Preclinical effects of APOE ε4 on cerebrospinal fluid Aβ42 concentrations
Lautner et al. Alzheimer's Research & Therapy
Preclinical effects of APOE ε4 on cerebrospinal fluid Aβ42 concentrations
Ronald Lautner 0 1 3
Philip S. Insel 2 7 8
Tobias Skillbäck 0 1 3
Bob Olsson 0 1 3
Mikael Landén 1 6
Giovanni B. Frisoni 5
Sanna-Kaisa Herukka 10
Harald Hampel 9
Anders Wallin 1
Lennart Minthon 2 4
Oskar Hansson 2 4
Kaj Blennow 0 1 3
Niklas Mattsson 2 11
Henrik Zetterberg 0 1 3 12
0 Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital , Mölndal , Sweden
1 Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, Sahlgrenska Academy at the University of Gothenburg , Gothenburg , Sweden
2 Clinical Memory Research Unit, Department of Clinical Sciences Malmö, Lund University , Lund , Sweden
3 Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital , Mölndal , Sweden
4 Memory Clinic, Skåne University Hospital , Malmö , Sweden
5 Istituto di Ricovero e Cura a Carattere Scientifico Centro San Giovanni di Dio Fatebenefratelli , Brescia , Italy
6 Department of Medical Epidemiology and Biostatistics, Karolinska Institutet , Stockholm , Sweden
7 Department of Radiology and Biomedical Imaging, University of California , San Francisco, CA , USA
8 Department of Veterans Affairs Medical Center, Center for Imaging of Neurodegenerative Diseases , San Francisco, CA , USA
9 AXA Research Fund and UPMC Chair , Sorbonne Universités , Université Pierre et Marie Curie (UPMC) Paris 06, Inserm, CNRS, Institut du cerveau et de la moelle (ICM), Département de Neurologie, Institut de la Mémoire et de la Maladie d'Alzheimer (IM2A) , Hôpital Pitié-Salpêtrière, Boulevard de l'hôpital, F-75013 Paris , France
10 Department of Neurology, University of Eastern Finland, Kuopio University Hospital , Kuopio , Finland
11 Department of Neurology, Skåne University Hospital , Lund , Sweden
12 Department of Molecular Neuroscience, UCL Institute of Neurology , Queen Square, London WC1N 3BG , UK
Background: From earlier studies it is known that the APOE ε2/ε3/ε4 polymorphism modulates the concentrations of cerebrospinal fluid (CSF) beta-amyloid1-42 (Aβ42) in patients with cognitive decline due to Alzheimer's disease (AD), as well as in cognitively healthy controls. Here, in a large cohort consisting solely of cognitively healthy individuals, we aimed to evaluate how the effect of APOE on CSF Aβ42 varies by age, to understand the association between APOE and the onset of preclinical AD. Methods: APOE genotype and CSF Aβ42 concentration were determined in a cohort comprising 716 cognitively healthy individuals aged 17-99 from nine different clinical research centers. Results: CSF concentrations of Aβ42 were lower in APOE ε4 carriers than in noncarriers in a gene dose-dependent manner. The effect of APOE ε4 on CSF Aβ42 was age dependent. The age at which CSF Aβ42 concentrations started to decrease was estimated at 50 years in APOE ε4-negative individuals and 43 years in heterozygous APOE ε4 carriers. Homozygous APOE ε4 carriers showed a steady decline in CSF Aβ42 concentrations with increasing age throughout the examined age span. Conclusions: People possessing the APOE ε4 allele start to show a decrease in CSF Aβ42 concentration almost a decade before APOE ε4 noncarriers already in early middle age. Homozygous APOE ε4 carriers might deposit Aβ42 throughout the examined age span. These results suggest that there is an APOE ε4-dependent period of early alterations in amyloid homeostasis, when amyloid slowly accumulates, that several years later, together with other downstream pathological events such as tau pathology, translates into cognitive decline.
