1. Medicine
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APOE2 is associated with longevity independent of Alzheimer’s disease

  1. Mitsuru Shinohara  Is a corresponding author
  2. Takahisa Kanekiyo
  3. Masaya Tachibana
  4. Aishe Kurti
  5. Motoko Shinohara
  6. Yuan Fu
  7. Jing Zhao
  8. Xianlin Han
  9. Patrick M Sullivan
  10. G William Rebeck
  11. John D Fryer
  12. Michael G Heckman
  13. Guojun Bu  Is a corresponding author
  1. Department of Neuroscience, Mayo Clinic, United States
  2. Department of Aging Neurobiology, National Center for Geriatrics and Gerontology, Japan
  3. Neuroscience Graduate Program, Mayo Clinic, United States
  4. United Graduate School of Child Development, Osaka University, Japan
  5. Barshop Institute for Longevity and Aging Studies, University of Texas Health Science Center at San Antonio, United States
  6. Duke University School of Medicine, Durham Veterans Health Administration Medical Center's Geriatric Research, Education and Clinical Center, United States
  7. Department of Neuroscience, Georgetown University Medical Center, United States
  8. Division of Biomedical Statistics and Informatics, Mayo Clinic, United States
Research Article
Cite this article as: eLife 2020;9:e62199 doi: 10.7554/eLife.62199
4 figures, 1 table and 2 additional files

Figures

APOE associate with lifespan irrespective of AD in clinical cohorts.

(A) Kaplan-Meier survival curve according to APOE genotype. (B) Effects of APOE4 (ε3/ε4 or ε4/ε4) or APOE2 (ε2/ε3 or ε2/ε2) on survival compared to APOE3 (ε3/ε3) as a reference in all subjects (‘All subjects’), when stratifying by AD diagnosis at last visit (‘No AD’ or ‘AD’), in subjects with neuropathologically-assessment (‘Patho-assessed’), and subjects with minimal amyloid pathology (‘Minimal amyloid’). HR = hazard ratio. CI = confidence interval. HRs and 95% CIs result from Cox proportional hazards regression models. Models for all subjects were adjusted for sex, race, cognitive status at last visit, presence of AD at last visit, and cardiovascular factors. The models for subjects with neuropathological assessment were adjusted for sex, race, CERAD diffuse plaque score, CERAD neuritic plaque score, Braak NFT stage, presence of vascular pathology, and cardiovascular factors. All other models were adjusted for sex, race, and cardiovascular factors.

APOE2 benefits lifespan and preserved activity levels in animal models.

(A) The timeline of the survival cohort. The OFA and EPM were performed at both young (4–7 months) and old (21–24 months) ages. Rotarod test was also performed at old age. (B) Kaplan-Meier survival curve of apoE-TR and Apoe-KO mouse models (n = 118), categorized by APOE carrier status with number of mice at risk. *p<0.05, **p<0.01, ***p<0.001 after Bonferroni correction for multiple comparisons; calculated by Cox proportional hazards regression models that were adjusted for sex. Median survival for each group is the point at which the Kaplan-Meier survival curves intersects with the dotted horizontal line. (C) Diagram of OFA. (D–I) Total distance traveled (D and G), percent time spent mobile (E), and number of rearing events (F and H) in the OFA were compared among APOE genotype groups at old age (D–F) or between young and old ages within the same APOE genotype (G and H) after adjusting for sex (n = 17–20 mice/group). (I–J) Total distance traveled (I), percent time spent mobile (J), and number of rearing events (K) in the OFA performed at old age are plotted against the age at death. (L and M) Ratios of time stayed at open arm vs. closed arm measured by EPM test at old age were compared among APOE genotype groups after adjusting for sex (L), and plotted against following age at death (M) (n = 17–20 mice/group). (N and O) Latency to fall off at each session of rotarod test at old age was compared among APOE genotype groups after adjusting for sex (N), and plotted against following age at death (O) (n = 17–20 mice/group). Data are presented as adjusted means ± standard errors of the means. *p<0.05, **p<0.01, ***p<0.001, ****p<0.0001; compared among APOE genotype groups using the Tukey’s HSD test (D-F and L) or repeated-measures one-way ANOVA followed by Tukey-Kramer test (N)., or #p<0.05, ##p<0.01, ###p<0.001, ####p<0.0001; compared with young mice using two-sided Student’s t test (G and H). (I-K, M and O) Correlation coefficients (r) and p-values were calculated using the Pearson correlation test. N.S. = not significant.

