ORIGINAL CONTRIBUTION
Event-Related Potential Changes in Groups
at Increased Risk for Alzheimer Disease
Joanne Green, PhD; Allan I. Levey, MD, PhD
Background: Individuals who have a family history
(FH) of Alzheimer disease (AD) or who carry the apolipoprotein E e4 allele are at increased risk for developing
AD. Abnormalities in brain event-related potentials
(ERPs) have been observed in patients diagnosed as having AD.
Objective: To determine whether groups of nonsymp-
tomatic, middle-aged individuals at increased risk for AD
exhibited ERP changes consistent with this disease.
Design: In a case-control study, ERPs were elicited us-
ing an auditory oddball paradigm, and a brief neuropsychological battery was administered.
or noncarriers (e4−; n = 8), and these subgroups were compared with the FH− group.
Main Outcome Measures: The latency and amplitudes of P3, N2, and P2 components of the ERP were
quantified and analyzed statistically.
Results: Compared with the FH− group, both the whole
FH+ group and the FH+/e4+ subgroup showed abnormal
prolongation in the latency of the P3 component. In addition, the FH+/e4+ subgroup showed abnormal prolongation
in the latency of the N2 component. These changes were
observed in the absence of neuropsychological deficits.
Conclusions: The findings indicate that groups at in-
Setting: University laboratory facilities.
Subjects: We compared age-matched and educationmatched groups with a positive family history (FH+;
n = 24) or a negative family history (FH−; n = 23) of AD.
Within the FH+ group, subgroups were identified as either carriers of the apolipoprotein E e4 allele (e4+; n = 9)
I
From the Department of
Neurology, Emory University
School of Medicine, Wesley
Woods Center, Atlanta, Ga.
creased risk for developing AD show ERP changes consistent with those observed in patients diagnosed as having AD. The results support accumulating evidence that
AD has a preclinical phase and that early detection may
be possible.
Arch Neurol. 1999;56:1398-1403
NDIVIDUALS WHO have a family
history (FH) of Alzheimer disease (AD) or who carry the apolipoprotein E (APOE) e4 allele
(E4+) are at increased risk for
AD.1-7 For blood relatives of patients with
AD, the risk of developing the disease approaches 50% after the age of 85 years.1,2
The APOE e4 allele is a major risk factor
for both late-onset familial and sporadic
AD.4-7 Greater APOE e4 allele dose (carrying 2 e4 alleles rather than 1) is associated with both increased risk and earlier
disease onset.4,7
There is mounting evidence that AD
has a long preclinical phase during which
individuals may exhibit subtle changes in
neuropsychological8-10 and metabolic indices.11,12 The present study examined
whether preclinical AD might also be associated with abnormalities in brain eventrelated potentials (ERPs). We hypothesized that the P3 component of the ERP
would show abnormalities because of the
following: (1) it reflects activities, such as
memory and attention,13,14 that are impaired in patients with AD; (2) its genera-
ARCH NEUROL / VOL 56, NOV 1999
1398
tion involves neuroanatomical regions (ie,
temporal and parietal lobes)15-17 that are
dysfunctional early in the course of AD18-21;
(3) it is sensitive to neurochemical changes
(ie, cholinergic)22 that occur early in AD;
and (4) it has shown abnormalities in patients diagnosed as having AD.23,24 We predicted that a nonsymptomatic, positive FH
(FH+) group would show abnormal prolongation of P3 latency23,24 and, moreover, that a group with an FH+ of lateonset AD who also carried the APOE e4
allele would show particularly pronounced P3 changes. For purposes of comparison, we also evaluated the N2 and P2
components, which precede the P3 component.
RESULTS
NEUROPSYCHOLOGICAL AND
BEHAVIORAL DATA
Neuropsychological and behavioral data
are shown in the Table. There were no significant differences between groups, ei-
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SUBJECTS AND METHODS
SUBJECTS
Twenty-four FH+ individuals were compared with 23 individuals with a negative family history (FH−). Subjects were
excluded if they had a history of neurologic, psychiatric,
or other disease that might predispose them to cognitive
dysfunction or cerebral ischemia. Each of the subjects reported normal hearing. Individuals in the FH+ group met
2 criteria: (1) they had at least 1 parent with a progressive
dementia diagnosed as late-onset AD by a physician; and
(2) they had another relative in that lineage who had either physician-diagnosed AD or a dementia of unidentified origin consistent with AD based on available information. The mean (SD) age of disease onset for the parents of
the FH+ group was 72.9 (5.0) years, based on subject report. The FH+ and FH− groups did not differ significantly
in years of age (mean [SD]: FH+, 55.5 [5.0]; FH−,55.4 [4.4])
or years of education (mean [SD]: FH+, 14.4 [2.0]; FH−,
15.1 [2.3]). Subjects were recruited through newsletter advertisements and signed informed consent forms that were
approved by the Emory University Human Investigations
Committee, Atlanta, Ga.
