Transcript A MINUTE ALZHEIMER SCREEN

APOE Genotype Effects on
Alzheimer’s Disease Clinical
Onset, Epidemiology, and
Gompertzian Aging Functions
J.Wesson Ashford, M.D., Ph.D.
Stanford / VA Alzheimer Center
Palo Alto, CA
New York Academy of Sciences
May 29-30, 2003
(several slides removed to save space, see other lectures)
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
Estimating Age of Onset
Clinical history

Asking family members
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(considerable consistency, unclear validity)
Review of old medical records
Estimation of dementia severity

Time-index back calculation to onset
Functional brain scan severity analysis
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Back calculation to onset
Assessment
History Of The Development Of The Dementia
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Ask the Patient What Problem Has Brought Him to See You
Ask the Family, Companion about the Problem (necessary)
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
Ask about the current level of difficulties
Review of old medical records
Psychological Exam (MMSE)
SPECT scan (ECD)
Relation of SPECT severity to
duration of dementia (years)
Shih et al., 2000
SPECT severity SPECT grade Dementia Duration
Normal
0
0
Near-Normal
1
1
Mild
2
2
Mild-moderate
3
3
Moderate
4
4
Moderate-severe
5
5
Severe
6
6
Severe-profound
7
7
Profound
8
8
Factors Influencing
Variation in Age of Onset
Genetics (especially APOE), family history
Neurological factors

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Stroke
Brain injury
Medical factors


Vascular disease
Medications: NSAIDS, statins, female HRT
Education
Gender
Ageism (more concern for younger individuals)
Problem of Pre-Alzheimer
Condition
Mild Cognitive Impairment (MCI) may
= early Alzheimer’s disease
MCI =
1. Memory complaint
2. Objective memory assessment showing
dysfunction
3. No impairment in daily living skills
4. If memory impairment is not present, one
other cognitive domain shows dysfunction
Presymptomatic AD?
12% of ‘normal’ elderly meet NIA-RI
criteria for AD. These individuals show
memory declines 3 years before death
-- Schmitt, et al., 2000, Neurology
~60% of cases with questionable
dementia (CDR=0.5) progress to clinical
AD over a three year interval.
-- Morris et al., 2001, Archives of Neurology
MCI appears to be early AD
PREVALENCE
Estimated 4 million cases in US (2000)

(2000 - 46 million individuals over 60 y/o)
Age is the main factor associated with AD
Increase with age
1% of
 2% of
 4% of
 8% of
 16% of

