Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

In vivo-measured Lewy body pathology is associated with neuropsychiatric symptoms across the Alzheimer’s disease continuum

Molecular Psychiatry (2025)Cite this article

Subjects

Abstract

Intracellular alpha-synuclein aggregates, known as Lewy bodies (LB), are commonly observed in Alzheimer’s disease (AD) dementia. Post-mortem studies have shown a higher frequency of neuropsychiatric symptoms among individuals with AD and LB co-pathology. However, the effects of in vivo-measured LB pathology on neuropsychiatric symptoms in AD remain underexplored. This study aimed to evaluate cross-sectional and longitudinal effects of in vivo-measured LB pathology on neuropsychiatric symptoms across the AD continuum. We analyzed data from 1169 participants from the Alzheimer’s Disease Neuroimaging Initiative (ADNI). Participants had in vivo measures of LB pathology (assessed using an alpha-synuclein seed amplification assay), amyloid-beta (Aβ) and phosphorylated tau (p-tau) levels in cerebrospinal fluid, and neuropsychiatric symptoms evaluated using the Neuropsychiatric Inventory-Questionnaire (NPI-Q). Logistic and Cox proportional hazards regression models were used to assess cross-sectional and longitudinal effects, respectively, adjusting for age, sex, and cognitive status. Participants had a mean baseline age of 73.05 (SD 7.22) years, 47.13% were women, 426 (36.44%) cognitively unimpaired, and 743 (63.56%) cognitively impaired. In cross-sectional analyses, LB pathology was associated with higher rates of anxiety, apathy, motor disturbances, and appetite disturbances. In longitudinal analyses, LB pathology increased the risk of developing psychosis and anxiety. These effects were independent of Aβ and p-tau. Our results suggest that in vivo-measured LB pathology is closely associated with neuropsychiatric symptoms across the AD continuum. These findings underscore the potential of in vivo LB detection as a marker for identifying individuals at increased risk of neuropsychiatric symptoms, both in clinical trials and in clinical practice.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on SpringerLink
  • Instant access to the full article PDF.

USD 39.95

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Cross-sectional associations between LB and neuropsychiatric symptoms.
Fig. 2: Effects of LB, Aβ, and p-tau on neuropsychiatric symptoms at baseline.
Fig. 3: Effects of LB on the development of neuropsychiatric symptoms.

Similar content being viewed by others

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.

References

  1. Robinson JL, Richardson H, Xie SX, Suh E, Van Deerlin VM, Alfaro B, et al. The development and convergence of co-pathologies in Alzheimer’s disease. Brain. 2021;144:953–62.

    Article  PubMed  PubMed Central  Google Scholar 

  2. DeTure MA, Dickson DW. The neuropathological diagnosis of Alzheimer’s disease. Mol Neurodegener. 2019;14:32.

    Article  PubMed  PubMed Central  Google Scholar 

  3. Taylor J-P, McKeith IG, Burn DJ, Boeve BF, Weintraub D, Bamford C, et al. New evidence on the management of lewy body dementia. The Lancet Neurology. 2020;19:157–69.

    Article  PubMed  Google Scholar 

  4. Baiardi S, Hansson O, Levin J, Parchi P. In vivo detection of Alzheimer’s and Lewy body disease concurrence: Clinical implications and future perspectives. Alzheimer’s & Dementia. 2024;20:5757–70.

    Article  Google Scholar 

  5. Quadalti C, Palmqvist S, Hall S, Rossi M, Mammana A, Janelidze S, et al. Clinical effects of lewy body pathology in cognitively impaired individuals. Nature Medicine. 2023;29:1964–70.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  6. Collij LE, Mastenbroek SE, Mattsson-Carlgren N, Strandberg O, Smith R, Janelidze S, et al. Lewy body pathology exacerbates brain hypometabolism and cognitive decline in Alzheimer’s disease. Nat Commun. 2024;15:8061.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  7. Mega MS, Cummings JL, Fiorello T, Gornbein J. The spectrum of behavioral changes in Alzheimer’s disease. Neurology. 1996;46:130–5.

