Polygenic risk discriminates Lewy body dementia from Alzheimer's disease

IF 11.1 1区医学 Q1 CLINICAL NEUROLOGY Alzheimer's & Dementia Pub Date : 2025-01-24 DOI:10.1002/alz.14381

Anna McKeever, Peter Swann, Maura Malpetti, Paul C. Donaghy, Alan Thomas, Elijah Mak, Stephen F. Carter, Jerry H. K. Tan, Young T. Hong, Tim D. Fryer, Amanda Heslegrave, Henrik Zetterberg, Li Su, Leonidas Chouliaras, James B. Rowe, John T. O'Brien

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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.

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多基因风险区分路易体痴呆和阿尔茨海默病

路易体痴呆（LBD）与阿尔茨海默病（AD）具有相同的遗传危险因素，包括载脂蛋白E (APOE)，但在全基因组水平上是可区分的。因此，多基因风险评分（PRS）可以改善诊断分类。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Alzheimer's & Dementia 医学-临床神经学

CiteScore

14.50

自引率

5.00%

发文量

299

审稿时长

3 months

期刊介绍： Alzheimer's & Dementia is a peer-reviewed journal that aims to bridge knowledge gaps in dementia research by covering the entire spectrum, from basic science to clinical trials to social and behavioral investigations. It provides a platform for rapid communication of new findings and ideas, optimal translation of research into practical applications, increasing knowledge across diverse disciplines for early detection, diagnosis, and intervention, and identifying promising new research directions. In July 2008, Alzheimer's & Dementia was accepted for indexing by MEDLINE, recognizing its scientific merit and contribution to Alzheimer's research.