Post on 14-Dec-2015
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 Deficits1. Memory Impairment 2. Other Cognitive Impairment
B. Deficits Impair Social/Occupational C. Course Shows Gradual Onset And DeclineD. Deficits Are Not Due to:
1. Other CNS Conditions2. Substance Induced Conditions
E. Do Not Occur Exclusively during DeliriumF. Not Due to Another Psychiatric Disorder
Estimating Age of Onset
Clinical historyAsking family members
(considerable consistency, unclear validity)Review of old medical records
Estimation of dementia severityTime-index back calculation to onset
Functional brain scan severity analysisBack calculation to onset
AssessmentHistory Of The Development Of The Dementia
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 historyNeurological factors Stroke Brain injury
Medical factors Vascular disease Medications: NSAIDS, statins, female HRT
EducationGenderAgeism (more concern for younger individuals)
Problem of Pre-Alzheimer Condition
Mild Cognitive Impairment (MCI) may = early Alzheimer’s disease
MCI =1. Memory complaint2. Objective memory assessment showing dysfunction3. No impairment in daily living skills4. If memory impairment is not present, one other
cognitive domain shows dysfunction
Presymptomatic AD?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 (prevalence)1% of 60 - 65 (10.7m) = 107,000 2% of 65 - 70 ( 9.4m) = 188,0004% of 70 - 75 ( 8.7m) = 350,0008% of 75 - 80 ( 7.4m) = 595,00016% of 80 - 85 ( 5.0m) = 800,000
0%
10%
20%
30%
40%
50%
60%
70%
80%
90%
100%
Age
Perc
enta
ge AD
MCI
Non-Affected
Yesavage et al., 2002
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)Roca, 1994
ETIOLOGY - considerations (AD is a disease of cerebral memory mechanisms
Ashford & Jarvik, 1985)
GENETICSAPO-E (19) – e4 accounts for 50% cases IDE? (10), APP (21), PS (14,1)
EDUCATION (? design vs protection)MEDICAL STRESSES
cerebrovascular disease, surgeryENVIRONMENTAL STRESSORS
trauma, loss, ?aluminum, ? virusesENVIRONMENTAL FACTORS
diet, exercise, smoking (? nicotine)
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 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
Study Patients (n = 54)APOE genotype
Possible AD
Probable AD
Definite AD
Dementia NOS
2/3 2 1
2/4 1
3/3 10 5 5
3/4 7 7 3 3
4/4 4 1 3 2
Age at Onset (Hx, MMSE, SPECT)age of onset for 3/3 vs 4/4, p<0.02; for 3/3 vs 3/4, p<0.05
(Ashford, Kindy, Shih, Aleem, Cobb, Tsanatos, Cool)
APOE genotype
Number Mean age of onset (years)
Standard deviation (years
3/3 20 73.6 4.7
3/4 20 69.5 6.7
4/4 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%) (Pygmies - Sardinians)
e4 -- 15% of the population (5% - 41%) (Mayans - Pygmies)
(Fullerton et al., 2000)
3/3 - average age of onset = 74 y/o
3/4 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 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 ADNEUROPLASTIC MECHANISMS AFFECTED AT ALL LEVELS
(Ashford, Mattson, Kumar, 1998)
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
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 calculationsThose at risk can seek more frequent testing This is the best opportunity for early recognition
Those at risk will be better advocates for researchSpecific 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)
New test to screen patients for Alzheimer’s disease using the World-Wide Web – based testing
Test only takes 1-minute
Test can be repeated often (quarterly)
Any change over time can be detected
Test is at: www.ibaglobal.com/BLT
For info, see: www.medafile.com