APOE ε4 increases risk for dementia in pure synucleinopathies

Debby Tsuang, James B. Leverenz, Oscar L. Lopez, Ronald L. Hamilton, David A. Bennett, Julie A. Schneider, Aron S. Buchman, Eric B. Larson, Paul K. Crane, Jeffrey Kaye, Patricia Kramer, Randall (Randy) Woltjer, John Q. Trojanowski, Daniel Weintraub, Alice S. Chen-Plotkin, David J. Irwin, Jacqueline Rick, Gerard D. Schellenberg, G. Stennis Watson, Walter KukullPeter T. Nelson, Gregory A. Jicha, Janna H. Neltner, Doug Galasko, Eliezer Masliah, Joseph Quinn, Kathryn (Kathy) Chung, Dora Yearout, Ignacio F. Mata, Jia Y. Wan, Karen L. Edwards, Thomas J. Montine, Cyrus P. Zabetian

Research output: Contribution to journalArticle

135 Citations (Scopus)

Abstract

Objective: To test for an association between the apolipoprotein E (APOE) ε4 allele and dementias with synucleinopathy. Design: Genetic case-control association study. Setting: Academic research. Patients: Autopsied subjects were classified into 5 categories: dementia with high-level Alzheimer disease (AD) neuropathologic changes (NCs) but without Lewy body disease (LBD) NCs (AD group; n=244), dementia with LBDNCs and high-level ADNCs (LBD-AD group; n=224), dementia with LBDNCs and no or low levels of ADNCs (pure DLB [pDLB] group; n=91), Parkinson disease dementia (PDD) with no or low levels of ADNCs (n=81), and control group (n=269). Main Outcome Measure: The APOE allele frequencies. Results: The APOE ε4 allele frequency was significantly higher in the AD (38.1%), LBD-AD (40.6%), pDLB (31.9%), and PDD (19.1%) groups compared with the control group (7.2%; overall Χ42= 185.25; P=5.56 × 10-39), and it was higher in the pDLB group than the PDD group (P=.01). In an age-adjusted and sex-adjusted dominant model, e4 was strongly associated with AD (odds ratio, 9.9; 95% CI, 6.4-15.3), LBD-AD (odds ratio, 12.6; 95% CI, 8.1-19.8), pDLB (odds ratio, 6.1; 95% CI, 3.5-10.5), and PDD (odds ratio, 3.1; 95% CI, 1.7-5.6). Conclusions: The APOE e4 allele is a strong risk factor across the LBD spectrum and occurs at an increased frequency in pDLB relative to PDD. This suggests that e4 increases the likelihood of presenting with dementia in the context of a pure synucleinopathy. The elevated e4 frequency in the pDLB and PDD groups, in which the overall brain neuritic plaque burden was low, indicates that apoE might contribute to neurodegeneration through mechanisms unrelated to amyloid processing.

Original languageEnglish (US)
Pages (from-to)223-228
Number of pages6
JournalJAMA Neurology
Volume70
Issue number2
DOIs
StatePublished - 2013

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Apolipoprotein E4
Dementia
Lewy Body Disease
Alzheimer Disease
Parkinson Disease
Apolipoproteins E
Odds Ratio
Gene Frequency
Alleles
Control Groups
Amyloid Plaques
Amyloid
Case-Control Studies

ASJC Scopus subject areas

  • Clinical Neurology

Cite this

Tsuang, D., Leverenz, J. B., Lopez, O. L., Hamilton, R. L., Bennett, D. A., Schneider, J. A., ... Zabetian, C. P. (2013). APOE ε4 increases risk for dementia in pure synucleinopathies. JAMA Neurology, 70(2), 223-228. https://doi.org/10.1001/jamaneurol.2013.600

