1. 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)

2. 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

3. Estimating Age of Onset Clinical history Asking family members (considerable consistency, unclear validity) Review of old medical records Estimation of dementia severity Time-index back calculation to onset Functional brain scan severity analysis Back calculation to onset

4. 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 (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)

5. Relation of SPECT severity to duration of dementia (years) Shih et al., 2000 SPECT severitySPECT gradeDementia Duration Normal00 Near-Normal11 Mild22 Mild-moderate33 Moderate44 Moderate-severe55 Severe66 Severe-profound77 Profound88

6. Factors Influencing Variation in Age of Onset Genetics (especially APOE), family history Neurological factors Stroke Brain injury Medical factors Vascular disease Medications: NSAIDS, statins, female HRT Education Gender Ageism (more concern for younger individuals)

7. 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

8. 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

9. 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) = 188,000 4% of 70 - 75 ( 8.7m) = 350,000 8% of 75 - 80 ( 7.4m) = 595,000 16% of 80 - 85 ( 5.0m) = 800,000

10. Yesavage et al., 2002

11. RELATIVE RISK FACTORS FOR ALZHEIMER’S DISEASE Family history of dementia3.5 (2.6 - 4.6) Family history - Downs 2.7 (1.2 - 5.7) Family history - Parkinson’s2.4 (1.0 - 5.8) Maternal age > 40 years1.7 (1.0 - 2.9) Head trauma (with LOC)1.8 (1.3 - 2.7) History of depression1.8 (1.3 - 2.7) History of hypothyroidism2.3 (1.0 - 5.4) History of severe headache0.7 (0.5 - 1.0) Roca, 1994

12. 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)

13. 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

14. 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)

15. Study Patients (n = 54) APOE genotype Possible AD Probable AD Definite AD Dementia NOS  2/3 21  2/4 1  3/3 1055  3/4 7733  4/4 4132

16. 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 NumberMean age of onset (years) Standard deviation (years  3/3 2073.64.7  3/4 2069.56.7  4/4 1068.35.6 MALE VETERANS - Memory Disorders Clinic; n=50

17. 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

18. 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

19. APOE AND CHOLESTEROL CHOLESTEROL METABOLISM IS A CENTRAL PART OF SYNAPTIC PLASTICITY (Koudinov & Koudinov, 2001)

20. BIOPSYCHOSOCIAL SYSTEMS AFFECTED BY AD NEUROPLASTIC 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

21. 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.

22. 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

23. 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.

24. 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/BLTwww.ibaglobal.com/BLT For info, see: www.medafile.comwww.medafile.com