Clinical and Biomarker Changes in Dominantly Inherited Alzheimer’s Disease

TLDR: In this paper, a longitudinal study of 128 patients with Alzheimer's disease was conducted, where the authors used the participant's age at baseline assessment and the parent's age to calculate the estimated years from expected symptom onset (age of the participant minus parent's ages at symptom onset).

Abstract: A B S T R AC T BACKGROUND The order and magnitude of pathologic processes in Alzheimer’s disease are not well understood, partly because the disease develops over many years. Autosomal dominant Alzheimer’s disease has a predictable age at onset and provides an opportunity to determine the sequence and magnitude of pathologic changes that culminate in symptomatic disease. METHODS In this prospective, longitudinal study, we analyzed data from 128 participants who underwent baseline clinical and cognitive assessments, brain imaging, and cerebrospinal fluid (CSF) and blood tests. We used the participant’s age at baseline assessment and the parent’s age at the onset of symptoms of Alzheimer’s disease to calculate the estimated years from expected symptom onset (age of the participant minus parent’s age at symptom onset). We conducted cross-sectional analyses of baseline data in relation to estimated years from expected symptom onset in order to determine the relative order and magnitude of pathophysiological changes. RESULTS Concentrations of amyloid-beta (Aβ)42 in the CSF appeared to decline 25 years before expected symptom onset. Aβ deposition, as measured by positron-emission tomography with the use of Pittsburgh compound B, was detected 15 years before expected symptom onset. Increased concentrations of tau protein in the CSF and an increase in brain atrophy were detected 15 years before expected symptom onset. Cerebral hypometabolism and impaired episodic memory were observed 10 years before expected symptom onset. Global cognitive impairment, as measured by the Mini–Mental State Examination and the Clinical Dementia Rating scale, was detected 5 years before expected symptom onset, and patients met diagnostic criteria for dementia at an average of 3 years after expected symptom onset. CONCLUSIONS We found that autosomal dominant Alzheimer’s disease was associated with a series of pathophysiological changes over decades in CSF biochemical markers of Alzheimer’s disease, brain amyloid deposition, and brain metabolism as well as progressive cognitive impairment. Our results require confirmation with the use of longitudinal data and may not apply to patients with sporadic Alzheimer’s disease. (Funded by the National Institute on Aging and others; DIAN ClinicalTrials.gov number, NCT00869817.)

Figures

Table 2. Clinical, Cognitive, Imaging, and Biochemical Estimates in Mutation Carriers and Noncarriers.*

Table 2. Clinical, Cognitive, Imaging, and Biochemical Estimates in Mutation Carriers and Noncarriers.*

Table 1. Characteristics of the Study Participants.*

Full text

Washington University School of Medicine Washington University School of Medicine
Digital Commons@Becker Digital Commons@Becker
Open Access Publications
2012
Clinical and biomarker changes in dominantly inherited Clinical and biomarker changes in dominantly inherited
Alzheimer's disease Alzheimer's disease
Randall J. Bateman
Washington University School of Medicine in St. Louis
Anne M. Fagan
Washington University School of Medicine in St. Louis
David M. Holtzman
Washington University School of Medicine in St. Louis
Anna Santacruz
Washington University School of Medicine in St. Louis
Virginia Buckles
Washington University School of Medicine in St. Louis
See next page for additional authors
Follow this and additional works at: https://digitalcommons.wustl.edu/open_access_pubs
Recommended Citation Recommended Citation
Bateman, Randall J.; Fagan, Anne M.; Holtzman, David M.; Santacruz, Anna; Buckles, Virginia; Oliver,
Angela; Moulder, Krista; Morris, John C.; and et al, ,"Clinical and biomarker changes in dominantly inherited
Alzheimer's disease." The New England Journal of Medicine. 367,9. 795-804. (2012).
https://digitalcommons.wustl.edu/open_access_pubs/2763
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Authors Authors
Randall J. Bateman, Anne M. Fagan, David M. Holtzman, Anna Santacruz, Virginia Buckles, Angela Oliver,
Krista Moulder, John C. Morris, and et al
This open access publication is available at Digital Commons@Becker: https://digitalcommons.wustl.edu/
open_access_pubs/2763

