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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

Abstract

Attention-deficit/hyperactivity disorder (ADHD) persists in older age and is postulated as a risk factor for cognitive impairment and Alzheimer’s Disease (AD). However, these findings rely primarily on electronic health records and can present biased estimates of disease prevalence. An obstacle to investigating age-related cognitive decline in ADHD is the absence of large-scale studies following patients with ADHD into older age. Alternatively, this study aimed to determine whether genetic liability for ADHD, as measured by a well-validated ADHD polygenic risk score (ADHD-PRS), is associated with cognitive decline and the development of AD pathophysiology in cognitively unimpaired (CU) older adults. We calculated a weighted ADHD-PRS in 212 CU individuals without a clinical diagnosis of ADHD (55–90 years). These individuals had baseline amyloid-β (Aβ) positron emission tomography, longitudinal cerebrospinal fluid (CSF) phosphorylated tau at threonine 181 (p-tau181), magnetic resonance imaging, and cognitive assessments for up to 6 years. Linear mixed-effects models were used to test the association of ADHD-PRS with cognition and AD biomarkers. Higher ADHD-PRS was associated with greater cognitive decline over 6 years. The combined effect between high ADHD-PRS and brain Aβ deposition on cognitive deterioration was more significant than each individually. Additionally, higher ADHD-PRS was associated with increased CSF p-tau181 levels and frontoparietal atrophy in CU Aβ-positive individuals. Our results suggest that genetic liability for ADHD is associated with cognitive deterioration and the development of AD pathophysiology. Findings were mostly observed in Aβ-positive individuals, suggesting that the genetic liability for ADHD increases susceptibility to the harmful effects of Aβ pathology.

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Fig. 1: Higher ADHD-PRS is associated with longitudinal cognitive decline over 6 years in CU older adults.
Fig. 2: Aβ-positivity and high ADHD-PRS potentiated longitudinal cognitive impairment in CU older adults.
Fig. 3: ADHD-PRS is associated with the development of tau pathology over 6 years only in Aβ-positive individuals.
Fig. 4: ADHD-PRS is associated with longitudinal brain atrophy over 6 years in the frontal and parietal cortices of CU Aβ-positive older individuals.

Data availability

Data used in preparation of this article were obtained from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database (adni.loni.usc.edu). As such, the investigators within the ADNI contributed to the design and implementation of ADNI and/or provided data but did not participate in analysis or writing of this report. A complete listing of ADNI investigators can be found at http://adni.Loni.usc.edu/wp-content/uploads/how_to_apply/ADNI_Acknowledgement_List.pdf.