    Article  PubMed  CAS  Google Scholar 

  8. Lyketsos CG, Steinberg M, Tschanz JT, Norton MC, Steffens DC, Breitner JC. Mental and behavioral disturbances in dementia: findings from the cache county study on memory in aging. Am J Psychiatry. 2000;157:708–14.

    Article  PubMed  CAS  Google Scholar 

  9. Lyketsos CG, Lopez O, Jones B, Fitzpatrick AL, Breitner J, DeKosky S. Prevalence of neuropsychiatric symptoms in dementia and mild cognitive impairment: results from the cardiovascular health study. Jama. 2002;288:1475–83.

    Article  PubMed  Google Scholar 

  10. Sink KM, Covinsky KE, Newcomer R, Yaffe K. Ethnic differences in the prevalence and pattern of dementia-related behaviors. J Am Geriatr Soc. 2004;52:1277–83.

    Article  PubMed  Google Scholar 

  11. Macedo AC, Therriault J, Tissot C, Aumont É, Servaes S, Rahmouni N, et al. Modeling the progression of neuropsychiatric symptoms in Alzheimer’s disease with PET-based Braak staging. Neurobiol Aging. 2024;144:127–37.

    Article  PubMed  CAS  Google Scholar 

  12. Scarmeas N, Brandt J, Blacker D, Albert M, Hadjigeorgiou G, Dubois B, et al. Disruptive behavior as a predictor in Alzheimer disease. Arch Neurol. 2007;64:1755–61.

    Article  PubMed  PubMed Central  Google Scholar 

  13. Scarmeas N, Brandt J, Albert M, Hadjigeorgiou G, Papadimitriou A, Dubois B, et al. Delusions and hallucinations are associated with worse outcome in Alzheimer disease. Arch Neurol. 2005;62:1601–8.

    Article  PubMed  PubMed Central  Google Scholar 

  14. Gallagher-Thompson D, Brooks JO III, Bliwise D, Leader J, Yesavage JA. The relations among caregiver stress, “sundowning” symptoms, and cognitive decline in Alzheimer’s disease. J Am Geriatr Soc. 1992;40:807–10.

    Article  PubMed  CAS  Google Scholar 

  15. Chung EJ, Babulal GM, Monsell SE, Cairns NJ, Roe CM, Morris JC. Clinical features of alzheimer disease with and without lewy bodies. JAMA Neurology. 2015;72:789–96.

    Article  PubMed  PubMed Central  Google Scholar 

  16. Devanand DP, Lee S, Huey ED, Goldberg TE. Associations between neuropsychiatric symptoms and neuropathological diagnoses of alzheimer disease and related dementias. JAMA Psychiatry. 2022;79:359–67.

    Article  PubMed  PubMed Central  Google Scholar 

  17. Bayram E, Shan G, Cummings JL. Associations between comorbid TDP-43, lewy body pathology, and neuropsychiatric symptoms in Alzheimer’s disease. Journal of Alzheimer’s Disease. 2019;69:953–61.

    Article  PubMed  PubMed Central  Google Scholar 

  18. Gibson LL, Grinberg LT, Ffytche D, Leite REP, Rodriguez RD, Ferretti-Rebustini REL, et al. Neuropathological correlates of neuropsychiatric symptoms in dementia. Alzheimer’s & Dementia. 2023;19:1372–82.

    Article  Google Scholar 

  19. Tosun D, Hausle Z, Iwaki H, Thropp P, Lamoureux J, Lee EB, et al. A cross-sectional study of α-synuclein seed amplification assay in Alzheimer’s disease neuroimaging initiative: prevalence and associations with Alzheimer’s disease biomarkers and cognitive function. Alzheimer’s & Dementia. 2024;20:5114–31.

    Article  CAS  Google Scholar 

  20. 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 

  21. Kaufer DI, Cummings JL, Ketchel P, Smith V, MacMillan A, Shelley T, et al. Validation of the NPI-Q, a brief clinical form of the neuropsychiatric inventory. J Neuropsychiatry Clin Neurosci. 2000;12:233–9.