Alzheimer's disease; APOE; Cerebrospinal fluid; Beta amyloid
Alzheimer’s disease (AD) is a neurodegenerative disease
characterized by the accumulation of extracellular
betaamyloid (Aβ) plaques and intracellular tau tangles [
pathology is multifactorial with both genetic and
environmental risk factors, with the most prominent susceptibility
gene being apolipoprotein E (APOE) [
]. The APOE gene
is polymorphic, with three different alleles, of which the
ε4 allele is associated with an increased risk, as well as a
lower age at onset, of AD. Heterozygous APOE ε4 carriers
have an approximately 3-fold increase of risk compared
with individuals lacking the ε4 allele, whereas the increase
of risk is up to 12-fold in homozygous APOE ε4 carriers
]. The underlying pathophysiological mechanisms for
this strong genetic association are still unknown, but may
involve direct or indirect effects on Aβ aggregation or
Measurement of the 42 amino acid isoform of Aβ (Aβ42)
in the cerebrospinal fluid (CSF) is used alongside CSF total
tau (T-tau) and CSF phosphorylated tau (P-tau) as a
diagnostic tool for AD [
]. Decreased concentrations of CSF
Aβ42 are indicative of cerebral amyloid pathology during
the entire course of the disease, from preclinical
asymptomatic disease to mild cognitive impairment (MCI) and
dementia, and may even indicate disturbed amyloid
metabolism before amyloid deposition may be visualized by
amyloid PET imaging [
]. An association between the APOE
genotype and CSF concentrations of Aβ42 has been
described previously among patients with AD and MCI, as
well as in healthy controls, with the APOE ε4 allele being
associated with lower CSF Aβ42 concentrations in a gene
dose-dependent manner [
]. However, because most
studies have only analyzed older people, it is not clear
whether this effect is present in all age groups irrespective
of preexisting amyloid pathology, especially since an earlier
study showed the effect to be absent in a small cohort of
younger cognitively healthy individuals .
Consequently, the question that arises is at what age the
potential effects of APOE ε4 on CSF Aβ42 can be
detected. To tackle this question, we analyzed CSF Aβ42 as
well as the APOE ε4 genotype in a large cohort consisting
of 716 cognitively healthy individuals from 17 to 99 years
of age. Specifically, we tested how CSF Aβ42
concentrations differ by age in the different APOE ε4 carrier groups.
The total cohort consisted of 716 cognitively healthy
individuals from nine different centers in Sweden, Finland,
Germany, and Italy with age ranging from 17 to 99 years.
All centers were specialized memory clinics, except one,
which is a psychiatry clinic specialized in affective
disorders. All subjects underwent neurological examination
as well as cognitive testing to exclude cognitive
impairment. One of the subcohorts contained 138 patients
with bipolar disorder, whereas the rest of the
participants (n = 578) were healthy volunteers. Most study
participants (except the bipolar disorder patients, who were
recruited among patients at the specialized affective
disorders clinic) were recruited by advertisement or among
relatives or friends of patients who were evaluated on
suspicion of cognitive dysfunction.
CSF samples were obtained by lumbar puncture in the
L3/4 or L4/5 interspace, collected in polypropylene tubes,
centrifuged, and stored frozen at –80 °C until analysis
according to standard operating procedures [
]. The time
frame during which samples were collected in each center
in relation to the time of sample analysis was less than
5 years in all cohorts. Long-term stability of CSF Aβ42 at
–80 °C has been evaluated in several studies [
of which show that CSF Aβ42 is stable at –80 °C. The
majority of the biomarker analyses were performed at the
Clinical Neurochemistry Laboratory at the Sahlgrenska
University Hospital, Gothenburg, Sweden, but samples
from Kuopio, Finland and Munich, Germany as well as
from Italy were analyzed in local laboratories.