previously described.26 The primary interest was in the
P3 recorded at Pz, an electrode location at which abnormalities in patients with AD have been observed.23,24 Data
also were recorded at locations Fz and Cz. The P3 component was identified as the largest positive peak between
250 and 500 milliseconds following the oddball tone and
having maximal parietocentral amplitude. The P3 peak
amplitude was computed by subtracting the 150millisecond prestimulus baseline, and the peak latency was
computed relative to stimulus onset. The P2 and N2 components were identified and quantified using conventional
procedures.26
Subjects underwent a brief neuropsychological battery including behavioral measures, particularly of delayed memory, that are sensitive to symptoms of early AD.27,28
The battery included the California Verbal Learning Test
(Trial 1-5 cumulative learning, Trial 5 recall, long-delay free
recall, and long-delay discriminability),29 Wechsler Adult
Intelligence Scale-Revised Block Design (total points)30 and
Digit Symbol (total points),30 and the Beck Depression Inventory.31 One FH− subject was unable to complete the battery due to time constraints, and 1 FH+ subject did not complete the Beck Depression Inventory.
DATA ANALYSIS
DNA EXTRACTION AND APOE GENOTYPING
The APOE genotyping was performed in 17 of 24 of the FH+
subjects using procedures described previously.25 The 7 remaining FH+ subjects were unable to return for blood sampling. Among the 17 FH+ subjects, the genotypes were as follows: 4 were 4/4, 5 were 3/4, 6 were 3/3, and 2 were 2/3. Thus,
9 (53%) of the sampled subjects carried at least 1 APOE e4
allele, and 8 (47%) of the FH+ subjects did not carry an APOE
e4 allele (E4−). The percentage of the FH+ subjects carrying
the APOE e4 allele is higher than previously reported (32%
and 36%),11,12 but this may reflect either the small sample size
or the requirement that the FH+ subjects have 2 blood relatives (not just 1) in the same lineage with probable AD. The
2 FH+ subgroups did not differ significantly in years of age
(mean [SD]: FH+/e4+, 58 [5.1]; FH+/e4−, 54 [4.7]) or years
of education (mean [SD]: FH+/e4+, 14.7 [2.2]; FH+/e4−, 15
[2.3]), nor did they differ significantly from the FH− group.
PROCEDURES
The P3 component was assessed with an auditory oddball
paradigm using data collection and analysis procedures
ther when classified on the basis of FH alone or on the
basis of risk.
P3 COMPONENT
Comparison of FH Groups
The P3 latency varied significantly as a function of
electrode location (F2,90 = 23.6; P,.01). The mean (SE)
latency at Pz (386 [5.3] milliseconds; P,.01) was
longer than at Fz (357 [5.1] milliseconds or Cz (363
[6.0] milliseconds; each at P,.001). This pattern of
prolonged P3 latency at more posterior recording locations has been observed previously.24,26,32 As illustrated
ARCH NEUROL / VOL 56, NOV 1999
1399
Two sets of comparisons were made for each variable. The
first set compared groups as a function of FH alone (FH+
compared with FH−). The second set compared groups in
terms of relative risk: (1) the FH+/e4+ subgroup with an
increased risk due to FH and APOE e4 genotype; (2) the
FH+/e4− subgroup with an increased risk due to FH but
not APOE e4 genotype; and (3) the FH− group with a low
risk due to FH.
For each ERP component, latency and amplitude
were analyzed separately. Data meeting assumptions of
homogeneity of variance were analyzed using a mixed
design analysis of variance with group (either FH or APOE
e4 genotype) as a between-groups factor and electrode (Fz,
Cz, and Pz) as a repeated measure. Significant interactions
were analyzed by planned comparison of means. If
assumptions of homogeneity of variance were violated,
groups were compared at each electrode location using
nonparametric statistics (Kruskal-Wallis or MannWhitney test). A similar approach was used in making
group comparisons of each of the neuropsychological
measures and of the median reaction time obtained from
the auditory oddball paradigm.
in Figure 1, there also tended to be a group difference as a function of electrode location (F 2,90 = 2.8;
P = .06). The mean (SE) P3 latency at Pz was significantly longer for the FH+ group (397 [8.2] milliseconds) than it was for the FH− group (375 [6.2] milliseconds) (t45 = 2.0; P = .047), although the latency of
the 2 groups did not differ at the other electrode locations (P = .84 and P = .71 for Cz and Pz, respectively).
