1. Introduction
Alzheimer’s disease (AD) is a slowly progressive disease that leads to
the degeneration of brain cells. It is the major type of dementia, characterized by
the decline of thinking ability and independence of daily activities [1]. On the other hand, mild
cognitive impairment (MCI) is a disorder in which subjects exhibit objectively
cognitive dysfunction and their ability to engage in activities of daily living
is minimally affected [2, 3]. The apolipoprotein E (APOE) is a central
regulator of cholesterol and is closely related to AD pathology due to the
homeostasis of lipid and protein [4, 5]. The APOE gene has three alleles
(ε4, ε3, and ε2) responsible for three major
APOE subtypes (APOE4, APOE3, and APOE2) [6]. The APOE
ε4 allele is the most common genetic risk factor for AD [7], and it is
related to increased production of an amyloid- (A) [8] other than
reduced clearance of cerebral A compared to ε2 and
ε3 alleles [9, 10]. Consequently, subjects with APOE
ε4 demonstrate increased cerebral A deposition [11], and
APOE ε4 carriers have amyloid positive onset earlier than
non-carriers [12]. In contrast, other subtypes of APOE are supposed to
be protective (APOE2) or neutral (APOE3) for AD risk [13, 14, 15].
Tau pathology is a crucial aspect of AD, and the tau burden can predict cognitive
decline in AD [16]. MCI individuals with high tau levels show an increased risk of
cognitive decline [17]. However, the relationship between APOE and tau
pathology is less clear and controversial. [18] has reported a
significant physiological link between cerebrospinal fluid (CSF) levels of
APOE and CSF tau in neurologically healthy, cognitively intact
individuals. In contrast [19], other studies have reported no effect of APOE
ε2 or ε4 on CSF tau in cognitively normal aging.
Post-mortem evaluations suggested that APOE ε2 and
ε4 alleles were not related to paired helical filament (PHF) tau
tangles in the absence of A [20]. However, there was evidence that
APOE ε4 significantly influenced tau-mediated
neurodegeneration independently of A in a mouse model of tauopathy [21].
Recent studies have shown that the ε4+ group has a higher rate of tau
accumulation, and the enhanced effect of APOE ε4 on tau
accumulation still exists after adjusting the A load in the cortex [22]. So
far, there is no study on the relationship between APOE ε3
and tau pathology. In addition, there were no studies that explored the effect of
APOE alleles on tau as measured by CSF dependently or independently of
A in a group of individuals that spans the spectrum of cognition.
Similarly, the relationship between cognition and APOE allele
status is also controversial. Previous researches reported a positive association
[23, 24, 25, 26, 27, 28, 29]. These findings were generally interpreted to
suggest that the influences of APOE ε4 on late-life cognitive
impairment were mediated by the cascade of APOE that was APOE
ε4 led A deposition, then tau tangles, finally cognitive
dysfunction [30]. However, other studies showed no relationship
between cognition and APOE ε4 [31, 32, 33, 34, 35].
There were few studies on the relationship between cognition and
APOE ε2 and ε3 in MCI and AD.
Is there a new pathological cascade that explains the cognitive impairment in
the AD continuum? Therefore, the associations of APOE alleles with tau
and cognition and whether A mediates these associations need to
be further elucidated. In this article, we test
hypothesis that the associations of APOE alleles status with CSF tau and
cognitive function differ according to the presence and absence of A
deposition.
2. Materials and methods
2.1 Database description and participants
Data used in this article were from the Alzheimer’s Disease Neuroimaging
Initiative (ADNI) database (https://adni.loni.usc.edu/) [36].
We selected 1119 participants who had completed lumbar puncture,
genotyping for APOE allele status, Alzheimer’s disease assessment scale
(ADAS)-cog, Mini-Mental State Examination (MMSE), and Clinical Dementia Rating
scale (CDR). Selected participants were divided into cognitively normal (CN, n =
275), MCI (n = 629), and AD (n = 215). The criteria for CN included an MMSE score
equal to or greater than 24 and a CDR score of 0 [37]. The criteria for MCI were
subjects with an MMSE score equal to or greater than 24 and a CDR of 0.5,
preservation of activities of daily living, and an absence of other
neuropsychiatric diseases [38]. Except for the NINCDS/ADRDA standards, the MMSE
score of AD patients ranged from 20 to 26, and the CDR was 0.5 or 1.0. [39].
2.2 Standard protocol approvals, registrations, and patient
consents
The Institutional Review Boards approved the ADNI study
of all the participating institutions. Informed written consent was obtained from
all participants at every center.
2.3 APOE Genotyping
Subjects with at least one ε4 allele are called ε4
carriers [20]. Individuals who have two ε3 alleles are considered as
ε3 carriers. Participants with one ε2 allele and one
ε3 allele or two ε2 alleles are considered as ε2
carriers [40]. All APOE genotyping data used were
from ADNI files “APOERES.csv” (accessed November 2020).
2.4 CSF analyses
As mentioned earlier, A42, total-tau (T-tau), and phosphorylated-tau
(P-tau) at threonine 181 in CSF were measured by using the Innogenetics INNO-BIA
AlzBio3 immunoassay reagents and multiplex xMAP Luminex platform [41]. Subjects
were classified as with significant A deposition (A positive or
A+) or without significant A deposition (A negative or
A-) using a previously established cut-off of CSF A42 (192
pg/mL) [41]. All CSF data used were from the ADNI files
“UPENNBIOMK5-8.csv” and “FAGANLAB_07_15_2015.csv” (accessed November
2020).