APOE2 is associated with preserved activity in clinical cohorts.

(A) Odds ratio with 95% CIs of APOE2 or APOE4 on ‘dropped activities and interests’, ‘total GDS score’, and ‘memory problem’ compared to APOE3, as calculated by logistic regression models that were adjusted for sex, race, and age at the time of the GDS questionnaire. (B) Kaplan–Meier survival curve of subjects with/without ‘dropped activities and interests’; dropped activities and interests were associated with poorer survival (Hazard ratio = 1.20, p=0.010). *p<0.05; calculated by Cox proportional hazards regression analysis adjusting for sex, race, and APOE genotype group.

ApoE and lipid levels correlate with activity.

(A) The timeline of biochemically assessed cohort. The OFA was performed within one month before harvest. (B–D) Total distance traveled (B), percent time spent mobile (C), and number of rearing events (D) were compared between young and old mice within the same APOE genotype after adjusting for sex (n = 16–28 mice/group). (E–H) ApoE levels in the brain cortex (CX, E, and F), CSF (G) and plasma (H) are plotted against the total distance traveled (E, G and H), or number of rearing events in the OFA (F). (I) Levels of cholesterol in the brain cortex of old male mice were compared among APOE genotypes (n = 3–4 mice/group) and are plotted against apoE levels in the cortex (J) and total distance traveled in the OFA (K). (L–R) Plasma HDL-cholesterol levels (L and M) or triglyceride levels (N–P) were compared among APOE genotypes in old mice (L and N) or between young and old mice within the same APOE genotype (Q and R) after adjusting for sex and plotted against the number of rearing events in the OFA (M and O) or plasma apoE levels (P) (n = 9–27 mice/group). Data are presented as adjusted means ± standard errors of the means. *p<0.05, **p<0.01, ***p<0.001, ****p<0.0001; compared among APOE genotypes using the Tukey-Kramer test (I), Tukey’s HSD test (L and N), or #p<0.05, ##p<0.01, ###p<0.001, ####p<0.0001; compared between young and old mice using two-sided Student’s t test (B-D, Q, and R). (E-H, J, K, M, O, and P) Correlation coefficients (r) and p-values were calculated using the Pearson correlation test. N.S. = not significant.

Tables

Key resources table
Reagent type
(species) or resource
DesignationSource or referenceIdentifiersAdditional information
Genetic reagent (Mus. musculus)Apoetm1(APOE*2)Mae or apoE2-TRSullivan et al., 1998RRID:MGI:3695702
Genetic reagent (Mus. musculus)Apoetm2(APOE*3)Maeor apoE3-TRSullivan et al., 1997RRID:MGI:3695698
Genetic reagent (Mus. musculus)Apoetm3(APOE*4)Maeor apoE4-TRKnouff et al., 1999RRID:MGI:4355228
Genetic reagent (Mus. musculus)Apoetm1Unc or Apoe-KOPiedrahita et al., 1992RRID:MGI:4358709
AntibodyGoat polyclonal anti-ApoE-biotinMeridian Life ScienceCat#: K74180BELISA detection (1:4000)
AntibodyGoat polyclonal anti-Apolipoprotein E AntibodyMilliporeCat#: AB947ELISA capture (1:4000)
Peptide, recombinant proteinApoE3FitzgeraldCat#: 30 R-2381ELISA standard
Commercial assay or kitCholesterol EWakoCat. #: 999–02601
Commercial assay or kitL-Type Triglyceride MWakoCat. #: 994–02891
Commercial assay or kitHDL-Cholesterol EWakoCat. #: 997–01301
Software, algorithmSASSAS Institute, Incversion 9.4
Software, algorithmR Statistical SoftwareR Foundation for Statistical Computingversion 3.2.3
Software, algorithmJMP ProSAS Institute, Incversion 12
Software, algorithmAnyMaze softwareStoelting CoAnimal behavior test