n engl j med 367 ;9 nejm.org august 30, 2012
795
The new england
journal
of medicine
established in 1812
august 30, 2012
vol. 367 no. 9
Clinical and Biomarker Changes in Dominantly Inherited
Alzheimer’s Disease
Randall J. Bateman, M.D., Chengjie Xiong, Ph.D., Tammie L.S. Benzinger, M.D., Ph.D., Anne M. Fagan, Ph.D.,
Alison Goate, Ph.D., Nick C. Fox, M.D., Daniel S. Marcus, Ph.D., Nigel J. Cairns, Ph.D., Xianyun Xie, M.S.,
Tyler M. Blazey, B.S., David M. Holtzman, M.D., Anna Santacruz, B.S., Virginia Buckles, Ph.D., Angela Oliver, R.N.,
Krista Moulder, Ph.D., Paul S. Aisen, M.D., Bernardino Ghetti, M.D., William E. Klunk, M.D., Eric McDade, M.D.,
Ralph N. Martins, Ph.D., Colin L. Masters, M.D., Richard Mayeux, M.D., John M. Ringman, M.D.,
Martin N. Rossor, M.D., Peter R. Schofield, Ph.D., D.Sc., Reisa A. Sperling, M.D., Stephen Salloway, M.D.,
and John C. Morris, M.D., for the Dominantly Inherited Alzheimer Network
A B S TR AC T
The authors’ affiliations are listed in the
Appendix. Address reprint requests to
Dr. Bateman at the Washington Univer-
sity School of Medicine, Department of
Neurology, 660 S. Euclid Ave., Box 8111,
St. Louis, MO 63110, or at batemanr@
wustl.edu.
This article was published on July 11, 2012,
and updated on July 23, 2012, at NEJM.org.
N Engl J Med 2012;367:795-804.
DOI: 10.1056/NEJMoa1202753
Copyright © 2012 Massachusetts Medical Society.
BACKGROUND
The order and magnitude of pathologic processes in Alzheimer’s disease are not well
understood, partly because the disease develops over many years. Autosomal domi-
nant Alzheimer’s disease has a predictable age at onset and provides an opportunity
to determine the sequence and magnitude of pathologic changes that culminate in
symptomatic disease.
METHODS
In this prospective, longitudinal study, we analyzed data from 128 participants who
underwent baseline clinical and cognitive assessments, brain imaging, and cerebro-
spinal fluid (CSF) and blood tests. We used the participant’s age at baseline assess-
ment and the parent’s age at the onset of symptoms of Alzheimer’s disease to calcu-
late the estimated years from expected symptom onset (age of the participant minus
parent’s age at symptom onset). We conducted cross-sectional analyses of baseline
data in relation to estimated years from expected symptom onset in order to deter-
mine the relative order and magnitude of pathophysiological changes.
RESULTS
Concentrations of amyloid-beta (Aβ)
42
in the CSF appeared to decline 25 years before
expected symptom onset. Aβ deposition, as measured by positron-emission tomog-
raphy with the use of Pittsburgh compound B, was detected 15 years before expected
symptom onset. Increased concentrations of tau protein in the CSF and an increase
in brain atrophy were detected 15 years before expected symptom onset. Cerebral
hypometabolism and impaired episodic memory were observed 10 years before ex-
pected symptom onset. Global cognitive impairment, as measured by the Mini–Mental
State Examination and the Clinical Dementia Rating scale, was detected 5 years be-
fore expected symptom onset, and patients met diagnostic criteria for dementia at
an average of 3 years after expected symptom onset.
CONCLUSIONS
We found that autosomal dominant Alzheimer’s disease was associated with a se-
ries of pathophysiological changes over decades in CSF biochemical markers of
Alzheimer’s disease, brain amyloid deposition, and brain metabolism as well as
progressive cognitive impairment. Our results require confirmation with the use of
longitudinal data and may not apply to patients with sporadic Alzheimer’s disease.
(Funded by the National Institute on Aging and others; DIAN ClinicalTrials.gov
number, NCT00869817.)
The New England Journal of Medicine
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T h e
n e w e n g l a n d j o u r na l
o f
m e d i c i n e
n engl j med 367 ;9 nejm.org august 30, 2012
796
A
lzheimer’s disease is the most com-
mon cause of dementia and is currently
estimated to affect more than 5 million
people in the United States, with an expected in-
crease to 13 million by the year 2050. The typical
clinical presentation is progressive loss of mem-
ory and cognitive function, ultimately leading to
a loss of independence and causing a heavy per-
sonal toll on the patient and the family. The costs
of care of patients with Alzheimer’s disease in
2010 were estimated at more than $172 billion in
the United States, an annual cost that is predict-
