It Is Time to Study Overlapping Molecular and Circuit Pathophysiologies in Alzheimer’s and Lewy Body Disease Spectra

Abstract

Alzheimer’s disease (AD) is the leading cause of dementia due to neurodegeneration and is characterized by extracellular senile plaques composed of amyloid β1–42 (Aβ) as well as intracellular neurofibrillary tangles consisting of phosphorylated tau (p-tau). Dementia with Lewy bodies constitutes a continuous spectrum with Parkinson’s disease, collectively termed Lewy body disease (LBD). LBD is characterized by intracellular Lewy bodies containing α-synuclein (α-syn). The core clinical features of AD and LBD spectra are distinct, but the two spectra share common cognitive and behavioral symptoms. The accumulation of pathological proteins, which acquire pathogenicity through conformational changes, has long been investigated on a protein-by-protein basis. However, recent evidence suggests that interactions among these molecules may be critical to pathogenesis. For example, Aβ/tau promotes α-syn pathology, and α-syn modulates p-tau pathology. Furthermore, clinical evidence suggests that these interactions may explain the overlapping pathology between AD and LBD in molecular imaging and post-mortem studies. Additionally, a recent hypothesis points to a common mechanism of prion-like progression of these pathological proteins, via neural circuits, in both AD and LBD. This suggests a need for understanding connectomics and their alterations in AD and LBD from both pathological and functional perspectives. In AD, reduced connectivity in the default mode network is considered a hallmark of the disease. In LBD, previous studies have emphasized abnormalities in the basal ganglia and sensorimotor networks; however, these account for movement disorders only. Knowledge about network abnormalities common to AD and LBD is scarce because few previous neuroimaging studies investigated AD and LBD as a comprehensive cohort. In this paper, we review research on the distribution and interactions of pathological proteins in the brain in AD and LBD, after briefly summarizing their clinical and neuropsychological manifestations. We also describe the brain functional and connectivity changes following abnormal protein accumulation in AD and LBD. Finally, we argue for the necessity of neuroimaging studies that examine AD and LBD cases as a continuous spectrum especially from the proteinopathy and neurocircuitopathy viewpoints. The findings from such a unified AD and Parkinson’s disease (PD) cohort study should provide a new comprehensive perspective and key data for guiding disease modification therapies targeting the pathological proteins in AD and LBD.

Bidirectional Relationship Between Sleep Disturbances and Parkinson's Disease

“…Moreover, vascular factors contribute to both AD and PD pathology ( 58 , 103 ). Consideration of these overlapping and interacting pathologies during the prodromal stages is essential for developing disease-modifying therapeutic and/or preventive methods for PD ( 104 ). Sleep is an emerging attractive candidate for such preventive methods that could affect the abovementioned pathologies.…”

Single cell analysis of gene expression in the substantia nigra pars compacta of a pesticide-induced mouse model of Parkinson’s disease

“…GSEA of biological process in astrocytes showed significant enrichment in positive regulation of neurofibrillary tangle assembly, inclusion body assembly and low-density lipoprotein particle remodeling, together with negative regulation of amyloid fibril formation. These biological processes are involved in Alzheimer’s disease, which has mechanistic overlaps with PD (Wakasugi and Hanakawa, 2021). In oligodendrocytes, enrichment was observed in ensheathment of neurons and axon, central nervous system myelination, oligodendrocyte differentiation and glial cell development.…”

Immunohistochemical Demonstration of the pGlu79 α-Synuclein Fragment in Alzheimer’s Disease and Its Tg2576 Mouse Model

“…The present study was performed to reveal whether the pGlu79-aSyn variant recently identified in the PD brain [ 21 ] is also associated with Aβ pathology in the brains of AD subjects and its transgenic Tg2576 mouse model. Interactions between pathological proteins typical for different clinical conditions have been known for a long time and have been studied best for aSyn and Aβ peptides [ 46 , 49 , 70 , 71 , 72 ]. In particular, specific interaction sites between membrane-bound aSyn and Aβ proteins have been identified [ 73 ], and aSyn overexpression was shown to lead to the accumulation of mouse Aβ in a mouse model of PD [ 44 ].…”