CSF Aβ42 concentrations were measured using a sandwich
enzyme-linked immunosorbent assay (INNOTEST
]; Fujirebio, Ghent, Belgium) designed to
detect the 1st and 42nd amino acids in the Aβ protein as
described previously . A subset of the samples was
analyzed using a multiplex semiautomated assay platform
(xMAP Luminex AlzBio3; Fujirebio) as described previously
]. All analyses were performed by experienced laboratory
technicians who were blinded to all clinical information.
To adjust for variation in biomarker concentrations
between the different laboratories, data were normalized by
defining the largest center cohort as the reference group
and then calculating factors between the APOE ε4-negative
individuals from each participating center and the APOE
ε4-negative individuals in the reference group. These
factors were then applied to all data, hence relating biomarker
concentrations in all of the different center cohorts to those
in the reference group. There were no significant
correlations between age and CSF Aβ42 concentrations in all but
one of the subcohorts (in which the effect was minor, r2 = –
0.036, P = 0.037), which points toward a lack of a primary
relation between these two parameters. Note that since the
center cohort that was defined as the reference group used
the xMAP Luminex AlzBio3 assay, the normalized
concentrations of Aβ42 in this material were lower than the
corresponding concentrations when using the INNOTEST
Genotyping for APOE (gene map locus 19q13.2) was
performed using allelic discrimination technology
(TaqMan; Applied Biosystems) or equivalent techniques.
Genotypes were obtained for the two single nucleotide
polymorphisms that define the ε2, ε3, and ε4 alleles.
Comparisons of biomarker concentrations between
APOE ε4 carrier groups were performed by one-way
analysis of variance (ANOVA) for several independent
samples. Comparisons of genotype frequencies between
patients with bipolar disorder and healthy volunteers
were performed using Pearson’s chi-squared test.
Statistical significance was defined at P < 0.05 and all
statistical calculations were performed using SPSS version 19
(SPSS Inc., Chicago, IL, USA).
The trajectory of CSF Aβ42 concentrations with
respect to age in different APOE ε4 carrier groups was
modeled using restricted cubic splines and ordinary least
squares regression. The Akaike Information Criterion
selected the optimal model to be estimated using three
spline knots. Regression models included gender and the
interaction between the two-parameter spline
representation of age and APOE ε4 group and the main effects
for age and APOE ε4 group. Age at the initial decline of
CSF Aβ42 concentrations was taken to be the maximum
Aβ42 concentration prior to a monotone descent with
increasing age. Confidence intervals for age at initial
decline were estimated using the margins (2.5 and 97.5
percentiles) of 500 bootstrap samples.
Demographic, genetic, and biochemical data
The majority of individuals in the total cohort (70.7%)
lacked the APOE ε4 allele, with 26.5% being heterozygous
and 2.8% being homozygous APOE ε4 carriers (Table 1).
The subcohort consisting of patients with bipolar disorder
had similar APOE ε4 genotype frequency (P = 0.633) as well
as similar concentrations of CSF Aβ42 (P = 0.302)
compared to the healthy volunteers and was therefore pooled
with the rest of the total cohort (data not shown). There
were neither any gender differences with regards to APOE
ε4 genotype frequency (P = 0.586) or CSF Aβ42
concentrations (P = 0.534). Table 2 presents detailed demographic
and biochemical data for all of the subcohorts included in
CSF Aβ42 concentrations in relation to APOE genotype
In the total cohort, CSF Aβ42 concentrations were lower
in APOE ε4 carriers than in noncarriers in a gene
dosedependent manner (P < 0.001, Table 1), which is in
keeping with earlier findings [
]. However, when dividing the
total cohort into tertiles according to age, the effect was
present in the middle and upper tertiles among individuals
aged 46 or older (P < 0.001, Table 1), whereas in the lower
tertile, containing individuals aged 45 or younger, the
difference was nonsignificant (P = 0.203, Table 1).