The small but significant difference in P3 latency at Pz
is further illustrated in the ERP wave forms for the
FH+ and FH− groups shown in Figure 2. Thus, consistent with the initial hypothesis, the FH+ group
showed abnormal prolongation of P3 latency measured at Pz.
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Neuropsychological and Behavioral Measures as a Function of Family History and Apolipoprotein E e4 Genotype Groups*
Measure
FH− (n = 24)
FH+ (n = 23)
FH+/e4+ (n = 9)
FH+/e4− (n = 8)
56.0 (7.8)
13.3 (3.8)
12.1 (2.6)
95.4 (4.6)
57.0 (6.4)
13.6 (1.7)
13.2 (1.9)
95.9 (3.1)
53.4 (8.2)
13.3 (2.4)
12.4 (2.8)
96.2 (4.3)
60.0 (3.9)
13.5 (1.2)
13.6 (1.2)
96.8 (2.0)
29.5 (9.0)
56.6 (12.8)
5.4 (4.8)
437 (122.7)
31.8 (6.5)
53.7 (8.4)
6.5 (6.7)
410 (84.5)
33.1 (5.8)
56.8 (7.9)
6.1 (5.9)
418 (68.4)
32.9 (7.9)
52.3 (9.5)
3.4 (2.9)
411 (92.8)
29
California Verbal Learning Test
Cumulative learning, Trials 1-5
Recall, Trial 5
Long-delay free recall
Long-delay discriminability
Wechsler Adult Intelligence Scale-Revised30
Block Design, total points
Digit Symbol, total points
Beck Depression Inventory31
Reaction time (auditory oddball paradigm)
*Data are given as mean (SD). There were no significant differences among the groups. FH− indicates negative family history; FH+, positive family history;
e4+, carrier for the apolipoprotein E e4 allele; and e4−, noncarrier for the apoplipoprotein E e4 allele.
The mean (SE) P3 amplitude was 12.9 (0.8) µV and
did not vary significantly as a function of FH (P = .75) or
electrode location (P = .10).
N2 COMPONENT
Comparison of FH Groups
Neither N2 latency nor amplitude showed significant
variation as a function of FH or electrode location. In
Figure 2, although the mean (SE) amplitude of the N2
component appears to be smaller for the FH+ group
(3.4 [6.5] µV) than it is for the FH− group (5.8 [8.6]
µV), this difference did not approach statistical significance (P = .57).
Comparison of Risk Groups
The N2 latency varied significantly between risk groups
(F2,37 = 4.5; P = .02) as illustrated in Figure 5. Averaged
across electrodes, the N2 latency of the FH+/e4+ group
(254 [5.7] milliseconds) was significantly longer than that
of the FH+/e4− group (231 [3.7] milliseconds; P = .02)
or the FH− group (235 [2.6] milliseconds; P = .04). This
pattern was consistent among all 3 electrode locations.
ARCH NEUROL / VOL 56, NOV 1999
1400
P3 Latency, ms
Figure 3 shows the P3 latency data for the 3 risk groups.
There were significant group differences at electrodes Pz
(H2 = 6.8; P = .03) and Cz (H2 = 6.2; P = .04). At each of these
electrodes, the P3 latency of the FH+/e4+ subgroup was significantly longer than that for the FH− group (P = .009 and
P = .02 for Cz and Pz, respectively). Other between-group
comparisons did not reveal significant differences. The P3
latency difference between the FH− and FH+/e4+ groups
is further illustrated in the ERP wave forms shown in
Figure 4. Thus, the abnormal prolongation of P3 latency
was pronounced for the FH+/e4+ subgroup.
The P3 amplitude did not vary significantly as a function of risk group but did vary as a function of electrode
(F2,74 = 3.3; P = .04). The mean (SE) P3 amplitude was larger
at Pz (13.7 [0.9] µV) than it was at Fz (12.5 [0.8] µV)
(P = .02). However, the mean (SE) Cz amplitude (12.4 [1.0]
µV) did not differ from that at the other 2 locations.
FH– Group
FH+ Group
400
380
360
340
320
300
Fz
Cz
Pz
Electrode
Figure 1. P3 latency for the family history groups. Values are means, and
error bars indicate SE. At electrode Pz, P3 latency was significantly longer for
the positive family history (FH+) group than for the negative family history
(FH−) group ( P = .047).
