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Original Investigation
October 2016

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

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. 2016;73(10):1231-1237. doi:10.1001/jamaneurol.2016.2539
Key Points

Question  What is the contribution of cardiovascular risk factors and stroke to the risk for late-onset Alzheimer disease (LOAD)?

Findings  In this assessment of data from 2 longitudinal studies, in families multiply affected with LOAD, hypertension was associated with decreased disease risk, whereas a history of stroke was associated with a 2-fold increased risk for developing the disease in familial and sporadic forms.

Meaning  A history of stroke increases the risk for LOAD and by mediating the effect of cardiovascular risk factors.


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.