Abstract
We examined the association between APOE ε2/ε4 with incident Alzheimer’s disease (AD) and mild cognitive impairment (MCI) among African Americans using the national dataset from the National Alzheimer’s Coordinating Center (NACC) from 2005 to September 2019. Compared to ε3/ε3 carriers, ε2/ε4 carriers exhibited a similar risk of incident AD (adjusted hazard ratio [aHR] = 0.85, 95% CI [0.39, 1.84]) among the AD cohort and similar risk of incident MCI (aHR = 0.88, 95% CI [0.51, 1.50]) among the MCI cohort. Our findings suggest that, unlike the increased risk of AD and MCI in non-Latino whites, APOE ε2/ε4 genotype is not associated with the incidence of AD and MCI among African Americans.
Keywords: African American, Alzheimer’s disease, APOE, ε2/ε4 genotype, mild cognitive impairment
INTRODUCTION
The APOE gene is widely recognized as a major susceptibility factor for Alzheimer’s disease (AD) [1-4]. Its three common alleles (ε2, ε3, and ε4) give rise to six genotypes (ε2/ε2, ε2/ε3, ε3/ε3, ε2/ε4, ε3/ε4, and ε4/ε4). The ε3 is the most common allele and considered to play a “neutral” role for the onset of AD. Meanwhile, ε4 (ε3/ε4 or ε4/ε4) represents the largest genetic risk factor for AD, and ε2 (ε2/ε2 or ε2/ε3) may confer a protective effect against AD [5-9]. There is a paucity of studies on the effect of the APOE ε2/ε4 genotype on phenotype due to both the relative rarity of the ε2/ε4 genotype in the population and the counteractive effects of the ε2 and ε4 alleles. Our and others’ recent research linking APOE ε2/ε4 and AD demonstrates that APOE ε2/ε4 has a statistically significant effect on increased risk of AD and mild cognitive impairment (MCI) among non-Latino whites [10, 11]. Nevertheless, African Americans remain a genetically understudied group, although the incidence of AD is higher within this group than among whites [4, 12]. To date, only a few studies have investigated the association between APOE ε2/ε4 and the onset of AD and MCI among African Americans. In this study, we evaluated the effects of APOE ε2/ε4 on the incident AD and MCI among African Americans, using a large national dataset provided by the National Alzheimer’s Coordinating Center (NACC).
METHODS
The NACC recruited and followed-up participants starting in 2005, and this analysis includes participants recruited through September 2019 (N = 41,459). A consensus diagnosis of AD and MCI was established using standardized clinical criteria [13, 14] in the NACC dataset. The details on NACC patient recruitment, evaluation, and institutional review board approval have been previously published [14, 15]. Based on APOE genotyping, NACC participants were classified into four groups: ε2ε4, ε2 (ε2/ε2, ε2/ε3), ε4 (ε3/ε4, ε4/ε4), and using ε3/ε3 as reference. Participants’ demographics, including sex, age, education, cognitive status at initial visit and the calendar year of the initial visit, were collected. Incidence of AD and MCI were defined from NACC-derived variables.
Our analysis was restricted to the African American ethnic group. Additionally, the included participants had to have an APOE genotype available and made at least two visits. The AD cohort was defined as dementia free at their first visit, and the MCI cohort was defined as both dementia and MCI free at their first visit. Based on these criteria, two cohorts were constructed for analyses: an AD cohort (N = 2,007) and an MCI cohort (N = 1,480) (Fig. 1).
Fig. 1.
Consort diagram displaying derivation of study sample for the analyses with source of exclusion. AD, Alzheimer’s disease; MCI, mild cognitive impairment; APOE, apolipoprotein.
Statistical analysis
Descriptive statistics of participants’ baseline were summarized for both the AD and MCI cohorts. The group differences of demographics across the four APOE groups were compared by using one-way ANOVA and chi-square tests (Table 1). Both unadjusted and adjusted Cox proportional hazards models were performed to examine the association between APOE genotype and incident AD dementia and MCI in each defined cohort. The adjusted model was controlled for demographics including age, sex, education, cognitive status at initial visit, and the calendar year of initial visit (Table 2). Survival time was defined as the length of time in years from the initial visit to the first event of interest (AD diagnosis for the AD cohort; Dementia or MCI diagnosis for the MCI cohort) or death without incident event. Otherwise, survival time was calculated as time from first visit to last follow-up evaluation. The proportional hazard assumption was tested based on the Schoenfeld residuals. In addition, sensitivity analyses with a competing risk subdistribution hazard model were conducted. In this model, we considered death as a competing risk event instead of censoring (Supplementary Table 1). All statistical analyses were made using SAS 9.4 and STATA 16.