Data availability

All source data files of animal experiments (Figure 2, Figure 4, Supplementary File 1d, and Supplementary File 1f) are included in the manuscript and supporting files. The clinical data are available from NACC (https://www.alz.washington.edu/WEB/researcher_home.html) upon request: distributing any data to a third party, who is not a collaborator or co-authors, is strictly prohibited by NACC.

Additional files

Supplementary file 1

Supplementary information of additional analyses etc.

(a) Subject characteristics in the overall NACC cohort. The sample median (minimum, maximum) is given for continuous variables. Information was unavailable regarding hypertension (N = 28), transient ischemic attack (N = 116), pacemaker (N = 260), angioplasty/endarterectomy/stent (N = 19), heart attack/cardiac arrest (N = 42), cardiac bypass procedure (N = 9), atrial fibrillation (N = 48), hypercholesterolemia (N = 102), congestive heart failure (N = 25), and stroke (N = 45). (b) Subject characteristics for individuals in the NACC cohort with a neuropathological assessment. The sample median (minimum, maximum) is given for continuous variables. Information was unavailable regarding hypertension (N = 3), transient ischemic attack (N = 24), pacemaker (N = 1), heart attack/cardiac arrest (N = 4), atrial fibrillation (N = 3), hypercholesterolemia (N = 17), congestive heart failure (N = 4), stroke (N = 7),. density of neocortical neuritic plaques CERAD score (N = 12), density of diffuse plaques CERAD score (N = 328), Braak NFT stage (N = 55), presence of vascular pathology (N = 51), and minimal amyloid pathology. (c) Association between APOE genotype and survival using the NACC data. HR = hazard ratio; CI = confidence interval; AD = Alzheimer’s disease; CV = cardiovascular. HRs, 95% CIs, and p-values result from Cox proportional hazards regression models. 1 These analyses were only performed when considering all subjects. 2 Cognitive status at final visit and AD at final visit were adjusted for only in the model involving all subjects. 3 CV factors included hypertension, transient ischemic attack, pacemaker, angioplasty/endarterectomy/stent, heart attack/cardiac arrest, atrial fibrillation, hypercholesterolemia, congestive heart failure, and stroke. 4 For the neuropathological assessment cohort, all models were additionally adjusted for CERAD diffuse plaque score, CERAD neuritic plaque score, Braak NFT stage, and the presence of vascular pathology. p-values<0.025 are considered as statistically significant after applying a Bonferroni correction for multiple testing for the two primary comparisons of survival that were made (i.e. between APOE3 and APOE4 subjects, and between APOE3 and APOE2 subjects). (d) Summary of mouse cohorts. For continuous data, values are means ± SD [range]. P-values were calculated using one-way ANOVA (continuous data), the Pearson’s chi-square test (categorical value) or log-rank test (median age at death). (e) Effects of APOE on ‘Dropped activities and interests’ and other GDS items in cognitively normal subjects over 60 years old. ORs, 95% CIs, and p-values result from binary logistic regression models for analysis of individual GDS items, and from proportional odds logistic regression models for analysis of the ordinal total GDS score, which is described as the mean (25th percentile, 75th percentile). Information was unavailable for GDS items for a maximum of 23 subjects. (f) Associations between activity levels in the OFA and protein/lipid levels across APOE genotype groups at old age. Correlation coefficients (r) and p-values were calculated using the Pearson correlation test. P-values were corrected by Bonferroni test adjusted for the number of protein/lipids analyzed in the entire cohort. CX = cortical, HP = hippocampal. (g) List of NACC contributors.

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