Understanding the Role of Alzheimer’s Disease Pathology in Mild Behavioral Impairment

University Of Michigan At Ann Arbor, Ann Arbor MI

Investigators

Abstract

Project Summary An estimated 6.7 million US adults live with Alzheimer’s disease (AD) and related dementias (ADRD); a figure that is expected to more than double by 2060 unless new prevention strategies or treatments emerge. Although later-life neuropsychiatric symptoms have been associated with a greater risk of dementia, they are all too often viewed and treated as independent of ADRD. This traditional approach overlooks the possibility that neuropsychiatric symptoms emerge as pathology accumulates in brain regions or networks that differ from those affected by the more common “memory first” phenotype. Thus, the proposed project leverages a recently developed mild behavioral impairment (MBI) diagnostic framework that standardizes the assessment of neuropsychiatric symptoms in older adults during the pre-dementia phase(s). MBI is not equivalent to mild cognitive impairment (MCI), but a “complementary behavioral analog” to MCI. While MBI is typically linked with regional atrophy of the medial temporal lobes, this is likely an over simplistic approach that fails to distinguish between MCI and MBI. Thus, our central hypothesis is that MBI arises from a network-level impact of AD pathology on the neural circuitry primarily implicated in the processing and integration of emotional experience - i.e., the salience and default-mode networks. To test this, we will investigate the network-level structure-function relations associated with MBI (Aim 1) and assess blood-based AD biomarkers’ association with MBI symptoms and network-level indices of neurodegeneration (Aim 2) using data from a well-characterized longitudinal cohort of over 690 individuals of the NIA P30-funded Michigan Alzheimer’s Disease Research Center. We will then perform an open-label pilot study to test the effect of network-level neuromodulation on MBI using high-definition transcranial direct current stimulation (HD-tDCS) in those with MBI (Aim 3). The proposed project integrates and directly complements my training plan to address a critical gap in understanding why those with MBI are at risk for conversion to dementia. This is the first study to integrate blood-based biomarkers with network-level correlates of MBI and propose a network-based individualized neuromodulation-based intervention in those with MBI. This study will advance our understanding of network-level patterns of brain atrophy, changes in functional connectivity, and accumulating AD pathology, thereby further validating MBI as a novel marker of preclinical AD. The project also translates gained knowledge into actionable treatment plans for those with MBI by testing individualized HD-tDCS to mitigate network level dysfunction. The combination of these findings and the novel skills developed through my training plan are vital for a future R01 as an independent investigator that will examine the effects of HD-tDCS on emotional processing in those with MBI.