2.5 Statistical methods
Chi-square analyses were used to test the difference of APOE genotypes
among the groups; all probability p values 0.05 were reported.
Differences between APOE ε4, ε3, and ε2
carriers and noncarriers in every diagnostic group were tested by using the
chi-square analyses for gender and A status (A- or
A+), and Mann-Whitney U test for age, education, A42, T-tau,
P-tau, and ADAS-cog. Bonferroni correction was used for multiple comparison
correction.
To analyze the differences in the association of APOE
ε4 with T-tau, P-tau, and ADAS-cog in individuals with and without
significant A deposition, we fitted linear regression models with an
interaction term between APOE ε4 and A status. Then
we conducted stratified analyses regressing APOE ε4 status on
T-tau, P-tau, and ADAS-cog in individuals with and without significant A
deposition. Finally, we also conducted stratified analyses regressing
APOE ε4 status on T-tau, P-tau, and ADAS-cog for CN, MCI, and
AD, respectively. All models adjusted for sex, age, and education. Similar
analyses were performed for APOE ε3 and ε2
genotypes. In these models, variables were log-transformed to fit a
normal distribution. Statistical significance was defined as p 0.05.
Bonferroni correction was used for multiple comparison correction. All statistics
were done using R (v. 3.4.2) and SPSS version 20.
3. Results
3.1 Demographic results
Demographic and clinical characteristics of subjects by diagnosis and
APOE allele status are shown in Tables 1,2,3. There were no differences
in age, sex, and education among the groups. APOE ε4
carriership was more common in MCI and AD than in CN (p 0.001 for
both) and in AD than in MCI (p 0.001). APOE
ε4 was present in 42.2% of individuals with significant
A deposition and only 6.0% of individuals without significant
A deposition in all participants (p 0.001). APOE
ε4 existed in 17.5%, 42.4%, and 73.0% of individuals with
significant A deposition and only 8.4%, 7.0%, and 0.0% of individuals
without significant A deposition in CN (p = 0.001), MCI
(p 0.001), and AD (p 0.001), respectively (Table 1).
Table 1.Demographic and clinical characteristics of APOE4 carriers and noncarriers.
Characteristics |
CN |
MCI |
AD |
All |
ε4- |
ε4+ |
ε4- |
ε4+ |
ε4- |
ε4+ |
ε4- |
ε4+ |
N (n %) |
204 (74.2%) |
71 (25.8%) |
318 (50.6%) |
311 (49.4%) |
58 (27.0%) |
157 (73.0%) |
580 (51.8%) |
539 (48.2%) |
Age (years) |
74.6 (5.7) |
73.5 (6.6) |
73.3 (7.8) |
71.5 (7.1) |
76.4 (9.0) |
73.9 (7.6) |
74.2 (7.4) |
72.5 (7.3) |
Sex (F %) |
103 (50.5%) |
35 (49.3%) |
129 (40.6%) |
130 (41.8%) |
23 (39.7%) |
68 (43.3%) |
255 (44.0%) |
233 (43.1%) |
Education (years) |
16.3 (2.6) |
16.0 (2.9) |
16.2 (2.7) |
16.0 (2.8) |
16.0 (2.9) |
15.2 (3.0) |
16.2 (2.7) |
15.8 (2.9) |
A42 (pg/mL) |
210.5 (48.0) |
167.5 (53.5) |
194.6 (51.9) |
147.5 (42.3) |
137.8 (23.0) |
127.5 (23.1) |
194.5 (52.4) |
144.3 (41.6) |
T-tau (pg/mL) |
66.3 (30.4) |
75.2 (35.9) |
73.1 (43.5) |
110.0 (60.5) |
134.8 (60.9) |
130.3 (61.7) |
76.9 (46.0) |
111.2 (60.5) |
P-tau (pg/mL) |
28.1 (14.8) |
37.0 (23.2) |
32.3 (20.0) |
46.5 (24.5) |
53.2 (29.8) |
53.5 (30.5) |
32.9 (19.8) |
47.3 (26.7) |
ADAS-cog |
6.0 (3.0) |
6.4 (3.2) |
9.1 (4.3) |
11.0 (4.8) |
19.7 (7.0) |
19.5 (6.7) |
9.4 (6.0) |
12.8 (6.9) |
A- (n %) |
136 (49.5%) |
23 (8.4%) |
173 (27.5%) |
44 (7.0%) |
0 (0.0%) |
0 (0.0%) |
309 (27.6%) |
67 (6.0%) |
A+ (n %) |
68 (24.7%) |
48 (17.5%) |
145 (23.1%) |
267 (42.4%) |
58 (27.0%) |
157 (73.0%) |
271 (24.2%) |
472 (42.2%) |
The measured data are represented by mean and standard deviation. Abbreviations:
A-, without significant A deposition; A+, with
significant A deposition; CN, cognitively normal; MCI, mild cognitive
impairment; AD, Alzheimer’s disease; ADAS-cog, Alzheimer’s disease assessment
scale-cog. |
APOE ε3 carriership was more common in CN than MCI and AD
(p 0.001 for both), and in MCI than in AD (p 0.001).
