Co-pathologies are common in dementia with Lewy bodies and other dementia disorders. We investigated cerebrovascular and Alzheimer's disease co-pathologies in patients with dementia with Lewy bodies in comparison with patients with mild cognitive impairment, Alzheimer's disease, mixed dementia, vascular dementia or Parkinson's disease with dementia and cognitively unimpaired participants. We assessed the association of biomarkers of cerebrovascular and Alzheimer's disease co-pathologies with medial temporal atrophy and global cognitive performance. Additionally, we evaluated whether the findings were specific to dementia with Lewy bodies. We gathered a multi-cohort dataset of 4549 participants (dementia with Lewy bodies = 331, cognitively unimpaired = 1505, mild cognitive impairment = 1489, Alzheimer's disease = 708, mixed dementia = 268, vascular dementia = 148, Parkinson's disease with dementia = 120) from the MemClin Study, Karolinska Imaging in Dementia Study, Gothenburg H70 Birth Cohort Studies and the European DLB Consortium. Cerebrovascular co-pathology was assessed with visual ratings of white matter hyperintensities using the Fazekas scale through structural imaging. Alzheimer's disease biomarkers of β-amyloid and phosphorylated tau were assessed in the cerebrospinal fluid for a subsample (N = 2191). Medial temporal atrophy was assessed with visual ratings and global cognition with the mini-mental state examination. Differences and associations were assessed through regression models, including interaction terms. In dementia with Lewy bodies, 43% had a high white matter hyperintensity load, which was significantly higher than that in cognitively unimpaired (14%), mild cognitive impairment (26%) and Alzheimer's disease (27%), but lower than that in vascular dementia (62%). In dementia with Lewy bodies, white matter hyperintensities were associated with medial temporal atrophy, and the interaction term showed that this association was stronger than that in cognitively unimpaired and mixed dementia. However, the association between white matter hyperintensities and medial temporal atrophy was non-significant when β-amyloid was included in the model. Instead, β-amyloid predicted medial temporal atrophy in dementia with Lewy bodies, in contrast to the findings in mild cognitive impairment where medial temporal atrophy scores were independent of β-amyloid. Dementia with Lewy bodies had the lowest performance on global cognition, but this was not associated with white matter hyperintensities. In Alzheimer's disease, global cognitive performance was lower in patients with more white matter hyperintensities. We conclude that white matter hyperintensities are common in dementia with Lewy bodies and are associated with more atrophy in medial temporal lobes, but this association depended on β-amyloid-related pathology in our cohort. The associations between biomarkers were overall stronger in dementia with Lewy bodies than in some of the other diagnostic groups.

Ageing Epidemiology Research Unit School of Public Health Imperial College London SW7 2AZ London UK

Aging and Inflammation Theme Karolinska University Hospital 171 76 Stockholm Sweden

Alzheimer Center Amsterdam Neurology Vrije Universiteit Amsterdam Amsterdam UMC location Vumc 1081 HV Amsterdam The Netherlands

Amsterdam Neuroscience Neurodegeneration Vrije Universiteit Amsterdam Amsterdam UMC location Vumc 1081 HV Amsterdam The Netherlands

Applied Neuroscience Research Group CEITEC Masaryk University 625 00 Brno Czech Republic

Center for Age Related Medicine Stavanger University Hospital 4011 Stavanger Norway

Centre for Ageing and Health University of Gothenburg 413 46 Gothenburg Sweden

Day Hospital of Geriatrics Memory Resource and Research Centre of Strasbourg Department of Geriatrics Hopitaux Universitaires de Strasbourg 67098 Strasbourg France

Department of Clinical Neuroscience Karolinska Institutet 171 77 Stockholm Sweden

Department of Medicine Aging Sciences University G d'Annunzio of Chieti Pescara Chieti 66100 Chieti Italy

Department of Neuroimaging Centre for Neuroimaging Sciences Institute of Psychiatry Psychology and Neuroscience King's College London SE5 8AF London UK

Department of Neurology IRCCS Ospedale Policlinico San Martino 16132 Genoa Italy

Department of Neurology University Medical Center 1000 Ljubljana Slovenia

Department of Neuroscience Rehabilitation Ophthalmology Genetics Maternal and Child Health University of Genoa 16132 Genoa Italy

Department of Old Age Psychiatry Institute of Psychiatry Psychology and Neuroscience King's College London SE5 8AF London UK

Department of Radiology Karolinska University Hospital 171 76 Stockholm Sweden

Department of Radiology Stanford University Stanford 94305 5105 CA USA

Division of Clinical Geriatrics Center for Alzheimer Research Department of Neurobiology Care Sciences and Society Karolinska Institutet 171 77 Stockholm Sweden

