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.

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