Polygenic risk scores for Alzheimer's disease are related to dementia risk in APOE ɛ4 negatives

Jenna Najar; Sven J van der Lee; Erik Joas; Hanna Wetterberg; John Hardy; Rita Guerreiro; Jose Bras; Margda Waern; Silke Kern; Henrik Zetterberg; Kaj Blennow; Ingmar Skoog; Anna Zettergren

doi:10.1002/dad2.12142

Polygenic risk scores for Alzheimer's disease are related to dementia risk in APOE ɛ4 negatives

Alzheimers Dement (Amst). 2021 Jan 22;13(1):e12142. doi: 10.1002/dad2.12142. eCollection 2021.

Authors

Jenna Najar^{1

2}, Sven J van der Lee^{3

4}, Erik Joas¹, Hanna Wetterberg¹, John Hardy^{5

6

7

8

9}, Rita Guerreiro¹⁰, Jose Bras¹⁰, Margda Waern^{1

11}, Silke Kern^{1

2}, Henrik Zetterberg^{5

6

12

13}, Kaj Blennow^{12

13}, Ingmar Skoog^{1

2}, Anna Zettergren¹

Affiliations

¹ Department of Psychiatry and Neurochemistry Neuropsychiatric Epidemiology Unit Institute of Neuroscience and Physiology the Sahlgrenska Academy Centre for Ageing and Health (AGECAP) at the University of Gothenburg Mölndal Sweden.
² Region Västra Götaland Sahlgrenska University Hospital, Psychiatry, Cognition and Old Age Psychiatry Clinic Gothenburg Sweden.
³ Section Genomics of Neurdegenerative Diseases and Aging Department of Clinical Genetics Vrije Universiteit Amsterdam, Amsterdam UMC Amsterdam The Netherlands.
⁴ Alzheimer Center Amsterdam Department of Neurology, Amsterdam Neuroscience Vrije Universiteit Amsterdam, Amsterdam UMC Amsterdam The Netherlands.
⁵ Department of Neurodegenerative Disease UCL Institute of Neurology London UK.
⁶ UK Dementia Research Institute at UCL London UK.
⁷ Reta Lila Weston Institute UCL Queen Square Institute of Neurology London UK.
⁸ NIHR University College London Hospitals Biomedical Research Centre London UK.
⁹ Institute of Advanced Study the Hong Kong University of Science and Technology Hong Kong SAR China.
¹⁰ Center for Neurodegenerative Science Van Andel Institute Grand Rapids Michigan USA.
¹¹ Region Västra Götaland Sahlgrenska University Hospital, Psychosis Clinic Gothenburg Sweden.
¹² Department of Psychiatry and Neurochemistry Institute of Neuroscience and Physiology The Sahlgrenska Academy at the University of Gothenburg Mölndal Sweden.
¹³ Clinical Neurochemistry Laboratory Sahlgrenska University Hospital Mölndal Sweden.

Abstract

Introduction: Studies examining the effect of polygenic risk scores (PRS) for Alzheimer's disease (AD) and apolipoprotein E (APOE) genotype on incident dementia in very old individuals are lacking.

Methods: A population-based sample of 2052 individuals ages 70 to 111, from Sweden, was followed in relation to dementia. AD-PRSs including 39, 57, 1333, and 13,942 single nucleotide polymorphisms (SNPs) were used.

Results: AD-PRSs (including 39 or 57 SNPs) were associated with dementia (57-SNPs AD-PRS: hazard ratio 1.09, confidence interval 1.01-1.19, P = .03), particularly in APOE ɛ4 non-carriers (57-SNPs AD-PRS: 1.15, 1.05-1.27, P = 4 × 10^-3, 39-SNPs AD-PRS: 1.22, 1.10-1.35, P = 2 × 10^-4). No association was found with the other AD-PRSs. Further, APOE ɛ4 was associated with increased risk of dementia (1.60, 1.35-1.92, P = 1 × 10^-7). In those aged ≥95 years, the results were similar for the AD-PRSs, while APOE ɛ4 only predicted dementia in the low-risk tertile of AD-PRSs.

Discussion: These results provide information to identify individuals at increased risk of dementia.

Keywords: Alzheimer's disease; apolipoprotein E genotype; dementia; polygenic risk score; risk factors in epidemiology.

Abstract

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