CSF Aβ42 concentrations across different age groups
The estimated curves showed an initial upslope of CSF
Aβ42 concentrations in APOE ε4-negative individuals and
heterozygous APOE ε4 carriers followed by a steep
descent (Fig. 1). Aβ42 concentrations in homozygous APOE
ε4 carriers, however, descended from an early age lacking
the initial upslope. The age of initial descent, defined as
the age at which CSF Aβ42 reaches its maximum, was
estimated at 50 (95% confidence interval (CI) 42–54) years
for APOE ε4-negative individuals and 43 (95% CI 17–48)
years for heterozygous APOE ε4 carriers. This number
could not be estimated in homozygous APOE ε4 carriers,
as they lacked the initial upslope.
We conducted a large multicenter study to assess how
effects of the APOE ε2/ε3/ε4 polymorphism on CSF Aβ42
concentrations vary by age in cognitively healthy individuals.
The main findings were that: the APOE ε4 allele was
associated with lower CSF Aβ42 concentrations overall in
cognitively healthy people; the effects of APOE ε4 were present in
older people but not in young people; and CSF Aβ42 started
to decline at age 50 in people without the APOE ε4 allele, at
age 43 in people carrying one APOE ε4 allele, and even
earlier in people carrying two APOE ε4 alleles. Taken together,
these findings show that APOE ε4 strongly modulates the
effect of age on CSF Aβ42 in cognitively healthy people, and
points to important age-dependent effects of APOE ε4 on
the development of preclinical AD.
Comparisons of CSF Aβ42 and amyloid PET imaging in
cognitively healthy people suggest that the first decline in
CSF Aβ42 does not always translate to widespread cerebral
amyloid deposition [
7, 8, 21
]. The age at which CSF Aβ42
*P values indicate comparisons of CSF Aβ42 concentrations between the APOE ε4 carrier groups (for the total cohort as well as for each of the tertiles)
APOE apolipoprotein E, Aβ42 beta-amyloid1–42, CSF cerebrospinal fluid, SD standard deviation
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concentrations start to decrease may therefore be the
starting point for preclinical pathological disturbances in
amyloid homeostasis, which ultimately results in amyloid
accumulation that later becomes detectable on amyloid
PET imaging. The data from this study suggest that the
disturbed amyloid homeostasis occurs on average from age 50
in APOE ε4-negative individuals, and almost a decade
earlier in APOE ε4 heterozygous people. In APOE ε4
homozygous people we estimated a descent in CSF Aβ42 already
from age 17, but the sparsity of data among young
homozygous APOE ε4 carriers makes this estimate uncertain, and
we can only conclude that the decline in CSF Aβ42 starts
considerably earlier in homozygous APOE ε4 carriers
compared with heterozygous APOE ε4 carriers or noncarriers.
Importantly, previous studies provide convergent evidence
that emerging amyloid pathology, defined as decreased CSF
Aβ42 concentrations, or CSF Aβ42 concentrations slightly
above conventional thresholds for amyloid positivity, may
have deleterious effects on brain structure, brain function,
and cognition [
]. This highlights the importance of
detecting the earliest effects of APOE ε4 on CSF Aβ42 in
order to provide very early diagnostics and potentially
initiate prevention of AD.
The fact that APOE ε4 affected CSF Aβ42
concentrations already from 43 years of age is interesting
since a previous study found that APOE ε4 was
associated with cognitive decline only after 50 years of
]. We therefore suggest that there is an
intermediate period of early alterations in amyloid
homeostasis before cognitive decline becomes
], when amyloid accumulation slowly builds
up together with downstream pathological events
(including spread of tau tangles), which ultimately
translate to cognitive decline several years later.
This study has several limitations. First, we used
crosssectional data from several cohorts and several assays to
measure CSF Aβ42. Although we employed normalization
measures to bridge all results, the variability in cohorts and
assays increases the variance of our models and estimates.
