more frequent testing– This is the best opportunity for early recognition
• Those at risk will be better advocates for research• Specific preventive treatments can be developed
for each genetic factor
U.S. Census 2000 by age
0
250,000
500,000
750,000
1,000,000
1,250,000
1,500,000
1,750,000
2,000,000
2,250,000
2,500,000
0 10 20 30 40 50 60 70 80 90 100
Age
# p
eo
ple
Males,138,053,563Females,143,368,343
Total = 281,421,906>60 = 45,809,291>65 = 35,003,844>85 = 4,251,678>100= 62,545
www.census.gov
JW Ashford, MD PhD, 2003
U.S. mortality by age - 1999
0
5,000
10,000
15,000
20,000
25,000
30,000
35,000
40,000
45,000
0 10 20 30 40 50 60 70 80 90 100
Age
Nu
mb
er
of
pe
op
le
Males, 1,175,460
Females, 1,215,939
www.cdc.gov
JW Ashford, MD PhD, 2003
JW Ashford, MD PhD, 2003
U.S. mortality rate by age1999 CDC / 2000 census
0.0001
0.0010
0.0100
0.1000
1.0000
0 10 20 30 40 50 60 70 80 90 100Age
Yea
rly
Haz
ard
Males, 2t = 8.2yrsFemales, 2t = 7.5 yrsAlzheimer incidence
Probability Not Demented
00.10.20.30.40.50.60.70.80.9
1
50 60 70 80 90 100
Age
Pro
po
rtio
n o
f p
op
ula
tio
n
JW Ashford, MD PhD, 2003
U.S. Alzheimer Incidence
(4 million / 8yr)
02000400060008000
10000120001400016000
50 60 70 80 90 100
Age
# /
yr
male=170,603
female=329,115
JW Ashford, MD PhD, 2003
JW Ashford, MD PhD, 2003
(Incidence for a to a + 1 year)
Probability Not Demented
00.10.20.30.40.50.60.70.80.9
1
50 60 70 80 90 100
Age
Pro
po
rtio
n o
f p
op
ula
tio
n
mean rate
APOE 4/4
APOE 3/4
APOE 3/3
JW Ashford, MD PhD, 2003
JW Ashford, MD PhD, 2000
U.S. AD Incidence by APOE(proportion of cases)
00.10.20.30.40.50.60.70.80.9
1
50 60 70 80 90 100Age
Pro
po
rtio
n /
Yea
r 4/4
3/43/3
Probability of Dementia Onset
0
0.01
0.02
0.03
0.04
50 60 70 80 90 100
Age (single mortality correction)
pro
b/ y
r *
live
po
pu
lati
on APOE 4/4-M
APOE 4/4-FAPOE 3/4-MAPOE 3/4-FAPOE 3/3-MAPOE 3/3-F
JW Ashford, MD PhD, 2003
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• Specific treatments now available
– May slow underlying disease process– May delay nursing home placement longer if started
earlier
Need for 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
Need for a Brief Screening Test for 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
Alzheimer Warning SignsTop Ten
Alzheimer Association
1. Recent memory loss affecting job2. Difficulty performing familiar tasks3. Problems with language4. Disorientation to time or place5. Poor or decreased judgment6. Problems with abstract thinking7. Misplacing things8. Changes in mood or behavior9. Changes in personality 10. Loss of initiative
Available Screening Tests• MMSE 10 -- 15 min
• Too long
• 7-Minute Screen 7 – 10 min• Too complex
• Clock Drawing Test 2 – 4 min• Not sensitive
• Mini-cog 3 – 5 min• Complex scoring, unclear adequacy
• Memory Impairment Screen 4 min• Need for slightly shorter, easier test
• (a suitably accurate test that takes less than 2 minutes is not available)
Animals named in 1 min (mms>19) - CERAD data set
0
2
4
6
8
10
12
0 10 20 30 40
number of animals named
pe
rce
nt
of
tota
l
Normal Controls, CS = 1, n = 386
Alzheimer patients, CS = 0, n = 380
Animals named in 30 seconds (mms>19)
0
2
4
6
8
10
12
14
16
0 5 10 15 20 25
number of animals named
pe
rce
nt
of
tota
l
Normal Controls, n=386
Mild Alzheimer Patients, n=380JW Ashford, MD PhD, 2001
Animal naming ROCs (AUC 15: 0.74; 30: 0.83; 45: 0.86; 60: 0.87)
5
6
7
8
7
8
9
10
11
.
10
11
12
13
1415
16 17
0
10
20
30
40
50
60
70
80
90
100
0 10 20 30 40 50 60 70 80 90 100
False Positive Rate (%)
Sen
sitiv
ity (%
) animals in 15 secs
animals in 30 secs
animals in 45 secs
animals in 60 secs
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
0
10
20
30
40
50
60
70
80
90Pe
rcen
t of V
alid
atio
n Sa
mpl
e
3-22 23 24 25 26 27-39
BAS Score
Mild AD
Control
JW Ashford, MD PhD, 2001 Mendiondo et al., 2004
BRIEF ALZHEIMER SCREEN (Normal vs Mild AD, MMS>19)
9
20
1413
1211
10
9
6
7
8
2627
25
0
10
20
30
40
50
60
70
80
90
100
0 10 20 30 40 50 60 70 80 90 100
False Positive Rate (%) (1-Specificity)
Tru
e P
osi
tiv
e R
ate
(%
) (
Se
nsi
tiv
ity)
animals 1 m AUC = 0.868
animals 30 s AUC = 0.828
MMSE AUC = 0.965
Date+3 Rec AUC = 0.875
BAS AUC = 0.983
JW Ashford, MD PhD, 2003
CONCLUSIONS on the BAS
• A single cut-off score provides reasonable sensitivity and specificity for the diagnosis of AD within 2 – 3 minutes
• Two cut-off points divide the population into 3 tiers– the first cut-off indicates a low likelihood of dementia– the second indicates a high likelihood of dementia– the remaining group falls into a ‘gray area’ in need of
closer scrutiny, follow-up, and more extensive testing
• A suitably short screen can be administered yearly to individuals over 60 y/o as a 6th vital sign
• Next direction – use of IRT to locate level of impairment
BLT/Ashford 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• Test is at: www.ibaglobal.com/BLT• For info, new tests, see: www.medafile.com,
www.brainlane.net
