Neuropathology-based APOE genetic risk score better quantifies Alzheimer's risk

Yuetiva Deming; Eva Vasiljevic; Autumn Morrow; Jiacheng Miao; Carol Van Hulle; Erin Jonaitis; Yue Ma; Vanessa Whitenack; Gwendlyn Kollmorgen; Norbert Wild; Ivonne Suridjan; Leslie M Shaw; Sanjay Asthana; Cynthia M Carlsson; Sterling C Johnson; Henrik Zetterberg; Kaj Blennow; Barbara B Bendlin; Qiongshi Lu; Corinne D Engelman; Alzheimer's Disease Neuroimaging Initiative

doi:10.1002/alz.12990

Neuropathology-based APOE genetic risk score better quantifies Alzheimer's risk

Alzheimers Dement. 2023 Aug;19(8):3406-3416. doi: 10.1002/alz.12990. Epub 2023 Feb 16.

Authors

Yuetiva Deming^{1

2

3}, Eva Vasiljevic^{2

4}, Autumn Morrow², Jiacheng Miao⁵, Carol Van Hulle^{1

3}, Erin Jonaitis^{3

6}, Yue Ma^{1

3}, Vanessa Whitenack¹, Gwendlyn Kollmorgen⁷, Norbert Wild⁷, Ivonne Suridjan⁸, Leslie M Shaw⁹, Sanjay Asthana^{1

3

10}, Cynthia M Carlsson^{1

3

10}, Sterling C Johnson^{1

3

10}, Henrik Zetterberg^{11

12

13

14

15}, Kaj Blennow^{11

12}, Barbara B Bendlin^{1

3}, Qiongshi Lu^{4

5}, Corinne D Engelman^{2

3

4}; Alzheimer's Disease Neuroimaging Initiative

Affiliations

¹ Department of Medicine, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, Wisconsin, USA.
² Department of Population Health Sciences, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, Wisconsin, USA.
³ Wisconsin Alzheimer's Disease Research Center, University of Wisconsin-Madison, Madison, Wisconsin, USA.
⁴ Center for Demography of Health and Aging, University of Wisconsin-Madison, Madison, Wisconsin, USA.
⁵ Department of Biostatistics and Medical Informatics, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, Wisconsin, USA.
⁶ Wisconsin Alzheimer's Institute, University of Wisconsin-Madison, Madison, Wisconsin, USA.
⁷ Roche Diagnostics GmbH, Penzberg, Germany.
⁸ Roche Diagnostics International Ltd, Rotkreuz, Switzerland.
⁹ Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
¹⁰ William S. Middleton Memorial Veterans Hospital, Geriatric Research Education and Clinical Center, Madison, Wisconsin, USA.
¹¹ Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at University of Gothenburg, Mölndal, Sweden.
¹² Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden.
¹³ UK Dementia Research Institute at UCL, London, UK.
¹⁴ Department of Neurodegenerative Disease, UCL Institute of Neurology, London, UK.
¹⁵ Hong Kong Center for Neurodegenerative Diseases, Hong Kong, China.

Abstract

Introduction: Apolipoprotein E (APOE) ε4-carrier status or ε4 allele count are included in analyses to account for the APOE genetic effect on Alzheimer's disease (AD); however, this does not account for protective effects of APOE ε2 or heterogeneous effect of ε2, ε3, and ε4 haplotypes.

Methods: We leveraged results from an autopsy-confirmed AD study to generate a weighted risk score for APOE (APOE-npscore). We regressed cerebrospinal fluid (CSF) amyloid and tau biomarkers on APOE variables from the Wisconsin Registry for Alzheimer's Prevention (WRAP), Wisconsin Alzheimer's Disease Research Center (WADRC), and Alzheimer's Disease Neuroimaging Initiative (ADNI).

Results: The APOE-npscore explained more variance and provided a better model fit for all three CSF measures than APOE ε4-carrier status and ε4 allele count. These findings were replicated in ADNI and observed in subsets of cognitively unimpaired (CU) participants.

Discussion: The APOE-npscore reflects the genetic effect on neuropathology and provides an improved method to account for APOE in AD-related analyses.

Keywords: APOE; Alzheimer's disease; amyloid beta; biomarkers; cerebrospinal fluid endophenotypes; phosphorylated tau.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Alzheimer Disease* / pathology
Amyloid beta-Peptides / cerebrospinal fluid
Apolipoprotein E4 / genetics
Apolipoproteins E / genetics
Genotype
Humans
Risk Factors
tau Proteins / cerebrospinal fluid
tau Proteins / genetics

Substances

Amyloid beta-Peptides
Apolipoprotein E4
Apolipoproteins E
tau Proteins
ApoE protein, human

Abstract

Publication types

MeSH terms

Substances

Grants and funding