. 2025 Feb;21(2):e14381.

doi: 10.1002/alz.14381. Epub 2025 Jan 24.

Polygenic risk discriminates Lewy body dementia from Alzheimer's disease

Anna McKeever^{1

2}, Peter Swann¹, Maura Malpetti^{3

4}, Paul C Donaghy⁵, Alan Thomas⁵, Elijah Mak¹, Stephen F Carter¹, Jerry H K Tan¹, Young T Hong^{3

6}, Tim D Fryer^{3

6}, Amanda Heslegrave^{7

8}, Henrik Zetterberg^{7

8

9

10

11

12}, Li Su^{1

13}, Leonidas Chouliaras^{1

14}, James B Rowe^{3

4}, John T O'Brien^{1

2

4}

Affiliations

¹ Department of Psychiatry, University of Cambridge School of Clinical Medicine, Cambridge Biomedical Campus, Cambridge, UK.
² Cambridgeshire and Peterborough NHS Foundation Trust, Cambridge, UK.
³ Department of Clinical Neurosciences, University of Cambridge School of Clinical Medicine, Cambridge Biomedical Campus, Cambridge, UK.
⁴ Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK.
⁵ Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, UK.
⁶ Wolfson Brain Imaging Centre, Department of Clinical Neurosciences, University of Cambridge, Cambridge Biomedical Campus, Cambridge, UK.
⁷ Department of Neurodegenerative Disease, UCL Queen Square Institute of Neurology, London, UK.
⁸ Dementia Research Institute, UCL, London, UK.
⁹ Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, The Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
¹⁰ Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Gothenburg, Sweden.
¹¹ Hong Kong Center for Neurodegenerative Diseases, Hong Kong Science Park, Hong Kong, Hong Kong.
¹² Wisconsin Alzheimer's Disease Research Center, University of Wisconsin School of Medicine and Public Health, University of Wisconsin-Madison, Madison, Wisconsin, USA.
¹³ Neuroscience Institute, University of Sheffield, Sheffield, UK.
¹⁴ Specialist Dementia and Frailty Service, Essex Partnership University NHS Foundation Trust, Essex, UK.

PMID: 39853853
PMCID: PMC11848393
DOI: 10.1002/alz.14381

Polygenic risk discriminates Lewy body dementia from Alzheimer's disease

Anna McKeever et al. Alzheimers Dement. 2025 Feb.

. 2025 Feb;21(2):e14381.

doi: 10.1002/alz.14381. Epub 2025 Jan 24.

Authors

Affiliations

¹ Department of Psychiatry, University of Cambridge School of Clinical Medicine, Cambridge Biomedical Campus, Cambridge, UK.
² Cambridgeshire and Peterborough NHS Foundation Trust, Cambridge, UK.
³ Department of Clinical Neurosciences, University of Cambridge School of Clinical Medicine, Cambridge Biomedical Campus, Cambridge, UK.
⁴ Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK.
⁵ Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, UK.
⁶ Wolfson Brain Imaging Centre, Department of Clinical Neurosciences, University of Cambridge, Cambridge Biomedical Campus, Cambridge, UK.
⁷ Department of Neurodegenerative Disease, UCL Queen Square Institute of Neurology, London, UK.
⁸ Dementia Research Institute, UCL, London, UK.
⁹ Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, The Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
¹⁰ Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Gothenburg, Sweden.
¹¹ Hong Kong Center for Neurodegenerative Diseases, Hong Kong Science Park, Hong Kong, Hong Kong.
¹² Wisconsin Alzheimer's Disease Research Center, University of Wisconsin School of Medicine and Public Health, University of Wisconsin-Madison, Madison, Wisconsin, USA.
¹³ Neuroscience Institute, University of Sheffield, Sheffield, UK.
¹⁴ Specialist Dementia and Frailty Service, Essex Partnership University NHS Foundation Trust, Essex, UK.

PMID: 39853853
PMCID: PMC11848393
DOI: 10.1002/alz.14381

Abstract

Introduction: Lewy body dementia (LBD) shares genetic risk factors with Alzheimer's disease (AD), including apolipoprotein E (APOE), but is distinguishable at the genome-wide level. Polygenic risk scores (PRS) may therefore improve diagnostic classification.

Methods: We assessed diagnostic classification using AD-PRS excluding APOE (AD-PRS_no _APOE), APOE risk score (APOE-RS), and plasma phosphorylated tau 181 (p-tau181), in 83 participants with LBD, 27 with positron emission tomography amyloid beta (Aβ)positive mild cognitive impairment or AD (MCI+/AD), and 57 controls.