Division of Psychiatry University College London W1T 7NF London UK

Facultad de Ciencias de la Salud Universidad Fernando Pessoa Canarias 35016 Las Palmas España

ICube Laboratory and Federation de Medecine Translationnelle de Strasbourg ICONE 67000 Strasbourg France

Institute of Public Health and Clinical Nutrition University of Eastern Finland 70211 Kuopio Finland

Medical Faculty University of Ljubljana 1000 Ljubljana Slovenia

Medical Unit Allied Health Professionals Women´s Health Karolinska University Hospital 171 76 Stockholm Sweden

Memory Clinic Department of Neurology 2nd Faculty of Medicine Charles University and Motol University Hospital 150 06 Prague Czech Republic

Memory Clinic Landspitali 105 Reykjavik Iceland

Neurology Unit Department of Clinical and Experimental Sciences University of Brescia 25123 Brescia Italy

Neuropsychiatric Epidemiology Unit Department of Psychiatry and Neurochemistry Institute of Neuroscience and Physiology Sahlgrenska Academy at the University of Gothenburg 431 41 Mölndal Sweden

Parkinson and Movement Disorders Unit Study Center on Neurodegeneration 35129 Padova Italy

Psychiatry Cognition and Old Age Psychiatry Clinic Region Västra Götaland Sahlgrenska University Hospital 431 41 Gothenburg Sweden

St Margaret's Hospital Essex Partnership University NHS Foundation Trust CM16 6TN Essex UK

Stavanger Medical Imaging Laboratory Department of Radiology Stavanger University Hospital 4016 Stavanger Norway

The Norwegian Centre for Movement Disorders Stavanger University Hospital 4011 Stavanger Norway

Translational and Clinical Research Institute Faculty of Medical Sciences Newcastle University NE1 7RU Newcastle upon Tyne UK

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McKeith  IG, Boeve  BF, Dickson  DW, et al.  Diagnosis and management of dementia with Lewy bodies: Fourth consensus report of the DLB consortium. Neurology. 2017;89(1):88–100. PubMed PMC

Hijazi  Z, Yassi  N, O'Brien  JT, Watson  R. The influence of cerebrovascular disease in dementia with Lewy bodies and Parkinson's disease dementia. Eur J Neurol. 2022;29(4):1254–1265. PubMed

Toledo  JB, Abdelnour  C, Weil  RS, et al.  Dementia with Lewy bodies: Impact of co-pathologies and implications for clinical trial design. Alzheimers Dement. 2023;19(1):318–332. PubMed PMC

Dubois  B, Villain  N, Frisoni  GB, et al.  Clinical diagnosis of Alzheimer's disease: Recommendations of the International Working Group. Lancet Neurol. 2021;20(6):484–496. PubMed PMC

Iadecola  C, Duering  M, Hachinski  V, et al.  Vascular cognitive impairment and dementia: JACC scientific expert panel. J Am Coll Cardiol. 2019;73(25):3326–3344. PubMed PMC

Rabinovici  GD, Carrillo  MC, Forman  M, et al.  Multiple comorbid neuropathologies in the setting of Alzheimer's disease neuropathology and implications for drug development. Alzheimers Dement (N Y). 2017;3(1):83–91. PubMed PMC

Kapasi  A, DeCarli  C, Schneider  JA. Impact of multiple pathologies on the threshold for clinically overt dementia. Acta Neuropathol. 2017;134(2):171–186. PubMed PMC

Duering  M, Biessels  GJ, Brodtmann  A, et al.  Neuroimaging standards for research into small vessel disease—Advances since 2013. Lancet Neurol. 2023;22(7):602–618. PubMed

Ferreira  D, Nedelska  Z, Graff-Radford  J, et al.  Cerebrovascular disease, neurodegeneration, and clinical phenotype in dementia with Lewy bodies. Neurobiol Aging. 2021;105:252–261. PubMed PMC

Chen  T-Y, Chan  P-C, Tsai  C-F, Wei  C-Y, Chiu  P-Y. White matter hyperintensities in dementia with Lewy bodies are associated with poorer cognitive function and higher dementia stages. Front Aging Neurosci. 2022;14:935652. PubMed PMC

Hu  H-Y, Ou  Y-N, Shen  X-N, et al.  White matter hyperintensities and risks of cognitive impairment and dementia: A systematic review and meta-analysis of 36 prospective studies. Neurosci Biobehav Rev. 2021;120:16–27. PubMed