ed to increase to a trillion dollars by 2050 unless
disease-modifying treatments are developed.
1
Alzheimer’s disease has been hypothesized to
begin decades before the first symptoms mani-
fest.
2-4
Thus, longitudinal studies of Alzheimer’s
disease biomarkers take many years to show the
full pathologic cascade of events that lead to de-
mentia. Furthermore, trials of disease-modifying
treatment require large numbers of patients over
extended periods owing to the slow progression of
cognitive symptoms.
5,6
Therefore, well-validated
biomarkers of Alzheimer’s disease processes are
needed to improve the design of clinical trials,
develop more effective therapeutics, and offer the
opportunity for prevention trials.
7
On the basis of the amyloid hypothesis,
8
amyloid-beta (Aβ) is currently the most common
disease-modifying target. Recent research indi-
cates that the targeting of amyloidosis in familial
amyloid polyneuropathy improves clinical out-
comes.
9-11
However, the order and timing of amy-
loidosis and other Alz hei mer’s disease processes
that lead to clinical dementia are not well under-
stood. We hypothesized that autosomal domi-
nant Alz hei mer’s disease and the more common
late-onset Alz hei mer’s disease
12
have similar
pathophysiological features. Although autosomal
dominant Alz hei mer’s disease accounts for a
relatively small proportion (approximately 1%) of
cases of Alz hei mer’s disease, increasing evidence
13
suggests that it overlaps with sporadic Alz hei mer’s
disease. Mutations in one of three genes (APP,
PSEN1, and PSEN2) have been identified that cause
alterations in Aβ processing and lead to Alz hei-
mer’s disease with complete penetrance. The age at
clinical onset of autosomal dominant Alz hei mer’s
disease is similar between generations
14
and is
affected mostly by the mutation type and back-
ground family genetics.
15
We compared a wide
range of pathophysiological markers between mu-
tation carriers and noncarriers as a function of
the parental age at onset in order to evaluate the
cascade of events that lead to dementia. Clinical,
cognitive, imaging, and biochemical measures
were compared between mutation carriers and
noncarriers in the first large international cohort
of families with autosomal dominant Alz hei mer’s
disease.
M e t hod s
STUDY DESIGN
Participants at risk for carrying a mutation for
autosomal dominant Alz hei mer’s disease were
enrolled in the Dominantly Inherited Alzheimer
Network (DIAN) study at 1 of 10 sites. Each par-
ticipant was a member of a pedigree with a known
mutation for autosomal dominant Alz hei mer’s
disease. DIAN participants are assessed at base-
line and in subsequent years with comprehensive
clinical, cognitive, imaging, and biochemical as-
sessments. Data from all 128 participants who
were enrolled and who had completed baseline
assessments between January 26, 2009, and the
first data-cutoff point (April 28, 2011) went through
quality-control checks and were included in the
analysis (see the Methods section in the Supple-
mentary Appendix, available with the full text of
this article at NEJM.org). All participants provided
written informed consent or assent with proxy con-
sent. All study procedures were approved by the
Washington University Human Research Protec-
tion Office and the local institutional review boards
of the participating sites. All authors vouch for the
accuracy of the data and the fidelity of the study to
the protocol (available at NEJM.org).
CLINICAL ASSESSMENTS
Participants underwent clinical assessments of
cognitive change with the use of the Clinical De-
mentia Rating (CDR)
16
scale, with CDR 0 indicat-
ing normal cognitive function, CDR 0.5 very mild
impairment, and CDR 1 mild impairment. The
DIAN assessments ascertained family history of
Alz hei mer’s disease and medical history, and par-
ticipants underwent a physical examination, in-
cluding a neurologic evaluation (see the study
protocol). Clinicians who performed the assess-
ments were not aware of the mutation status of
participants. The parental age at onset was deter-
mined by a semistructured interview in which
family members were asked about the age of first
progressive cognitive decline (Fig. S1 in the Sup-
plementary Appendix). Clinical feedback was
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Domina n tly Inher ited Al zheimer’s Dise a se
n engl j med 367 ;9 nejm.org august 30, 2012
797
provided to participants if medically indicated.