17.5
FH– Group
FH+ Group
14.0
10.5
Pz Amplitude, µV
Comparison of Risk Groups
420
7.0
3.5
0
–3.5
–7.0
–10.5
100
200
300
400
500
600
Time, ms
Figure 2. Brain event-related potential wave form recorded at electrode Pz
for the negative family history (FH−) and positive family history (FH+)
groups. The P3 component is the third positive (upward) wave form. P3
latency was significantly prolonged ( P = .047) for the FH+ group.
This prolongation in N2 latency is illustrated in the wave
form shown in Figure 4.
Although Figure 4 suggests that the N2 amplitude
was reduced for the FH+/e4+ group, the risk groups
did not show significant variation (P = .36). The N2
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420
400
FH– Group
FH+/ε4– Group
FH+/ε4+ Group
260
380
N2 Latency, ms
P3 Latency, ms
280
FH– Group
FH+/ε4– Group
FH+/ε4+ Group
360
340
240
220
200
320
180
300
Fz
Cz
Fz
Pz
Cz
Electrode
Figure 3. P3 latency for the risk groups. FH+/e4+ indicates positive family
history with the apolipoprotein E e4 allele; FH+/e4−, positive family history
without the apolipoprotein E e4 allele; and FH−, negative family history. Values
are means, and error bars indicate SE. The P3 latency of the FH+/e4+ subgroup
was significantly longer than that of the FH− group at electrodes Pz ( P = .02)
and Cz ( P = .009). Other comparisons among the groups were not significant.
17.5
10.5
Pz Amplitude, µV
Figure 5. N2 latency for the risk groups. Values are means, and error bars
indicate SE. FH+/e4− indicates positive family history without the
apolipoprotein E e4 allele; and FH−, negative family history.The N2 latency of
the positive family history with the apolipoprotein E e4 allele (FH+/e4+)
subgroup was significantly longer than that of the FH+/e4− ( P = .02) or FH−
( P = .04). This abnormality was consistent among electrode locations.
(SE) P2 amplitude was greater at Fz (4.0 [0.5] µV) than
it was at Pz (2.5 [0.5] µV; P,.001), but the mean (SE)
amplitude did not vary significantly between these electrodes and Cz (3.3 [0.6] µV; P = .13 for Fz compared with
Cz; P = .10 for Pz compared with Cz).
FH– Group
FH+/ε4– Group
FH+/ε4+ Group
14.0
Pz
Electrode
7.0
Comparison of Risk Groups
3.5
0
Neither P2 latency nor P2 amplitude showed significant
variation as a function of risk group or electrode.
–3.5
–7.0
RELIABILITY ANALYSIS
–10.5
100
200
300
400
500
600
Time, ms
Figure 4. Brain event-related potential wave form recorded at electrode Pz
for the risk groups. FH+/e4+ indicates positive family history with the
apolipoprotein E e4 allele; FH+/e4−, positive family history without the
apolipoprotein E e4 allele; and FH−, negative family history. The P3 component
is the third positive (upward) wave form. For the FH+/e4+ subgroup, the P3
latency was significantly prolonged ( P = .02) in comparison to the FH− group.
The N2 component is the second negative (downward) component. The
FH+/e4+ subgroup also showed significant N2 latency prolongation in
comparison to the FH+/e4− ( P = .02) or FH− ( P = .04) group.
amplitude did vary significantly as a function of electrode location (F 2,74 = 11.5; P,.01). The mean (SE)
was larger at Cz (7.3 [1.0] µV) than it was at Fz (3.6
[0.8] µV) or Pz (3.2 [0.9] µV; each at P,.001).
P2 COMPONENT
Comparison of FH Groups
Neither P2 latency nor amplitude varied significantly as
a function of FH (P = .18 and P = .96, respectively). The
P2 latency did show small but significant variation as a
function of electrode location (F2,90 = 4.0; P = .02). The
mean (SE) P2 latency was shorter at Cz (178 [2.4] milliseconds) than it was at Pz (184 [4.2] milliseconds;
P = .02) or Fz (185 [2.4] milliseconds; P = .01). The P2
amplitude also showed significant variation as a function of electrode location (F2,90 = 5.1; P = .01). The mean
ARCH NEUROL / VOL 56, NOV 1999
1401
The reliability of ERP measures showing significant variation as a function of FH or risk group was examined. For
each subject, the first and second halves of the ERP trials were signal averaged separately, and the latency was
identified for each half. The Pearson r correlation was
computed between the latencies of the first and second
half of the trials and then adjusted with the SpearmanBrown formula to determine the split-half reliability. The
number of data pairs available for these analyses varied
because inclusion of only half of the data in the signal
averaging resulted in a noisy ERP wave form that made
it impossible to identify some components and peak latencies for a few subjects.