Table 1.
Demographic Characteristics of Participants at Initial Visit
| AD Cohort (N = 2,007) | ||||||
|---|---|---|---|---|---|---|
| All (N = 2,007) |
ε3/ε3 (n = 919, 45.79%) |
ε2 (ε2/ε2 & ε2/ε3) (n = 301, 15.0%) |
ε4 (ε3/ε4 & ε4/ε4) (n = 688, 34.28%) |
ε2/ε4 (n = 99, 4.93%) |
p | |
| Age (y) (Mean ± SD) | 71.2 ± 8.31 | 71.5 ± 8.41 | 71.2 ± 8.67 | 70.9 ± 8.07 | 70.8 ± 7.96 | 0.54 |
| Age (n, %) | 0.27 | |||||
| < 65 | 401 (19.98) | 174 (18.93) | 70 (23.26) | 138 (20.06) | 19 (19.19) | |
| 65–74 | 902 (44.94) | 415 (45.16) | 118 (39.20) | 320 (46.51) | 49 (49.49) | |
| 75–84 | 595 (29.65) | 273 (29.71) | 92 (30.56) | 203 (29.51) | 27 (27.27) | |
| > 85 | 109 (5.43) | 57 (6.20) | 21 (6.98) | 27 (3.92) | 4 (4.04) | |
| Sex (n, %) | 0.007 | |||||
| Male | 533 (26.56) | 221 (24.05) | 75 (24.92) | 215 (31.25) | 22 (22.22) | |
| Female | 1474 (73.44) | 698 (75.95) | 226 (75.08) | 473 (68.75) | 77 (77.78) | |
| Education (y) (Mean ± SD) | 14.4 ± 3.19 | 14.5 ± 3.20 | 14.4 ± 3.03 | 14.3 ± 3.26 | 14.3 ± 3.15 | 0.86 |
| Education (n, %) | 0.66 | |||||
| ≤12 y | 667 (33.2) | 302 (32.9%) | 93 (30.9) | 236 (34.3) | 36 (36.4) | |
| > 12 y | 1340 (66.8) | 617 (67.1) | 208 (69.1) | 452 (65.7) | 63 (63.6) | |
| Diagnosis of MCI (n, %) | 527 (26.2) | 228 (24.81) | 63 (20.93) | 208 (30.23) | 28 (28.28) | 0.07 |
| Year of Initial Visit (n, %) | 0.14 | |||||
| 2005–2007 | 753 (37.59) | 352 (38.30) | 124 (41.33) | 238 (34.74) | 39 (39.39) | |
| 2008–2012 | 737 (36.79) | 332 (36.13) | 92 (30.67) | 278 (40.58) | 35 (35.35) | |
| 2013–2017 | 513 (25.61) | 235 (25.57) | 84 (28.00) | 169 (24.67) | 25 (25.25) | |
| MCI Cohort (N= 1,480) | ||||||
| All (N = 1,480) |
ε3/ε3 (n = 691, 46.69%) |
ε2 (ε2/ε2 & ε2/ε3) (n = 238, 16.08%) |
ε4 (ε3/ε4 & ε4/ε4) (n = 480, 32.43%) |
ε2/ε4 (n = 71, 4.80%) |
p | |
| Age (y) (Mean ± SD) | 70.8 ± 8.32 | 71.0 ± 8.37 | 71.0 ± 8.59 | 70.5 ± 8.23 | 69.3 ± 7.38 | 0.27 |
| Age (n, %) | 0.21 | |||||
| < 65 | 309 (20.88) | 135 (19.54) | 55 (23.11) | 102 (21.25) | 17 (23.94) | |
| 65–74 | 685 (46.28) | 325 (47.03) | 95 (39.92) | 231 (48.13) | 34 (47.89) | |
| 75–84 | 410 (27.70) | 188 (27.21) | 74 (31.09) | 128 (26.67) | 20 (28.17) | |
| > 85 | 76 (5.14) | 43 (6.22) | 14 (5.88) | 19 (3.96) | 0 (0.00) | |
| Sex (n, %) | 0.11 | |||||
| Male | 353 (23.85) | 152 (22.00) | 54 (22.69) | 133 (27.71) | 14 (19.72) | |
