TY - JOUR
T1 - APOE «4 is associated with severity of Lewy body pathology independent of Alzheimer pathology
AU - Dickson, Dennis W.
AU - Heckman, Michael G.
AU - Murray, Melissa E.
AU - Soto, Alexandra I.
AU - Walton, Ronald L.
AU - Diehl, Nancy N.
AU - Van Gerpen, Jay A.
AU - Uitti, Ryan J.
AU - Wszolek, Zbigniew K.
AU - Ertekin-Taner, Nilüfer
AU - Knopman, David S.
AU - Petersen, Ronald C.
AU - Graff-Radford, Neill R.
AU - Boeve, Bradley F.
AU - Bu, Guojun
AU - Ferman, Tanis J.
AU - Ross, Owen A.
N1 - Funding Information:
The Mayo Clinic is a Morris K. Udall Centers of Excellence in Parkinson’s Disease Research (P50 NS072187), Lewy Body Dementia Association (LBDA) Research Center of Excellence, American Parkinson Disease Association (APDA) Center for Advanced Research, an Alzheimer’s Disease Research Center (P50 AG16574), and is supported by the National Institute of Neurological Disorders and Stroke R01 NS078086, National Institute on Aging R01 AG015866, Mayo Clinic AD and related dementias genetics program, The Little Family Foundation, and the Mangurian Foundation for Lewy body research.
Funding Information:
D. Dickson: receives support from P50-AG016574, P50-NS072187, P01-AG003949, and CurePSP: Foundation for PSP | CBD and Related Disorders. D.W.D. is an editorial board member of Acta Neuropathologica, Annals of Neurology, Brain, Brain Pathology, and Neuropathology and is editor in chief of American Journal of Neurodegenerative Disease and International Journal of Clinical and Experimental Pathology.M. Heckman: editorial board member of Parkinsonism & Related Disorders. M. Murray, A. Soto, R. Walton, N. Diehl, and J. van Gerpen report no disclosures relevant to the manuscript. R. Uitti: associate editor of Neurology®. Z. Wszolek: receives research support from P50-NS072187, NIH/NIA (primary) and NIH/NINDS (secondary) 1U01AG045390-01A1, Mayo Clinic Center for Regenerative Medicine, the gift from Carl Edward Bolch, Jr., and Susan Bass Bolch, the Sol Goldman Charitable Trust, and Donald G. and Jodi P. Heeringa, and serves as co–editor in chief of Neurologia i Neurochirurgia Polska and is on the editorial boards of European Journal of Clinical and Experimental Medicine, Clinical and Experimental Medical Letters, and Wiadomo´sci Lekarskie; holds and has contractual rights for receipt of future royalty payments from patents for “A Novel Polynucleotide Involved in Heritable Parkinson’s Disease”; and received royalties from publishing Parkinsonism and Related Disorders (Elsevier, 2016, 2017) and the European Journal of Neurology (Wiley Blackwell, 2016, 2017). N. Ertekin-Taner: receives support from the NIH (R01 NS080820, U01 AG046139, RF1 AG051504), Florida State Ed and Ethel Moore Alzheimer’s Disease Research Program (7AZ17); and has consulted for Cytox. D. Knop-man: serves on a data safety monitoring board for the DIAN study; is an investigator in clinical trials sponsored by Biogen, Lilly Pharmaceuticals, and the University of Southern California; and receives research support from the NIH. R. Petersen: has served on the scientific advisory boards of Pfizer, Janssen Alzheimer Immunotherapy, Elan Pharmaceuticals, Wyeth Pharmaceuticals, and GE Healthcare; has received publishing royalties from Oxford University Press; has been a consultant for Roche Incorporated, Merck, Genentech, Biogen, and Eli Lilly; has received research support from the NIH; and has served on the National Advisory Council on Aging. N. Graff-Radford: has served on the editorial board of Alzheimer’s Research & Therapy; has received publishing royalties from UpToDate; and has received research support from Lilly, Biogen, Novartis, Janssen, and the NIH. B. Boeve: has served as an investigator for clinical trials sponsored by GE Healthcare and FORUM Pharmaceuticals; receives royalties from the publication of a book titled Behavioral Neurology of Dementia (Cambridge Medicine, 2009); serves on the scientific advisory board of the Tau Consortium; has consulted for Isis Pharmaceuticals and Ionis Pharmaceuticals; and receives research support from the NIH, GE Healthcare, FORUM Pharmaceuticals, C2N Diagnostics, the Little Family Foundation, and the Mangurian Foundation. G. Bu: received support from P50AG016574, RF1AG051504, R01AG027924, R01AG035355, R01AG046205, P01NS074969, and a grant from the Cure Alzheimer’s fund. T. Ferman: received support from NIA R01AG015866. O. Ross: received support from R01-NS078086, P50-NS072187, and U54 NS100693, The Little Family Foundation, and the Michael J. Fox Foundation. O.A.R.