APOE ε3 was present in 21.7% of persons with significant
A deposition and 22.7% of persons without significant A
deposition in all participants (p = 1.782). APOE ε3
existed in 21.8%, 20.7%, and 24.7% of individuals with significant A
deposition and 37.8%, 23.8%, and 0.0% of individuals without significant
A deposition in CN (p 0.001), MCI (p = 0.525), and
AD (p 0.001), respectively (Table 2).
Table 2.Demographic and clinical characteristics of APOE3 carriers and noncarriers.
Characteristics |
CN |
MCI |
AD |
All |
ε3- |
ε3+ |
ε3- |
ε3+ |
ε3- |
ε3+ |
ε3- |
ε3+ |
N (n %) |
111 (40.4%) |
164 (59.6%) |
349 (55.5%) |
280 (44.5%) |
162 (75.3%) |
53 (24.7%) |
622 (55.6%) |
497 (44.4%) |
Age (years) |
73.6 (6.2) |
74.9 (5.8) |
71.8 (7.2) |
73.4 (7.9) |
74.1 (7.7) |
75.5 (9.2) |
72.7 (7.2) |
74.1 (7.4) |
Sex (F %) |
58 (52.3%) |
84 (51.2%) |
145 (41.5%) |
114 (40.7%) |
69 (42.6%) |
22 (41.5%) |
272 (43.7%) |
220 (44.3%) |
Education (years) |
16.0 (2.9) |
16.4 (2.5) |
15.9 (2.8) |
16.2 (2.7) |
15.1 (2.9) |
16.1 (3.0) |
15.7 (2.9) |
16.3 (2.7) |
A42 (pg/mL) |
190.8 (59.9) |
205.7 (46.9) |
154.1 (46.4) |
194.2 (52.5) |
128.1 (23.4) |
137.5 (23.1) |
154.1 (49.1) |
191.9 (52.1) |
T-tau (pg/mL) |
68.8 (32.5) |
68.4 (32.0) |
106.3 (60.9) |
72.9 (41.9) |
131.6 (62.5) |
133.0 (57.8) |
106.0 (60.7) |
77.9 (45.2) |
P-tau (pg/mL) |
32.0 (20.9) |
28.9 (15.0) |
44.4 (23.4) |
32.5 (18.3) |
53.6 (30.7) |
53.8 (30.6) |
44.5 (26.0) |
33.6 (20.3) |
ADAS-cog |
6.0 (3.0) |
6.2 (3.1) |
10.8 (4.8) |
9.1 (4.3) |
19.6 (6.7) |
21.3 (7.2) |
12.2 (6.9) |
9.5 (6.1) |
A- (n %) |
55 (20.0%) |
104 (37.8%) |
67 (10.7%) |
150 (23.8%) |
0 (0.0%) |
0 (0.0%) |
122 (10.9%) |
254 (22.7%) |
A+ (n %) |
56 (20.4%) |
60 (21.8%) |
282 (44.8%) |
130 (20.7%) |
162 (75.3%) |
53 (24.7%) |
500 (44.7%) |
243 (21.7%) |
The measured data are represented by mean and standard deviation. Abbreviations:
A-, without significant A deposition; A+, with
significant A deposition; CN, cognitively normal; MCI, mild cognitive
impairment; AD, Alzheimer’s disease; ADAS-cog, Alzheimer’s disease assessment
scale-cog. |
Similar to APOE ε3, APOE ε2 carriership
was also more common in CN than MCI and AD (p 0.001 for both), but
in MCI not than in AD (p = 0.057). APOE ε2 was
present in 2.7% of individuals with significant A deposition and 5.0%
of individuals without significant A deposition in all participants
(p = 0.012). APOE ε2 carriership was present in
2.9%, 2.7%, and 2.3% of individuals with significant A deposition and
11.6%, 3.8%, and 0.0% of individuals without significant A deposition
in CN (p 0.001), MCI (p = 0.789), and AD (p =
0.075), respectively (Table 3).
Table 3.Demographic and clinical characteristics of APOE2 carriers and noncarriers.
