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

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

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

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

5. 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? Background

6. Sources of bias in clinical studies 1.Men more often diagnosed with vascular dementia 2.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. Neuropathological features of AD Neurofibrillary tangles (NFT) Amyloid- deposition (A)

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

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

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

12. Proportion attaining NFT Stages I,II, & III 0 0.25 0.5 0.75 1 5565758595 Age (years) Proportion Stage I Stage II Stage III

13. NFT Stage for Men & Women 1 2 3 5565758595 Age (years) Mean NFT Stage Men Women

14. APOE genotype and NT stage

15. A  Stage for Men & Women 0 1 2 5565758595 Age (years) Mean A Stage 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  (SE)p-value Intercept 0.16 (0.04)<0.0001 Decade of age*NFT stage 0.11 (0.006)<0.0001 Number of  4 alleles 0.30 (0.07)<0.0001 APOE  4 gene dose for women aged 60 to 75 0.65 (0.18) 0.0002 One or two  2 alleles-0.13 (0.08) 0.11 SP stage for isocortical NFT stages IV to VI Predictor  (SE)p-value Intercept 2.18 (0.25)<0.0001 Decade of agefrom 50 to 99-0.01 (0.03) 0.77 NFT stage 0.15 (0.05) 0.002 Number of APOE  4 alleles 0.09 (0.06) 0.15 One or two APOE  2 alleles-0.15 (0.05) 0.002

18. Table 2. APOE genotype and selective mortality Age (years)  2/-  3/3  3/4  4/4 Total 20-59 11% ( 44)63% (259)22% ( 92)4% (16) 411 60-6913% ( 30)66% (151)18% ( 42)3% ( 7) 230 70-7913% ( 32)62% (151)21% ( 50)4% (10) 243 80-8914% ( 51)63% (232)21% ( 78)1% ( 5) 366 90-10518% ( 13)62% ( 45)20% ( 15)0% ( 0) 73 Sample 13% (170)63% (838)21% (277)3% (38)1323 Germany4515%60%28% were  4/- 1031 Germany4616%61%25% were  4/- 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