Investigating Pathways from Adverse Pregnancy Outcomes to Alzheimer's Disease and Related Dementias: the nuMoM2b-Brain Study

PROJECT SUMMARY/ABSTRACT Placentally-mediated adverse pregnancy outcomes (APO), including hypertensive disorders of pregnancy, preterm birth, and fetal growth restriction, may play an underrecognized role in the development of Alzheimer's disease and related dementias (ADRD). These APO may contribute to maternal ADRD risk through biological

processes such as vascular endothelial dysfunction and angiogenic dysregulation. However, these pathways remain poorly characterized due to lack of well-phenotyped prospective pregnancy data with longitudinal follow up of mothers. This study will capitalize on a multi-ethnic prospective cohort study, the Nulliparous Pregnancy

Outcomes Study: Monitoring Mothers-to-be Heart Health Study (nuMoM2b-HHS) to understand how APO may influence maternal ADRD risk. From 2010-2013, the nuMoM2b study enrolled a diverse cohort of 10,038 healthy nulliparous individuals at 8 US academic medical centers who were followed from the first trimester

through the delivery of their first child. Pregnancies were phenotyped in detail, and APO occurred in >20% of participants. The follow-up nuMoM2b-HHS followed nuMoM2b participants to characterize subsequent pregnancy outcomes and accumulation of cardiovascular risk factors. This unique cohort, now 10-15-years

from their index pregnancy, currently consists of approximately 6500 individuals. The latest wave of in-person visits began in 2022 and will continue through 2027. This wave already includes neurocognitive assessments in all nuMoM2b-HHS participants, and brain magnetic resonance imaging (MRI) in a subset of 250 participants

at Columbia University. We propose a new nuMoM2b-HHS ancillary study to investigate pathways by which APO may lead to ADRD, using a combination of imaging and blood biomarkers. We will collect MRI data from participants at three additional study sites (University of Pittsburgh Medical Center, Northwestern University,

and Indiana University), augmenting the racial, ethnic and socioeconomic diversity of the MRI sub-cohort. Neuroimaging outcomes of interest will include gray matter volume, white matter hyperintensity volume, global and regional cortical thickness, global and regional cerebral blood flow, and diffusion tensor imaging-based

fractional anisotropy. We will 1) determine whether those with and without history of APO differ in MRI ADRD risk markers and 2) correlate placental growth factor (PlGF) levels measured during and after the index pregnancy with the same MRI markers, in participants with and without a history of APO. PlGF, an angiogenic

regulatory protein, was selected as an exposure of interest due to its well-established status as a marker of placental dysfunction during pregnancy, and recently recognized reliability as a later life biomarker for vascular cognitive impairment and dementia. We hypothesize that lower 2nd-trimester PlGF levels and higher post-

pregnancy PlGF levels will correlate with early markers of neurodegeneration, global and regional changes in cerebral blood flow, and white matter microstructural damage. This will be the first prospective study to investigate the relationship between APO, angiogenic dysfunction, and future maternal ADRD risk.