    Article  PubMed  CAS  Google Scholar 

  22. Concha-Marambio L, Pritzkow S, Shahnawaz M, Farris CM, Soto C. Seed amplification assay for the detection of pathologic alpha-synuclein aggregates in cerebrospinal fluid. Nat Protoc. 2023;18:1179–96.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  23. 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  Google Scholar 

  24. Blennow K, Shaw LM, Stomrud E, Mattsson N, Toledo JB, Buck K, et al. Predicting clinical decline and conversion to Alzheimer’s disease or dementia using novel Elecsys Aβ(1-42), pTau and tTau CSF immunoassays. Sci Rep. 2019;9:19024.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  25. Benjamini Y, Hochberg Y. Controlling the false discovery rate: a practical and powerful approach to multiple testing. J R Stat Soc Series B (Methodological). 1995;57:289–300.

  26. Ballard C, Aarsland D, Francis P, Corbett A. Neuropsychiatric symptoms in patients with dementias associated with cortical lewy bodies: pathophysiology, clinical features, and pharmacological management. Drugs & Aging. 2013;30:603–11.

    Article  CAS  Google Scholar 

  27. Ballard C, Holmes C, McKeith I, Neill D, O’Brien J, Cairns N, et al. Psychiatric morbidity in dementia with lewy bodies: a prospective clinical and neuropathological comparative study with Alzheimer’s disease. American Journal of Psychiatry. 1999;156:1039–45.

    Article  PubMed  CAS  Google Scholar 

  28. Segers K, Benoit F, Meyts JM, Surquin M. Anxiety symptoms are quantitatively and qualitatively different in dementia with lewy bodies than in Alzheimer’s disease in the years preceding clinical diagnosis. Psychogeriatrics. 2020;20:242–6.

    Article  PubMed  Google Scholar 

  29. Borroni B, Agosti C, Padovani A. Behavioral and psychological symptoms in dementia with Lewy-bodies (DLB): frequency and relationship with disease severity and motor impairment. Arch Gerontol Geriatr. 2008;46:101–6.

    Article  PubMed  CAS  Google Scholar 

  30. Aarsland D, Brønnick K, Ehrt U, De Deyn PP, Tekin S, Emre M, et al. Neuropsychiatric symptoms in patients with Parkinson’s disease and dementia: frequency, profile and associated care giver stress. J Neurol Neurosurg Psychiatry. 2007;78:36–42.

    Article  PubMed  CAS  Google Scholar 

  31. Schwertner E, Pereira JB, Xu H, Secnik J, Winblad B, Eriksdotter M, et al. Behavioral and psychological symptoms of dementia in different dementia disorders: a large-scale study of 10,000 individuals. Journal of Alzheimer’s Disease. 2022;87:1307–18.

    Article  PubMed  PubMed Central  Google Scholar 

  32. Rossi M, Candelise N, Baiardi S, Capellari S, Giannini G, Orrù CD, et al. Ultrasensitive RT-QuIC assay with high sensitivity and specificity for lewy body-associated synucleinopathies. Acta Neuropathol. 2020;140:49–62.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  33. Donovan NJ, Locascio JJ, Marshall GA, Gatchel J, Hanseeuw BJ, Rentz DM, et al. Longitudinal association of amyloid beta and anxious-depressive symptoms in cognitively normal older adults. Am J Psychiatry. 2018;175:530–7.

    Article  PubMed  PubMed Central  Google Scholar 

  34. Babulal GM, Ghoshal N, Head D, Vernon EK, Holtzman DM, Benzinger TLS, et al. Mood changes in cognitively normal older adults are linked to alzheimer disease biomarker levels. Am J Geriatr Psychiatry. 2016;24:1095–104.

    Article  PubMed  PubMed Central  Google Scholar 

  35. Ballard CG, Jacoby R, Ser TD, Khan MN, Munoz DG, Holmes C, et al. Neuropathological substrates of psychiatric symptoms in prospectively studied patients with autopsy-confirmed dementia with lewy bodies. American Journal of Psychiatry. 2004;161:843–9.