| Female | 1127 (76.15) | 539 (78.00) | 184 (77.31) | 347 (72.29) | 57 (80.28) | |
| Education (y) (Mean ± SD) | 14.6 ± 3.16 | 14.7 ± 3.17 | 14.4 ± 2.92 | 14.4 ± 3.24 | 14.8 ± 3.32 | 0.27 |
| Education (n, %) | 0.72 | |||||
| ≤12 y | 448 (30.3) | 206 (29.8) | 67 (28.2) | 154 (32.1) | 21 (29.6) | |
| > 12 y | 1032 (69.7) | 485 (70.2) | 171 (71.8) | 326 (67.9) | 50 (70.4) | |
| Year of Initial Visit (n, %) | 0.25 | |||||
| 2005–2007 | 520 (35.23) | 243 (35.17) | 91 (38.40) | 158 (33.12) | 28 (39.44) | |
| 2008–2012 | 560 (37.94) | 259 (37.48) | 75 (31.65) | 199 (41.72) | 27 (38.03) | |
| 2013–2017 | 396 (26.83) | 189 (27.35) | 71 (29.96) | 120 (25.16) | 16 (22.54) | |
Table 2.
Hazard Ratio of APOE Genotype from Cox Proportional Hazards Model
| AD Cohort (N = 2,007) |
MCI Cohort (N = 1,480) |
|||||||
|---|---|---|---|---|---|---|---|---|
| Unadjusted Model |
Adjusted Model* |
Unadjusted Model |
Adjusted Model* |
|||||
| HR (95% CI) | p | HR (95% CI) | p | HR (95% CI) | p | HR (95% CI) | p | |
| ε2/ε3 (Reference group) | ||||||||
| ε2 (ε2/ε2 & ε2/ε3) | 0.66 (0.40, 1.09) | 0.103 | 0.75 (0.45, 1.24) | 0.262 | 0.90 (0.65, 1.24) | 0.529 | 0.88 (0.63, 1.21) | 0.427 |
| ε4 (ε3/ε4 & ε4/ε4) | 1.99 (1.50, 2.66) | < 0.0001 | 2.04 (1.52, 2.73) | < 0.0001 | 1.38 (1.09, 1.75) | 0.009 | 1.40 (1.10, 1.78) | 0.006 |
| ε2/ε4 | 0.74 (0.34, 1.61) | 0.453 | 0.85 (0.39, 1.84) | 0.679 | 0.92 (0.54, 1.57) | 0.763 | 0.88 (0.51, 1.50) | 0.637 |
| ε2/ε4 compared to other genotypes as reference group | ||||||||
| ε2/ε4 versus ε2 | 1.13 (0.47, 2.68) | 0.787 | 1.13 (0.47, 2.70) | 0.78 | 1.02 (0.57, 1.82) | 0.94 | 1.00 (0.56, 1.79) | 0.991 |
| ε2/ε4 versus ε4 | 0.37 (0.17, 0.80) | 0.011 | 0.42 (0.19, 0.90) | 0.026 | 0.67 (0.39, 1.14) | 0.141 | 0.63 (0.37, 1.08) | 0.091 |
Models were adjusted for age, sex, education, baseline cognitive status, and year of initial visit.
RESULTS
Demographic characteristics are displayed in Table 1. Participants in the AD (N = 2,007) and MCI (N = 1,480) cohorts were similar: mean age at enrollment was approximately 71 years, participants were predominantly female (over 70%), and average education level was 14 years. We observed statistically significant differences of sex distribution across the four APOE groups for the AD cohort.
