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Updated: Mar 16, 2026
Author Spotlight: Exploring Sex-Specific Glial Signatures and Therapeutic Leads for Alzheimer's Disease
Published on: May 20, 2024
APOE-mediated sex differences in microvascular pathology and AD-associated proteinopathies in the medial temporal
Francesco Bax1,2, Jan Oltmer3, Corinne A Auger4,5
1J. Philip Kistler Stroke Research Center, Department of Neurology, Harvard Medical School, Massachusetts General Hospital, Boston, Massachusetts, USA.
Introduction:
Cerebral small vessel disease (CSVD) contributes to the development of Alzheimer's disease (AD) dementia and co-occurs with AD-associated proteinopathies. However, how sex modulates the interaction between CSVD and AD-associated proteinopathies in the medial temporal lobe (MTL) remains unclear.
Methods:
One hundred fifty-two autopsy cases from the Massachusetts Alzheimer's Disease Research Center were included. Deep-learning and semiquantitative scores were applied to MTL histological sections to obtain quantitative measures of proteinopathies and CSVD (cerebral amyloid angiopathy [CAA] and arteriolosclerosis). The effect of sex on AD-associated proteinopathies and the interaction between sex, CSVD, and apolipoprotein E (APOE) genotype were analyzed using linear mixed-effect models.
Results:
In women, higher CAA burden was associated with lower amyloid beta (Aβ) plaques but higher tau tangles density. No interaction effect was found for arteriolosclerosis. Women <75 years of age carrying the APOE ε4 allele had higher Aβ plaque burden than ε4 non-carriers.
Discussion:
Our results highlight the complex effect of sex on microvascular and AD-associated pathologies in the MTL.
Insights
Sex influences Alzheimer's disease (AD) pathologies in the medial temporal lobe. Women with cerebral amyloid angiopathy (CAA) had less amyloid beta (Aβ) but more tau tangles, highlighting sex-specific AD progression.
Area of Science:
- Neuropathology
- Neurodegenerative Diseases
- Vascular Dementia
Background:
- Cerebral small vessel disease (CSVD) is a known contributor to Alzheimer's disease (AD) dementia.
- CSVD often co-occurs with AD-associated proteinopathies.
- The modulating role of sex in the interaction between CSVD and AD pathologies in the medial temporal lobe (MTL) is not well understood.
Purpose of the Study:
- To investigate the effect of sex on AD-associated proteinopathies.
- To analyze the interaction between sex, CSVD, and apolipoprotein E (APOE) genotype in the MTL.
Main Methods:
- Analysis of 152 autopsy cases from the Massachusetts Alzheimer's Disease Research Center.
- Application of deep-learning and semiquantitative scores to MTL histological sections.
- Quantitative measurement of proteinopathies and CSVD (cerebral amyloid angiopathy [CAA] and arteriolosclerosis).
- Linear mixed-effect models used to analyze the effects of sex, CSVD, and APOE genotype.
Main Results:
- In women, increased CAA burden correlated with decreased amyloid beta (Aβ) plaques but increased tau tangles density.
- Arteriolosclerosis showed no interaction effect with sex.
- Younger women (<75 years) with the APOE ε4 allele had a higher Aβ plaque burden compared to non-carriers.
Conclusions:
- Sex exerts a complex influence on the interplay between microvascular disease and AD-associated pathologies in the MTL.
- Findings suggest sex-specific mechanisms in AD pathogenesis involving vascular and proteinopathy interactions.
