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From attention-deficit hyperactivity disorder to sporadic Alzheimer’s disease—Wnt/mTOR pathways hypothesis

Alzheimer’s disease (AD) is the most common neurodegenerative disorder with the majority of patients classified as sporadic AD (sAD), in which etiopathogenesis remains unresolved. Though sAD is argued to be a polygenic disorder, apolipoprotein E (APOE) ε4, was found three decades ago to pose the str...

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Autores principales: Grünblatt, Edna, Homolak, Jan, Babic Perhoc, Ana, Davor, Virag, Knezovic, Ana, Osmanovic Barilar, Jelena, Riederer, Peter, Walitza, Susanne, Tackenberg, Christian, Salkovic-Petrisic, Melita
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2023
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Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9978448/
https://www.ncbi.nlm.nih.gov/pubmed/36875654
http://dx.doi.org/10.3389/fnins.2023.1104985
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author Grünblatt, Edna
Homolak, Jan
Babic Perhoc, Ana
Davor, Virag
Knezovic, Ana
Osmanovic Barilar, Jelena
Riederer, Peter
Walitza, Susanne
Tackenberg, Christian
Salkovic-Petrisic, Melita
author_facet Grünblatt, Edna
Homolak, Jan
Babic Perhoc, Ana
Davor, Virag
Knezovic, Ana
Osmanovic Barilar, Jelena
Riederer, Peter
Walitza, Susanne
Tackenberg, Christian
Salkovic-Petrisic, Melita
author_sort Grünblatt, Edna
collection PubMed
description Alzheimer’s disease (AD) is the most common neurodegenerative disorder with the majority of patients classified as sporadic AD (sAD), in which etiopathogenesis remains unresolved. Though sAD is argued to be a polygenic disorder, apolipoprotein E (APOE) ε4, was found three decades ago to pose the strongest genetic risk for sAD. Currently, the only clinically approved disease-modifying drugs for AD are aducanumab (Aduhelm) and lecanemab (Leqembi). All other AD treatment options are purely symptomatic with modest benefits. Similarly, attention-deficit hyperactivity disorder (ADHD), is one of the most common neurodevelopmental mental disorders in children and adolescents, acknowledged to persist in adulthood in over 60% of the patients. Moreover, for ADHD whose etiopathogenesis is not completely understood, a large proportion of patients respond well to treatment (first-line psychostimulants, e.g., methylphenidate/MPH), however, no disease-modifying therapy exists. Interestingly, cognitive impairments, executive, and memory deficits seem to be common in ADHD, but also in early stages of mild cognitive impairment (MCI), and dementia, including sAD. Therefore, one of many hypotheses is that ADHD and sAD might have similar origins or that they intercalate with one another, as shown recently that ADHD may be considered a risk factor for sAD. Intriguingly, several overlaps have been shown between the two disorders, e.g., inflammatory activation, oxidative stress, glucose and insulin pathways, wingless-INT/mammalian target of rapamycin (Wnt/mTOR) signaling, and altered lipid metabolism. Indeed, Wnt/mTOR activities were found to be modified by MPH in several ADHD studies. Wnt/mTOR was also found to play a role in sAD and in animal models of the disorder. Moreover, MPH treatment in the MCI phase was shown to be successful for apathy including some improvement in cognition, according to a recent meta-analysis. In several AD animal models, ADHD-like behavioral phenotypes have been observed indicating a possible interconnection between ADHD and AD. In this concept paper, we will discuss the various evidence in human and animal models supporting the hypothesis in which ADHD might increase the risk for sAD, with common involvement of the Wnt/mTOR-pathway leading to lifespan alteration at the neuronal levels.