APOE genotype and incidence of AD
Among AD cohort participants (N = 2,007), ε2/ε4 accounted for 4.9%, ε2/ε2 & ε2/ε3 15%, ε3/ε3 & ε4/ε4 34.3%, and ε3/ε3 45.8%. The average follow-up time was 4.6 years. Overall, 216 (10.8%) developed AD, with the following percentages for each allele carrier: 7 of 99 (7.1%) ε2/ε4, 108 of 688 (15.7%) ε3/ε4 & ε4/ε4, 19 of 301 (6.31%) ε2/ε2 & ε2/ε3, and 82 of 919 (8.92%) ε3/ε3. Using a multivariable Cox proportional hazards model (Table 2), compared to ε3/ε3 carriers, we observed that ε2/ε4 carriers exhibited a similar risk for AD (7.1% versus 8.9%; aHR = 0.85, 95% CI [0.39, 1.84], p = 0.679). Meanwhile, ε2/ε2 & ε2/ε3 carriers exhibited a 25% decreased risk of AD (aHR = 0.75, 95% CI [0.45, 1.24], p = 0.262), although the decrease was not statistically significant. In contrast, ε3/ε4 & ε4/ε4 carriers revealed double the risk of AD (aHR = 2.04, 95% CI [1.52, 2.73], p < 0.0001).
APOE genotype and incidence of MCI
Among MCI cohort participants (N = 1,480), ε2/ε4 accounted for 4.8%, ε2/ε2 & ε2/ε3 16.1%, ε3/ε4 & ε4/ε4 32.4%, and ε3/ε3 46.7%. The average follow-up time was 4.5 years. In total, 15 of 71 (21.1%) ε2/ε4, 127 of 480 (26.5%) ε3/ε4 & ε4/ε4, 50 of 238 (21.0%) ε2/ε2 & ε2/ε3, and 144 of 691 (20.8%) ε3/ε3 carriers developed MCI. Overall, 336 (22.7%) participants in the MCI cohort developed AD or MCI.
Following a multivariable Cox proportional hazards model (Table 2), compared to ε3/ε3 carriers, we observed that ε2/ε4 carriers exhibited a similar risk for MCI (aHR = 0.88, 95% CI [0.51, 1.50], p = 0.64). Meanwhile, individuals with ε2/ε2 & ε2/ε3 exhibited a 12% decreased risk of MCI (aHR = 0.88, 95% CI [0.63, 1.21], p = 0.43), although the decrease was not statistically significant. In contrast, individuals with ε3/ε4 & ε4/ε4 revealed a 40% increased risk of MCI (aHR = 1.40, 95% CI [1.10, 1.78], p = 0.006) compared to ε3/ε3 carriers.
Our sensitivity analysis, using a competing risk subdistribution hazard model, yielded results similar to the Cox proportional hazards model (Supplementary Table 1).
DISCUSSION
Using the national NACC dataset, which comprised approximately 2,000 African Americans without dementia, we found no associations between APOE ε2/ε4 and the incidence of AD and MCI. Moreover, consistent with the literature, we confirmed that compared to ε3/ε3 carriers, individuals carrying ε4 (ε3/ε4 and ε4/ε4) demonstrated statistically significant elevated risk of AD and MCI [12]. Our prior studies have shown that ε2/ε4 increases the risk of AD and MCI among non-Latino whites [11]. However, in this study, we observed a “protective” trend of ε2/ε4 on AD (aHR = 0.85; 95% CI [0.39, 1.84]) and MCI (aHR = 0.88; 95% CI [0.51–1.50]) among African Americans, although this trend was not statistically significant. Furthermore, the magnitude of increased risk of ε4 (ε3/ε4 and ε4/ε4) was much weaker than what we found among non-Latino whites [11]. This suggests the much lower “risk” effect of the ε4 allele on AD and MCI among African Americans. African Americans carrying the ε2/ε4 genotype manifest a trend of decreased incidence of AD and MCI, which is more like ε2 than ε4, although this trend is not statistically significant.
