Dr. Senckenbergische Anatomie Department of Clinical Neuroanatomy

1. Dr. Senckenbergische Anatomie Department of Clinical Neuroanatomy J. W. Goethe-University Frankfurt/Main, Germany Gender Difference in Alzheimer’s Disease NeuropathologyEH Corder, E Ghebremedhin, M Taylor, DR Thal, TG Ohm, H Braak

2. Definition Alzheimer’s Disease (AD) is a progressive, neurodegenerative disorder, characterized by loss of memory and other cognitive abilities

3. Population Affected 35 30 25 20 15 Prevalence of AD (%) 10 5 0 90+ 85-89 75-79 80-84 30-59 60-64 65-69 70-74 Age (Years) Prevalence of AD with Age Source: The prevalence of AD in Europe: A collaborative study of 1980-1990 findings (EURODEM)

4. Risk Factors • Advanced age • 4-allele of apolipoprotein E-Gene (ApoE) • Female gender?

5. Background • Prevalence: About 2-3 times as many women as men have AD-- Women live longer. • Incidence: Are women at higher risk at each age? • Does gender make a difference in the pathogenesis of AD?

6. Sources of bias in clinical studies • Men more often diagnosed with vascular dementia • Women live longer from the onset of symptoms until diagnosis • 3. Women more often live alone lacking social and instrumental support triggering diagnosis

7. Objective To compare AD changes for men and women at each age. Are women more susceptible? Do men and women have the same pathologic substrate for AD dementia?

8. Amyloid- deposition (A) Neurofibrillary tangles (NFT) Neuropathological features of AD

9. A-Stage A A-Stage B A-Stage C Neuropathological staging of AD I Amyloid  = A Braak and Braak 1991

10. NFT-Stages I-II (Entorhinal stages) NFT-Stages III-IV (Limbic stages) NFT-Stages V-VI (Neocortical stages) Neuropathological staging of AD II Braak and Braak 1991 Neurofibrillary tangles = NFT

11. Study sample and methods • 5615 (3165 men and 2450 women) consecutive autopsy cases aged 20 – 105 years • All brains were assessed forNFT- and A- pathology • Linear regression analysis was used to predict stage by age and gender

12. 1 Stage I Stage II 0.75 Stage III 0.5 Proportion 0.25 0 55 65 75 85 95 Age (years) Proportion attaining NFT Stages I,II, & III

13. 3 Women Men 2 Mean NFT Stage 1 55 65 75 85 95 Age (years) NFT Stage for Men & Women

14. APOE genotype and NT stage

15. 2 Women Men 1 Mean A Stage 0 55 65 75 85 95 Age (years) A Stage for Men & Women

16. SP stage given NFT stage for women

17. Table 1. SP stage in relation to NFT stage, age, gender and APOE genotype SP stage at allocortical NFT stages 0 to III Predictor b (SE) p-value Intercept 0.16 (0.04) <0.0001 Decade of age*NFT stage 0.11 (0.006) <0.0001 Number of e4 alleles 0.30 (0.07) <0.0001 APOE e4 gene dose for women aged 60 to 75 0.65 (0.18) 0.0002 One or two e2 alleles -0.13 (0.08) 0.11 SP stage for isocortical NFT stages IV to VI Predictor b (SE) p-value Intercept 2.18 (0.25) <0.0001 Decade of age from 50 to 99 -0.01 (0.03) 0.77 NFT stage 0.15 (0.05) 0.002 Number of APOE e4 alleles 0.09 (0.06) 0.15 One or two APOEe2 alleles -0.15 (0.05) 0.002

18. Table 2. APOE genotype and selective mortality Age (years) e2/- e3/3 e3/4 e4/4 Total 20-59 11% ( 44) 63% (259) 22% ( 92) 4% (16) 411 60-69 13% ( 30) 66% (151) 18% ( 42) 3% ( 7) 230 70-79 13% ( 32) 62% (151) 21% ( 50) 4% (10) 243 80-89 14% ( 51) 63% (232) 21% ( 78) 1% ( 5) 366 90-105 18% ( 13) 62% ( 45) 20% ( 15) 0% ( 0) 73 Sample 13% (170) 63% (838) 21% (277) 3% (38) 1323 Germany45 15% 60% 28% were e4/- 1031 Germany46 16% 61% 25% were e4/- 1557

19. Summary • Women have a 3-year acceleration in tangle neuropathology associated with APOE4 • APOE4+ women have a large jump in senile plaque distribution in late middle age

20. Conclusion • The pathologic substrate for dementia may differ for men and women • Older women likely have greater losses of hippocampal pyramidal neurons