Transcript Gender Difference in Alzheimer‘s Disease Neuropathology

Dr. Senckenbergische Anatomie
Department of Clinical Neuroanatomy
J. W. Goethe-University
Frankfurt/Main, Germany
Gender Difference in Alzheimer’s
Disease Neuropathology
EH Corder, E Ghebremedhin, M Taylor, DR Thal, TG Ohm,
H Braak
Definition
Alzheimer’s Disease (AD) is a progressive,
neurodegenerative disorder, characterized by
loss of memory and other cognitive abilities
Prevalence of AD with Age
35
Population Affected
Prevalence of AD (%)
30
25
20
15
10
5
0
Age (Years)
Source: The prevalence of AD in Europe: A collaborative study of 19801990 findings (EURODEM)
Risk Factors
• Advanced age
•
4-allele of apolipoprotein E-Gene (ApoE)
• Female gender?
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?
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)
Neuropathological staging of AD I
A-Stage A
Amyloid  = A
A-Stage B
A-Stage C
Braak and Braak 1991
Neuropathological staging of AD II
NFT-Stages I-II
(Entorhinal stages)
NFT-Stages III-IV
(Limbic stages)
Neurofibrillary tangles = NFT
NFT-Stages V-VI
(Neocortical stages)
Braak and Braak 1991
Study sample and methods
• 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
Proportion attaining
NFT Stages I,II, & III
1
Stage I
Stage II
Proportion
0.75
Stage III
0.5
0.25
0
55
65
75
85
Age (years)
95
NFT Stage for Men & Women
3
Women
Mean NFT Stage
Men
2
1
55
65
75
Age (years)
85
95
APOE genotype and NT stage
4
NFT Stage
3
2
1
0
50
60
70
80
Age (years)
2/3 w
3/3 w
3/4 w
2/3 m
3/3 m
3/4 m
A Stage for Men & Women
Mean A Stage
2
Women
Men
1
0
55
65
75
85
Age (years)
95
SP stage given NFT stage for women
SP stage
3
2
1
0
0
1
2
3
4
5
85
95
NFT stage
45
55
65
75
6
Table 1. SP stage in relation to NFT stage, age, gender and APOE genotype
SP stage at allocortical NFT stages 0 to III
Predictor
Intercept
Decade of age*NFT stage
Number of 4 alleles
APOE 4 gene dose for women aged 60 to 75
One or two 2 alleles
 (SE)
0.16 (0.04)
0.11 (0.006)
0.30 (0.07)
0.65 (0.18)
-0.13 (0.08)
p-value
<0.0001
<0.0001
<0.0001
0.0002
0.11
SP stage for isocortical NFT stages IV to VI
Predictor
Intercept
Decade of age from 50 to 99
NFT stage
Number of APOE 4 alleles
One or two APOE 2 alleles
 (SE)
2.18 (0.25)
-0.01 (0.03)
0.15 (0.05)
0.09 (0.06)
-0.15 (0.05)
p-value
<0.0001
0.77
0.002
0.15
0.002
Table 2. APOE genotype and selective mortality
Age (years)
2/-
3/3
20-59
60-69
70-79
11% ( 44) 63% (259) 22% ( 92) 4% (16)
13% ( 30) 66% (151) 18% ( 42) 3% ( 7)
13% ( 32) 62% (151) 21% ( 50) 4% (10)
411
230
243
80-89
90-105
14% ( 51) 63% (232) 21% ( 78) 1% ( 5)
18% ( 13) 62% ( 45) 20% ( 15) 0% ( 0)
366
73
Sample
13% (170) 63% (838) 21% (277) 3% (38)
1323
Germany45
Germany46
15%
16%
60%
61%
3/4
4/4
28% were 4/25% were 4/-
Total
1031
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