APOE ε4 increases risk for dementia in pure synucleinopathies. / Tsuang, Debby; Leverenz, James B.; Lopez, Oscar L.; Hamilton, Ronald L.; Bennett, David A.; Schneider, Julie A.; Buchman, Aron S.; Larson, Eric B.; Crane, Paul K.; Kaye, Jeffrey; Kramer, Patricia; Woltjer, Randall (Randy); Trojanowski, John Q.; Weintraub, Daniel; Chen-Plotkin, Alice S.; Irwin, David J.; Rick, Jacqueline; Schellenberg, Gerard D.; Watson, G. Stennis; Kukull, Walter; Nelson, Peter T.; Jicha, Gregory A.; Neltner, Janna H.; Galasko, Doug; Masliah, Eliezer; Quinn, Joseph; Chung, Kathryn (Kathy); Yearout, Dora; Mata, Ignacio F.; Wan, Jia Y.; Edwards, Karen L.; Montine, Thomas J.; Zabetian, Cyrus P.

In: JAMA Neurology, Vol. 70, No. 2, 2013, p. 223-228.

Research output: Contribution to journalArticle

Tsuang, D, Leverenz, JB, Lopez, OL, Hamilton, RL, Bennett, DA, Schneider, JA, Buchman, AS, Larson, EB, Crane, PK, Kaye, J, Kramer, P, Woltjer, RR, Trojanowski, JQ, Weintraub, D, Chen-Plotkin, AS, Irwin, DJ, Rick, J, Schellenberg, GD, Watson, GS, Kukull, W, Nelson, PT, Jicha, GA, Neltner, JH, Galasko, D, Masliah, E, Quinn, J, Chung, KK, Yearout, D, Mata, IF, Wan, JY, Edwards, KL, Montine, TJ & Zabetian, CP 2013, 'APOE ε4 increases risk for dementia in pure synucleinopathies', JAMA Neurology, vol. 70, no. 2, pp. 223-228. https://doi.org/10.1001/jamaneurol.2013.600
Tsuang D, Leverenz JB, Lopez OL, Hamilton RL, Bennett DA, Schneider JA et al. APOE ε4 increases risk for dementia in pure synucleinopathies. JAMA Neurology. 2013;70(2):223-228. https://doi.org/10.1001/jamaneurol.2013.600
Tsuang, Debby ; Leverenz, James B. ; Lopez, Oscar L. ; Hamilton, Ronald L. ; Bennett, David A. ; Schneider, Julie A. ; Buchman, Aron S. ; Larson, Eric B. ; Crane, Paul K. ; Kaye, Jeffrey ; Kramer, Patricia ; Woltjer, Randall (Randy) ; Trojanowski, John Q. ; Weintraub, Daniel ; Chen-Plotkin, Alice S. ; Irwin, David J. ; Rick, Jacqueline ; Schellenberg, Gerard D. ; Watson, G. Stennis ; Kukull, Walter ; Nelson, Peter T. ; Jicha, Gregory A. ; Neltner, Janna H. ; Galasko, Doug ; Masliah, Eliezer ; Quinn, Joseph ; Chung, Kathryn (Kathy) ; Yearout, Dora ; Mata, Ignacio F. ; Wan, Jia Y. ; Edwards, Karen L. ; Montine, Thomas J. ; Zabetian, Cyrus P. / APOE ε4 increases risk for dementia in pure synucleinopathies. In: JAMA Neurology. 2013 ; Vol. 70, No. 2. pp. 223-228.
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title = "APOE ε4 increases risk for dementia in pure synucleinopathies",