No other research data, including genetic status,
were provided to research participants as part of
the study.
NEUROPSYCHOLOGICAL TESTING
Participants underwent a comprehensive battery
of neuropsychological tests, but results of only
two tests are reported here because of space lim-
itations; both tests are widely used in research on
Alz hei mer’s disease. The Mini–Mental State Ex-
amination (MMSE)
17
is a measure of general cog-
nitive function, with scores ranging from 0 (se-
vere impairment) to 30 (no impairment). Story A
from the Logical Memory subtest of the Wechsler
Memory Scale–Revised
18
is a measure of episodic
memory. Participants recall as many details as they
can from a short story containing 25 bits of infor-
mation after it is read aloud by the examiner and
again after a 30-minute delay, with scores rang-
ing from 0 (no recall) to 25 (complete recall).
BRAIN IMAGING
Volumetric magnetic resonance imaging (MRI)
was performed with the use of qualified 3-tesla
scanners at each site; initial and ongoing quality
control and matching between site scanners were
performed according to the Alz hei mer’s Disease
Neuroimaging Initiative (ADNI) protocol.
19
All
images were reviewed for image quality and com-
pliance with the acquisition protocol by the ADNI
imaging core laboratories. The T
1
-weighted MRI
scans from DIAN participants were processed
through FreeSurfer (for details, see the Supplemen-
tary Appendix). Images obtained through positron-
emission tomography (PET) with the use of fluo-
rodeoxyglucose (FDG) and Pittsburgh compound B
(PIB) (FDG-PET and PIB-PET, respectively) were
then coregistered with individual MRI images
for region-of-interest determination. For each
FreeSurfer region of interest, the standardized
uptake value ratio (SUVR) was calculated with
the use of a hand-drawn reference region en-
compassing the brain stem. An increased PIB
SUVR indicates increased binding to fibrillar
amyloid, and a decreased FDG SUVR indicates
decreased metabolism.
BIOCHEMICAL ANALYSIS
Cerebrospinal fluid (CSF) and blood were collect-
ed in the morning under fasting conditions by
means of lumbar puncture and venipuncture, re-
spectively. Samples were shipped on dry ice to
the DIAN biomarker core laboratory. Concentra-
tions in the CSF of Aβ
1-42
, total tau, and tau
phosphorylated at threonine 181 were measured
by immunoassay (INNOTEST β-Amyloid
1-42
and
INNO-BIA AlzBio3, Innogenetics), as were levels
of plasma Aβ species (Aβ
1-40
, Aβ
1-42
, Aβ
x-40
, and
Aβ
x-42
) (INNO-BIA Plasma Aβ Forms Multiplex
Assay, Innogenetics). All values had to meet
quality-control standards, including a coefficient
of variation of 25% or less, kit “controls” within
the expected range as defined by the manufac-
turer, and measurement consistency between
plates of a common sample that was included in
each run.
STATISTICAL ANALYSIS
The estimated years from expected symptom on-
set were calculated as the age of the participant
at the time of the study assessment minus the
age of the parent at symptom onset. For example,
if the participant’s age was 35 years, and the par-
ent’s age at onset was 45 years, then the esti-
mated years from expected symptom onset would
be −10. The parental age at the onset of clinical
symptoms was determined by a semistructured
interview with the use of all available historical
data (Fig. S1 in the Supplementary Appendix).
Clinical, cognitive, imaging, and biochemical
measures were compared as a function of esti-
mated years from expected symptom onset be-
tween mutation carriers and noncarriers. Statis-
tical analyses (see the Supplementary Appendix
for details) were conducted with the use of the
PROC MIXED procedure in SAS software, version
9.3 (SAS Institute). With each marker treated as a
Table 1. Characteristics of the Study Participants.*
Characteristic
Carriers
(N = 88)
Noncarriers
(N = 40) P Value
Age — yr 39.1±10.3 39.5±8.9 0.92
Male sex — no. (%) 36 (41) 17 (42) 0.85
Education level — yr 13.9±2.5 15.0±2.5 0.04
Cognitive status — no. (%)†
Symptomatic 43 (49) 1 (2) 0.29
Asymptomatic 45 (51) 39 (98)
Positive for apolipoprotein E
ε4 allele — no. (%)
22 (25) 9 (22) 0.69
* Plus–minus values are means ±SD.
† Participants were defined as asymptomatic if they had Cognitive Dementia
Rating scores of 0 (no cognitive decline) and as symptomatic if they had
scores greater than 0.
The New England Journal of Medicine
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Frequently asked questions