Ferreira  D, Przybelski  SA, Lesnick  TG, et al.  β-Amyloid and tau biomarkers and clinical phenotype in dementia with Lewy bodies. Neurology. 2020;95(24):e3257–e3268. PubMed PMC

Roseborough  A, Ramirez  J, Black  SE, Edwards  JD. Associations between amyloid β and white matter hyperintensities: A systematic review. Alzheimers Dement. 2017;13(10):1154–1167. PubMed

Wahlund  L-O, Westman  E, Westen  D, et al.  Imaging biomarkers of dementia: Recommended visual rating scales with teaching cases. Insights Imaging. 2017;8(1):79–90. PubMed PMC

Burton  EJ, Barber  R, Mukaetova-Ladinska  EB, et al.  Medial temporal lobe atrophy on MRI differentiates Alzheimer's disease from dementia with Lewy bodies and vascular cognitive impairment: A prospective study with pathological verification of diagnosis. Brain. 2009;132(1):195–203. PubMed

Harper  L, Fumagalli  GG, Barkhof  F, et al.  MRI visual rating scales in the diagnosis of dementia: Evaluation in 184 post-mortem confirmed cases. Brain. 2016;139(Pt 4):1211–1225. PubMed PMC

van der Zande  JJ, Steenwijk  MD, ten Kate  M, Wattjes  MP, Scheltens  P, Lemstra  AW. Gray matter atrophy in dementia with Lewy bodies with and without concomitant Alzheimer's disease pathology. Neurobiol Aging. 2018;71:171–178. PubMed

Nedelska  Z, Ferman  TJ, Boeve  BF, et al.  Pattern of brain atrophy rates in autopsy-confirmed dementia with Lewy bodies. Neurobiol Aging. 2015;36(1):452–461. PubMed PMC

Ferreira  D, Przybelski  SA, Lesnick  TG, et al.  Cross-sectional associations of β-amyloid, tau, and cerebrovascular biomarkers with neurodegeneration in probable dementia with Lewy bodies. Neurology. 2023;100(8):e846–e859. PubMed PMC

Oppedal  K, Borda  MG, Ferreira  D, Westman  E, Aarsland  D. European DLB consortium: Diagnostic and prognostic biomarkers in dementia with Lewy bodies, a multicenter international initiative. Neurodegener Dis Manag. 2019;9(5):247–250. PubMed

Rydberg Sterner  T, Ahlner  F, Blennow  K, et al.  The Gothenburg H70 birth cohort study 2014–16: Design, methods and study population. Eur J Epidemiol. 2019;34(2):191–209. PubMed PMC

Shams  S, Martola  J, Charidimou  A, et al.  Topography and determinants of magnetic resonance imaging (MRI)-visible perivascular spaces in a large memory clinic cohort. J Am Heart Assoc. 2017;6(9):e006279. PubMed PMC

Ekman  U, Ferreira  D, Muehlboeck  JS, et al.  The MemClin project: A prospective multi memory clinics study targeting early stages of cognitive impairment. BMC Geriatr. 2020;20(1):93. PubMed PMC

Folstein  MF, Folstein  SE, McHugh  PR. Mini-mental state”: A practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res. 1975;12(3):189–198. PubMed

Fazekas  F, Chawluk  JB, Alavi  A, Hurtig  HI, Zimmerman  RA. MR signal abnormalities at 1.5 T in Alzheimer's dementia and normal aging. AJR Am J Roentgenol. 1987;149(2):351. PubMed

Joki  H, Higashiyama  Y, Nakae  Y, et al.  White matter hyperintensities on MRI in dementia with Lewy bodies, Parkinson's disease with dementia, and Alzheimer's disease. J Neurol Sci. 2018;385:99–104. PubMed

Scheltens  P, Leys  D, Barkhof  F, et al.  Atrophy of medial temporal lobes on MRI in “probable” Alzheimer's disease and normal ageing: Diagnostic value and neuropsychological correlates. J Neurol Neurosurg Psychiatry. 1992;55(10):967–972. PubMed PMC

Ferreira  D, Cavallin  L, Larsson  EM, et al.  Practical cut-offs for visual rating scales of medial temporal, frontal and posterior atrophy in Alzheimer's disease and mild cognitive impairment. J Intern Med. 2015;278(3):277–290. PubMed

Ferreira  D, Shams  S, Cavallin  L, et al.  The contribution of small vessel disease to subtypes of Alzheimer's disease: A study on cerebrospinal fluid and imaging biomarkers. Neurobiol Aging. 2018;70:18–29. PubMed

Mårtensson  G, Ferreira  D, Cavallin  L, et al.  AVRA: Automatic visual ratings of atrophy from MRI images using recurrent convolutional neural networks. Neuroimage Clin. 2019;23:101872. PubMed PMC