Characteristics |
CN |
MCI |
AD |
All |
ε2- |
ε2+ |
ε2- |
ε2+ |
ε2- |
ε2+ |
ε2- |
ε2+ |
N (n %) |
235 (85.5%) |
40 (14.5%) |
588 (93.5%) |
41 (6.5%) |
210 (97.7%) |
5 (2.3%) |
1033 (92.3%) |
86 (7.7%) |
Age (years) |
74.5 (6.1) |
73.5 (5.4) |
72.4 (7.5) |
72.9 (7.8) |
74.5 (8.2) |
77.8 (7.8) |
73.3 (7.4) |
73.6 (7.0) |
Sex (F %) |
114 (48.9%) |
28 (66.7%) |
342 (58.9%) |
28 (58.3%) |
126 (60.1%) |
4 (50.5%) |
582 (57.0%) |
60 (61.2%) |
Education (years) |
16.3 (2.6) |
15.8 (3.1) |
16.1 (2.8) |
16.0 (2.9) |
15.5 (3.0) |
15.4 (1.9) |
16.0 (2.8) |
15.9 (2.9) |
A42 (pg/mL) |
194.0 (51.7) |
229.5 (49.5) |
170.1 (52.8) |
185.7 (54.0) |
130.0 (23.4) |
136.6 (24.7) |
167.4 (52.5) |
200.5 (57.4) |
T-tau (pg/mL) |
70.1 (32.8) |
60.3 (26.4) |
92.6 (55.8) |
74.7 (51.6) |
129.5 (59.1) |
182.5 (93.8) |
94.8 (55.7) |
77.3 (57.1) |
P-tau (pg/mL) |
31.0 (16.4) |
27.4(24.1) |
40.0 (22.9) |
32.0 (16.1) |
53.6 (30.6) |
50.2 (29.1) |
40.7 (24.6) |
31.5 (20.8) |
ADAS-cog |
6.3 (3.1) |
5.3 (2.4) |
10.0 (4.6) |
9.6 (4.8) |
19.9 (6.9) |
20.0 (6.0) |
11.2 (6.7) |
8.6 (5.7) |
A- (n %) |
127 (46.2%) |
32 (11.6%) |
193 (30.7%) |
24 (3.8%) |
0 (0.0%) |
0 (0.0%) |
320 (28.6%) |
56(5.0%) |
A+ (n %) |
108 (39.3%) |
8 (2.9%) |
395 (62.8%) |
17 (2.7%) |
210 (97.7%) |
5 (2.3%) |
713 (63.7%) |
30 (2.7%) |
The measured data are represented by mean and standard deviation. Abbreviations:
A-, without significant A deposition; A+, with
significant A deposition; CN, cognitively normal; MCI, mild cognitive
impairment; AD, Alzheimer’s disease; ADAS-cog, Alzheimer’s disease assessment
scale-cog. |
3.2 CSF biomarkers differ by APOE allele status
CSF A42 concentrations were significantly lower in APOE
ε4 carriers compared with those who were APOE ε4
noncarriers in any group (p = 0.009 for AD, p 0.001 for
others) (Table 1). CSF P-tau was higher in APOE ε4 carriers
than APOE ε4 noncarriers in MCI and all participants
(p 0.001 for both), but there were no differences in CN (p
= 1.161) and AD (p = 0.474) groups. The results of CSF T-tau were
similar to that of P-tau (Table 1).
Contrary to APOE ε4, CSF A42 concentrations were
higher in APOE ε3 carriers compared with those who were
APOE ε3 noncarriers in MCI (p 0.001), AD
(p = 0.027), and all participants (p 0.001), but not CN
(p = 0.123), as shown in Table 2. CSF P-tau was lower in APOE
ε3 carriers than APOE ε3 noncarriers in MCI and
all participants (p 0.001 for both), but there were no differences
in CN (p = 1.392) and AD (p = 2.586) groups. The results of CSF
T-tau were also similar to that of P-tau (Table 2).
CSF A42 concentrations were significantly higher in APOE
ε2 carriers compared with those who were APOE ε2
noncarriers in CN and all participants (p 0.001 for both), but not
in MCI (p = 0.162) and AD (p = 1.596), as shown in Table 3. CSF
P-tau was lower in APOE ε2 carriers than APOE
ε2 noncarriers in CN (p = 0.036), MCI (p = 0.042),
and all participants (p 0.001), but there were no differences in AD
(p = 2.055) group. CSF T-tau was lower in APOE ε2
carriers than APOE ε2 noncarriers in MCI (p = 0.015)
and all participants (p 0.001), but there were no differences in CN
(p = 0.270) and AD (p = 0.282) groups (Table 3).
3.3 ADAS-cog scores differ by APOE allele status
ADAS-cog scores were higher in APOE ε4 carriers compared
with APOE ε4 noncarriers in MCI and all participants
(p 0.001 for both), but there were no significant differences in CN
(p = 1.161) and AD (p = 0.474) groups (Table 1).
Contrary to APOE ε4, ADAS-cog scores were lower in
APOE ε3 carriers than APOE ε3 noncarriers
in MCI and all participants (p 0.001 for both), but there were also
no significant differences between APOE ε3 carriers and
APOE ε3 noncarriers in CN (p = 2.208) and AD
(p = 0.318) groups (Table 2).
Though ADAS-cog scores were lower in APOE ε2 carriers than
APOE ε2 noncarriers in all participants (p
0.001), there were no significant differences between APOE
ε2 carriers and APOE ε2 noncarriers in
CN (p = 0.252), MCI (p = 1.455), and AD (p = 2.556)
groups (Table 3).
3.4 The associations of APOE with T-tau, P-tau, and ADAS-cog in all
participants with and without significant A deposition
The associations of APOE with T-tau, P-tau, and ADAS-cog were first
tested in linear regression models with an interaction term between APOE
ε4, ε3, and 2ε status and the presence of
A, adjusting for age, sex, and education. The interaction was
significant between APOE ε4 and ε3 allele status
and the presence of A for T-tau, P-tau, and ADAS-cog (Tables 4,5).
However, the ε2 by A interaction was not significant, as
shown in Table 6.
Table 4.Linear regression results of APOE4 status
and the presence of A.
