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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


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 ( 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


  1. Faraone SV, Banaschewski T, Coghill D, Zheng Y, Biederman J, Bellgrove MA, et al. The World Federation of ADHD International Consensus Statement: 208 Evidence-based Conclusions about the Disorder. Neurosci Biobehav Rev. 2021

  2. Caye A, Spadini AV, Karam RG, Grevet EH, Rovaris DL, Bau CHD, et al. Predictors of persistence of ADHD into adulthood: a systematic review of the literature and meta-analysis. Eur Child Adolesc Psychiatry. 2016;25:1151–9.

    Article  PubMed  Google Scholar 

  3. Kooij JJS, Michielsen M, Kruithof H, Bijlenga D. ADHD in old age: a review of the literature and proposal for assessment and treatment. Expert Rev Neurother. 2016;16:1371–81.

    Article  CAS  PubMed  Google Scholar 

  4. Dobrosavljevic M, Solares C, Cortese S, Andershed H, Larsson H. Prevalence of attention-deficit/hyperactivity disorder in older adults: A systematic review and meta-analysis. Neurosci Biobehav Rev. 2020;118:282–9.

    Article  PubMed  Google Scholar 

  5. Callahan BL, Bierstone D, Stuss DT, Black SE. Adult ADHD: Risk factor for dementia or phenotypic mimic? Front Aging Neurosci. 2017;9:1–15.

    Article  Google Scholar 

  6. Du Rietz E, Brikell I, Butwicka A, Leone M, Chang Z, Cortese S, et al. Mapping phenotypic and aetiological associations between ADHD and physical conditions in adulthood in Sweden: a genetically informed register study. Lancet Psychiatry. 2021;8:774–83. Available from:

  7. Zhang L, Du Rietz E, Kuja-Halkola R, Dobrosavljevic M, Johnell K, Pedersen NL, et al. Attention-deficit/hyperactivity disorder and Alzheimer’s disease and any dementia: A multi-generation cohort study in Sweden. Alzheimer’s Dement. 2020;2021:1–9.

    Google Scholar 

  8. Dobrosavljevic M, Zhang L, Garcia-Argibay M, Du Rietz E, Andershed H, Chang Z, et al. Attention-deficit/hyperactivity disorder as a risk factor for dementia and mild cognitive impairment: A population-based register study. Eur Psychiatry. 2022;65:e3.

    Article  Google Scholar 

  9. Becker S, Sharma MJ, Callahan BL. ADHD and Neurodegenerative Disease Risk: A Critical Examination of the Evidence. Front Aging Neurosci. 2022;13.

  10. Ronald A, de Bode N, Polderman TJC. Systematic review: how the attention-deficit/hyperactivity disorder polygenic risk score adds to our understanding of ADHD and associated traits. J Am Acad Child Adolesc Psychiatry. 2021;60:1234–77.

  11. Thapar A. Discoveries on the genetics of ADHD in the 21st Century: New findings and their implications. Am J Psychiatry. 2018;175:943–50.

    Article  PubMed  Google Scholar 

  12. Petersen RC, Aisen PS, Beckett LA, Donohue MC, Gamst AC, Harvey DJ, et al. Alzheimer’s Disease Neuroimaging Initiative (ADNI): clinical characterization. Neurology. 2010;74:201–9.

    Article  PubMed  PubMed Central  Google Scholar 

  13. Zettergren A, Lord J, Ashton NJ, Benedet AL, Karikari TK, Lantero Rodriguez J, et al. Association between polygenic risk score of Alzheimer’s disease and plasma phosphorylated tau in individuals from the Alzheimer’s Disease Neuroimaging Initiative. Alzheimers Res Ther. 2021;13:17.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Demontis D, Walters RK, Martin J, Mattheisen M, Als TD, Agerbo E, et al. Discovery of the first genome-wide significant risk loci for attention deficit/hyperactivity disorder. Nat Genet. 2019;51:63–75.

    Article  CAS  PubMed  Google Scholar 

  15. Euesden J, Lewis CM, O’Reilly PF. PRSice: Polygenic Risk Score software. Bioinformatics. 2015;31:1466–8.

    Article  CAS  PubMed  Google Scholar 

  16. Chang CC, Chow CC, Tellier LC, Vattikuti S, Purcell SM, Lee JJ. Second-generation PLINK: rising to the challenge of larger and richer datasets. Gigascience. 2015;4:7.

    Article  PubMed  PubMed Central  Google Scholar 

  17. Donohue MC, Sperling RA, Salmon DP, Rentz DM, Raman R, Thomas RG, et al. The preclinical Alzheimer cognitive composite: Measuring amyloid-related decline. JAMA Neurol. 2014;71:961–70.

    Article  PubMed  PubMed Central  Google Scholar 

  18. Gibbons LE, Carle AC, Mackin RS, Harvey D, Mukherjee S, Insel P, et al. A composite score for executive functioning, validated in Alzheimer’s Disease Neuroimaging Initiative (ADNI) participants with baseline mild cognitive impairment. Brain Imaging Behav. 2012;6:517–27.

    Article  PubMed  PubMed Central  Google Scholar 

  19. Crane PK, Carle A, Gibbons LE, Insel P, Mackin RS, Gross A, et al. Development and assessment of a composite score for memory in the Alzheimer’s Disease Neuroimaging Initiative (ADNI). Brain Imaging Behav. 2012;6:502–16.

    Article  PubMed  PubMed Central  Google Scholar 

  20. Jack CRJ, Bernstein MA, Fox NC, Thompson P, Alexander G, Harvey D, et al. The Alzheimer’s Disease Neuroimaging Initiative (ADNI): MRI methods. J Magn Reson Imaging. 2008;27:685–91.