Prior studies generally have excluded participants carrying the ε2/ε4 genotype because of 1) the relative rarity of the ε2/ε4 genotype in the population and 2) the counteractive effect of ε2 and ε4 allele. Our and others’ prior research has investigated the association between APOE ε2/ε4 and incident AD and MCI among non-Latino whites [10, 11]. However, few studies have evaluated such relationships among African Americans. For example, one meta-analysis has examined the association of ε2/ε4 with AD in populations of various ethnic group and reported no association among African Americans (OR = 1.8; 95% CI [0.4, 8.1]; p = 0.27); however, this study included only 10 ε2/ε4 carriers [4]. Another population-based longitudinal study reported similar findings (OR = 1.34; 95% CI [0.44, 4.13]; p = 0.61), and it included only slightly more ε2/ε4 carriers (n = 19) [16]. Indeed, given such small sample size of ε2/ε4 carriers included in these studies, the parameter estimates of the effect of the ε2/ε4 may be neither stable nor reliable. In contrast, we took advantage of the large national NACC dataset and examined this association with a much larger sample size (99 ε2/ε4 carriers in the AD cohort; 71 ε2/ε4 carriers in the MCI cohort). Similar to previous studies, we found no effect of ε2/ε4 on AD and MCI. However, the direction of association was toward “protection” rather than “risk”, although not statistically significant. These inconsistent findings warrant further research on the effects of APOE ε2/ε4 on AD and MCI among African Americans.
Although the large NACC sample size confers strength on our study, we must acknowledge several limitations. First, the individuals assessed at the Alzheimer’s Disease Research Center are not representative of the general population, and this inherent sampling bias may limit the generalizability of our findings. Second, we had 99 and 71 ε2/ε4 carriers in our analytical sample of the AD and MCI cohorts, respectively, which were still small number relative to other genotype groups. Although our sample was far larger than that published in prior studies, the findings should be replicated with even larger samples. Lastly, given the observational nature of this study, the potential for unmeasured confounding variables may have influenced our findings.
Supplementary Material
ACKNOWLEDGMENTS
This work was partially supported by US National Institutes of Health grants (R03AG068413). The NACC database is funded by NIA/NIH Grant U01 AG016976. NACC data are contributed by the NIA-funded ADCs: P30 AG019610 (PI Eric Reiman, MD), P30 AG013846 (PI Neil Kowall, MD), P30 AG062428–01 (PI James Leverenz, MD) P50 AG008702 (PI Scott Small, MD), P50 AG025688 (PI Allan Levey, MD, PhD), P50 AG047266 (PI Todd Golde, MD, PhD), P30 AG010133 (PI Andrew Saykin, PsyD), P50 AG005146 (PI Marilyn Albert, PhD), P30 AG062421–01 (PI Bradley Hyman, MD, PhD), P30 AG062422–01 (PI Ronald Petersen, MD, PhD), P50 AG005138 (PI Mary Sano, PhD), P30 AG008051 (PI Thomas Wisniewski, MD), P30 AG013854 (PI Robert Vassar, PhD), P30 AG008017 (PI Jeffrey Kaye, MD), P30 AG010161 (PI David Bennett, MD), P50 AG047366 (PI Victor Henderson, MD, MS), P30 AG010129 (PI Charles DeCarli, MD), P50 AG016573 (PI Frank LaFerla, PhD), P30 AG062429–01(PI James Brewer, MD, PhD), P50 AG023501 (PI Bruce Miller, MD), P30 AG035982 (PI Russell Swerdlow, MD), P30 AG028383 (PI Linda Van Eldik, PhD), P30 AG053760 (PI Henry Paulson, MD, PhD), P30 AG010124 (PI John Trojanowski, MD, PhD), P50 AG005133 (PI Oscar Lopez, MD), P50 AG005142 (PI Helena Chui, MD), P30 AG012300 (PI Roger Rosenberg, MD), P30 AG049638 (PI Suzanne Craft, PhD), P50 AG005136 (PI Thomas Grabowski, MD), P30 AG062715–01 (PI Sanjay Asthana, MD, FRCP), P50 AG005681 (PI John Morris, MD), P50 AG047270 (PI Stephen Strittmatter, MD, PhD).This manuscript was edited for lexicogrammar, mechanics, cohesion, and coherence prior to submission by Brian Greene, EdD, Director for International Affairs at the University of Pittsburgh, School of Nursing.
Authors’ disclosures available online (https://www.j-alz.com/manuscript-disclosures/20-1613r1).
Footnotes
SUPPLEMENTARY MATERIAL
The supplementary material is available in the electronic version of this article: https://dx.doi.org/10.3233/JAD-201613.