Future studies are needed to verify these results in a
monocenter setting, obviating the need for data normalization
across cohorts. Second, the low number of APOE ε4
homozygous people, along with the sparsity of data in the age
span between 85 and 100 years, limits our ability to model
effects of APOE ε4 homozygosity and effects in the final
part of the natural life span. Also, the lack of APOE ε4
homozygous people between age 35 and 50 makes it
impossible to define whether there is a plateau in Aβ42
concentrations before decline or whether the concentrations
drop directly from age 17 in homozygous APOE ε4 carriers.
To sum up, the results of this study suggest that the
process of preclinical Aβ pathology might start in early
middle age in APOE ε4 carriers. Hence, we hypothesize
that the APOE ε4 allele affects CSF Aβ42 concentrations
by speeding up the process of preclinical Aβ
accumulation and deposition in the brain. Studies addressing the
molecular mechanisms behind the association between
ApoE and cerebral Aβ build-up are needed to verify this.
AD: Alzheimer’s disease; ANOVA: Analysis of variance; APOE: Apolipoprotein E;
Aβ42: Beta-amyloid1–42; CI: Confidence interval; CSF: Cerebrospinal fluid;
MCI: Mild cognitive impairment; PET: Positron emission tomography;
Ptau: Phosphorylated tau; T-tau: Total tau
This study was supported by grants from the Swedish Research Council, the
European Research Council, Frimurarestiftelsen, Stiftelsen Gamla Tjänarinnor,
the Swedish Alzheimer Foundation, the Swedish Brain Foundation, the Knut
and Alice Wallenberg Foundation, the Marianne and Marcus Wallenberg
Foundation, and the Torsten Söderberg Foundation. HH is supported by the
AXA Research Fund, the Fondation Université Pierre et Marie Curie, and the
Fondation pour la Recherche sur Alzheimer, Paris, France. The research
leading to these results has received funding from the program
“Investissements d’avenir” ANR-10-IAIHU-06 (to HH).
Availability of data and materials
The datasets used and/or analyzed during the current study are available
from the corresponding author on reasonable request.
RL, KB, NM, and HZ created the concept and design for the study. RL, BO, ML,
GBF, S-KH, HH, AW, OH, KB, NM, and HZ acquired, analyzed, and interpreted
data. RL, PSI, NM, and HZ drafted the manuscript. RL, PSI, and NM performed
the statistical analyses. The study was supervised by NM and HZ. All authors
contributed critical revision for important intellectual content and read and
approved the final manuscript.
Ethics approval and consent to participate
The study received approval from regional ethical committees at the
Universities of Gothenburg and Lund (Sweden), Brescia (Italy), Kuopio
(Finland), and Munich (Germany) and followed the tenets of the Helsinki
declaration. Written informed consent was obtained from all participants.
Consent for publication
ML declares that, over the past 36 months, he has received lecture honoraria from
Lundbeck and AstraZeneca Sweden, and served as scientific consultant for EPID
Research Oy; he has no other equity ownership, profit-sharing agreements,
royalties, or patents. HH declares no competing financial interests related to the
present article; he serves as Senior Associate Editor for the journal Alzheimer's &
Dementia; he has been a scientific consultant and/or speaker and/or attended
scientific advisory boards of Axovant, Anavex, Eli Lilly and company, GE Healthcare,
Cytox, Qynapse, Roche, Biogen Idec, Takeda-Zinfandel, Oryzon Genomics; he
receives research support from the Fondation for Alzheimer Research (Paris),
COLAM Initiatives (Paris), IHU-A-ICM (Paris), Pierre and Marie Curie University (Paris),
Pfizer & Avid (paid to institution); and he has patents as inventor, but received no
royalties. OH has acquired research support (for the institution) from Roche, GE
Healthcare, Biogen, AVID Radiopharmaceuticals, Fujirebio, and Euroimmun; in the
past 2 years, he has received consultancy/speaker fees (paid to the institution)
from Lilly, Roche, and Fujirebio. KB has served as a consultant or on advisory
boards for Alzheon, BioArctic, Biogen, Eli Lilly, Fujirebio Europe, IBL International,
Pfizer, and Roche Diagnostics. HZ has served on the scientific advisory board for
Roche Diagnostics, Eli Lilly and Pharmasum Therapeutics. KB and HZ are
cofounders of Brain Biomarker Solutions in Gothenburg AB, a GU Ventures-based
platform company at the University of Gothenburg. RL, PSI, TS, BO, GBF, S-KH, AW,
LM, and NM declare that they have no competing interests.
