You are here
Investigation of the independent role of a rare APOE variant (L28P; APOE*4Pittsburgh) in late-onset Alzheimer disease.
Tuesday,2023-02-28 14:56 America/Los_Angeles — ecterry
| Title | Investigation of the independent role of a rare APOE variant (L28P; APOE*4Pittsburgh) in late-onset Alzheimer disease. |
| Publication Type | Journal Article |
| Year of Publication | 2023 |
| Authors | Fan, KH, Francis, L, M Aslam, M, Bedison, MA, Lawrence, E, Acharya, V, Snitz, BE, Ganguli, M, DeKosky, ST, Lopez, OL, Feingold, E, M Kamboh, I |
| Journal | Neurobiol Aging |
| Volume | 122 |
| Pagination | 107-111 |
| Date Published | 2023 Feb |
| ISSN | 1558-1497 |
| Keywords | Alleles, Alzheimer Disease, Animals, Apolipoprotein E3, Apolipoprotein E4, Apolipoproteins E, Genotype, Heterozygote |
| Abstract | <p>A rare missense APOE variant (L28P; APOE*4Pittsburgh), which is present only in populations with European ancestry, has been reported to be a risk factor for late-onset Alzheimer's disease (LOAD). However, due to the complete linkage disequilibrium of L28P with APOE*4 (C112R), its independent genetic association is uncertain. The original association study implicating L28P with LOAD risk was carried out in a relatively small sample size. In the current study, we have re-evaluated this association in a large case-control sample of 15,762 White U.S. subjects and investigated its independent effect in APOE 3/4 subjects, as L28P has been observed only in the heterozygous state of APOE*4 carriers and 3/4 is the most common genotype containing the APOE*4 allele. The heterozygous carrier frequency of L28P, all with APOE*4, was about 3-fold higher in AD cases than in cognitively intact controls (0.845% vs. 0.277%). The age- and sex-adjusted meta-analysis odds ratio (OR) was 2.87 (95% CI: 1.34 - 6.13; = 0.0066). Among APOE 3/4 subjects, age- and sex-adjusted meta-analysis OR was 1.53 (95% CI: 0.70 - 3.36; p = 0.28), indicating its effect was independent of APOE*4. The lack of statistical significance appears mainly due to the low power of 4138 subjects with the 3/4 genotype (12% power at α= 0.05) compared to the required sample of 139,088 subjects with the 3/4 genotype to detect an OR of 1.5 at α= 0.05 and 80% power. Our data suggesting that L28P has an independent genetic effect on AD risk is reinforced by earlier experimental findings showing that this mutation leads to significant structural and conformational changes in the ApoE4 molecule and can induce functional defects associated with neuronal Aβ42 accumulation and oxidative stress. Additional functional studies in cell-based systems and animal models will help to delineate its functional significance in the etiology of AD.</p> |
| DOI | 10.1016/j.neurobiolaging.2022.11.007 |
| Alternate Journal | Neurobiol Aging |
| PubMed ID | 36528961 |
| PubMed Central ID | PMC9839598 |
| Grant List | U01 AG049506 / AG / NIA NIH HHS / United States R01 AG023629 / AG / NIA NIH HHS / United States U01 AG057659 / AG / NIA NIH HHS / United States U01 AG052411 / AG / NIA NIH HHS / United States HHSN268201100012C / HL / NHLBI NIH HHS / United States R01 NS017950 / NS / NINDS NIH HHS / United States U54 HG003079 / HG / NHGRI NIH HHS / United States HHSN268201100010C / HL / NHLBI NIH HHS / United States U01 HL096917 / HL / NHLBI NIH HHS / United States U01 AG052410 / AG / NIA NIH HHS / United States HHSN268201100008C / HL / NHLBI NIH HHS / United States N01HC85080 / HL / NHLBI NIH HHS / United States R01 AG064877 / AG / NIA NIH HHS / United States U01 AG052409 / AG / NIA NIH HHS / United States U01 HL080295 / HL / NHLBI NIH HHS / United States U01 AT000162 / AT / NCCIH NIH HHS / United States U24 AG021886 / AG / NIA NIH HHS / United States HHSN268201100007C / HL / NHLBI NIH HHS / United States R01 AG020098 / AG / NIA NIH HHS / United States HHSN268201200036C / HL / NHLBI NIH HHS / United States R01 AG049607 / AG / NIA NIH HHS / United States HHSN268201100011C / HL / NHLBI NIH HHS / United States U01 AG049508 / AG / NIA NIH HHS / United States U01 AG032984 / AG / NIA NIH HHS / United States R37 AG023651 / AG / NIA NIH HHS / United States U01 AG049505 / AG / NIA NIH HHS / United States U01 AG016976 / AG / NIA NIH HHS / United States N01HC85082 / HL / NHLBI NIH HHS / United States T32 MH019986 / MH / NIMH NIH HHS / United States HHSN268201500001I / HL / NHLBI NIH HHS / United States R01 AG023651 / AG / NIA NIH HHS / United States N01HC55222 / HL / NHLBI NIH HHS / United States R01 AG054076 / AG / NIA NIH HHS / United States U24 AG041689 / AG / NIA NIH HHS / United States N01HC85079 / HL / NHLBI NIH HHS / United States U01 HL096902 / HL / NHLBI NIH HHS / United States N01HC85083 / HL / NHLBI NIH HHS / United States U01 HL096812 / HL / NHLBI NIH HHS / United States R01 HL070825 / HL / NHLBI NIH HHS / United States N01HC85086 / HL / NHLBI NIH HHS / United States R01 AG033040 / AG / NIA NIH HHS / United States U01 HL096899 / HL / NHLBI NIH HHS / United States P50 AG005133 / AG / NIA NIH HHS / United States UF1 AG047133 / AG / NIA NIH HHS / United States N01HC25195 / HL / NHLBI NIH HHS / United States U54 HG003067 / HG / NHGRI NIH HHS / United States U54 AG052427 / AG / NIA NIH HHS / United States U54 HG003273 / HG / NHGRI NIH HHS / United States HHSN268201100005C / HL / NHLBI NIH HHS / United States R01 AG033193 / AG / NIA NIH HHS / United States R01 AG015928 / AG / NIA NIH HHS / United States R01 AG030653 / AG / NIA NIH HHS / United States HHSN268201100009C / HL / NHLBI NIH HHS / United States U01 HL130114 / HL / NHLBI NIH HHS / United States P30 AG066468 / AG / NIA NIH HHS / United States HHSN268201100006C / HL / NHLBI NIH HHS / United States R01 AG041718 / AG / NIA NIH HHS / United States U01 HL096814 / HL / NHLBI NIH HHS / United States HHSN268200800007C / HL / NHLBI NIH HHS / United States N01HC85081 / HL / NHLBI NIH HHS / United States U01 AG049507 / AG / NIA NIH HHS / United States |
ePub date:
23/02