Results: Together AD-PRS_no _APOE and APOE-RS performed similarly to p-tau181 in discriminating MCI+/AD from controls (area under the curve 76% vs. 79%) and LBD (71% vs. 72%). In LBD, Aβ positivity was significantly associated with APOE-RS, but not with AD-PRS_no _APOE, or p-tau181. Combining AD-PRS_no _APOE, APOE-RS, and p-tau181 improved the discrimination of MCI+/AD from controls (81%) and LBD (75%), and the detection of Aβ in LBD (82%).

Discussion: Aβ deposition in LBD was associated with APOE, while MCI+/AD was also associated with AD-PRS beyond APOE. AD-PRS explains phenotypic variance not captured by APOE or p-tau181.

Highlights: We investigated Alzheimer's disease (AD) polygenic risk score (PRS), apolipoprotein E (APOE), and plasma phosphorylated tau 181 (p-tau181) to classify AD and Lewy body dementia (LBD). AD-PRS with APOE achieved similar classification accuracy to p-tau181. AD-PRS without APOE significantly contributed to discriminating AD from LBD. Amyloid beta positivity in LBD was associated with APOE but not AD-PRS without APOE or p-tau181. Combining AD-PRS, APOE, and p-tau181 improved diagnostic classification accuracy.

Keywords: Alzheimer's disease; Lewy body dementia; plasma biomarkers; plasma phosphorylated tau; polygenic risk score.

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Conflict of interest statement

M.M. has acted as a consultant for Astex Pharmaceuticals. P.C.D. has received grant or academic support from Alzheimer's Research UK, Alzheimer's Society, and received honoraria (paid to institution) for educational presentations for the Lewy Body Academy. H.Z. has served on scientific advisory boards and/or as a consultant for Abbvie, Acumen, Alector, Alzinova, ALZPath, Amylyx, Annexon, Apellis, Artery Therapeutics, AZTherapies, Cognito Therapeutics, CogRx, Denali, Eisai, Merry Life, Nervgen, Novo Nordisk, Optoceutics, Passage Bio, Pinteon Therapeutics, Prothena, Red Abbey Labs, reMYND, Roche, Samumed, Siemens Healthineers, Triplet Therapeutics, and Wave; has given lectures in symposia sponsored by Alzecure, Biogen, Cellectricon, Fujirebio, Lilly, Novo Nordisk, and Roche; and is a co‐founder of Brain Biomarker Solutions in Gothenburg AB (BBS), which is a part of the GU Ventures Incubator Program (outside submitted work). L.S. acted as a Research Strategy Council Member, Alzheimer's Society. L.C. was supported by an NIHR Clinical Lectureship, the Academy of Medical Sciences (SGL019∖1035), the Fernblanc Foundation and Alzheimer's Research UK (ARUK‐PPG2018B‐016), and acted as a Clinical Hub Advisor for the Early Detection of Alzheimer's Disease Initiative (EDoN). J.B.R. served on scientific advisory boards and/or as a consultant for Asceneuron Astex, Astronautx, ClinicalInk, CumulusNeuro, Cerevance Curasen, Eisai, ICG, Invicro, Prevail, and Dementia Mission; has received grant or academic support from Janssen, Lilly, GSK, AstraZeneca, Medical Research Council, NIHR, Wellcome Trust, PSP Association, and Alzheimer's Research UK; royalties from Oxford University Press; and is a trustee of the Guarantors of Brain, Darwin College, and the PSP Association. J.T.O'B. has acted as a consultant for TauRx, Novo Nordisk, Biogen, Roche, Lilly GE Healthcare, and Okwin and received grant or academic support from Avid/ Lilly, Merck, and Alliance Medical. A.T., E.M., S.F.C., J.H.T., Y.T.H., T.D.F., and A.H. have nothing to disclose. Author disclosures are available in the supporting information.

Figures

**FIGURE 1**
Classification accuracy using AD polygenic risk (AD‐PRS_no *_APOE* and *APOE*‐RS), p‐tau181 (which has also been described in this cohort previously ³² ), and a combination of AD polygenic risk (AD‐PRS_no *_APOE* and *APOE*‐RS) and p‐tau181. Age and sex are included in all models as control covariates. Abbreviations: AD polygenic risk, Alzheimer's disease polygenic risk; AD‐PRS_no *_APOE* , Alzheimer's disease polygenic risk score excluding the apolipoprotein E locus; *APOE*, apolipoprotein E; *APOE*‐RS, apolipoprotein E risk score; AUC, area under the curve; LBD, Lewy body dementia; LBD PET Aβ−, Lewy body dementia, amyloid beta positron emission tomography negative; LBD PET Aβ+, Lewy body dementia, amyloid beta positron emission tomography positive; MCI+/AD, positron emission tomography amyloid beta positive mild cognitive impairment / Alzheimer's disease dementia; p‐tau, phosphorylated tau.

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References

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Polygenic risk discriminates Lewy body dementia from Alzheimer's disease

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Polygenic risk discriminates Lewy body dementia from Alzheimer's disease

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