Sex Differences in the Associations between Education, Neuropathology, and Cognition
- 1McGill University
Abstract
IMPORTANCEAutopsy evidence on sex-specific associations of education with neuropathology and cognition is limited.
OBJECTIVETo test sex differences in education associations with neuropathologic burden and cognition.
DESIGNCohort study of data collected from September 2005 through August 2024.
SETTINGMulticenter autopsy cohort from the National Alzheimers Coordinating Center.
PARTICIPANTSAdults aged 55 years or older; cross-sectional eligibility required a final CDR-SB assessment within 2 years before death, and longitudinal eligibility additionally required at least 3 assessments.
EXPOSURESYears of formal education.
MAIN OUTCOMES AND MEASURESNeuropathologic measures and the Clinical Dementia Rating Scale Sum of Boxes (CDR-SB). Linear regression and mixed-effects models tested associations and interactions of education with sex, neuropathology, and linear and quadratic time. Benjamini-Hochberg correction addressed multiple comparisons.
RESULTSAmong 2592 participants (mean [SD] age at death, 81.6 [10.8] years; 1188 [45.8%] female), 1969 contributed to longitudinal analyses. In female participants, higher education was associated with lower Thal amyloid phase, diffuse plaques, neuritic plaques, and Braak stage ({beta} range, -0.097 to -0.071; qFDR<.026); none was significant among male participants. Education-by-sex interactions supported differences in Thal amyloid phase, and diffuse and neuritic plaques ({beta} range, -0.119 to -0.097; qFDR<.045). Education was unrelated to final CDR-SB among female ({beta}, -0.007; 95% CI, -0.052 to 0.038; P=.767) and male participants ({beta}, -0.026; 95% CI, -0.071 to 0.019; P=.254), with no education-by-sex interaction (P=.660). The education-by-Braak-stage-by-sex interaction indicated that higher education was associated with a weaker Braak stage-CDR-SB association among females than males ({beta}, -0.104; 95% CI, -0.171 to -0.038; qFDR=.022). Longitudinally, education was unrelated to linear CDR-SB change in either sex. Education-by-quadratic-time associations were observed among females ({beta}, 0.002; 95% CI, 0.001-0.003; P<.001) and male participants ({beta}, 0.001; 95% CI, 0-0.002; P=.037). The corresponding interaction with sex was also significant (P=.043).
CONCLUSIONS AND RELEVANCEAmong female participants, higher education was associated with lower selected Alzheimers disease neuropathologic measures and weaker associations of tau pathology with cognition. Longitudinal trajectories were nonlinear, with slower earlier decline followed by later acceleration at higher education levels.
Key PointsO_ST_ABSQuestionC_ST_ABSDo associations between education, neuropathologic burden and cognition differ by sex?
FindingsIn this cohort study of 2592 autopsy participants, higher education was associated with lower Alzheimers disease neuropathologic burden among female but not male participants, and education-by-sex interactions were significant for Thal amyloid phase, diffuse and neuritic plaques. Higher education was associated with a weaker Braak stage-CDR-SB association among female than male participants and with lower CDR-SB five years before death in both sexes. The associations persisted after adjustment for neuropathologic burden.
MeaningEducation-neuropathology associations and the clinical expression of neuropathology may be sex-specific.
