Potential Mechanisms Underlying Resistance to Dementia in Non-Demented Individuals with Alzheimer’s Disease Neuropathology

Abstract

Alzheimer’s disease (AD) is the most common form of dementia and typically characterized by the accumulation amyloid-β plaques and tau tangles. Intriguingly, there also exists a group of elderly which do not develop dementia during their life, despite the AD neuropathology, the so-called non-demented individuals with AD neuropathology (NDAN). In this review, we provide extensive background on AD pathology and normal aging and discuss potential mechanisms that enable these NDAN individuals to remain cognitively intact. Studies presented in this review show that NDAN subjects are generally higher educated and have a larger cognitive reserve. Furthermore, enhanced neural hypertrophy could compensate for hippocampal and cingulate neural atrophy in NDAN individuals. On a cellular level, these individuals show increased levels of neural stem cells and ‘von Economo neurons’. Furthermore, in NDAN brains, binding of Aβ oligomers to synapses is prevented, resulting in decreased glial activation and reduced neuroinflammation. Overall, the evidence stated here strengthens the idea that some individuals are more resistant to AD pathology, or at least show an elongation of the asymptomatic state of the disease compared to others. Insights into the mechanisms underlying this resistance could provide new insight in understanding normal aging and AD itself. Further research should focus on factors and mechanisms that govern the NDAN cognitive resilience in order to find clues on novel biomarkers, targets, and better treatments of AD.

Amyloid-Eszett (Aß), a false positive of amyloid-beta (Aβ), in the neurodegenerative disease literature: A bibliometric assessment

“…Aβ is a centrally important compound in neurodegenerative diseases such as AD. When Aβ plaques and neuro brillary tangles are abnormally deposited, this causes synaptic damage that potentiates cognitive impairment, leading to memory loss, AD, and other neurodegenerative diseases (Kok et al, 2022). In AD, when Aβ oligomers bind to the postsynaptic membrane, this induces synaptotoxicity, so several treatment options to improve AD target Aβ to prevent or reduce Aβ-synaptic binding (Pinheiro & Faustino, 2019;Kok et al, 2022).…”

Structural polymorphism and cytotoxicity of brain‐derived β‐amyloid extracts

“…In non‐demented subjects with Aβ plaques, toxic Aβ oligomers were not localized in postsynaptic densities and therefore did not induce synaptic loss (Zolochevska et al, 2018 ). In a recent review investigating possible mechanisms preventing non‐demented individuals with Aβ plaques from cognitive impairment, it was found that Aβ oligomers do not bind to synapses and therefore do not induce synaptotoxicity and inflammation through glial activation (Kok et al, 2022 ).…”

Intrathecal Pseudodelivery of Drugs in the Therapy of Neurodegenerative Diseases: Rationale, Basis and Potential Applications

“…Disease-distinctive proteins exist in different states that aggregate between them: soluble monomers aggregate together to form dimers and oligomers, that can form soluble protofibrils. In turn, protofibrils aggregate to form insoluble fibrils, that eventually deposit in the form of plaques or tangles [ 8 ]. Soluble proteins are present in the CSF, and in equilibrium—either direct or inverse, depending on the molecule and the stage of the disease—with the concentration in the ISF ( Figure 1 ).…”

“…The process is dynamic and bidirectional, therefore complex aggregates can disaggregate into less complex aggregates. Modified from Kok et al, 2022 [ 8 ].…”