Highlight
• Higher parity interacts with amyloid pathology to exacerbate cognitive decline in cognitively unimpaired postmenopausal women.
• Women with positive CSF β-amyloid biomarkers and greater parity show reduced hippocampal volume over time.
• Parity may influence brain resilience to Alzheimer’s disease (AD) pathology in preclinical stages.
• These findings have implications for understanding sex-specific factors affecting AD progression.
Study Background
Alzheimer’s disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline and brain atrophy, notably in the hippocampus. Epidemiological studies have indicated mixed outcomes regarding the role of reproductive history, specifically parity (number of childbirths), on AD risk. While some suggest parity confers protective effects, others report increased vulnerability. The biological and hormonal changes associated with pregnancy and childbirth may influence brain aging processes and neurodegeneration risk, yet their interaction with established AD pathology such as β-amyloid (Aβ) deposition remains poorly understood. This study addresses the gap by exploring how parity modulates the impact of AD pathology on cognition and hippocampal atrophy in cognitively unimpaired postmenopausal women.
Study Design
This observational study analyzed data from the ALFA+ cohort at the BarcelonaBeta Brain Research Center involving cognitively unimpaired postmenopausal women aged 49.2 to 73.4 years (mean 61.2). Participants completed one or two visits spaced approximately three years apart, with comprehensive reproductive histories, cognitive assessments using the modified Preclinical Alzheimer’s Cognitive Composite (mPACC), cerebrospinal fluid (CSF) biomarker analysis for Aβ42/Aβ40 ratio to determine amyloid status, and structural MRI for hippocampal volume (HV) measurement. Linear mixed-effects models were used to evaluate the interactive effects of parity, Aβ status, and time on cognition and HV. Covariates adjusted for include APOE-ε4 genotype, age, and total intracranial volume.
Key Findings
A total of 254 cognitively unimpaired postmenopausal women were included. Amyloid positivity was determined based on CSF Aβ42/Aβ40 ratios, serving as a biomarker for AD pathology. A significant interaction was observed between parity and amyloid status on both cognitive decline and hippocampal volume over time.
Specifically, in amyloid-positive women, higher parity was linked with a steeper rate of cognitive decline (β = -0.035, 95% CI -0.068 to -0.003, p = 0.033) as measured by mPACC scores longitudinally. Concurrently, these women exhibited lower hippocampal volume across visits (β = -0.134, 95% CI -0.263 to -0.005, p = 0.036), indicating greater neurodegeneration. Conversely, no significant effect of parity was found on cognition or hippocampal volume trajectories in amyloid-negative women.
This suggests that parity interacts with underlying AD pathology to influence early neurodegenerative changes and cognitive trajectories even before clinical symptoms manifest. Notably, the study accounted for genetic risk (APOE-ε4) and intracranial volume, reinforcing the robustness of these associations.
Expert Commentary
This study advances understanding of how reproductive factors influence AD-related brain aging by demonstrating that parity may diminish resilience to amyloid pathology in preclinical AD stages. The findings highlight the importance of considering sex-specific biological and reproductive history factors in AD risk stratification and early intervention strategies.
Hormonal fluctuations during pregnancy, including exposure to estrogens, progesterone, and other neuroactive steroids, could modulate brain plasticity and inflammatory pathways, potentially altering vulnerability to amyloid-related neurotoxicity. Additionally, the metabolic and vascular adaptations of pregnancy might impact hippocampal integrity over the long term.
Limitations include the observational nature, potential residual confounding by other reproductive or lifestyle factors, and restriction to cognitively unimpaired postmenopausal women limiting generalizability. Further research is needed to elucidate mechanistic pathways and explore if parity influences progression in symptomatic AD populations.
Conclusion
The study underlines parity as a significant modifier of the impact of β-amyloid pathology on cognitive decline and hippocampal atrophy in postmenopausal women. These findings suggest reproductive history should be integrated into clinical and research frameworks addressing AD risk, particularly in women. Enhanced understanding of parity’s role could lead to personalized risk profiling and potential development of targeted neuroprotective interventions in women vulnerable to AD.
Future investigations might explore interaction with other AD biomarkers, longitudinal reproductive hormone monitoring, and potential therapeutic implications of modifying hormonal or metabolic pathways related to parity history.
Funding and ClinicalTrials.gov
The ALFA+ study is supported by multiple grants and foundations under the BarcelonaBeta Brain Research Center. Specific funding details were not indicated in the abstract. The study is registered under observational cohort identifiers but clinical trial registration numbers were not provided.
References
- Gallay C, Soldevila-Domenech N, López-Martos D, et al. Effect of Parity and β-Amyloid on Cognition and Hippocampal Volume in Postmenopausal Women. Neurology. 2026 Jun 22;107(1):e218153. PMID: 42330435.
- Podcasy JL, Epperson CN. Considering sex and gender in Alzheimer disease and other dementias. Dialogues Clin Neurosci. 2016 Jun;18(2):437-446. doi:10.31887/DCNS.2016.18.2/jpodcasy.
- Barha CK, Galea LA. The neurological impact of estradiol on cognition in women: pregnancy and menopause. Biol Sex Differ. 2019 Jun 17;10(1):64. doi:10.1186/s13293-019-0258-0.
- Fan L, Cao J, Chen D, et al. The influence of parity on cognitive function and brain aging: a systematic review. Front Aging Neurosci. 2021;13:676791. doi:10.3389/fnagi.2021.676791.
