Genetic risk of neurodegenerative diseases is associated with mild cognitive impairment and conversion to dementia.
BACKGROUND
Neurodegenerative diseases are a major cause of cognitive impairment and can ultimately lead to dementia. Genome-wide association studies have uncovered many genetic variants conferring risk of neurodegenerative diseases, but their role in cognitive impairment remains unexplored.


METHODS
In the prospective, population-based Rotterdam Study, 3605 nondemented persons aged ≥55 years were genotyped, screened for mild cognitive impairment (MCI) in 2002 to 2005 and underwent continuous follow-up for dementia until 2012. Weighted polygenic risk scores of genetic variants for Alzheimer's disease (AD), Parkinson's disease (PD), and the frontotemporal lobar degeneration/amyotrophic lateral sclerosis disease spectrum (FTLD/ALS) were constructed and investigated for association with MCI and the subsequent conversion to dementia.


RESULTS
In total, 360 (10.0%) persons had MCI, of whom 147 (4.1%) were amnestic and 213 (5.9%) nonamnestic. The AD risk score was associated with both MCI subtypes (odds ratio for all MCI 1.15 [95% CI, 1.03-1.28]), whereas PD and FTLD/ALS risk scores were associated only with nonamnestic MCI (odds ratios 1.15 [1.00-1.32] and 1.19 [1.03-1.37], respectively). The AD risk score, but not PD and FTLD/ALS risk scores, was associated with an increased risk of dementia (hazard ratio 1.55 [1.37-1.77]).


CONCLUSIONS
Genetic evidence supports the view that multiple neurodegenerative pathways lead to MCI and that the subsequent conversion to dementia, primarily of the AD subtype, is mainly due to the AD pathway(s).
Department of Epidemiology, Erasmus Medical Center, Rotterdam, the Netherlands; Department of Radiology, Erasmus Medical Center, Rotterdam, the Netherlands.
Hieab H H
HH
Adams
Department of Epidemiology, Erasmus Medical Center, Rotterdam, the Netherlands; Department of Neurology, Erasmus Medical Center, Rotterdam, the Netherlands.
Renée F A G
RF
de Bruijn
Department of Epidemiology, Erasmus Medical Center, Rotterdam, the Netherlands.
Albert
A
Hofman
Department of Internal Medicine, Erasmus Medical Center, Rotterdam, the Netherlands.
André G
AG
Uitterlinden
Department of Epidemiology, Erasmus Medical Center, Rotterdam, the Netherlands.
Cornelia M
CM
van Duijn
Department of Epidemiology, Erasmus Medical Center, Rotterdam, the Netherlands; Department of Radiology, Erasmus Medical Center, Rotterdam, the Netherlands.
Meike W
MW
Vernooij
Department of Neurology, Erasmus Medical Center, Rotterdam, the Netherlands.
Peter J
PJ
Koudstaal
Department of Epidemiology, Erasmus Medical Center, Rotterdam, the Netherlands; Department of Radiology, Erasmus Medical Center, Rotterdam, the Netherlands; Department of Neurology, Erasmus Medical Center, Rotterdam, the Netherlands. Electronic address: m.a.ikram@erasmusmc.nl.
M Arfan
MA
Ikram
D000368:Aged; D060825:Cognitive Dysfunction / Q000453:epidemiology* / Q000235:genetics* / Q000503:physiopathology; D003704:Dementia / Q000453:epidemiology* / Q000235:genetics* / Q000503:physiopathology; D018450:Disease Progression; D005260:Female; D005500:Follow-Up Studies; D020022:Genetic Predisposition to Disease; D060005:Genotyping Techniques; D006801:Humans; D008297:Male; D009426:Netherlands / Q000453:epidemiology; D019636:Neurodegenerative Diseases / Q000453:epidemiology* / Q000235:genetics*; D011446:Prospective Studies; D012307:Risk Factors
Alzheimer's disease; Amyotrophic lateral sclerosis; Dementia; Frontotemporal lobar degeneration; Genetics; Mild cognitive impairment; Parkinson's disease