REFERENCES
- [1].Harold D, Abraham R, Hollingworth P, Sims R, Gerrish A, Hamshere ML, Pahwa JS, Moskvina V, Dowzell K, Williams A, Jones N, Thomas C, Stretton A, Morgan AR, Lovestone S, Powell J, Proitsi P, Lupton MK, Brayne C, Rubinsztein DC, Gill M, Lawlor B, Lynch A, Morgan K, Brown KS, Passmore PA, Craig D, McGuinness B, Todd S, Holmes C, Mann D, Smith AD, Love S, Kehoe PG, Hardy J, Mead S, Fox N, Rossor M, Collinge J, Maier W, Jessen F, Schürmann B, Heun R, van den Bussche H, Heuser I, Kornhuber J, Wiltfang J, Dichgans M, Frölich L, Hampel H, Hüll M, Rujescu D, Goate AM, Kauwe JS, Cruchaga C, Nowotny P, Morris JC, Mayo K, Sleegers K, Bettens K, Engelborghs S, De Deyn PP, Van Broeckhoven C, Livingston G, Bass NJ, Gurling H, McQuillin A, Gwilliam R, Deloukas P, Al-Chalabi A, Shaw CE, Tsolaki M, Singleton AB, Guerreiro R, Mühleisen TW, Nöthen MM, Moebus S, Jöckel KH, Klopp N, Wichmann HE, Carrasquillo MM, Pankratz VS, Younkin SG, Holmans PA, O’Donovan M, Owen MJ, Williams J (2009) Genome-wide association study identifies variants at CLU and PICALM associated with Alzheimer’s disease. Nat Genet 41, 1088–1093. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [2].Lambert JC, Heath S, Even G, Campion D, Sleegers K, Hiltunen M, Combarros O, Zelenika D, Bullido MJ, Tavernier B, Letenneur L, Bettens K, Berr C, Pasquier F, Fiévet N, Barberger-Gateau P, Engelborghs S, De Deyn P, Mateo I, Franck A, Helisalmi S, Porcellini E, Hanon O; European Alzheimer’s Disease Initiative Investigators, de Pancorbo MM, Lendon C, Dufouil C, Jaillard C, Leveillard T, Alvarez V, Bosco P, Mancuso M, Panza F, Nacmias B, Bossù P, Piccardi P, Annoni G, Seripa D, Galimberti D, Hannequin D, Licastro F, Soininen H, Ritchie K, Blanché H, Dartigues JF, Tzourio C, Gut I, Van Broeckhoven C, Alpérovitch A, Lathrop M, Amouyel P (2009) Genome-wide association study identifies variants at CLU and CR1 associated with Alzheimer’s disease. Nat Genet 41, 1094–1099. [DOI] [PubMed] [Google Scholar]
- [3].Corder EH, Saunders AM, Strittmatter WJ, Schmechel DE, Gaskell PC, Small GW, Roses AD, Haines JL, Pericak-Vance MA (1993) Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer’s disease in late onset families. Science 261, 921–923. [DOI] [PubMed] [Google Scholar]
- [4].Farrer LA, Cupples LA, Haines JL, Hyman B, Kukull WA, Mayeux R, Myers RH, Pericak-Vance MA, Risch N, van Duijn CM (1997) Effects of age, sex, and ethnicity on the association between apolipoprotein E genotype and Alzheimer disease. A meta-analysis. APOE and Alzheimer Disease Meta Analysis Consortium. JAMA 278, 1349–1356. [PubMed] [Google Scholar]
- [5].Genin E, Hannequin D, Wallon D, Sleegers K, Hiltunen M, Combarros O, Bullido MJ, Engelborghs S, De Deyn P, Berr C, Pasquier F, Dubois B, Tognoni G, Fiévet N, Brouwers N, Bettens K, Arosio B, Coto E, Del Zompo M, Mateo I, Epelbaum J, Frank-Garcia A, Helisalmi S, Porcellini E, Pilotto A, Forti P, Ferri R, Scarpini E, Siciliano G, Solfrizzi V, Sorbi S, Spalletta G, Valdivieso F, Vepsäläinen S, Alvarez V, Bosco P, Mancuso M, Panza F, Nacmias B, Bossù P, Hanon O, Piccardi P, Annoni G, Seripa D, Galimberti D, Licastro F, Soininen H, Dartigues JF, Kamboh MI, Van Broeckhoven C, Lambert JC, Amouyel P, Campion D (2011) APOE and Alzheimer disease: A major gene with semi-dominant inheritance. Mol Psychiatry 16, 903–907. