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. Author manuscript; available in PMC: 2006 Oct 23.
Published in final edited form as: J Int Neuropsychol Soc. 2006 Sep;12(5):707–735. doi: 10.1017/S1355617706060863

Neuroimaging Studies of Preclinical Alzheimer's Disease

Part A. Longitudinal structural MRI studies examining development of Alzheimer's disease
Authors Number and
Type of
Subjects;
Methodological
Comments		 Age (A = mean
years unless
otherwise indicated)
Gender
(G = percent male)
Education Level
(E = mean years)		 Regions Examined Results
Fox et al. (1996) 3FH+ cases
4FH+ controls
(All 7 from a
familial AD
pedigree) 38
normal controls

3-year study		 FH+
A = 45
G = 86% male
E = NR

Normal controls
A = 48
G = 50% male
E = NR		 Hippocampal formation volume In the 3 subjects who developed AD, significant,
asymmetric hippocampal atrophy was detectable
before the development of symptoms
The 4 FH+ subjects who remained well did
not differ from NCs on hippocampal volume
Fox et al. (2001) 4 FH+ cases
(All 4 from a
familial AD
pedigree) 20
normal controls

8-year study		 FH+
A = median 43
G = NR
E = NR

Normal controls
A = median 51
G = NR
E = NR		 Whole brain FH+ subjects had higher annual rates of
global volume loss, particularly in the medial
temporal lobe, inferolateral temporal lobe,
parietal lobe, and posterior cingulate
Kaye et al. (1997) 12 cases
18 controls

Mean length
of follow-up
was 3.5 years		 Cases
A = 90
G = 42% male
E = 15

Controls
A = 87
G = 44% male
E = 14		 Supratentorial intracranial cavity
volume;
Temporal lobe tissue volume;
Parahippocampal gyrus volume;
Hippocampal volume		 Subjects who developed AD had smaller hippo-
campal and temporal lobe tissue volumes at
baseline and showed greater temporal lobe
atrophy over time.
Hippocampal and temporal lobe tissue volumes
at baseline and rate of temporal lobe volume loss
were significant predictors of group status.
Part B. Longitudinal structural MRI study comparing nondemented ε4+ and ε4− subjects
Cohen et al. (2001) 16 ε4+
9 ε4−

2-year study

Groups also compared
on neuropsychological
performance (see find-
ings reported above)		 ε4+
A = 55
G = 0% male
E = NR

ε4−
A = 61
G = 0% male
E = NR		 Hippocampal volume Compared with ε4− subjects, ε4+ subjects
demonstrated greater hippocampal volume
loss
Part C. Longitudinal functional imaging study comparing nondemand ε4+ ε4− subjects
Authors Number and
Type of
Subjects;
Methodological
Comments		 Age (A = mean
years unless
otherwise indicated)
Gender (G = percent male)
Education Level
(E = mean years)		 Tasks Used Results
Reiman et al. (2001) 10 ε4+
15 ε4−

All subjects were FH+
2-year study

Groups also compared
on neuropsychological
performance (see find-
ings reported above)		 ε4+
A = 56
G = 30% male
E = 15
ε4−
A = 57
G = 33% male
E = 16		 Resting PET examining regional
rates of glucose metabolism		 ε4+ subjects had significantly greater
glucose metabolism declines over 2 years
in temporal, posterior cingulate, prefrontal
cortex, basal forebrain, parahippocampal
gyrus, and thalamus
Part D. Cross-sectional structural MRI studies comparing nondemented ε4+ and ε4− subjects
Authors Number and
Type of
Subjects;
Methodological
Comments		 Age (A = mean
years unless
otherwise indicated)
Gender
(G = percent male)
Education Level
(E = mean years)		 Regions Examined Results
den Heijer et al. (2002) 117 ε4+
259 ε3/ε3
52 ε2+		 A = 72
G = 48% male
E = NR		 Hippocampal and amygdalar
volume		 ε4+ subjects had smaller hippocampal and
amygdalar volumes bilaterally
No significant differences between ε2+ subjects
and ε3/ε3 subjects
Jack et al. (1998) 30 ε4+
95 ε4−		 ε4+
A = 80
E = 13

ε4−
A = 79
E = 13

G = 26% male		 Hippocampal volume Trend toward smaller hippocampi in the
ε4+ group
Jernigan et al. (2001) 21 ε4+
22 ε4−		 A = NR
G = NR
E = NR		 Whole brain ε4+ subjects had lower subcortical gray matter volumes
than did ε4− subjects; the difference was due to lower
lenticular nucleus volumes in the ε4+ subjects
Plassman et al. (1997) 3 ε4+ twin pairs
7ε4− twin pairs		 ε4+
A = 65
G = 33% male
E = 15