Parameters |
Models |
A (SE), pc |
APOE ε4 (SE), p |
A + APOE ε4 (Interaction) (SE), p |
T-tau |
Model 1 |
0.54 (0.03), 0.001 |
- |
- |
|
Model 2 |
- |
0.4 (0.03), 0.001 |
- |
|
Model 3 |
0.4 (0.04), 0.001 |
0.1 (0.06), 0.360 |
0.24 (0.07), 0.018 |
P-tau |
Model 1 |
0.58 (0.03), 0.001 |
- |
- |
|
Model 2 |
- |
0.38 (0.03), 0.001 |
- |
|
Model 3 |
0.47 (0.04), 0.001 |
0.07 (0.06), 0.870 |
0.11 (0.07), 0.036 |
ADAS-cog |
Model 1 |
0.48 (0.04), 0.001 |
- |
- |
|
Model 2 |
- |
0.38 (0.04), 0.001 |
- |
|
Model 3 |
0.31 (0.05), 0.001 |
0.02 (0.08), 2.310 |
0.25 (0.09), 0.015 |
Table 4 indicated coefficient, Standard error (SE), and p value from
the models. Model 1 = age + sex + education + A; Model 2 = age + sex +
education + APOE ε4; Model 3 = age + sex + education +
A + APOE ε4 + interaction of APOE
ε4 and A. Abbreviations: ADAS-cog, Alzheimer’s disease
assessment scale-cog; APOE, apolipoprotein E. |
Table 5.Linear regression results of APOE3 status
and the presence of A.
Parameters |
Models |
A (SE), p |
APOE ε3 (SE), p |
A + APOE ε3 (Interaction) (SE), p |
T-tau |
Model 1 |
0.54 (0.03), 0.001 |
- |
- |
|
Model 2 |
- |
–0.31 (0.03), 0.001 |
- |
|
Model 3 |
0.61 (0.05), 0.001 |
–0.02 (0.05), 2.160 |
–0.24 (0.06), 0.009 |
P-tau |
Model 1 |
0.58 (0.03), 0.001 |
- |
- |
|
Model 2 |
- |
–0.29 (0.03), 0.001 |
- |
|
Model 3 |
0.64 (0.05), 0.001 |
0.00 (0.05), 2.910 |
–0.16 (0.07), 0.036 |
ADAS-cog |
Model 1 |
0.48 (0.04), 0.001 |
- |
- |
|
Model 2 |
- |
–0.30 (0.04), 0.001 |
- |
|
Model 3 |
0.65 (0.06), 0.001 |
0.07 (0.06), 0.870 |
–0.32 (0.08), 0.001 |
Table 5 indicated coefficient, Standard error (SE), and p value from
the models. Model 1 = age + sex + education + A; Model 2 = age + sex +
education + APOE ε3; Model 3 = age + sex + education +
A + APOE ε3 + interaction of APOE
ε3 and A. Abbreviations: ADAS-cog, Alzheimer’s disease
assessment scale-cog; APOE, apolipoprotein E. |
Table 6.Linear regression results of APOE2 status
and the presence of A.
Parameters |
Models |
A (SE), p |
APOE ε2 (SE), p |
A + APOE ε2 (Interaction) (SE), p |
T-tau |
Model 1 |
0.54 (0.03), 0.001 |
- |
- |
|
Model 2 |
- |
–0.23 (0.06), 0.001 |
- |
|
Model 3 |
0.54 (0.03), 0.001 |
–0.04 (0.07), 1.770 |
–0.11 (0.1), 0.870 |
P-tau |
Model 1 |
0.58 (0.03), 0.001 |
- |
- |
|
Model 2 |
- |
–0.24 (0.06), 0.001 |
- |
|
Model 3 |
0.59 (0.03), 0.001 |
–0.04 (0.07), 1.560 |
–0.09 (0.1), 1.140 |
ADAS-cog |
Model 1 |
0.48 (0.04), 0.001 |
- |
- |
|
Model 2 |
- |
–0.27 (0.07), 0.001 |
- |
|
Model 3 |
0.47 (0.04), 0.001 |
–0.13 (0.08), 0.330 |
–0.03 (0.12), 2.490 |
Table 6 indicated coefficient, Standard error (SE), and p value from
the models Model 1 = age + sex + education + A; Model 2 = age + sex +
education + APOE ε2; Model 3 = age + sex + education +
A + APOE ε2 + interaction of APOE
ε2 and A. Abbreviations: ADAS-cog, Alzheimer’s disease
assessment scale-cog; APOE, apolipoprotein E. |
Next, we carried out separate regression analyses for persons with (n = 743) and
without (n = 376) significant A deposition. In individuals with
significant A deposition, the APOE ε4 allele
is associated with increased T-tau, P-tau, and ADAS-cog (Table 7). We did
not observe an association among individuals without significant A
deposition (Table 7). APOE ε3 was related to decreased T-tau, P-tau, and ADAS-cog levels in individuals with significant A
deposition but not individuals without significant A deposition (Table 7).
However, in this model, APOE ε2 was not associated with
levels of T-tau, P-tau, and ADAS-cog levels in individuals with or without significant
A deposition, as shown in Table 7.
Table 7.Correlation of APOE4, APOE3, and APOE2 status with T-tau, P-tau, and
ADAS-cog.