For the data in the FH group comparison, there was
a significant correlation between the first and second half
P3 latency at Pz (r47 = 0.55; P,.001). For data in the risk
group analysis, there were significant correlations between first and second half P3 latency at either Cz or Pz
(r39 = 0.87 and r39 = 0.62, respectively; each at P,.001)
and for N2 latency at Fz, Cz, or Pz (r37 = 0.84, r36 = 0.88,
and r37 = 0.73, respectively; each at P,.001). These findings support the reliability of these measures.
COMMENT
The purpose of this study was to evaluate the hypothesis that ERP components would show abnormal change
in groups of nonsymptomatic, middle-aged individuals
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at increased risk for AD. The results supported the hypothesis. The FH+ group had abnormally prolonged P3
latency compared with the FH− group. Furthermore, the
FH+/e4+ subgroup had significant P3 latency prolongation compared with the FH− group, while the FH+/e4−
subgroup did not show this prolongation.
In addition, the FH+/e4+ subgroup also showed
abnormality in N2 latency. The N2 component reflects
processing activities involved in stimulus classification33 preceding more memory-dependent processes reflected in the P3 component.34 In patients with AD, N2
latency prolongation sometimes accompanies P3 latency abnormality,24,35,36 and the N2 may be the first ERP
component to show latency abnormality in very mild AD.37
Therefore, the finding of N2 latency abnormality in the
FH+/e4+ subgroup supports the existence of ERP abnormalities in preclinical AD.
The significant P3 and N2 changes are particularly
impressive since they occurred in individuals, some of
whom will never develop AD and are considerably younger
than their affected relatives. Although the latency prolongation in the FH+/e4+ subgroup was small, the mean subject age of 58 years is 15 years younger than the age at which
their affected relatives became clinically symptomatic. Thus,
even those individuals who will eventually develop AD are
in a preclinical phase during which electrophysiological
dysfunction may be subtle. In addition, the true P3 latency abnormality associated with preclinical AD is probably diluted in the present study because not all of the FH+/
e4+ individuals will develop AD6,38 and some of the FH+/
e4− individuals will develop AD.
In this study, the FH+/e4− subgroup did not show
P3 or N2 abnormalities compared with the FH− group.
Since APOE e4 allele dose has been related to both disease risk and age of disease onset,4 the FH+/e4− subgroup may have normal P3 components because most
members will never develop AD or are currently at an
earlier preclinical stage compared with the FH+/e4+ group.
The absence of ERP abnormalities in the FH+/e4− subgroup is consistent with the absence of metabolic abnormalities observed by others.11,12
These results augment those of a previous study that
associated ERP abnormalities with an FH+ of AD. Boutros
and colleagues39 observed that nonsymptomatic individuals who had first-degree relatives with autopsyproven AD exhibited abnormally increased P3 amplitude, although the P3 latency was not abnormal. Elevation
of P3 amplitude may reflect abnormal exertion of mental effort in patients with brain disease.26 However, even
when we recalculated P3 amplitude using their peak-topeak approach, we did not observe P3 amplitude abnormality in either the FH+ group or the FH+/e4+ subgroup. Important methodological differences may explain
the variations in findings, including subject selection and
technical aspects of eliciting and measuring the P3 amplitude. Nevertheless, both our study and that of Boutros
and colleagues are consistent in observing P3 abnormalities in groups at increased risk for AD.
In summary, the results support accumulating evidence that AD has a preclinical phase. These findings augment previous research in suggesting that groups at
increased risk for AD show changes in the P3 and N2
ARCH NEUROL / VOL 56, NOV 1999
1402
components of the ERP, in addition to the metabolic and
neuropsychological changes previously described by others.8-12 The findings raise the possibility that assessment
of ERPs may contribute to early detection of AD, and future research should examine approaches for increasing
the sensitivity of these measures for detecting abnormality in individual patients.
Accepted for publication September 22, 1998.
This work was supported by the Emory University
Alzheimer’s Disease Center, Atlanta, Ga, and grant
AG-10130 from the National Institute on Aging, Bethesda, Md.
We are grateful to Suzanne S. Mirra, MD, Marla Gearing, PhD, and Douglas C. Wallace, PhD, for performing the
genotyping, and to Brett E. Sirockman, Stella C. Harper,
and Amy Cosby for assistance in data collection.
Reprints: Joanne Green, PhD, Department of Neurology, Emory University School of Medicine, Wesley Woods
Center, 1841 Clifton Rd, Atlanta, GA 30329 (e-mail:
[email protected]).
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