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Acknowledgements

DTL is supported by a CNPq postdoctoral fellowship (#166407/2020-8), and supported by a NARSAD Young Investigator Grant from the Brain & Behavior Research Foundation (#29486). JPF-S receives financial support from CAPES (#88887.627297/2021-00). CT receives funding from Faculty of Medicine McGill and IPN McGill. PCLF is supported by the Alzheimer’s Association (#AARFD-22-923814). WSB is supported by CAPES (#88887.372371/2019-00 and #88887.596742/2020-00). TKK is funded by the Swedish Research Council’s career establishment fellowship (#2021-03244), the Alzheimer’s Association Research Fellowship (#850325), the BrightFocus Foundation (#A2020812F), the International Society for Neurochemistry’s Career Development Grant, the Swedish Alzheimer Foundation (Alzheimerfonden; #AF-930627), the Swedish Brain Foundation (Hjärnfonden; #FO2020-0240), the Swedish Dementia Foundation (Demensförbundet), the Swedish Parkinson Foundation (Parkinsonfonden), Gamla Tjänarinnor Foundation, the Aina (Ann) Wallströms and Mary-Ann Sjöbloms Foundation, the Agneta Prytz-Folkes & Gösta Folkes Foundation (#2020-00124), the Gun and Bertil Stohnes Foundation, and the Anna Lisa and Brother Björnsson’s Foundation. ERZ receives financial support from CNPq (#435642/2018-9 and #312410/2018- 2), Instituto Serrapilheira (#Serra-1912-31365), Brazilian National Institute of Science and Technology in Excitotoxicity and Neuroprotection (#465671/2014-4), FAPERGS/MS/CNPq/SESRS–PPSUS (#30786.434.24734.231120170), ARD/FAPERGS (#54392.632.30451.05032021), and Alzheimer’s Association (#AARGD-21-850670). TAP is supported by the NIH (#R01AG075336 and #R01AG073267) and the Alzheimer’s Association (#AACSF-20-648075). Data collection and sharing for this project was funded by the Alzheimer’s Disease Neuroimaging Initiative (ADNI) (National Institutes of Health Grant U01 AG024904) and DOD ADNI (Department of Defense award number W81XWH-12-2-0012). ADNI is funded by the National Institute on Aging, the National Institute of Biomedical Imaging and Bioengineering, and through generous contributions from the following: AbbVie, Alzheimer’s Association; Alzheimer’s Drug Discovery Foundation; Araclon Biotech; BioClinica, Inc.; Biogen; Bristol-Myers Squibb Company; CereSpir, Inc.; Cogstate; Eisai Inc.; Elan Pharmaceuticals, Inc.; Eli Lilly and Company; EuroImmun; F. Hoffmann-La Roche Ltd and its affiliated company Genentech, Inc.; Fujirebio; GE Healthcare; IXICO Ltd.; Janssen Alzheimer Immunotherapy Research & Development, LLC.; Johnson & Johnson Pharmaceutical Research & Development LLC.; Lumosity; Lundbeck; Merck & Co., Inc.; Meso Scale Diagnostics, LLC.; NeuroRx Research; Neurotrack Technologies; Novartis Pharmaceuticals Corporation; Pfizer Inc.; Piramal Imaging; Servier; Takeda Pharmaceutical Company; and Transition Therapeutics. The Canadian Institutes of Health Research is providing funds to support ADNI clinical sites in Canada. Private sector contributions are facilitated by the Foundation for the National Institutes of Health (www.fnih.org). The grantee organization is the Northern California Institute for Research and Education, and the study is coordinated by the Alzheimer’s Therapeutic Research Institute at the University of Southern California. ADNI data are disseminated by the Laboratory for Neuro Imaging at the University of Southern California.

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DTL and TAP conceived the study. DTL, JPF-S, BB, CT, PCLF, and TAP prepared the figures and tables. DTL drafted the manuscript with input from JPF-S, BB, CT, PCLF, WSB, AC, JL, PP, TM-S, LT-R, DLT, VLV, ADC, OLL, WEK, TKK, PR-N, EZ, BSGM, LAR, and TAP. DTL, JPF-S, BB, CT, PCLF, LAR, and TAP performed the acquisitions, processing, quality control, and/or interpretation of the data. TAP, LAG, and BSGM supervised this work. JL, PP, TM-S, and LT-R assisted in calculating the polygenic risk scores. DLT assisted in the statistical analyses. All authors revised and approved the final manuscript.

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Correspondence to Luis Augusto Rohde or Tharick A. Pascoal.

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LAR has received grant or research support from, served as a consultant to, and served on the speakers’ bureau of Aché, Bial, Medice, Novartis/Sandoz, Pfizer/Upjohn, and Shire/Takeda in the last three years. The ADHD and Juvenile Bipolar Disorder Outpatient Programs chaired by LAR have received unrestricted educational and research support from the following pharmaceutical companies in the last three years: Novartis/Sandoz and Shire/Takeda. LAR has received authorship royalties from Oxford Press and ArtMed. AC has acted as a consultant for Knight Therapeutics in the last three years.

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Leffa, D.T., Ferrari-Souza, J.P., Bellaver, B. et al. Genetic risk for attention-deficit/hyperactivity disorder predicts cognitive decline and development of Alzheimer’s disease pathophysiology in cognitively unimpaired older adults. Mol Psychiatry (2022). https://doi.org/10.1038/s41380-022-01867-2

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