A status |
Model |
APOE ε4 (SE), p |
APOE ε3 (SE), p |
APOE ε2 (SE), p |
A+ |
T-tau |
0.23 (0.04), 0.001 |
–0.21(0.04), 0.001 |
–0.14 (0.08), 0.279 |
|
P-tau |
0.19 (0.04), 0.001 |
–0.16(0.04), 0.001 |
–0.13 (0.08), 0.300 |
|
ADAS-cog |
0.27 (0.05), 0.001 |
–0.25(0.05), 0.001 |
–0.15 (0.1), 0.330 |
A- |
T-tau |
0.12 (0.05), 0.195 |
–0.04 (0.04), 1.180 |
–0.04 (0.06), 1.560 |
|
P-tau |
0.08 (0.06), 0.510 |
–0.01 (0.05), 2.430 |
–0.04 (0.06), 1.560 |
|
ADAS-cog |
0.05 (0.08), 1.440 |
0.06 (0.05), 1.110 |
–0.13 (0.08), 0.261 |
Table 7 presented coefficient, Standard error (SE), and p value from
the models considering all subjects as a whole. All models were adjusted for age,
sex, and education. Abbreviations: ADAS-cog, Alzheimer’s disease assessment
scale-cog; APOE, apolipoprotein E; A-, without significant
A deposition; A+, with significant A deposition. |
3.5 APOE status on levels of T-tau, P-tau, and ADAS-cog in CN, MCI,
and AD groups with and without significant A deposition
Finally, we performed stratified analyses regressing APOE ε4
status on levels of T-tau, P-tau, and ADAS-cog in CN, MCI, and AD groups with and
without significant A deposition. We found that APOE
ε4 strongly associated with increased levels of T-tau, P-tau, and
ADAS-cog in MCI group with significant A deposition ( = 0.27,
p 0.001; = 0.20, p 0.001; = 0.17,
p 0.001, respectively) (Fig. 1A–C), and increased levels of P-tau
in CN group with significant A deposition ( = 0.22, p
= 0.049) (Fig. 1B). However, we did not observe the same associations among
persons without significant A deposition, as shown in Fig. 1A–C.
Fig. 1.
APOE4 status on levels of T-tau, P-tau,
and ADAS-cog in CN, MCI, and AD with or without significant A
deposition. (A–C) The data are estimates (-coefficients) from
stratified analyses, and the confidence interval of regression is 95%. All
values are Log transformed. Effects were significant (*), for T-tau (A) In MCI
with significant A deposition ( = 0.27, p 0.001); for P-tau. (B) In CN and MCI with significant A deposition ( = 0.22, p = 0.049; = 0.20,
p 0.001, respectively); for ADAS-cog. (C) In MCI significant with
A deposition ( = 0.17, p 0.001).
Contrary to APOE ε4, APOE ε3 was
strongly related to decreased levels of T-tau, P-tau, and ADAS-cog in MCI group
with significant A deposition ( = –0.25, p 0.001;
= –0.18, p 0.001; = –0.18, p
0.001, respectively) (Fig. 2A–C). As shown in Fig. 2A–C, we did not
observe the same relationships among persons without significant A
deposition.
Fig. 2.
APOE3 status on levels of T-tau, P-tau,
and ADAS-cog in CN, MCI, and AD with or without significant A
deposition. (A–C) The data are estimates (-coefficients) from
stratified analyses, and the confidence interval of regression is 95%. All
values are Log transformed. Effects were significant (*), for T-tau (A) In MCI
with significant A deposition ( = –0.25, p 0.001); for P-tau. (B) In MCI with significant A deposition ( = –0.18, p 0.001); for ADAS-cog. (C) In MCI with
significant A deposition ( = –0.18, p
0.001).
We repeated the analysis for the APOE ε2 allele. Again, we found a
significant association of the APOE ε2 allele with decreased
T-tau levels only in the MCI group with significant A deposition (= -0.27, p = 0.036) (Fig. 3A).
Fig. 3.
APOE2 status on levels of T-tau, P-tau,
and ADAS-cog in CN, MCI, and AD with or without significant A
deposition. (A–C) The data are estimates (-coefficients) from
stratified analyses, and the confidence interval of regression is 95%. All
values are Log transformed. Effects were significant (*), for T-tau (A) In MCI
with significant A deposition ( = -0.27, p =
0.036).
4. Discussion
This work evaluated the effects of different APOE allele statuses on
T-tau, P-tau, and cognition in relation to A deposition in a large
cohort of subjects. We have the following main findings: Firstly, there were
significant differences between APOE allele carriers and noncarriers in
the measures of T-tau, P-tau, and ADAS-cog scores in MCI, but not in CN and AD.
Secondly, there was an interaction between APOE ε4 and
ε3 and the presence of A. Finally, APOE ε4
and APOE ε3 were associated with CSF tau and cognition in MCI
participants with A deposition, but not in AD participants with
A deposition.
