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Original Investigation |

The Role of Cardiovascular Risk Factors and Stroke in Familial Alzheimer Disease ONLINE FIRST

Giuseppe Tosto, MD, PhD1,2,3; Thomas D. Bird, MD4,5; David A. Bennett, MD6; Bradley F. Boeve, MD7; Adam M. Brickman, PhD1,2,3; Carlos Cruchaga, PhD8; Kelley Faber, MS9; Tatiana M. Foroud, PhD9; Martin Farlow, MD10; Alison M. Goate, DPhil11; Neill R. Graff-Radford, MD12; Rafael Lantigua, MD13; Jennifer Manly, PhD1,2,3; Ruth Ottman, PhD1,14; Roger Rosenberg, MD15,16; Daniel J. Schaid, PhD17; Nicole Schupf, PhD1,2,3,14; Yaakov Stern, PhD1,2,3; Robert A. Sweet, MD18,19,20; Richard Mayeux, MD, MSc1,2,3,14 ; for the National Institute on Aging Late-Onset Alzheimer Disease/National Cell Repository for Alzheimer Disease (NIA-LOAD/NCRAD) Family Study Group
[+] Author Affiliations
1Taub Institute for Research on Alzheimer’s Disease, The Aging Brain and the Gertrude H. Sergievsky Center, Columbia University College of Physicians and Surgeons, New York, New York
2Department of Neurology, Columbia University College of Physicians and Surgeons, New York, New York
3New York Presbyterian Hospital in New York City
4Department of Neurology, University of Washington, Seattle
5Department of Medicine, University of Washington, Seattle
6Rush Alzheimer’s Disease Center, Rush University Medical Center, Chicago, Illinois
7Department of Neurology, Mayo Clinic, Rochester, Minnesota
8Hope Center for Neurological Disorders, Washington University, St Louis, Missouri
9Department of Medical and Molecular Genetics, Indiana University, Indianapolis
10Department of Neurology, Indiana University Center for Alzheimer’s Disease and Related Disorders, Indianapolis
11Department of Neuroscience, Mount Sinai School of Medicine, New York, New York
12Department of Neurology, Mayo Clinic, Jacksonville, Florida
13Department of Medicine, Columbia University, New York, New York
14Department of Epidemiology, Columbia University, New York, New York
15Department of Neurology and Neurotherapeutics, University of Texas Southwestern Medical Center, Dallas
16Editor, JAMA Neurology
17Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota
18Department of Psychiatry, University of Pittsburgh, Pittsburgh, Pennsylvania
19Department of Neurology, University of Pittsburgh, Pittsburgh, Pennsylvania
20Department of Epidemiology, University of Pittsburgh, Pittsburgh, Pennsylvania
JAMA Neurol. Published online August 15, 2016. doi:10.1001/jamaneurol.2016.2539
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Importance  The contribution of cardiovascular disease (CV) and cerebrovascular disease to the risk for late-onset Alzheimer disease (LOAD) has been long debated. Investigations have shown that antecedent CV risk factors increase the risk for LOAD, although other investigations have failed to validate this association.

Objective  To study the contribution of CV risk factors (type 2 diabetes, hypertension, and heart disease) and the history of stroke to LOAD in a data set of large families multiply affected by LOAD.

Design, Setting, and Participants  The National Institute on Aging Late-Onset Alzheimer Disease/National Cell Repository for Alzheimer Disease family study (hereinafter referred to as NIA-LOAD study) is a longitudinal study of families with multiple members affected with LOAD. A multiethnic community-based longitudinal study (Washington Heights–Inwood Columbia Aging Project [WHICAP]) was used to replicate findings. The 6553 participants in the NIA-LOAD study were recruited from 23 US Alzheimer disease centers with ongoing data collection since 2003; the 5972 WHICAP participants were recruited at Columbia University with ongoing data collection since 1992. Data analysis was performed from 2003 to 2015.

Main Outcomes and Measures  Generalized mixed logistic regression models tested the association of CV risk factors (primary association) with LOAD. History of stroke was used for the secondary association. A secondary model adjusted for the presence of an apolipoprotein E (APOE) ε4 allele. A genetic risk score, based on common variants associated with LOAD, was used to account for LOAD genetic risk beyond the APOE ε4 effect. Mediation analyses evaluated stroke as a mediating factor between the primary association and LOAD.

Results  A total of 6553 NIA-LOAD participants were included in the analyses (4044 women [61.7%]; 2509 men [38.3%]; mean [SD] age, 77.0 [9] years), with 5972 individuals from the WHICAP study included in the replication sample (4072 women [68.2%]; 1900 men [31.8%]; mean [SD] age, 76.5 [7.0] years). Hypertension was associated with decreased LOAD risk (odds ratio [OR], 0.63; 95% CI, 0.55-0.72); type 2 diabetes and heart disease were not. History of stroke conferred greater than 2-fold increased risk for LOAD (OR, 2.23; 95% CI, 1.75-2.83). Adjustment for APOE ε4 did not alter results. The genetic risk score was associated with LOAD (OR, 2.85; 95% CI, 2.05-3.97) but did not change the independent association of LOAD with hypertension or stroke. In the WHICAP sample, hypertension was not associated with LOAD (OR, 0.99; 95% CI, 0.88-1.11), whereas history of stroke increased the risk for LOAD (OR, 1.96; 95% CI, 1.56-2.46). The effect of hypertension on LOAD risk was also mediated by stroke in the NIA-LOAD and the WHICAP samples.

Conclusions and Relevance  In familial and sporadic LOAD, a history of stroke was significantly associated with increased disease risk and mediated the association between selected CV risk factors and LOAD, which appears to be independent of the LOAD-related genetic background.

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