Gender Difference in Alzheimer’s Disease Neuropathology

EH Corder, E Ghebremedhin, M Taylor, DR Thal, TG Ohm, H Braak

Dr. Senckenbergische AnatomieDepartment of Clinical Neuroanatomy

J. W. Goethe-University Frankfurt/Main, Germany

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

Definition

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

30-5960-64

65-6970-74

75-7980-84

85-8990+

Population Affected

Pre

vale

nce

of

AD

(%

)

Age (Years)

Risk Factors

• Advanced age

• 4-allele of apolipoprotein E-Gene (ApoE)

• Female gender?

• 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

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

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?

Neuropathological features of AD

Neurofibrillary tangles (NFT) Amyloid- deposition (A)

Braak and Braak 1991

A-Stage A A-Stage B A-Stage C

Amyloid = A

Neuropathological staging of AD I

NFT-Stages I-II (Entorhinal stages)

NFT-Stages III-IV(Limbic stages)

NFT-Stages V-VI (Neocortical stages)

Braak and Braak 1991Neurofibrillary tangles = NFT

Neuropathological staging of AD II

• 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

Proportion attaining NFT Stages I,II, & III

0

0.25

0.5

0.75

1

55 65 75 85 95

Age (years)

Pro

port

ion

Stage I

Stage II

Stage III

NFT Stage for Men & Women

1

2

3

55 65 75 85 95

Age (years)

Mean

NFT

Sta

ge

Men

Women

0

1

2

3

4

50 60 70 80

Age (years)

NF

T S

tag

e

2/3 w 3/3 w 3/4 w

2/3 m 3/3 m 3/4 m

APOE genotype and NT stage

A Stage for Men & Women

0

1

2

55 65 75 85 95

Age (years)

Mean

A

Sta

ge

MenWomen

0

1

2

3

0 1 2 3 4 5 6

NFT stage

SP

sta

ge

45 55 65 75 85 95

SP stage given NFT stage for women

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-valueIntercept 0.16 (0.04) <0.0001Decade of age*NFT stage 0.11 (0.006) <0.0001Number of 4 alleles 0.30 (0.07) <0.0001APOE 4 gene dose for women aged 60 to 75 0.65 (0.18) 0.0002One or two 2 alleles -0.13 (0.08) 0.11 SP stage for isocortical NFT stages IV to VIPredictor (SE) p-valueIntercept 2.18 (0.25) <0.0001Decade of age from 50 to 99 -0.01 (0.03) 0.77NFT stage 0.15 (0.05) 0.002Number of APOE 4 alleles 0.09 (0.06) 0.15One or two APOE 2 alleles -0.15 (0.05) 0.002

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) 41160-69 13% ( 30) 66% (151) 18% ( 42) 3% ( 7) 23070-79 13% ( 32) 62% (151) 21% ( 50) 4% (10) 243

80-89 14% ( 51) 63% (232) 21% ( 78) 1% ( 5) 36690-105 18% ( 13) 62% ( 45) 20% ( 15) 0% ( 0) 73

Sample 13% (170) 63% (838) 21% (277) 3% (38) 1323

Germany45 15% 60% 28% were 4/- 1031Germany46 16% 61% 25% were 4/- 1557

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

Conclusion

•The pathologic substrate for dementia may differ for men and women

– Older women likely have greater losses of hippocampal pyramidal neurons