Compared with noncarriers, previous studies reported APOE ε4
carriers had higher deposition of A in the cerebral cortex in late-onset AD
[42, 43]. A low CSF A level is considered a marker of A
deposition in AD patients’s brains [44]. Consistent with the report by Vemuri
et al. [45], within CN, MCI, and AD group, APOE ε4
carriers had lower CSF A42 than noncarriers. In addition, in CN and MCI
groups, results demonstrated that APOE ε4 was
more common in individuals with significant A deposition than in
subjects without significant A deposition. There
were no individuals without significant A deposition in the AD group, suggesting
that APOE ε4 may relate strongly to CSF A in the
different phases of cognitive damage. On the contrary, APOE ε3 carriers had higher CSF A42
than noncarriers in any group. However, APOE ε2 carriers had
higher CSF A42 than noncarriers only in the CN group. APOE
ε3 and ε2 were widespread in individuals with significant
A deposition in the AD group, and they were prevalent in participants
without significant A deposition in the CN group. This phenomenon of
APOE ε3 and ε2 in the AD group may be related to
A deposition in all AD patients. Relative to APOE
ε4, we speculate that APOE ε3 and ε2
may have opposite effects in CN subjects.
There was no significant difference in T-tau and ADAS-cog scores
between APOE allele carriers and noncarriers among CN. Among MCI, T-tau, P-tau,
and ADAS-cog scores were significantly different between APOE allele
carriers and noncarriers. Interestingly, there was not a single difference
between APOE allele carriers and noncarriers in the measures of T-tau,
P-tau, and ADAS-cog scores in AD subjects. Our data show
significant differences in CSF A42 levels between APOE allele
carriers and noncarriers in all clinical groups. Still, there are no significant
differences in T-tau values between APOE allele carriers and noncarriers
in CN and AD individuals. In patients with clinically diagnosed cognitive
impairment, the effect of APOE genotype on cognitive decline is the most
consistent in MCI patients but not in AD patients. This is not to say that
APOE genotypes are not associated with neuropathological parameters.
When all individuals are combined, APOE ε4 significantly
increases the risk of more severe clinical damage and has higher levels of P-tau
and T-tau. However, APOE ε3 and ε2 have opposite
effects. APOE genotype is not deterministic because of many
ε4 carriers without dementia and many ε4 noncarriers with
dementia [45]. In contrast, there are many ε3 and ε2
carriers with dementia and many ε3 and ε2 noncarriers
without dementia.
In 2012, there was a change in the diagnostic criteria for AD neuropathology
[46], requiring the presence of A deposition for the neuropathological
diagnosis of AD. However, the previous view shows that even in the absence of
A, the appearance of neurofibrillary tangles (NFT) is the earliest
neuropathological manifestation of AD [47].Therefore, it has been argued that tau
tangles are a pathophysiological process different from AD in the absence of
A [20, 48]. Several studies revealed a relationship between
APOE and A pathology and tau pathology, indicating that the
association between APOE and tau pathology may be mediated by A [20, 49]. We found an interaction between APOE
ε4 and the presence of A such that the associations of
APOE ε4 with T-tau and P-tau were much more robust in persons
with A. When we considered all subjects as a whole, there was a
significant association between APOE ε4 and increased
CSF T-tau and P-tau concentrations in individuals with significant A
deposition. There is no similar phenomenon in individuals without significant
A deposition. In the stratified analyses regressing within CN, MCI, and
AD groups, we found that APOE ε4 was significantly related to
increased CSF T-tau and P-tau concentrations in MCI but not in AD to A status. Few studies have tested the relationship
between APOE ε3 and tau pathology.
However, there was also an interaction between APOE ε3 and
the presence of A such that the associations of APOE ε3
with T-tau and P-tau were much more robust in persons with A, and it
revealed that APOE ε3 was associated with decreased
concentrations of CSF T-tau and P-tau in individuals with A deposition.
In the stratified analyses regression within CN, MCI, and AD groups, the
APOE ε3 allele was significantly associated with decreased
CSF T-tau and CSF P-tau levels in the MCI with significant A
deposition. These results were not observed in individuals without significant
A deposition. Some studies reported that APOE
ε2 carriers had reduced NFT [50, 51], though inconsistent findings
exist [52, 53]. We did not find an interaction between
APOE ε2 and the presence of A related to tau.
APOE ε2 was only associated with decreased levels of CSF
T-tau in MCI individuals with significant A deposition. Our results show
that APOE ε4 and ε3 may only affect tau pathology
in MCI patients, and A mediates this effect. This work indirectly
supports the concept that APOE alleles influence tau pathology
dependently on A, and tau pathology without A may reflect a
different pathological process from MCI.
A longitudinal study has reported that the relationship between APOE and
global cognitive decline was mediated by A and tau [54]. It was also
found that the effects of APOE on a decline in episodic memory and
non-episodic cognition were mediated by A [30]. However, these findings
did not divide the subjects according to the severity of cognitive impairment.
We found an interaction between APOE ε4 and
ε3 and the presence of A such that the associations of
APOE ε4 and APOE ε3 with ADAS-cog were
much more robust in persons with A. When we considered all participants as
a whole, there was a significant correlation between APOE ε4
and increased ADAS-cog scores and between APOE ε3 and
decreased ADAS-cog scores in persons with significant A deposition but
not in persons without significant A deposition. However, APOE
ε2 was not associated with ADAS-cog in individuals with and without
significant A deposition. In the stratified analyses regressing within
CN, MCI, and AD groups, we revealed that APOE ε4 was only
significantly associated with increased ADAS-cog scores in the MCI individuals
with significant A deposition, and APOE ε3 was only
significantly associated with decreased ADAS-cog scores in the MCI individuals
with significant A deposition. APOE ε2 was not
associated with ADAS-cog in the MCI and AD individuals with or without
significant A deposition. Our work suggests that the effect of APOE
ε4 and APOE ε3 on cognitive decline is only
observed in MCI, and A also mediates this effect. In addition, it
demonstrates that APOE ε3 has a protective effect
on MCI but not AD, and APOE ε2 has no protective effect on
MCI and AD. These seem to differ from previous conclusions that
APOE ε3 is considered neutral and APOE ε2
is protective of AD risk. We do not know what the reason is, but we believe it is
an interesting question for further research.
