The role of cardiovascular risk factors and stroke in familial Alzheimer disease

Giuseppe Tosto, Thomas D. Bird, David A. Bennett, Bradley F. Boeve, Adam M. Brickman, Carlos Cruchaga, Kelley Faber, Tatiana Foroud, Martin Farlow, Alison M. Goate, Neill R. Graff-Radford, Rafael Lantigua, Jennifer Manly, Ruth Ottman, Roger Rosenberg, Daniel J. Schaid, Nicole Schupf, Yaakov Stern, Robert A. Sweet, Richard Mayeux

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Abstract

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) e4 allele. A genetic risk score, based on common variants associated with LOAD, was used to account for LOAD genetic risk beyond the APOE e4 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 e4 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.

Original languageEnglish (US)
Pages (from-to)1231-1237
Number of pages7
JournalJAMA Neurology
Volume73
Issue number10
DOIs
StatePublished - Oct 1 2016

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Alzheimer Disease
Stroke
Odds Ratio
Apolipoprotein E4
Cardiovascular Diseases
Hypertension
Apolipoproteins E
Type 2 Diabetes Mellitus
Longitudinal Studies
Heart Diseases
National Institute on Aging (U.S.)
Logistic Models
Cerebrovascular Disorders

ASJC Scopus subject areas

  • Clinical Neurology

Cite this

Tosto, G., Bird, T. D., Bennett, D. A., Boeve, B. F., Brickman, A. M., Cruchaga, C., ... Mayeux, R. (2016). The role of cardiovascular risk factors and stroke in familial Alzheimer disease. JAMA Neurology, 73(10), 1231-1237. https://doi.org/10.1001/jamaneurol.2016.2539

The role of cardiovascular risk factors and stroke in familial Alzheimer disease. / Tosto, Giuseppe; Bird, Thomas D.; Bennett, David A.; Boeve, Bradley F.; Brickman, Adam M.; Cruchaga, Carlos; Faber, Kelley; Foroud, Tatiana; Farlow, Martin; Goate, Alison M.; Graff-Radford, Neill R.; Lantigua, Rafael; Manly, Jennifer; Ottman, Ruth; Rosenberg, Roger; Schaid, Daniel J.; Schupf, Nicole; Stern, Yaakov; Sweet, Robert A.; Mayeux, Richard.

In: JAMA Neurology, Vol. 73, No. 10, 01.10.2016, p. 1231-1237.

Research output: Contribution to journalArticle

Tosto, G, Bird, TD, Bennett, DA, Boeve, BF, Brickman, AM, Cruchaga, C, Faber, K, Foroud, T, Farlow, M, Goate, AM, Graff-Radford, NR, Lantigua, R, Manly, J, Ottman, R, Rosenberg, R, Schaid, DJ, Schupf, N, Stern, Y, Sweet, RA & Mayeux, R 2016, 'The role of cardiovascular risk factors and stroke in familial Alzheimer disease', JAMA Neurology, vol. 73, no. 10, pp. 1231-1237. https://doi.org/10.1001/jamaneurol.2016.2539
Tosto G, Bird TD, Bennett DA, Boeve BF, Brickman AM, Cruchaga C et al. The role of cardiovascular risk factors and stroke in familial Alzheimer disease. JAMA Neurology. 2016 Oct 1;73(10):1231-1237. https://doi.org/10.1001/jamaneurol.2016.2539
Tosto, Giuseppe ; Bird, Thomas D. ; Bennett, David A. ; Boeve, Bradley F. ; Brickman, Adam M. ; Cruchaga, Carlos ; Faber, Kelley ; Foroud, Tatiana ; Farlow, Martin ; Goate, Alison M. ; Graff-Radford, Neill R. ; Lantigua, Rafael ; Manly, Jennifer ; Ottman, Ruth ; Rosenberg, Roger ; Schaid, Daniel J. ; Schupf, Nicole ; Stern, Yaakov ; Sweet, Robert A. ; Mayeux, Richard. / The role of cardiovascular risk factors and stroke in familial Alzheimer disease. In: JAMA Neurology. 2016 ; Vol. 73, No. 10. pp. 1231-1237.
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abstract = "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) e4 allele. A genetic risk score, based on common variants associated with LOAD, was used to account for LOAD genetic risk beyond the APOE e4 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 e4 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.",
author = "Giuseppe Tosto and Bird, {Thomas D.} and Bennett, {David A.} and Boeve, {Bradley F.} and Brickman, {Adam M.} and Carlos Cruchaga and Kelley Faber and Tatiana Foroud and Martin Farlow and Goate, {Alison M.} and Graff-Radford, {Neill R.} and Rafael Lantigua and Jennifer Manly and Ruth Ottman and Roger Rosenberg and Schaid, {Daniel J.} and Nicole Schupf and Yaakov Stern and Sweet, {Robert A.} and Richard Mayeux",
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T1 - The role of cardiovascular risk factors and stroke in familial Alzheimer disease

AU - Tosto, Giuseppe

AU - Bird, Thomas D.

AU - Bennett, David A.

AU - Boeve, Bradley F.

AU - Brickman, Adam M.

AU - Cruchaga, Carlos

AU - Faber, Kelley

AU - Foroud, Tatiana

AU - Farlow, Martin

AU - Goate, Alison M.

AU - Graff-Radford, Neill R.

AU - Lantigua, Rafael

AU - Manly, Jennifer

AU - Ottman, Ruth

AU - Rosenberg, Roger

AU - Schaid, Daniel J.

AU - Schupf, Nicole

AU - Stern, Yaakov

AU - Sweet, Robert A.

AU - Mayeux, Richard

PY - 2016/10/1

Y1 - 2016/10/1

N2 - 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) e4 allele. A genetic risk score, based on common variants associated with LOAD, was used to account for LOAD genetic risk beyond the APOE e4 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 e4 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.

AB - 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) e4 allele. A genetic risk score, based on common variants associated with LOAD, was used to account for LOAD genetic risk beyond the APOE e4 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 e4 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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