Springer Nature remains neutral with regard to jurisdictional claims in
published maps and institutional affiliations.
1. Blennow K , de Leon MJ , Zetterberg H . Alzheimer's disease . Lancet . 2006 ; 368 : 387 - 403 .
2. Corder EH , Saunders AM , Strittmatter WJ , Schmechel DE , Gaskell PC , Small GW , Roses AD , Haines JL , Pericak-Vance MA . Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer's disease in late onset families . Science . 1993 ; 261 : 921 - 3 .
3. Holtzman DM , Herz J , Bu G . Apolipoprotein E and apolipoprotein E receptors: normal biology and roles in Alzheimer disease . Cold Spring Harb Perspect Med . 2012 ; 2 : a006312 .
4. Castellano JM , Kim J , Stewart FR , Jiang H , DeMattos RB , Patterson BW , Fagan AM , Morris JC , Mawuenyega KG , Cruchaga C , et al. Human apoE isoforms differentially regulate brain amyloid-β peptide clearance . Sci Transl Med . 2011 ; 3 : 89ra57 .
5. Verghese PB , Castellano JM , Garai K , Wang Y , Jiang H , Shah A , Bu G , Frieden C , Holtzman DM . ApoE influences amyloid-β (Aβ) clearance despite minimal apoE/Aβ association in physiological conditions . Proc Natl Acad Sci U S A . 2013 ; 110 : E1807 - 16 .
6. Blennow K , Hampel H , Weiner M , Zetterberg H . Cerebrospinal fluid and plasma biomarkers in Alzheimer disease . Nat Rev Neurol . 2010 ; 6 : 131 - 44 .
7. Mattsson N , Insel PS , Donohue M , Landau S , Jagust WJ , Shaw LM , Trojanowski JQ , Zetterberg H , Blennow K , Weiner MW . Independent information from cerebrospinal fluid amyloid-β and florbetapir imaging in Alzheimer's disease . Brain . 2015 ; 138 : 772 - 83 .
8. Palmqvist S , Mattsson N , Hansson O . Cerebrospinal fluid analysis detects cerebral amyloid-β accumulation earlier than positron emission tomography . Brain . 2016 ; 139 : 1226 - 36 .
9. Blennow K , Mattsson N , Scholl M , Hansson O , Zetterberg H . Amyloid biomarkers in Alzheimer's disease . Trends Pharmacol Sci . 2015 ; 36 : 297 - 309 .
10. Galasko D , Chang L , Motter R , Clark CM , Kaye J , Knopman D , Thomas R , Kholodenko D , Schenk D , Lieberburg I , et al. High cerebrospinal fluid tau and low amyloid β42 levels in the clinical diagnosis of Alzheimer disease and relation to apolipoprotein E genotype . Arch Neurol . 1998 ; 55 : 937 - 45 .
11. Sunderland T , Mirza N , Putnam KT , Linker G , Bhupali D , Durham R , Soares H , Kimmel L , Friedman D , Bergeson J , et al. Cerebrospinal fluid β-amyloid1-42 and tau in control subjects at risk for Alzheimer's disease: the effect of APOE ε4 allele . Biol Psychiatry . 2004 ; 56 : 670 - 6 .
12. Shaw LM , Vanderstichele H , Knapik-Czajka M , Clark CM , Aisen PS , Petersen RC , Blennow K , Soares H , Simon A , Lewczuk P , et al. Cerebrospinal fluid biomarker signature in Alzheimer's disease neuroimaging initiative subjects . Ann Neurol . 2009 ; 65 : 403 - 13 .
