Aging of Emotion Circuitry and Risk for Alzheimer's disease: Impact of Sex, Immunity, and Fetal Origins - Summary Symptomatology associated with emotion dysregulation (including depression) has been identified as a critical early indicator of neurodegeneration preceding cognitive impairment in preclinical Alzheimer's disease (AD). One of the primary symptoms is loss of inhibitory control of negative affective arousal in the absence of significant cognitive complaints or dementia. When persistent and onsetting >age 50, it has been linked to increased risk of AD and predictor of accelerated cognitive decline, particularly in women. In AG057505, we have been investigating sex differences in the fetal immune programming of aging of brain regions associated with depression and associated loss of inhibitory control of negative emotion. These include hypothalamus, locus coeruleus (LC), amygdala, hippocampus, anterior cingulate, and prefrontal cortex, some of which are shared with memory circuitry, vulnerable to early AD in midlife, and highly sexually dimorphic. In this competing renewal of AG057505, we will test the hypothesis that neuroimmune and vascular pathways, in part, underlie shared dysregulation of emotion/mood and memory circuitries, the former of which will begin prior to memory decline and AD pathology, with women having greater risk for decline and AD pathology than men. We are uniquely poised to examine this given that, in AG057505, we prospectively followed 160 offspring (equally divided by sex) from our prenatal cohort from 2nd/3rd trimesters to ages 55-61. We will re-recruit over 5 years the 160 offspring at ages 61-70 and relate maternal prenatal immune activity to sex differences in emotion circuitry deficits/depression at ages 55-61 on memory circuitry, AD pathology, and neurovascular deficits at ages 61-70, and cognitive decline over the 5 years. As in AG057507, the same multimodal imaging (sMRI/fMRI/DTI) will be used coupled with hormones, autonomic and immune physiology, novel genomic approach assessing innate immune gene expression, and emotion regulation and cognitive measures. Further, we will add as outcomes an fMRI associative memory task, AD blood-based biomarkers, and novel ultra-high field imaging of neurovascular structure/function, and PET amyloid imaging for half the sample to localize amyloid accumulation. We predict that immune dysregulation, beginning prenatally, will lead to early alterations in microvascular circulation of the LC (site of early amyloid and tau deposition) and associated emotion circuitry dysregulation, that precedes development of AD pathology, neurovascular structural/functional deficits, and memory decline, that we predict will be worse in women than men. There is a lack of studies that can prospectively investigate the impact of emotion dysregulation/depression preceding cognitive decline and AD pathology and uniquely investigate the impact of sex. Our approach is innovative and may identify potential sex-selective targets (early risk modifiers) to attenuate disability and/or prevent memory decline and AD, such as immune system and/or neurovascular targets in early midlife for maintaining intact memory.
