Unravelling the relationship between amyloid accumulation and brain network function in normal aging and very mild cognitive decline: a longitudinal analysis

Abstract

Pathological changes in the brain begin accumulating decades before the appearance of cognitive symptoms in Alzheimer’s Disease. The deposition of amyloid-beta proteins and other neurotoxic changes occur, leading to disruption in functional connections between brain networks. Discrete characterization of the changes that take place in preclinical Alzheimer’s Disease has the potential to help treatment development by targeting the neuropathological mechanisms to prevent cognitive decline and dementia from occurring entirely. Previous research has focused on cross sectional differences in the brains of patients with mild cognitive impairment or Alzheimer’s Disease and healthy controls or has concentrated on the stages immediately preceding cognitive symptoms. The present study emphasizes early preclinical phases of neurodegeneration. We use a longitudinal approach to examine the brain changes that take place during early stages of cognitive decline in the Open Access Series of Imaging Studies-3 dataset. Among 1098 participants, 274 passed the inclusion criteria (i.e. had at least two cognitive assessments and two amyloid scans). Over 90% of participants were healthy at baseline. Over 8-10 years, some participants progressed to very mild cognitive impairment (n = 48) while others stayed healthy (n = 226). Participants with cognitive decline show faster amyloid accumulation in lateral temporal, motor, and parts of the lateral prefrontal cortex. These changes in amyloid levels were linked to longitudinal increases in functional connectivity of select networks, including default mode, frontoparietal and motor components. Our findings advance the understanding of amyloid staging and the corresponding changes in functional organization of large-scale brain networks during the progression of early preclinical Alzheimer’s Disease.

The effect of Alzheimer’s disease and its progression on pyramidal cell gain and connectivity

“…Connectivity changes in large-scale networks related to Alzheimer’s disease have been observed with both fMRI and M/EEG (Yu et al ., 2021). For example, Alzheimer’s disease pathology has been associated with changes to functional connectivity of the default-mode network and/or frontoparietal network (Engels et al ., 2015; Klaassens et al ., 2017; Mandal et al ., 2018; Zhao et al ., 2019; Wales and Leung, 2021; Yang et al ., 2021; Fathian et al ., 2022; Moffat et al ., 2022; Zhukovsky et al ., 2023) and networks responding in mismatch paradigms (Başar et al ., 2017; Jovicich et al ., 2019; Nguyen et al ., 2019; Cope et al ., 2022; Gjini et al ., 2022).…”

Autism Spectrum Disorder: Brain Areas Involved, Neurobiological Mechanisms, Diagnoses and Therapies

“…Interestingly, haploinsufficient mice are protected by the administration of growth hormone and also by early postnatal serotonin modulation [42]. ARID1B, therefore, appears to play an essential role in forebrain neurogenesis, inducing a pronounced role in inhibitory neural progenitors [40][41][42], with refinement of the ensuing progressive therapy [43]. In addition, available evidence has demonstrated that the role of ARID1B is not unique.…”

“…Within neurons, the structures and fractions most widely affected by ASD genes and proteins correspond to, and interact with, various types and components of synapses [44]. In addition to intellectual and social effects, disabilities and speech defects, the impairment mutations of chromatin remodeling induced by ARID1B regulate primarily the dendritic differentiation in the developing brain [43]. The dysfunction of dendrites, the post-synaptic fibers that receive the pre-synaptic inputs, are critical for synaptic function, and they are also relevant in sensory processing, cognition and conscious perception [44].…”

“…The dendrites with their post-synaptic responses to flat and spines are therefore sites of ASD gene effects [2,39,42,44]. In addition to the molecular complexes active as chromatin modifiers [42][43][44], ARID1B and its analogous subunits have been shown to govern other genes, encoding proteins localized at or near synapses [43][44][45] (Figure 2). Specific aspects of synapses affected by ASD action need to be considered in structural and functional terms.…”

Is Alzheimer's disease an individual-centered disease? Hypotheses from the atomic levels up to mathematical models for biological systems

“…This “dilution effect” may reduce the effect of anti-Aβ monoclonal antibodies. A further criticism toward the adoption of Aβ as AD biomarker is the fact that, among elderly patients with cerebral amyloid, some patients experience the accumulation of further Aβ and develop cognitive impairment, whereas others remain unaffected ( 26 , 27 ). This progression profile remains elusive at beginning.…”