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.