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [6].Liu CC, Liu CC, Kanekiyo T, Xu H, Bu G (2013) ApolipoproteinE and Alzheimerdisease: Risk, mechanisms and therapy. Nat Rev Neurol 9, 106–118. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [7].Seshadri S, Drachman DA, Lippa CF (1995) Apolipoprotein E epsilon 4 allele and the lifetime risk of Alzheimer’s disease: What physicians know, and what they should know. Arch Neurol 52, 1074–1079. [DOI] [PubMed] [Google Scholar]
- [8].Chartier-Harlin MC, Parfitt M, Legrain S, Pérez-Tur J, Brousseau T, Evans A, Berr C, Vidal O, Roques P, Gourlet V, Fruchart J-C, Delacourte A, Rossor M, Amouyel P (1994) Apolipoprotein E, epsilon 4 allele as a major risk factor for sporadic early and late-onset forms of Alzheimer’s disease: Analysis of the 19q13.2 chromosomal region. Hum Mol Genet 3, 569–574. [DOI] [PubMed] [Google Scholar]
- [9].Houlden H, Crook R, Backhovens H, Prihar G, Baker M, Hutton M, Rossor M, Martin JJ, Van Broeckhoven C, Hardy J (1998) ApoE genotype is a risk factor in nonpresenilin early-onset Alzheimer’s disease families. Am J Med Genet 81, 117–121. [DOI] [PubMed] [Google Scholar]
- [10].Oveisgharan S, Buchman AS, Yu L, Farfel J, Hachinski V, Gaiteri C, De Jager PL, Schneider JA, Bennett DA (2018) APOE ε2ε4 genotype, incident AD and MCI, cognitive decline, and AD pathology in older adults. Neurology 90, e2127–e2134. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [11].Ren D, Lopez OL, Lingler JH, Conley Y (2020) The effect of the APOE ε2ε4 genotype on the development of Alzheimer’s disease (AD) and mild cognitive impairment (MCI) in non-Latino whites. J Am Geriatr Soc 68, 1044–1049. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [12].Hendrie HC, Murrell J, Baiyewu O, Lane KA, Purnell C, Ogunniyi A, Unverzagt FW, Hall K, Callahan CM, Saykin AJ, Gureje O, Hake A, Foroud T, Gao S (2014) APOE ε4 and the risk for Alzheimer disease and cognitive decline in African Americans and Yoruba. Int Psychogeriatr 26, 977–985. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [13].Mendez MF (2006) The accurate diagnosis of early-onset dementia. Int J Psychiatry Med 36, 401–412. [DOI] [PubMed] [Google Scholar]
- [14].Beekly DL, Ramos EM, Lee WW, Deitrich WD, Jacka ME, Wu J, Hubbard JL, Koepsell TD, Morris JC, Kukull WA; NIA Alzheimer’s Disease Centers (2007) The National Alzheimer’s Coordinating Center (NACC) database: The Uniform DataSet. Alzheimer Dis Assoc Disord 21, 249–258. [DOI] [PubMed] [Google Scholar]
- [15].Morris JC, Weintraub S, Chui HC, Cummings J, Decarli C, Ferris S, Foster NL, Galasko D, Graff-Radford N, Peskind ER, Beekly D, Ramos EM, Kukull WA (2006) The Uniform Data Set (UDS): Clinical and cognitive variables and descriptive datafrom Alzheimer Disease Centers. Alzheimer Dis Assoc Disord 20, 210–216. [DOI] [PubMed] [Google Scholar]
- [16].Murrell JR, Price B, Lane KA, Baiyewu O, Gureje O, Ogunniyi A, Unverzagt FW, Smith-Gamble V, Gao S, Hendrie HC, Hall KS (2006) Association of apolipoprotein E genotype and Alzheimer disease in African Americans. Arch Neurol 63, 431–434. [DOI] [PMC free article] [PubMed] [Google Scholar]
Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.