Alzheimer’s disease (AD), the leading cause of dementia, is characterized by the accumulation of amyloid plaques and neurofibrillary tangles in the brain. This condition casts a significant shadow on global health due to its complex and multifactorial nature. In addition to genetic predispositions, the development of AD is influenced by a myriad of risk factors, including aging, systemic inflammation, chronic health conditions, lifestyle, and environmental exposures. Recent advancements in understanding the complex pathophysiology of AD are paving the way for enhanced diagnostic techniques, improved risk assessment, and potentially effective prevention strategies. These discoveries are crucial in the quest to unravel the complexities of AD, offering a beacon of hope for improved management and treatment options for the millions affected by this debilitating disease.

It is known that eyes-open (EO) and eyes-closed (EC) conditions invoke different organizations of brain functional networks, such as sensorimotor, attention, and salience networks in healthy participants. Functional connectivity (FC) extracted from resting-state functional magnetic resonance imaging data, under either EO or EC conditions, has been widely applied to explore the neural substrates of Alzheimer's disease (AD). However, the impact of eye conditions on FC within the AD continuum remains not fully understood.This study aims to investigate the effects of eye conditions on FC across the AD continuum.FC with the primary visual cortex (V1) seed was analyzed for both EO and EC conditions in 59 amyloid-β (Aβ)-positron emission tomography (PET)-negative cognitively normal (CN-), 14 Aβ-PET-positive CN+, 24 mild cognitive impairment (MCI+), and 15 AD individuals.EO and EC differently modulated FC between the V1 and cerebellum, especially the posterior vermis, in all groups. In CN-, CN+, and MCI+ groups, EO significantly facilitated FC between V1 and the cerebellum compared with the EC condition. However, the AD group showed the reverse pattern. Moreover, a sub-analysis demonstrated that the FC significantly correlated with a truncal balance measure under EO, but not EC, in participants with MCI+ and AD.The results show that the FC between the V1 and cerebellum changed in AD. This finding may partially explain the impaired truncal balance and tendency to fall down in AD. This study suggests that analyzing FC under EO and EC conditions may provide a new functional biomarker for AD.

We elucidate that the cerebellum displays striking resilience to neurodegenerative changes under aging or Alzheimer's disease (AD). We identify the neurobiological factors that underlie the natural neuroprotective characteristic of cerebellum, thereby obtaining innovative therapeutic directions that may duplicate this naturalistic neurorestorative response. We investigated the mass spectrometry/liquid chromatography-based proteomics profile from AD tissue: sparely affected cerebellum and highly affected hippocampus/cingulate/entorhinal cortex. We found 83 upregulated and 37 downregulated cerebellar genes. Top five upregulated genes were (hub-gene), these encode for neurorestorative processes, as axonal, dendritic, and myelination growth. Contrastingly, the top five downregulated genes were (hub-gene),. These encode for NADH-dehydrogenase subunit in mitochondria; their increased expression relates to mitochondrial-based ROS stress-based apoptosis; hence, their downregulation reduces apoptosis, reinforcing neural survival. Indeed, cerebellum displays unique neuroprotection, by coupling of two reciprocal cytometabolic fluxes: (1) hyperactivation of neural anabolic processing, as neuronal growth, and (2) hypoactivation of neural catabolic processing, as mitochondrial caspase-induced neural degradation. Hence, for inducing the endogenous neuroprotective response, one needs to pharmacologically modulate both these cytometabolic processes: (i) agonism of neural synaptotropic anabolic pathway, coupled to (ii) antagonism of mitochondrial catabolic neurotoxic pathway. We also observed that synaptic efficiency-encoding genes constitute majority (70%) of upregulated cerebellar genes. We noted the unexpected observations, namely that (a) the neuron is the most pivotal factor for the restorative response than any type of glial or other cells, (b) with respect to the neuron, the synaptogenesis process is much more critical than the neurogenesis process, and (c) collaterally, the hypomodulation of the mitochondrial NADHD ubiquinone activity is the key factor. A unique significance is that a naturally occurring neurorestorative response may be therapeutically harnessed in neurons, minimizing off-target effects that are often hazardous disadvantages of conventional dementia therapeutics.The online version contains supplementary material available at 10.1007/s13205-025-04264-y.© King Abdulaziz City for Science and Technology 2025. Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Connectivity of somatosensory cortex (S1) and cerebellum with the motor cortex (M1) is critical for balance control. While both S1-M1 and cerebellar-M1 connections are affected with aging, the implications of altered connectivity for balance control are not known. We investigated the relationship between S1-M1 and cerebellar-M1 connectivity and standing balance in middle-aged and older adults. Our secondary objective was to investigate how cognition affected the relationship between connectivity and balance. Our results show that greater S1-M1 and cerebellar-M1 connectivity was related to greater postural sway during standing. This may be indicative of an increase in functional recruitment of additional brain networks to maintain upright balance despite differences in network connectivity. Also, cognition moderated the relationship between S1-M1 connectivity and balance, such that those with lower cognition had a stronger relationship between connectivity and balance performance. It may be that individuals with poor cognition need increased recruitment of brain regions (compensation for cognitive declines) and in turn, higher wiring costs, which would be associated with increased functional connectivity.Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.

The cerebellar vermis plays an essential role in maintaining posture and balance by integrating sensory inputs from multiple modalities to effectively coordinate movement. By transforming convergent sensory information into precise motor commands, it ensures smooth, adaptive motor control, enabling the body to maintain stability in dynamic environments. This review examines recent findings that investigate the distinct neural computations performed by the anterior vermis and posterior vermis (nodulus/uvula). Specifically, we examine how Purkinje cells in these regions integrate vestibular and proprioceptive signals to convert self-motion information from a head-centered to a body-centered reference frame, which is essential for maintaining precise postural control in response to unexpected movements. Additionally, we consider recent findings showing that, during voluntary self-motion, Purkinje cells in the anterior vermis selectively suppress responses in the vestibulospinal pathway by integrating motor inputs with sensory signals. Given the anterior vermis's role in maintaining balance during voluntary behaviors such as locomotion, its suppression prevents counterproductive stabilizing reflexes, enabling goal-directed movement through space. In contrast, the posterior vermis, encompassing the nodulus and uvula, integrates vestibular inputs from both the otoliths and semicircular canals to maintain equilibrium relative to gravitational forces. We thus hypothesize that Purkinje cells in the nodulus/uvula do not generate suppression signals like those observed in the anterior vermis but instead continuously compute our orientation in space, regardless of whether movement is voluntarily generated or unexpected. If our hypothesis is correct, the nodulus/uvula would effectively provide consistent “ground truth” information about self-motion relative to gravity.