Q1. What have the authors contributed in "Clinical and biomarker changes in dominantly inherited alzheimer's disease" ?

In this paper, the authors found that the development of Alzheimer 's disease was associated with a series of pathophysiological changes over decades in CSF biochemical markers of brain amyloid deposition, and brain metabolism as well as progressive cognitive impairment. 

Q2. What have the authors stated for future works in "Clinical and biomarker changes in dominantly inherited alzheimer's disease" ?

Treatment and prevention trials can incorporate these pathophysiological changes to gauge the likelihood of future clinical success. PIB in a nondemented population: potential antecedent marker of Alzheimer disease. 

Q3. What is the typical clinical presentation of Alzheimer’s disease?

The typical clinical presentation is progressive loss of memory and cognitive function, ultimately leading to a loss of independence and causing a heavy personal toll on the patient and the family. 

Q4. What is the significance of the study?

The authors found that autosomal dominant Alzheimer’s disease was associated with a series of pathophysiological changes over decades in CSF biochemical markers of Alzheimer’s disease, brain amyloid deposition, and brain metabolism as well as progressive cognitive impairment. 

Q5. How long before the onset of Alzheimer’s disease?

Increased concentrations of tau protein in the CSF and an increase in brain atrophy were detected 15 years before expected symptom onset. 

Q6. How long before the onset of dementia?

Global cognitive impairment, as measured by the Mini–Mental State Examination and the Clinical Dementia Rating scale, was detected 5 years before expected symptom onset, and patients met diagnostic criteria for dementia at an average of 3 years after expected symptom onset. 

Q7. what are the genes that cause the alterations in A processing?

Mutations in one of three genes (APP, PSEN1, and PSEN2) have been identified that cause alterations in Aβ processing and lead to Alz heimer’s disease with complete penetrance. 

Q8. What is the common cause of dementia?

trials of disease-modifying treatment require large numbers of patients over extended periods owing to the slow progression of cognitive symptoms. 

Q9. What is the role of the adolescent in the study?

Autosomal dominant Alzheimer’s disease has a predictable age at onset and provides an opportunity to determine the sequence and magnitude of pathologic changes that culminate in symptomatic disease. 

Q10. How much is Alzheimer’s cost in the United States?

The costs of care of patients with Alzheimer’s disease in 2010 were estimated at more than $172 billion in the United States, an annual cost that is predicted to increase to a trillion dollars by 2050 unless disease-modifying treatments are developed. 

Q11. What are the benefits of using biomarkers of Alzheimer’s disease?

well-validated biomarkers of Alzheimer’s disease processes are needed to improve the design of clinical trials, develop more effective therapeutics, and offer the opportunity for prevention trials. 

Q12. What is the common form of dementia?

Alz hei mer’s disease accounts for a relatively small proportion (approximately 1%) of cases of Alz hei mer’s disease, increasing evidence13 suggests that it overlaps with sporadic 

Q13. How many people are affected by lzheimer’s disease?

T h e n e w e ngl a nd j o u r na l o f m e dic i n en engl j med 367;9 nejm.org august 30, 2012796A lzheimer’s disease is the most com-mon cause of dementia and is currently estimated to affect more than 5 million people in the United States, with an expected increase to 13 million by the year 2050. 

Q14. How long did the study take to complete?

In this prospective, longitudinal study, the authors analyzed data from 128 participants who underwent baseline clinical and cognitive assessments, brain imaging, and cerebrospinal fluid (CSF) and blood tests. 

Q15. what is the adolescent age of the adolescent?

The authors compared a wide range of pathophysiological markers between mutation carriers and noncarriers as a function ofthe parental age at onset in order to evaluate the cascade of events that lead to dementia. 

Q16. Why is the disease not well understood?

The order and magnitude of pathologic processes in Alzheimer’s disease are not well understood, partly because the disease develops over many years.