Wattjes  MP, Henneman  WJP, van der Flier  WM, et al.  Diagnostic imaging of patients in a memory clinic: Comparison of MR imaging and 64-detector row CT. Radiology. 2009;253(1):174–183. PubMed

Cedres  N, Ferreira  D, Machado  A, et al.  Predicting Fazekas scores from automatic segmentations of white matter signal abnormalities. Aging (Albany NY). 2020;12(1):894–901. PubMed PMC

Muehlboeck  JS, Westman  E, Simmons  A. TheHiveDB image data management and analysis framework. Front Neuroinform. 2014;7:49. PubMed PMC

Samuelsson  J, Kern  S, Zetterberg  H, et al.  A western-style dietary pattern is associated with cerebrospinal fluid biomarker levels for preclinical Alzheimer's disease—A population-based cross-sectional study among 70-year-olds. Alzheimers Dementia. 2021;7(1):e12183. PubMed PMC

Abdelnour  C, van Steenoven  I, Londos  E, et al.  Alzheimer's disease cerebrospinal fluid biomarkers predict cognitive decline in Lewy body dementia. Mov Disord. 2016;31(8):1203–1208. PubMed

Van Steenoven  I, Aarsland  D, Weintraub  D, et al.  Cerebrospinal fluid Alzheimer's disease biomarkers across the Spectrum of Lewy body diseases: Results from a large multicenter cohort. J Alzheimers Dis. 2016;54(1):287–295. PubMed PMC

Koikkalainen  J, Rhodius-Meester  H, Tolonen  A, et al.  Differential diagnosis of neurodegenerative diseases using structural MRI data. Neuroimage Clin. 2016;11:435–449. PubMed PMC

Gan  J, Shi  Z, Liu  S, et al.  White matter hyperintensities in cognitive impairment with Lewy body disease: A multicentre study. Eur J Neurol. 2023;30:3711–3721. PubMed

McAleese  KE, Firbank  M, Dey  M, et al.  Cortical tau load is associated with white matter hyperintensities. Acta Neuropathol Commun. 2015;3:60. PubMed PMC

McAleese  KE, Walker  L, Graham  S, et al.  Parietal white matter lesions in Alzheimer's disease are associated with cortical neurodegenerative pathology, but not with small vessel disease. Acta Neuropathol. 2017;134(3):459–473. PubMed PMC

Inguanzo  A, Poulakis  K, Mohanty  R, et al.  MRI data-driven clustering reveals different subtypes of dementia with Lewy bodies. NPJ Parkinsons Dis. 2023;9(1):5. PubMed PMC

Abdelnour  C, Ferreira  D, van de Beek  M, et al.  Parsing heterogeneity within dementia with Lewy bodies using clustering of biological, clinical, and demographic data. Alzheimers Res Ther. 2022;14(1):14. PubMed PMC

van den Berg  E, Geerlings  MI, Biessels  GJ, Nederkoorn  PJ, Kloppenborg  RP. White matter hyperintensities and cognition in mild cognitive impairment and Alzheimer's disease: A domain-specific meta-analysis. J Alzheimers Dis. 2018;63(2):515–527. PubMed

Möller Andersson  E, Johansson Hoff  E, Landqvist Waldö  M, Englund  E. Clinicopathological concordance in cognitive disease diagnostics. Clin Neuropathol. 2020;39(3):99–104. PubMed

Skogseth  R, Hortobágyi  T, Soennesyn  H, et al.  Accuracy of clinical diagnosis of dementia with Lewy bodies versus neuropathology. J Alzheimers Dis. 2017;59(4):1139–1152. PubMed

Okkels  N, Horsager  J, Labrador-Espinosa  M, et al.  Severe cholinergic terminal loss in newly diagnosed dementia with Lewy bodies. Brain. 2023;146:3690–3704. PubMed

Schumacher  J, Ray  NJ, Hamilton  CA, et al.  Free water imaging of the cholinergic system in dementia with Lewy bodies and Alzheimer's disease. Alzheimers Dement. 2023;19(10):4549–4563. PubMed

Schumacher  J, Ray  NJ, Hamilton  CA, et al.  Cholinergic white matter pathways in dementia with Lewy bodies and Alzheimer's disease. Brain. 2022;145(5):1773–1784. PubMed PMC

Barber  R, Gholkar  A, Scheltens  P, et al.  Medial temporal lobe atrophy on MRI in dementia with Lewy bodies. Neurology. 1999;52(6):1153–1158. PubMed

Cerebrovascular co-pathology and cholinergic white matter pathways along the Lewy body continuum