Impact of the polygenic risk scores for attention-deficit/hyperactivity disorder in Alzheimer's disease

IF 11.1 1区医学 Q1 CLINICAL NEUROLOGY Alzheimer's & Dementia Pub Date : 2025-02-25 DOI:10.1002/alz.70003

Douglas T. Leffa, Guilherme Povala, Bruna Bellaver, João Pedro Ferrari-Souza, Pamela C. L. Ferreira, Firoza Z. Lussier, Cristiano Schaffer Aguzzoli, Carolina Soares, Hussein Zalzale, Francieli Rohden, Guilherme Bauer-Negrini, Sarah Abbas, Maitê Schneider, Joseph Therriault, Oscar L. Lopez, Victor L. Villemagne, William E. Klunk, Dana L. Tudorascu, Ann D. Cohen, Pedro Rosa-Neto, Eduardo R. Zimmer, Thomas K. Karikari, Luis Augusto Rohde, Brooke S. G. Molina, Tharick A. Pascoal, the Alzheimer's Disease Neuroimaging Initiative

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Abstract

INTRODUCTION

Epidemiological studies indicate a link between attention-deficit/hyperactivity disorder (ADHD) and elevated risk of dementia. However, the impact of ADHD on cognition and Alzheimer's disease (AD) biomarkers in individuals with cognitive impairment remains unclear.

METHODS

We computed weighted ADHD polygenic risk scores (ADHD-PRS) in 938 cognitively impaired participants (674 mild cognitive impairment [MCI] and 264 dementia; mean age 73.5 years). A subset underwent cerebrospinal fluid (CSF) analysis for amyloid beta (Aβ) and phosphorylated tau, as well as fluorodeoxyglucose positron emission tomography ([¹⁸F]FDG-PET).

RESULTS

We observed lower executive function in individuals with high ADHD-PRS for both MCI and dementia participants. Higher levels of CSF phosphorylated tau, but not Aβ, were observed in dementia participants with higher ADHD-PRS. Increased ADHD-PRS was associated with glucose hypometabolism in the frontal and parietal cortices.

DISCUSSION

ADHD-PRS is associated with a more severe disease presentation in individuals with cognitive impairment due to dementia, characterized by impaired executive function, elevated tau pathology, and hypometabolism in the frontal and parietal cortices.

Highlights

We calculated the genetic liability for attention-deficit/hyperactivity disorder (ADHD) using polygenic risk scores (ADHD-PRS).
Elevated ADHD-PRS was associated with executive function deficits in individuals with mild cognitive impairment (MCI) or Alzheimer's disease (AD) dementia.
Higher levels of cerebrospinal fluid (CSF) phosphorylated tau, but not amyloid beta (Aβ), were observed in dementia participants with higher ADHD-PRS.
Higher ADHD-PRS was associated with brain hypometabolism in individuals with AD dementia.
Hypometabolism in the parietal cortex mediated the effects of ADHD-PRS on executive function.

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阿尔茨海默病中注意力缺陷/多动障碍多基因风险评分的影响

流行病学研究表明，注意缺陷/多动障碍（ADHD）与痴呆风险升高之间存在联系。然而，ADHD对认知障碍患者认知和阿尔茨海默病（AD）生物标志物的影响尚不清楚。方法：对938名认知障碍参与者(轻度认知障碍[MCI] 674名，痴呆264名；平均年龄73.5岁)。其中一部分患者接受了脑脊液（CSF）淀粉样蛋白（Aβ）和磷酸化tau蛋白的分析，以及氟脱氧葡萄糖正电子发射断层扫描（[18F]FDG-PET）。结果：我们观察到在MCI和痴呆参与者中，高ADHD-PRS个体的执行功能较低。在ADHD-PRS较高的痴呆患者中，脑脊液磷酸化的tau水平较高，但Aβ水平不高。增加的ADHD-PRS与额叶和顶叶皮质的葡萄糖代谢低下有关。ADHD-PRS与由痴呆引起的认知障碍患者更严重的疾病表现相关，其特征是执行功能受损、tau蛋白病理学升高以及额叶和顶叶皮质代谢低下。我们使用多基因风险评分（ADHD- prs）计算了注意力缺陷/多动障碍（ADHD）的遗传倾向。在轻度认知障碍（MCI）或阿尔茨海默病（AD）痴呆患者中，ADHD-PRS升高与执行功能缺陷有关。在ADHD-PRS较高的痴呆患者中，观察到脑脊液（CSF）磷酸化tau蛋白水平较高，但β淀粉样蛋白（Aβ）水平不高。在AD痴呆患者中，较高的ADHD-PRS与脑代谢低下有关。顶叶皮质代谢低下介导ADHD-PRS对执行功能的影响。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Alzheimer's & Dementia 医学-临床神经学

CiteScore

14.50

自引率

5.00%

发文量

299

审稿时长

3 months

期刊介绍： Alzheimer's & Dementia is a peer-reviewed journal that aims to bridge knowledge gaps in dementia research by covering the entire spectrum, from basic science to clinical trials to social and behavioral investigations. It provides a platform for rapid communication of new findings and ideas, optimal translation of research into practical applications, increasing knowledge across diverse disciplines for early detection, diagnosis, and intervention, and identifying promising new research directions. In July 2008, Alzheimer's & Dementia was accepted for indexing by MEDLINE, recognizing its scientific merit and contribution to Alzheimer's research.