Polygenic risk discriminates Lewy body dementia from Alzheimer's disease

• Published in: Alzheimer's & dementia 2025-02, Vol.21 (2), p.e14381-n/a
• Main Authors: McKeever, Anna, Swann, Peter, Malpetti, Maura, Donaghy, Paul C., Thomas, Alan, Mak, Elijah, Carter, Stephen F., Tan, Jerry H. K., Hong, Young T., Fryer, Tim D., Heslegrave, Amanda, Zetterberg, Henrik, Su, Li, Chouliaras, Leonidas, Rowe, James B., O'Brien, John T.
• Format: Article
• Language: English
• Subjects: Aged; Aged, 80 and over; Alzheimer Disease - genetics; Alzheimer's disease; Amyloid beta-Peptides - blood; Apolipoproteins E - genetics; Biomarkers - blood; Cognitive Dysfunction - genetics; Diagnosis, Differential; Female; Genetic Predisposition to Disease; Humans; Lewy body dementia; Lewy Body Disease - genetics; Male; Multifactorial Inheritance - genetics; Neurosciences; Neurovetenskaper; plasma biomarkers; plasma phosphorylated tau; polygenic risk score; Positron-Emission Tomography; Risk Factors; tau Proteins - blood; tau Proteins - genetics
• ISSN: 1552-5260; 1552-5279; 1552-5279
• DOI: 10.1002/alz.14381

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‐PRSnoAPOE), 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‐PRSnoAPOE 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‐PRSnoAPOE, or p‐tau181. Combining AD‐PRSnoAPOE, 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.