60 - 65
65 - 70
70 - 75
75 - 80
80 - 85
(10.7m)
( 9.4m)
( 8.7m)
( 7.4m)
( 5.0m)
(prevalence)
=
=
=
=
=
107,000
188,000
350,000
595,000
800,000
100%
90%
80%
60%
AD
MCI
Non-Affected
50%
40%
30%
20%
10%
Age
84
82
80
78
76
74
72
70
68
66
64
62
0%
60
Percentage
70%
Yesavage et al., 2002
RELATIVE RISK FACTORS
FOR ALZHEIMER’S
DISEASE
Family history of dementia
Family history - Downs
Family history - Parkinson’s
Maternal age > 40 years
Head trauma (with LOC)
History of depression
History of hypothyroidism
History of severe headache
3.5 (2.6 - 4.6)
2.7 (1.2 - 5.7)
2.4 (1.0 - 5.8)
1.7 (1.0 - 2.9)
1.8 (1.3 - 2.7)
1.8 (1.3 - 2.7)
2.3 (1.0 - 5.4)
0.7 (0.5 - 1.0)
Roca, 1994
ETIOLOGY -
considerations
(AD is a disease of cerebral memory mechanisms
Ashford & Jarvik, 1985)
GENETICS
 APO-E (19) – e4 accounts for 50% cases
 IDE? (10), APP (21), PS (14,1)
EDUCATION (? design vs protection)
MEDICAL STRESSES
 cerebrovascular disease, surgery
ENVIRONMENTAL STRESSORS
 trauma, loss, ?aluminum, ? viruses
ENVIRONMENTAL FACTORS
 diet, exercise, smoking (? nicotine)
Genes and Alzheimer’s disease
(60% - 80 % of causation)
(all known genes relate to bamyloid)
Familial AD (onset < 60 y/o) (<5%)
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Presenilin I, II (ch 14, 1)
APP (ch 21)
Non-familial (late onset)
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APOE
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Clinical studies suggest 40 – 50% due to e4
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 risk
46 Million in US > 60 y/o //// 4 Million have AD
(data from Saunders et al., 1993; Farrer et al., 1997)
GenT %pop %AD
#pop
E2/2
0.5M .004M 0.8%
.4 M
5.5M .18M 3.2%
1.5 M
1% 0.1%
4%
#AD
risk If all US
E2/3
12 %
E3/3
60%
35% 27.6M 1.4M 5.1%
2.3 M
E3/4
21%
42%
8.2 M
E4/4
2%
16%
9.6M 1.7M 18%
.9M
.6M 67%
30.7M
Study Patients (n = 54)
APOE
Possible
genotype AD
e2/3
Probable Definite
AD
AD
2
Dementia
NOS
1
e2/4
1
e3/3
10
5
e3/4
7
7
3
3
e4/4
4
1
3
2
5
Age at Onset
(Hx, MMSE, SPECT)
age of onset for e3/3 vs e4/4, p<0.02; for e3/3 vs e3/4, p<0.05
(Ashford, Kindy, Shih, Aleem, Cobb, Tsanatos, Cool)
APOE
Number
genotype
Mean age Standard
of onset deviation
(years)
(years
e3/3
20
73.6
4.7
e3/4
20
69.5
6.7
e4/4
10
68.3
5.6
MALE VETERANS - Memory Disorders Clinic; n=50
APO-E genotype and AD
onset
e2 -- 7% of the population
e3 -- 78% of the population (54% - 91%)
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(Pygmies - Sardinians)
e4 -- 15% of the population (5% - 41%)
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(Mayans - Pygmies)
(Fullerton et al., 2000)
e3/3 - average age of onset = 74 y/o
e3/4 and e4/4 average age = 69 y/o
APOE AND EVOLUTION
DOES APOE- e2 or e3 DO A SAFER JOB OF
SUPPORTING THE REMODELLING OF
DENDRITES, TO MINIMIZE THE STRESS ON
THE NEURON OVER TIME?
DEMENTED ELDERLY CAN NOT FOSTER
THEIR YOUNG OR COMPETE
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APOE AS AN AGENT TO SUPPORT SUCCESSFUL
AGING IN GRANDMOTHERS
APOE AS AN AGENT TO SUPPORT THE
DOMINANCE OF ELDERLY MALES
APOE AND
CHOLESTEROL
CHOLESTEROL METABOLISM IS A
CENTRAL PART OF SYNAPTIC
PLASTICITY (Koudinov & Koudinov, 2001)
BIOPSYCHOSOCIAL SYSTEMS AFFECTED BY AD
NEUROPLASTIC MECHANISMS AFFECTED AT ALL LEVELS
(Ashford, Mattson, Kumar, 1998)
SOCIAL SYSTEMS
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INSTRUMENTAL ADLs - EARLY
BASIC ADLs - LATE
PSYCHOLOGICAL SYSTEMS
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PRIMARY LOSS OF SHORT-TERM MEMORY
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LEARNING PROCESSES – CLASSICAL, OPERANT
LATER LOSS OF LEARNED SKILLS
NEURONAL MEMORY SYSTEMS
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CORTICAL GLUTAMATERGIC STORAGE
SUBCORTICAL
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(acetylcholine, norepinephrine, serotonin)
CELLULAR PLASTIC PROCESSES
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APP metabolism – early, broad cortical distribution
TAU hyperphosphorylation – late, focal effect, dementia related
Implications of Genotype
for Alzheimer diagnosis
APOE genotype provides major information
about an individuals risk of developing
Alzheimer’s disease!!
APOE genotype can strengthen or weaken
diagnostic considerations, particularly in
individuals with estimated age of onset less than
70 years of age.
APOE genotype may influence the relevance of
certain factors for prevention and treatment.
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
CONCLUSION
Non-familial AD is mainly caused by genetic factors.
APOE-e4 accounts for at least 50% of AD.
APOE genotype relative to e2 may explain more than
95% of AD cases.
Several other genetic factors account for an
additional proportion of AD.
Environmental factors are likely to cause neural injury
which leads to an unmasking and enhancement of
AD symptoms, affecting the probability of developing
and age of onset of AD.
BLT/Ashford Memory Test
(to detect AD onset)
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