Genetic Risk for Attention-Deficit/Hyperactivity Disorder Predicts Cognitive Decline and Development of Alzheimer’s Disease Pathophysiology in Cognitively Unimpaired Older Adults

Leffa, Douglas Teixeira; Ferrari‐Souza, João Pedro; Bellaver, Bruna; Tissot, Cécile; Ferreira, Pamela C.L.; Brum, Wagner S.; Caye, Arthur; Lord, Jodie; Proitsi, Petroula; Martins‐Silva, Thais; Tovo‐Rodrigues, Luciana; Tudorascu, Dana L.; Villemagne, Victor L.; Cohen, Annie; López, Oscar L.; Klunk, William E.; Karikari, Thomas K.; Rosa‐Neto, Pedro; Zimmer, Eduardo R.; Molina, Brooke S. G.; Rohde, Luis Augusto; Pascoal, Tharick A.

doi:10.1101/2022.04.05.22273464

Cited by 2 publications

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References 32 publications

(74 reference statements)

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“…These findings were comparable between MCI and ADHD for all domains, which, for clinicians, may result in misdiagnosis ( Mendonca et al, 2021 ). Then again, the study by Leffa et al (2022) in which 212 cognitively healthy controls were followed up for 6 years, including baseline and longitudinal AD biomarkers assessment (e.g., amyloid-β PET, MRI, cognitive assessments etc. ), showed an association between higher ADHD-PRS and cognitive decline.…”

Section: Epidemiological Evidence For Attention-deficit Hyperactivity...mentioning

confidence: 99%

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

et al. 2023

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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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Section: Epidemiological Evidence For Attention-deficit Hyperactivity...mentioning

confidence: 99%

“…At first glance, no common mechanism seems to link these two diseases together. However, several recent overviews have discussed their complementary phenomena ( Feltes et al, 2015 ; Callahan et al, 2017 ), and possible genetic overlaps ( Garcia-Argibay et al, 2022 ; Leffa et al, 2022 ).…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2023

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Cortical gradient perturbation in attention deficit hyperactivity disorder correlates with neurotransmitter-, cell type-specific and chromosome- transcriptomic signatures

Chen

Liu

et al. 2023

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Neurofunctional dysregulations in spatially discrete areas or isolated pathways have been suggested as neural markers for attention deficit hyperactivity disorder (ADHD). However, multiscale perspectives into the neurobiological underpins of ADHD spanning multiple biological systems remain sparse. This points to the need of multi-levels of analysis encompassing brain functional organization and its correlation with molecular and cell-specific transcriptional signatures are stressed. Here, we capitalized on diffusion mapping embedding model to derive the functional connectome gradient, and deployed multivariate partial least square (PLS) method to uncover the enrichment of neurotransmitomic, cellular and chromosomal connectome-transcriptional signatures of ADHD. Compared to typical control, ADHD children presented connectopic cortical perturbations in lateral orbito-frontal and superior temporal regions, which had also been validated in another independent sample. This gradient-derived variants in ADHD further aligned spatially with distributions of GABAA/BZ and 5-HT2A receptors and co-varied with genetic transcriptional expression. Cognitive decoding and gene-expression annotation showed the correlates of these variants in memory, emotional regulation and spatial attention. Moreover, the gradient-derived transcriptional signatures of ADHD exhibited enriched expression of oligodendrocyte precursors and endothelial cells, and were mainly involved as variants of chromosome 18, 19 and X. In conclusion, our findings bridged in-vivo neuroimging assessed functional brain organization patterns to a multi-level molecular pathway in ADHD, possibly shedding light on the interrelation of biological systems that may coalesce to the emergence of this disorder.

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Genetic Risk for Attention-Deficit/Hyperactivity Disorder Predicts Cognitive Decline and Development of Alzheimer’s Disease Pathophysiology in Cognitively Unimpaired Older Adults

Cited by 2 publications

References 32 publications

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

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

Cortical gradient perturbation in attention deficit hyperactivity disorder correlates with neurotransmitter-, cell type-specific and chromosome- transcriptomic signatures

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