PY - 2018/9/18
Y1 - 2018/9/18
N2 - Objective To evaluate whether APOE e4 is associated with severity of Lewy body (LB) pathology, independently of Alzheimer disease (AD) pathology. Methods Six hundred fifty-two autopsy-confirmed LB disease (LBD) cases and 660 clinical controls were genotyped for APOE. In case-control analysis, LBD cases were classified into 9 different groups according to severity of both LB pathology (brainstem, transitional, diffuse) and AD pathology (low, moderate, high) to assess associations between APOE e4 and risk of different neuropathologically defined LBD subgroups in comparison to controls. In LBD cases only, we also measured LB counts from 5 cortical regions and evaluated associations with e4 according to severity of AD pathology. Results As expected, APOE e4 was associated with an increased risk of transitional and diffuse LBD in cases with moderate or high AD pathology (all odds ratios ≥3.42, all p ≤ 0.004). Of note, e4 was also associated with an increased risk of diffuse LBD with low AD pathology (odds ratio = 3.46, p = 0.001). In the low AD pathology LBD subgroup, e4 was associated with significantly more LB counts in the 5 cortical regions, independently of Braak stage and Thal phase (all p ≤ 0.002). Conclusions Our results indicate that APOE e4 is independently associated with a greater severity of LB pathology. These findings increase our understanding of the mechanism behind reported associations of e4 with risk of dementia with Lewy bodies and Parkinson disease with dementia, and suggest that e4 may function as a modifier of processes that favor LB spread rather than acting directly to initiate LB pathology.
AB - Objective To evaluate whether APOE e4 is associated with severity of Lewy body (LB) pathology, independently of Alzheimer disease (AD) pathology. Methods Six hundred fifty-two autopsy-confirmed LB disease (LBD) cases and 660 clinical controls were genotyped for APOE. In case-control analysis, LBD cases were classified into 9 different groups according to severity of both LB pathology (brainstem, transitional, diffuse) and AD pathology (low, moderate, high) to assess associations between APOE e4 and risk of different neuropathologically defined LBD subgroups in comparison to controls. In LBD cases only, we also measured LB counts from 5 cortical regions and evaluated associations with e4 according to severity of AD pathology. Results As expected, APOE e4 was associated with an increased risk of transitional and diffuse LBD in cases with moderate or high AD pathology (all odds ratios ≥3.42, all p ≤ 0.004). Of note, e4 was also associated with an increased risk of diffuse LBD with low AD pathology (odds ratio = 3.46, p = 0.001). In the low AD pathology LBD subgroup, e4 was associated with significantly more LB counts in the 5 cortical regions, independently of Braak stage and Thal phase (all p ≤ 0.002). Conclusions Our results indicate that APOE e4 is independently associated with a greater severity of LB pathology. These findings increase our understanding of the mechanism behind reported associations of e4 with risk of dementia with Lewy bodies and Parkinson disease with dementia, and suggest that e4 may function as a modifier of processes that favor LB spread rather than acting directly to initiate LB pathology.
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U2 - 10.1212/WNL.0000000000006212
DO - 10.1212/WNL.0000000000006212
M3 - Article
C2 - 30143564
AN - SCOPUS:85054080429
VL - 91
SP - E1182-E1195
JO - Neurology
JF - Neurology
SN - 0028-3878
IS - 12
ER -