abstract = "Objective: To test for an association between the apolipoprotein E (APOE) ε4 allele and dementias with synucleinopathy. Design: Genetic case-control association study. Setting: Academic research. Patients: Autopsied subjects were classified into 5 categories: dementia with high-level Alzheimer disease (AD) neuropathologic changes (NCs) but without Lewy body disease (LBD) NCs (AD group; n=244), dementia with LBDNCs and high-level ADNCs (LBD-AD group; n=224), dementia with LBDNCs and no or low levels of ADNCs (pure DLB [pDLB] group; n=91), Parkinson disease dementia (PDD) with no or low levels of ADNCs (n=81), and control group (n=269). Main Outcome Measure: The APOE allele frequencies. Results: The APOE ε4 allele frequency was significantly higher in the AD (38.1{\%}), LBD-AD (40.6{\%}), pDLB (31.9{\%}), and PDD (19.1{\%}) groups compared with the control group (7.2{\%}; overall Χ42= 185.25; P=5.56 × 10-39), and it was higher in the pDLB group than the PDD group (P=.01). In an age-adjusted and sex-adjusted dominant model, e4 was strongly associated with AD (odds ratio, 9.9; 95{\%} CI, 6.4-15.3), LBD-AD (odds ratio, 12.6; 95{\%} CI, 8.1-19.8), pDLB (odds ratio, 6.1; 95{\%} CI, 3.5-10.5), and PDD (odds ratio, 3.1; 95{\%} CI, 1.7-5.6). Conclusions: The APOE e4 allele is a strong risk factor across the LBD spectrum and occurs at an increased frequency in pDLB relative to PDD. This suggests that e4 increases the likelihood of presenting with dementia in the context of a pure synucleinopathy. The elevated e4 frequency in the pDLB and PDD groups, in which the overall brain neuritic plaque burden was low, indicates that apoE might contribute to neurodegeneration through mechanisms unrelated to amyloid processing.",
author = "Debby Tsuang and Leverenz, {James B.} and Lopez, {Oscar L.} and Hamilton, {Ronald L.} and Bennett, {David A.} and Schneider, {Julie A.} and Buchman, {Aron S.} and Larson, {Eric B.} and Crane, {Paul K.} and Jeffrey Kaye and Patricia Kramer and Woltjer, {Randall (Randy)} and Trojanowski, {John Q.} and Daniel Weintraub and Chen-Plotkin, {Alice S.} and Irwin, {David J.} and Jacqueline Rick and Schellenberg, {Gerard D.} and Watson, {G. Stennis} and Walter Kukull and Nelson, {Peter T.} and Jicha, {Gregory A.} and Neltner, {Janna H.} and Doug Galasko and Eliezer Masliah and Joseph Quinn and Chung, {Kathryn (Kathy)} and Dora Yearout and Mata, {Ignacio F.} and Wan, {Jia Y.} and Edwards, {Karen L.} and Montine, {Thomas J.} and Zabetian, {Cyrus P.}",
year = "2013",
doi = "10.1001/jamaneurol.2013.600",
language = "English (US)",
volume = "70",
pages = "223--228",
journal = "JAMA Neurology",
issn = "2168-6149",
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TY - JOUR