    Article  PubMed  Google Scholar 

  36. Tosun D, Hausle Z, Thropp P, Concha-Marambio L, Lamoureux J, Lebovitz R, et al. Association of CSF α-synuclein seed amplification assay positivity with disease progression and cognitive decline: A longitudinal Alzheimer’s disease neuroimaging initiative study. Alzheimer’s & Dementia. 2024;20:8444–60.

    Article  CAS  Google Scholar 

  37. Silva-Rodríguez J, Labrador-Espinosa MA, Zhang L, Castro-Labrador S, López-González FJ, Moscoso A, et al. The effect of Lewy body (co-)pathology on the clinical and imaging phenotype of amnestic patients. Brain. 2025;148:2441–52.

    Article  PubMed  PubMed Central  Google Scholar 

  38. Mak E, Przybelski SA, Wiste HJ, Fought AJ, Schwarz CG, Senjem ML, et al. Influence of alpha-synuclein on glucose metabolism in Alzheimer’s disease continuum: Analyses of α-synuclein seed amplification assay and FDG-PET. Alzheimer’s & Dementia. 2025;21:e14571.

    Article  CAS  Google Scholar 

  39. Franzmeier N, Roemer-Cassiano SN, Bernhardt AM, Dehsarvi A, Dewenter A, Steward A, et al. Alpha synuclein co-pathology is associated with accelerated amyloid-driven tau accumulation in Alzheimer’s disease. Mol Neurodegener. 2025;20:31.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

Download references

Acknowledgements

Data collection and sharing for this project was funded by the Alzheimer’s Disease Neuroimaging Initiative (ADNI) NIH Grant U01 AG024904) and DOD ADNI (Department of Defense award number W81XWH-12-2-0012). The ADNI is funded by the National Institute on Aging (NIH), 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. T.A.P. is supported by National Institute on Aging awards 5R01AG073267 and 5R01AG075336. B.B., M.S.R., G.B.N., G.P., and P.C.L.F. are supported by the Alzheimer’s Association Research Fellowship to promote diversity (AARFD-22-974627; AARFD-24-1313939; AARFD-23-1150249; 24AARFD-1243899; AARFD-22-923814). C.S.A. is supported by the Global Brain Health Institute, Alzheimer’s Association, and Alzheimer’s Society (GBHI ALZ UK-23-971089), Alzheimer’s Association (24AACSF-1200375), and Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES, 88887.951210/2024-00). J.T. is funded by the McGill University Faculty of Medicine student fellowship, and the Colin J Adair foundation fellowship.

Author information

Authors and Affiliations

  1. Department of Psychiatry, University of Pittsburgh, 3811 O’Hara Street, Pittsburgh, PA, 15213, USA

    Douglas Teixeira Leffa, Guilherme Povala, Pamela C. L. Ferreira, Guilherme Bauer-Negrini, Matheus Scarpatto Rodrigues, Livia Amaral, Firoza Z. Lussier, Marina Scop Medeiros, Carolina Soares, Dana L. Tudorascu, Bruna Bellaver & Tharick A. Pascoal

  2. Graduate Program in Biological Sciences: Biochemistry, Universidade Federal do Rio Grande do Sul, 2600 Ramiro Barcelos, Porto Alegre, RS, 90035-003, Brazil

    João Pedro Ferrari-Souza & Eduardo R. Zimmer

  3. Brain Institute of Rio Grande do Sul, Pontifical Catholic University of Rio Grande do Sul, 6690 Avenida Ipiranga, Porto Alegre, RS, 90035-003, Brazil

    Marina Scop Medeiros & Cristiano Schaffer Aguzzoli

  4. Translational Neuroimaging Laboratory, McGill University Research Centre for Studies in Aging, McConnell Brain Imaging Centre (BIC), Montreal Neurological Institute, Montreal Neurological Institute-Hospital, 3801 Rue University, Montréal, QC, H3A 2B4, Canada

    Arthur C. Macedo, Joseph Therriault & Pedro Rosa-Neto

  5. The Peter O’Donnell Jr. Brain Institute (OBI), University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd, Dallas, TX, 75235, USA

    Pedro Rosa-Neto

  6. Institution: Douglas Hospital Research Centre, Centre intégré universitaire de santé et services sociaux de l’Ouest-de-l’Île-de-Montréal, Verdun, QC, H4H 1R3, Canada