Related
- Alzheimer’s Disease Neuropathology Plasma Biomarkers and Cognition in a Midlife Diverse Community-Based Cohort
- Blood Biomarkers of Alzheimer's Disease Neuropathology, Cognition, and Response to a Multidomain Lifestyle Intervention: Secondary analysis of the FINGER Randomized Controlled Dementia Risk Reduction Trial
- Genetic Associations with Alzheimer's, Lewy Body and Vascular Neuropathology Reveal Shared and Distinct Biological Pathways
- Fine-mapping HLA-II haplotypes in Alzheimer's disease and healthy longevity reveals distinct associations with microglial HLA-II load and neuropathology
- Associations of Antibodies Against Several Infections With Alzheimer Disease Neuropathology
BibTeX
@misc{raeesi2026differences,
title = {{Sex Differences in the Associations between Education, Neuropathology, and Cognition}},
author = {S. Raeesi and Y. Zeighami and C. Morrison and M. Dadar},
howpublished = {medRxiv},
year = {2026},
month = sep,
doi = {10.64898/2026.09.03.26362216},
url = {https://www.medrxiv.org/content/10.64898/2026.09.03.26362216v1},
note = {CC BY-NC-ND},
}
RIS
TY - UNPB
TI - Sex Differences in the Associations between Education, Neuropathology, and Cognition
AU - S. Raeesi
AU - Y. Zeighami
AU - C. Morrison
AU - M. Dadar
PY - 2026
DA - 2026/09/03
PB - medRxiv
DO - 10.64898/2026.09.03.26362216
UR - https://www.medrxiv.org/content/10.64898/2026.09.03.26362216v1
AB - IMPORTANCEAutopsy evidence on sex-specific associations of education with neuropathology and cognition is limited. OBJECTIVETo test sex differences in education associations with neuropathologic burden and cognition. DESIGNCohort study of data collected from September 2005 through August 2024. SETTINGMulticenter autopsy cohort from the National Alzheimers Coordinating Center. PARTICIPANTSAdults aged 55 years or older; cross-sectional eligibility required a final CDR-SB assessment within 2 years before death, and longitudinal eligibility additionally required at least 3 assessments. EXPOSURESYears of formal education. MAIN OUTCOMES AND MEASURESNeuropathologic measures and the Clinical Dementia Rating Scale Sum of Boxes (CDR-SB). Linear regression and mixed-effects models tested associations and interactions of education with sex, neuropathology, and linear and quadratic time. Benjamini-Hochberg correction addressed multiple comparisons. RESULTSAmong 2592 participants (mean [SD] age at death, 81.6 [10.8] years; 1188 [45.8%] female), 1969 contributed to longitudinal analyses. In female participants, higher education was associated with lower Thal amyloid phase, diffuse plaques, neuritic plaques, and Braak stage ({beta} range, -0.097 to -0.071; qFDR<.026); none was significant among male participants. Education-by-sex interactions supported differences in Thal amyloid phase, and diffuse and neuritic plaques ({beta} range, -0.119 to -0.097; qFDR<.045). Education was unrelated to final CDR-SB among female ({beta}, -0.007; 95% CI, -0.052 to 0.038; P=.767) and male participants ({beta}, -0.026; 95% CI, -0.071 to 0.019; P=.254), with no education-by-sex interaction (P=.660). The education-by-Braak-stage-by-sex interaction indicated that higher education was associated with a weaker Braak stage-CDR-SB association among females than males ({beta}, -0.104; 95% CI, -0.171 to -0.038; qFDR=.022). Longitudinally, education was unrelated to linear CDR-SB change in either sex. Education-by-quadratic-time associations were observed among females ({beta}, 0.002; 95% CI, 0.001-0.003; P<.001) and male participants ({beta}, 0.001; 95% CI, 0-0.002; P=.037). The corresponding interaction with sex was also significant (P=.043). CONCLUSIONS AND RELEVANCEAmong female participants, higher education was associated with lower selected Alzheimers disease neuropathologic measures and weaker associations of tau pathology with cognition. Longitudinal trajectories were nonlinear, with slower earlier decline followed by later acceleration at higher education levels. Key PointsO_ST_ABSQuestionC_ST_ABSDo associations between education, neuropathologic burden and cognition differ by sex? FindingsIn this cohort study of 2592 autopsy participants, higher education was associated with lower Alzheimers disease neuropathologic burden among female but not male participants, and education-by-sex interactions were significant for Thal amyloid phase, diffuse and neuritic plaques. Higher education was associated with a weaker Braak stage-CDR-SB association among female than male participants and with lower CDR-SB five years before death in both sexes. The associations persisted after adjustment for neuropathologic burden. MeaningEducation-neuropathology associations and the clinical expression of neuropathology may be sex-specific.
ER -