ε4−
A = 62
G = 29% male
E = 13		 Hippocampal volume Controlling for education, the ε4+ group had
smaller hippocampi than did the ε4− group;
there were no group differences in hippocampal
volume asymmetry.
Reiman et al. (1998) 11 ε4/ε4
22 ε4−

All subjects were FH+		 ε4+
A = 55
G = 27% male
E = 17

ε4−
A = 56
G = 27% male
E = 16		 Hippocampal volume ε4 homozygotes had 8% smaller left and right
hippocampal volumes, but the difference was not
statistically significant
Schmidt et al. (1996) 39 ε4+
175 ε4−

Groups also compared
on neuropsychological
performance (see find-
ings reported above)		 ε4+
A = 59
G = about 50% male
E = 11

ε4−
A = 61
G = about 50% male
E = 12		 Whole brain No differences in presence of infarcts, white
matter hyperintensities, sulcal widening,
ventricular enlargement, or hippocampal/
parahippocampal volumes
Tohgi et al. (1997) 14 ε4+
40 ε4−

Groups also compared
on neuropsychological
performance (see find-
ings reported above)		 A = 59
G = 52% male
E = 12		 Hippocampal volume Compared to ε4− subjects, ε4+ subjects had
smaller right hippocampal volumes
Part E. Cross-sectional functional imaging studies comparing at-risk subjects (ε4+ or FH+) to non-at-risk subjects (ε4− or FH−)
Authors Number and
Type of
Subjects;
Methodological
Comments		 Age (A = mean
years unless
otherwise indicated)
Gender
(G = percent male)
Education Level
(E = mean years)		 Tasks Used Results
Bookheimer et al. (2000) 16 ε4+
14 ε4−

fMRI		 ε4+
A = 63
G = 44% male
E = 15

ε4−
A = 62
G = 50% male
E = 15		 Word pair learning and recall task
compared with resting condition		 ε4+ subjects exhibited greater magnitude and
extent of activation in left hippocampal, parietal,
and prefrontal regions than did ε4− subjects
Burggren et al. (2002) 13 ε4+
12 ε4−

fMRI		 ε4+
A = 65
G = 38% male
E = 16

ε4−
A = 66
G = 42% male
E = 16		 Digit span forward task (1–8 digits) No significant group differences in activation,
even as task difficulty increased
Kennedy et al. (1995) 24 FH+ subjects
from a familial
AD pedigree
16 age-matched
control subjects

PET		 FH+
A = 45
G = NR
E = NR

Controls:
A = 50
G = NR
E = NR		 Resting PET examining global and
regional rates of glucose metabolism		 Compared to controls, the at-risk subjects had
lower global and temporoparietal glucose
metabolism
Reiman et al. (1996) 11 ε4/ε4
22 ε4−

All subjects
were FH+

PET		 ε4+
A = 55
G = 27% male
E = 17

ε4−
A = 56
G = 27% male
E = 16		 Resting PET examining regional rates
of glucose metabolism		 ε4 homozygotes had significantly lower glucose
metabolism in posterior cingulate and bilateral
parietal, temporal, and prefrontal regions
Reiman et al. (2004) 12 ε4+ (all
heterozygotes)
15 ε4−

PET		 ε4+
A = 31
G = 25% male
E = 16

ε4−
A = 31
G = 20% male
E = 16		 Resting PET examining regional rates
of glucose metabolism		 ε4+ subjects had significantly lower glucose
metabolism bilaterally in posterior cingulate,
parietal, temporal, and prefrontal regions
Smith et al. (1999) 14 ε4+, FH+
12 ε4−, FH−

fMRI		 ε4+, FH+
A = 52
G = 0% male
E = 15
ε4−, FH−
A = 53
G = 0% male
E = 15		 Visual naming
Letter fluency		 ε4+, FH+ subjects had lower activation in the
bilateral mid- and posterior inferotemporal
regions during both tasks

Abbreviations Used:

AD = Alzheimer's disease

ε4 = APOE ε4 allele

ε3 = APOE ε3 allele

ε2 = APOE ε2 allele

fMRI = Functional magnetic resonance imaging

FH = Family history of AD

MMSE = Mini-Mental State Examination

MRI = Magnetic resonance imaging

NC = Normal control

NR = Not reported

PET = Positron emission tomography