    Article  PubMed  PubMed Central  Google Scholar 

  21. Landau SM, Mintun MA, Joshi AD, Koeppe RA, Petersen RC, Aisen PS, et al. Amyloid deposition, hypometabolism, and longitudinal cognitive decline. Ann Neurol. 2012;72:578–86.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Hansson O, Seibyl J, Stomrud E, Zetterberg H, Trojanowski JQ, Bittner T, et al. CSF biomarkers of Alzheimer’s disease concord with amyloid-β PET and predict clinical progression: A study of fully automated immunoassays in BioFINDER and ADNI cohorts. Alzheimers Dement. 2018;14:1470–81.

    Article  PubMed  PubMed Central  Google Scholar 

  23. Mathotaarachchi S, Wang S, Shin M, Pascoal TA, Benedet AL, Kang MS, et al. VoxelStats: A MATLAB Package for multi-modal voxel-wise brain image analysis. 10, Front Neuroinformatics. 2016. Available from:

  24. Selya A, Rose J, Dierker L, Hedeker D, Mermelstein R. A Practical Guide to Calculating Cohen’s f2, a Measure of Local Effect Size, from PROC MIXED. Vol. 3, Front Psychol. 2012. Available from:

  25. Keller MC. Gene × environment interaction studies have not properly controlled for potential confounders: the problem and the (simple) solution. Biol Psychiatry. 2014;75:18–24.

    Article  PubMed  Google Scholar 

  26. Knopman DS, Amieva H, Petersen RC, Chételat G, Holtzman DM, Hyman BT, et al. Alzheimer disease. Nat Rev Dis Prim. 2021;7:33 Available from

    Article  PubMed  Google Scholar 

  27. Ferrari-Souza JP, Brum WS, Hauschild LA, Da Ros LU, Lukasewicz Ferreira PC, Bellaver B, et al. Vascular risk burden is a key player in the early progression of Alzheimer’s disease. medRxiv. 2021.12.18.21267994.

  28. Mendonca F, Sudo FK, Santiago-Bravo G, Oliveira N, Assuncao N, Rodrigues F, et al. Mild cognitive impairment or attention-deficit/hyperactivity disorder in older adults? A cross sectional study. Front Psychiatry. 2021;12:12–7.

    Article  Google Scholar 

  29. Ossenkoppele R, Binette AP, Groot C, Smith R, Strandberg O, Palmqvist S, et al. Amyloid and Tau PET positive cognitively unimpaired individuals: Destined to decline? medRxiv. 2022;2022.05.23.22275241.

  30. Donohue MC, Sperling RA, Petersen R, Sun CK, Weiner M, Aisen PS. Association between elevated brain amyloid and subsequent cognitive decline among cognitively normal persons. JAMA - J Am Med Assoc. 2017;317:2305–16.

    Article  CAS  Google Scholar 

  31. Strikwerda-Brown C, Hobbs DA, Gonneaud J, St-Onge F, Binette AP, Ozlen H, et al. Association of elevated amyloid and tau positron emission tomography signal with near-term development of alzheimer disease symptoms in older adults without cognitive impairment. JAMA Neurol. 2022;79:975–85.

  32. Jack CRJ, Wiste HJ, Therneau TM, Weigand SD, Knopman DS, Mielke MM, et al. Associations of Amyloid, Tau, and neurodegeneration biomarker profiles with rates of memory decline among individuals without dementia. JAMA. 2019;321:2316–25.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Hanseeuw BJ, Betensky RA, Jacobs HIL, Schultz AP, Sepulcre J, Becker JA, et al. Association of Amyloid and Tau with cognition in preclinical Alzheimer disease: A Longitudinal Study. JAMA Neurol. 2019;76:915–24.

    Article  PubMed  PubMed Central  Google Scholar 

  34. Long JM, Holtzman DM. Alzheimer Disease: An Update on Pathobiology and Treatment Strategies. Cell. 2019;179:312–39.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Jansen WJ, Janssen O, Tijms BM, Vos SJB, Ossenkoppele R, Visser PJ, et al. Prevalence estimates of amyloid abnormality across the alzheimer disease clinical spectrum. JAMA Neurol. 2022

  36. La Joie R, Bejanin A, Fagan AM, Ayakta N, Baker SL, Bourakova V, et al. Associations between [(18)F]AV1451 tau PET and CSF measures of tau pathology in a clinical sample. Neurology. 2018;90:e282–90.

    Article  PubMed  PubMed Central  Google Scholar 

  37. Frisoni GB, Fox NC, Jack CR Jr, Scheltens P, Thompson PM. The clinical use of structural MRI in Alzheimer disease. Nat Rev Neurol. 2010;6:67–77.

    Article  PubMed  PubMed Central  Google Scholar 

  38. Moreno-Alcázar A, Ramos-Quiroga JA, Radua J, Salavert J, Palomar G, Bosch R, et al. Brain abnormalities in adults with Attention Deficit Hyperactivity Disorder revealed by voxel-based morphometry. Psychiatry Res Neuroimaging. 2016;254:41–7.

    Article  PubMed  Google Scholar 

  39. Klein M, Souza-Duran FL, Menezes AKPM, Alves TM, Busatto G, Louzã MR. Gray matter volume in elderly adults With ADHD: Associations of symptoms and comorbidities with brain structures. J Atten Disord. 2021;25:829–38.

    Article  PubMed  Google Scholar 

  40. Fuermaier ABM, Tucha L, Koerts J, Aschenbrenner S, Weisbrod M, Lange KW, et al. Cognitive complaints of adults with attention deficit hyperactivity disorder. Clin Neuropsychol. 2014;28:1104–22.

    Article  PubMed  Google Scholar 

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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 ( 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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Competing interests

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).

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