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Polygenic risk of type 2 diabetes is associated with incident vascular dementia : a prospective cohort study

Dybjer, Elin LU ; Kumar, Atul LU orcid ; Nägga, Katarina LU ; Engström, Gunnar LU ; Mattsson-Carlgren, Niklas LU orcid ; Nilsson, Peter M. LU ; Melander, Olle LU orcid and Hansson, Oskar LU orcid (2023) In Brain Communications 5(2).
Abstract

Type 2 diabetes and dementia are associated, but it is unclear whether the two diseases have common genetic risk markers that could partly explain their association. It is also unclear whether the association between the two diseases is of a causal nature. Furthermore, few studies on diabetes and dementia have validated dementia end-points with high diagnostic precision. We tested associations between polygenic risk scores for type 2 diabetes, fasting glucose, fasting insulin and haemoglobin A1c as exposure variables and dementia as outcome variables in 29 139 adults (mean age 55) followed for 20–23 years. Dementia diagnoses were validated by physicians through data from medical records, neuroimaging and biomarkers in... (More)

Type 2 diabetes and dementia are associated, but it is unclear whether the two diseases have common genetic risk markers that could partly explain their association. It is also unclear whether the association between the two diseases is of a causal nature. Furthermore, few studies on diabetes and dementia have validated dementia end-points with high diagnostic precision. We tested associations between polygenic risk scores for type 2 diabetes, fasting glucose, fasting insulin and haemoglobin A1c as exposure variables and dementia as outcome variables in 29 139 adults (mean age 55) followed for 20–23 years. Dementia diagnoses were validated by physicians through data from medical records, neuroimaging and biomarkers in cerebrospinal fluid. The dementia end-points included all-cause dementia, mixed dementia, Alzheimer’s disease and vascular dementia. We also tested causal associations between type 2 diabetes and dementia through two-sample Mendelian randomization analyses. Seven different polygenic risk scores including single-nucleotide polymorphisms with different significance thresholds for type 2 diabetes were tested. A polygenic risk score including 4891 single-nucleotide polymorphisms with a P-value of <5e-04 showed the strongest association with different outcomes, including all-cause dementia (hazard ratio 1.11; Bonferroni corrected P = 3.6e-03), mixed dementia (hazard ratio 1.18; Bonferroni corrected P = 3.3e-04) and vascular dementia cases (hazard ratio 1.28; Bonferroni corrected P = 9.6e-05). The associations were stronger for non-carriers of the Alzheimer’s disease risk gene APOE ϵ4. There was, however, no significant association between polygenic risk scores for type 2 diabetes and Alzheimer’s disease. Furthermore, two-sample Mendelian randomization analyses could not confirm a causal link between genetic risk markers of type 2 diabetes and dementia outcomes. In conclusion, polygenic risk of type 2 diabetes is associated with an increased risk of dementia, in particular vascular dementia. The findings imply that certain people with type 2 diabetes may, due to their genetic background, be more prone to develop diabetes-associated dementia. This knowledge could in the future lead to targeted preventive strategies in clinical practice.

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author
; ; ; ; ; ; and
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
Alzheimer’s disease, Mendelian randomization, polygenic risk score, type 2 diabetes, vascular dementia
in
Brain Communications
volume
5
issue
2
article number
fcad054
publisher
Oxford University Press
external identifiers
  • pmid:37091584
  • scopus:85159837044
ISSN
2632-1297
DOI
10.1093/braincomms/fcad054
language
English
LU publication?
yes
id
c1ca544b-cd01-4c1d-a4c5-2b6fdf854d90
date added to LUP
2023-09-21 16:55:18
date last changed
2024-04-19 01:15:48
@article{c1ca544b-cd01-4c1d-a4c5-2b6fdf854d90,
  abstract     = {{<p>Type 2 diabetes and dementia are associated, but it is unclear whether the two diseases have common genetic risk markers that could partly explain their association. It is also unclear whether the association between the two diseases is of a causal nature. Furthermore, few studies on diabetes and dementia have validated dementia end-points with high diagnostic precision. We tested associations between polygenic risk scores for type 2 diabetes, fasting glucose, fasting insulin and haemoglobin A<sub>1c</sub> as exposure variables and dementia as outcome variables in 29 139 adults (mean age 55) followed for 20–23 years. Dementia diagnoses were validated by physicians through data from medical records, neuroimaging and biomarkers in cerebrospinal fluid. The dementia end-points included all-cause dementia, mixed dementia, Alzheimer’s disease and vascular dementia. We also tested causal associations between type 2 diabetes and dementia through two-sample Mendelian randomization analyses. Seven different polygenic risk scores including single-nucleotide polymorphisms with different significance thresholds for type 2 diabetes were tested. A polygenic risk score including 4891 single-nucleotide polymorphisms with a P-value of &lt;5e-04 showed the strongest association with different outcomes, including all-cause dementia (hazard ratio 1.11; Bonferroni corrected P = 3.6e-03), mixed dementia (hazard ratio 1.18; Bonferroni corrected P = 3.3e-04) and vascular dementia cases (hazard ratio 1.28; Bonferroni corrected P = 9.6e-05). The associations were stronger for non-carriers of the Alzheimer’s disease risk gene APOE ϵ4. There was, however, no significant association between polygenic risk scores for type 2 diabetes and Alzheimer’s disease. Furthermore, two-sample Mendelian randomization analyses could not confirm a causal link between genetic risk markers of type 2 diabetes and dementia outcomes. In conclusion, polygenic risk of type 2 diabetes is associated with an increased risk of dementia, in particular vascular dementia. The findings imply that certain people with type 2 diabetes may, due to their genetic background, be more prone to develop diabetes-associated dementia. This knowledge could in the future lead to targeted preventive strategies in clinical practice.</p>}},
  author       = {{Dybjer, Elin and Kumar, Atul and Nägga, Katarina and Engström, Gunnar and Mattsson-Carlgren, Niklas and Nilsson, Peter M. and Melander, Olle and Hansson, Oskar}},
  issn         = {{2632-1297}},
  keywords     = {{Alzheimer’s disease; Mendelian randomization; polygenic risk score; type 2 diabetes; vascular dementia}},
  language     = {{eng}},
  number       = {{2}},
  publisher    = {{Oxford University Press}},
  series       = {{Brain Communications}},
  title        = {{Polygenic risk of type 2 diabetes is associated with incident vascular dementia : a prospective cohort study}},
  url          = {{http://dx.doi.org/10.1093/braincomms/fcad054}},
  doi          = {{10.1093/braincomms/fcad054}},
  volume       = {{5}},
  year         = {{2023}},
}