T1 - APOE ε4 increases risk for dementia in pure synucleinopathies

AU - Tsuang, Debby

AU - Leverenz, James B.

AU - Lopez, Oscar L.

AU - Hamilton, Ronald L.

AU - Bennett, David A.

AU - Schneider, Julie A.

AU - Buchman, Aron S.

AU - Larson, Eric B.

AU - Crane, Paul K.

AU - Kaye, Jeffrey

AU - Kramer, Patricia

AU - Woltjer, Randall (Randy)

AU - Trojanowski, John Q.

AU - Weintraub, Daniel

AU - Chen-Plotkin, Alice S.

AU - Irwin, David J.

AU - Rick, Jacqueline

AU - Schellenberg, Gerard D.

AU - Watson, G. Stennis

AU - Kukull, Walter

AU - Nelson, Peter T.

AU - Jicha, Gregory A.

AU - Neltner, Janna H.

AU - Galasko, Doug

AU - Masliah, Eliezer

AU - Quinn, Joseph

AU - Chung, Kathryn (Kathy)

AU - Yearout, Dora

AU - Mata, Ignacio F.

AU - Wan, Jia Y.

AU - Edwards, Karen L.

AU - Montine, Thomas J.

AU - Zabetian, Cyrus P.

PY - 2013

Y1 - 2013

N2 - Objective: To test for an association between the apolipoprotein E (APOE) ε4 allele and dementias with synucleinopathy. Design: Genetic case-control association study. Setting: Academic research. Patients: Autopsied subjects were classified into 5 categories: dementia with high-level Alzheimer disease (AD) neuropathologic changes (NCs) but without Lewy body disease (LBD) NCs (AD group; n=244), dementia with LBDNCs and high-level ADNCs (LBD-AD group; n=224), dementia with LBDNCs and no or low levels of ADNCs (pure DLB [pDLB] group; n=91), Parkinson disease dementia (PDD) with no or low levels of ADNCs (n=81), and control group (n=269). Main Outcome Measure: The APOE allele frequencies. Results: The APOE ε4 allele frequency was significantly higher in the AD (38.1%), LBD-AD (40.6%), pDLB (31.9%), and PDD (19.1%) groups compared with the control group (7.2%; overall Χ42= 185.25; P=5.56 × 10-39), and it was higher in the pDLB group than the PDD group (P=.01). In an age-adjusted and sex-adjusted dominant model, e4 was strongly associated with AD (odds ratio, 9.9; 95% CI, 6.4-15.3), LBD-AD (odds ratio, 12.6; 95% CI, 8.1-19.8), pDLB (odds ratio, 6.1; 95% CI, 3.5-10.5), and PDD (odds ratio, 3.1; 95% CI, 1.7-5.6). Conclusions: The APOE e4 allele is a strong risk factor across the LBD spectrum and occurs at an increased frequency in pDLB relative to PDD. This suggests that e4 increases the likelihood of presenting with dementia in the context of a pure synucleinopathy. The elevated e4 frequency in the pDLB and PDD groups, in which the overall brain neuritic plaque burden was low, indicates that apoE might contribute to neurodegeneration through mechanisms unrelated to amyloid processing.

AB - Objective: To test for an association between the apolipoprotein E (APOE) ε4 allele and dementias with synucleinopathy. Design: Genetic case-control association study. Setting: Academic research. Patients: Autopsied subjects were classified into 5 categories: dementia with high-level Alzheimer disease (AD) neuropathologic changes (NCs) but without Lewy body disease (LBD) NCs (AD group; n=244), dementia with LBDNCs and high-level ADNCs (LBD-AD group; n=224), dementia with LBDNCs and no or low levels of ADNCs (pure DLB [pDLB] group; n=91), Parkinson disease dementia (PDD) with no or low levels of ADNCs (n=81), and control group (n=269). Main Outcome Measure: The APOE allele frequencies. Results: The APOE ε4 allele frequency was significantly higher in the AD (38.1%), LBD-AD (40.6%), pDLB (31.9%), and PDD (19.1%) groups compared with the control group (7.2%; overall Χ42= 185.25; P=5.56 × 10-39), and it was higher in the pDLB group than the PDD group (P=.01). In an age-adjusted and sex-adjusted dominant model, e4 was strongly associated with AD (odds ratio, 9.9; 95% CI, 6.4-15.3), LBD-AD (odds ratio, 12.6; 95% CI, 8.1-19.8), pDLB (odds ratio, 6.1; 95% CI, 3.5-10.5), and PDD (odds ratio, 3.1; 95% CI, 1.7-5.6). Conclusions: The APOE e4 allele is a strong risk factor across the LBD spectrum and occurs at an increased frequency in pDLB relative to PDD. This suggests that e4 increases the likelihood of presenting with dementia in the context of a pure synucleinopathy. The elevated e4 frequency in the pDLB and PDD groups, in which the overall brain neuritic plaque burden was low, indicates that apoE might contribute to neurodegeneration through mechanisms unrelated to amyloid processing.

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