Our data suggest that the APOE genotype may only influence CSF tau and cognition in MCI participants. Just as we know, APOE
ε4 likely predates the onset of A deposition [45], then
A deposition initiates the cascade. Once A triggers the downstream process is, other factors will lead to the AD’s
complete pathologic/clinical manifestations [55]. Therefore, we speculate
that tau pathology and cognition in AD may be more affected by other factors,
such as inflammatory factors, loss of cells, synapses, and dendrites and so on.
The other possibility is that the groups are defined by being in a
specific cognitive range, and the effect may not be noticed. However, future work
is needed to determine why APOE genotype is only related to tau
pathology and cognition in MCI patients. In addition, APOE ε3
was associated with lower amyloid (higher CSF A42).
Thus, it perhaps slows the trajectory of conversion from MCI to AD. However, its
downstream signaling mechanism is still unknown, which may be an exciting
topic in future research.
There are a few limitations. First of all, it lacks
longitudinal data, so it cannot observe the dynamic impact of APOE on
CSF tau and cognition. Secondly, it did not contain non-AD
neurodegenerative disorders. Finally, the ADNI database consists of self-selected,
highly educated volunteers interested in participating in AD research, which may
concern their cognition. As such, our findings will benefit from
replication in another population-based cohort.
5. Conclusion
We found that APOE ε4 and ε3 were
associated with CSF tau and ADAS-cog. However, APOE ε4 and
ε3 only affect tau pathology and cognitive function in MCI patients,
and A mediates these effects. Thus, in addition to positron emission
tomography (PET) data for A and tau, our findings highlight the need for
future longitudinal studies examining the effects of APOE on tau and
ADAS-cog.
Abbreviations
A, amyloid-; AD, Alzheimer’s disease; ADAS-cog, Alzheimer’s
disease assessment scale-cog; ADNI, Alzheimer’s disease Neuroimaging Initiative;
APOE, Apolipoprotein E; CDR, Clinical Dementia Rating scale; CN,
cognitively normal; CSF, cerebrospinal fluid; MCI, mild cognitive impairment;
MMSE, Mini-mental State Examination; NFT, neurofibrillary tangles; PET, positron
emission tomography; PHF, paired helical filament.
Author contributions
FX: manuscript drafting and composition of figures. TM: analysis of data. JT:
collection of data. JL: interpretation of data. HZ: concept and supervision of
the research.
Ethics approval and consent to participate
The Institutional Review Boards approved the ADNI study of all the participating institutions. In addition, informed written consent was obtained from all participants at every center.
Acknowledgment
Data collection and sharing for this project was funded by the Alzheimer’s
Disease Neuroimaging Initiative (ADNI) (National Institutes of Health Grant U01
AG024904) and DOD ADNI (Department of Defense award number W81XWH-12-2-0012).
ADNI is funded by the National Institute on Aging, the National Institute of
Biomedical Imaging and Bioengineering, and through generous contributions from
the following: AbbVie, Alzheimer’s Association; Alzheimer’s Drug Discovery
Foundation; Araclon Biotech; BioClinica, Inc.; Biogen; Bristol-Myers Squibb
Company; CereSpir, Inc.; Cogstate; Eisai Inc.; Elan Pharmaceuticals, Inc.; Eli
Lilly and Company; EuroImmun; F. Hoffmann-La Roche Ltd and its affiliated company
Genentech, Inc.; Fujirebio; GE Healthcare; IXICO Ltd.; Janssen Alzheimer
Immunotherapy Research & Development, LLC.; Johnson & Johnson Pharmaceutical
Research & Development LLC.; Lumosity; Lundbeck; Merck & Co., Inc.; Meso Scale
Diagnostics, LLC.; NeuroRx Research; Neurotrack Technologies; Novartis
Pharmaceuticals Corporation; Pfizer Inc.; Piramal Imaging; Servier; Takeda
Pharmaceutical Company; and Transition Therapeutics. The Canadian Institutes of
Health Research is providing funds to support ADNI clinical sites in Canada.
Private sector contributions are facilitated by the Foundation for the National
Institutes of Health (https://www.fnih.org/). The grantee organization is the Northern
California Institute for Research and Education, and the study is coordinated by
the Alzheimer’s Therapeutic Research Institute at the University of Southern
California. ADNI data are disseminated by the Laboratory for Neuro Imaging at the
University of Southern California.
Funding
This research was funded by the Medical Research Project of Chongqing Healthy
Committee, grant number 2018MSXM058.
Conflict of interest
The authors declare an interest in the Alzheimer’s Disease Neuroimaging Initiative.
Data availability statement
The datasets used and/or analyzed in this study may be obtained from the
corresponding author on reasonable request.