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spelling pubmed-99784482023-03-03 From attention-deficit hyperactivity disorder to sporadic Alzheimer’s disease—Wnt/mTOR pathways hypothesis Grünblatt, Edna Homolak, Jan Babic Perhoc, Ana Davor, Virag Knezovic, Ana Osmanovic Barilar, Jelena Riederer, Peter Walitza, Susanne Tackenberg, Christian Salkovic-Petrisic, Melita Front Neurosci Neuroscience Alzheimer’s disease (AD) is the most common neurodegenerative disorder with the majority of patients classified as sporadic AD (sAD), in which etiopathogenesis remains unresolved. Though sAD is argued to be a polygenic disorder, apolipoprotein E (APOE) ε4, was found three decades ago to pose the strongest genetic risk for sAD. Currently, the only clinically approved disease-modifying drugs for AD are aducanumab (Aduhelm) and lecanemab (Leqembi). All other AD treatment options are purely symptomatic with modest benefits. Similarly, attention-deficit hyperactivity disorder (ADHD), is one of the most common neurodevelopmental mental disorders in children and adolescents, acknowledged to persist in adulthood in over 60% of the patients. Moreover, for ADHD whose etiopathogenesis is not completely understood, a large proportion of patients respond well to treatment (first-line psychostimulants, e.g., methylphenidate/MPH), however, no disease-modifying therapy exists. Interestingly, cognitive impairments, executive, and memory deficits seem to be common in ADHD, but also in early stages of mild cognitive impairment (MCI), and dementia, including sAD. Therefore, one of many hypotheses is that ADHD and sAD might have similar origins or that they intercalate with one another, as shown recently that ADHD may be considered a risk factor for sAD. Intriguingly, several overlaps have been shown between the two disorders, e.g., inflammatory activation, oxidative stress, glucose and insulin pathways, wingless-INT/mammalian target of rapamycin (Wnt/mTOR) signaling, and altered lipid metabolism. Indeed, Wnt/mTOR activities were found to be modified by MPH in several ADHD studies. Wnt/mTOR was also found to play a role in sAD and in animal models of the disorder. Moreover, MPH treatment in the MCI phase was shown to be successful for apathy including some improvement in cognition, according to a recent meta-analysis. In several AD animal models, ADHD-like behavioral phenotypes have been observed indicating a possible interconnection between ADHD and AD. In this concept paper, we will discuss the various evidence in human and animal models supporting the hypothesis in which ADHD might increase the risk for sAD, with common involvement of the Wnt/mTOR-pathway leading to lifespan alteration at the neuronal levels. Frontiers Media S.A. 2023-02-16 /pmc/articles/PMC9978448/ /pubmed/36875654 http://dx.doi.org/10.3389/fnins.2023.1104985 Text en Copyright © 2023 Grünblatt, Homolak, Babic Perhoc, Davor, Knezovic, Osmanovic Barilar, Riederer, Walitza, Tackenberg and Salkovic-Petrisic. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Neuroscience
Grünblatt, Edna
Homolak, Jan
Babic Perhoc, Ana
Davor, Virag
Knezovic, Ana
Osmanovic Barilar, Jelena
Riederer, Peter
Walitza, Susanne
Tackenberg, Christian
Salkovic-Petrisic, Melita
From attention-deficit hyperactivity disorder to sporadic Alzheimer’s disease—Wnt/mTOR pathways hypothesis
title From attention-deficit hyperactivity disorder to sporadic Alzheimer’s disease—Wnt/mTOR pathways hypothesis
title_full From attention-deficit hyperactivity disorder to sporadic Alzheimer’s disease—Wnt/mTOR pathways hypothesis
title_fullStr From attention-deficit hyperactivity disorder to sporadic Alzheimer’s disease—Wnt/mTOR pathways hypothesis
title_full_unstemmed From attention-deficit hyperactivity disorder to sporadic Alzheimer’s disease—Wnt/mTOR pathways hypothesis
title_short From attention-deficit hyperactivity disorder to sporadic Alzheimer’s disease—Wnt/mTOR pathways hypothesis
title_sort from attention-deficit hyperactivity disorder to sporadic alzheimer’s disease—wnt/mtor pathways hypothesis
topic Neuroscience
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9978448/
https://www.ncbi.nlm.nih.gov/pubmed/36875654
http://dx.doi.org/10.3389/fnins.2023.1104985
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