    Pedro Rosa-Neto

  7. Graduate Program in Biological Sciences: Pharmacology and Therapeutics, Department of Pharmacology, Universidade Federal do Rio Grande do Sul, Ramiro Barcelos 2600, Porto Alegre, RS, 90050-170, Brazil

    Eduardo R. Zimmer

  8. Department of Pharmacology and Therapeutics, McGill University, 3655 Promenade Sir William Osler, Montréal, QC, H3G 1Y6, Canada

    Eduardo R. Zimmer

  9. Hospital Moinhos de Vento, Porto Alegre, Brazil

    Eduardo R. Zimmer

  10. Department of Neurology, University of Pittsburgh, 3471 Fifth Avenue, Pittsburgh, PA, 15213, USA

    Tharick A. Pascoal

Authors
  1. Douglas Teixeira Leffa
    View author publications

    Search author on:PubMed Google Scholar

  2. Guilherme Povala
    View author publications

    Search author on:PubMed Google Scholar

  3. Pamela C. L. Ferreira
    View author publications

    Search author on:PubMed Google Scholar

  4. João Pedro Ferrari-Souza
    View author publications

    Search author on:PubMed Google Scholar

  5. Guilherme Bauer-Negrini
    View author publications

    Search author on:PubMed Google Scholar

  6. Matheus Scarpatto Rodrigues
    View author publications

    Search author on:PubMed Google Scholar

  7. Livia Amaral
    View author publications

    Search author on:PubMed Google Scholar

  8. Firoza Z. Lussier
    View author publications

    Search author on:PubMed Google Scholar

  9. Marina Scop Medeiros
    View author publications

    Search author on:PubMed Google Scholar

  10. Carolina Soares
    View author publications

    Search author on:PubMed Google Scholar

  11. Cristiano Schaffer Aguzzoli
    View author publications

    Search author on:PubMed Google Scholar

  12. Arthur C. Macedo
    View author publications

    Search author on:PubMed Google Scholar

  13. Joseph Therriault
    View author publications

    Search author on:PubMed Google Scholar

  14. Pedro Rosa-Neto
    View author publications

    Search author on:PubMed Google Scholar

  15. Dana L. Tudorascu
    View author publications

    Search author on:PubMed Google Scholar

  16. Eduardo R. Zimmer
    View author publications

    Search author on:PubMed Google Scholar

  17. Bruna Bellaver
    View author publications

    Search author on:PubMed Google Scholar

  18. Tharick A. Pascoal
    View author publications

    Search author on:PubMed Google Scholar

Contributions

DTL and TAP conceived and designed the study. DTL and BB prepared the figures and tables. DTL drafted the manuscript with input from GP, PCLF, JPF-S, GB-N, MSR, LA, FZL, MSM, CS, CSA, ACM, JT, PR-S, DLT, ERZ, BB, and TAP. DTL and TAP performed the acquisitions and/or interpretation of the data. TAP supervised this work. DTL and DLT performed the statistical analyses. All authors revised and approved the final manuscript.

Corresponding authors

Correspondence to Douglas Teixeira Leffa or Tharick A. Pascoal.

Ethics declarations

Competing interests

J.T. has served as a paid consultant for Neurotorium and Alzheon Inc, outside of the scope of the current work. E.R.Z. has served on the scientific advisory board or as a consultant for Nintx, Novo Nordisk, Magdalena Biosciences and Masima. He is also a co-founder and minority shareholder of Masima.

Ethics approval and consent to participate

Institutional Review Boards of all participating sites approved the ADNI study, and all research participants or their authorized representatives provided written informed consent. All methods were performed in accordance with the relevant guidelines and regulations.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Leffa, D.T., Povala, G., Ferreira, P.C.L. et al. In vivo-measured Lewy body pathology is associated with neuropsychiatric symptoms across the Alzheimer’s disease continuum. Mol Psychiatry (2025). https://doi.org/10.1038/s41380-025-03400-7

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Version of record:

  • DOI: https://doi.org/10.1038/s41380-025-03400-7

Search

Advanced search

Quick links