13. Vemuri P , Wiste HJ , Weigand SD , Knopman DS , Shaw LM , Trojanowski JQ , Aisen PS , Weiner M , Petersen RC , Jack Jr CR . Effect of apolipoprotein E on biomarkers of amyloid load and neuronal pathology in Alzheimer disease . Ann Neurol . 2010 ; 67 : 308 - 16 .
14. Lautner R , Palmqvist S , Mattsson N , Andreasson U , Wallin A , Palsson E , Jakobsson J , Herukka SK , Owenius R , Olsson B , et al. Apolipoprotein E genotype and the diagnostic accuracy of cerebrospinal fluid biomarkers for Alzheimer disease . JAMA Psychiat . 2014 ; 71 : 1183 - 91 .
15. Prince JA , Zetterberg H , Andreasen N , Marcusson J , Blennow K. APOE ε4 allele is associated with reduced cerebrospinal fluid levels of Aβ42 . Neurology. 2004 ; 62 : 2116 - 8 .
16. Schipke CG , Jessen F , Teipel S , Luckhaus C , Wiltfang J , Esselmann H , Frolich L , Maier W , Ruther E , Heppner FL , et al. Long-term stability of Alzheimer's disease biomarker proteins in cerebrospinal fluid . J Alzheimers Dis . 2011 ; 26 : 255 - 62 .
17. Kuhlmann J , Andreasson U , Pannee J , Bjerke M , Portelius E , Leinenbach A , Bittner T , Korecka M , Jenkins RG , Vanderstichele H , et al. CSF Aβ1-42-an excellent but complicated Alzheimer's biomarker-a route to standardisation . Clin Chim Acta . 2017 ; 467 : 27 - 33 .
18. Bjerke M , Portelius E , Minthon L , Wallin A , Anckarsater H , Anckarsater R , Andreasen N , Zetterberg H , Andreasson U , Blennow K. Confounding factors influencing amyloid beta concentration in cerebrospinal fluid . Int J Alzheimers Dis . 2010 ; 2010 : 986310 .
19. Andreasen N , Hesse C , Davidsson P , Minthon L , Wallin A , Winblad B , Vanderstichele H , Vanmechelen E , Blennow K. Cerebrospinal fluid β- amyloid(1-42) in Alzheimer disease: differences between early- and lateonset Alzheimer disease and stability during the course of disease . Arch Neurol . 1999 ; 56 : 673 - 80 .
20. Olsson A , Vanderstichele H , Andreasen N , De Meyer G, Wallin A , Holmberg B , Rosengren L , Vanmechelen E , Blennow K. Simultaneous measurement of β-amyloid(1-42), total tau, and phosphorylated tau (Thr181) in cerebrospinal fluid by the xMAP technology . Clin Chem . 2005 ; 51 : 336 - 45 .
21. Morris JC , Roe CM , Xiong C , Fagan AM , Goate AM , Holtzman DM , Mintun MA . APOE predicts amyloid-beta but not tau Alzheimer pathology in cognitively normal aging . Ann Neurol . 2010 ; 67 : 122 - 31 .
22. Insel PS , Mattsson N , Donohue MC , Mackin RS , Aisen PS , Jack Jr CR , Shaw LM , Trojanowski JQ , Weiner MW . The transitional association between β-amyloid pathology and regional brain atrophy . Alzheimers Dement . 2015 ; 11 : 1171 - 9 .
23. Insel PS , Mattsson N , Mackin RS , Scholl M , Nosheny RL , Tosun D , Donohue MC , Aisen PS , Jagust WJ , Weiner MW . Accelerating rates of cognitive decline and imaging markers associated with β-amyloid pathology . Neurology . 2016 ; 86 : 1887 - 96 .
24. Mattsson N , Insel PS , Nosheny R , Tosun D , Trojanowski JQ , Shaw LM , Jack Jr CR , Donohue MC , Weiner MW . Emerging β-amyloid pathology and accelerated cortical atrophy . JAMA Neurol . 2014 ; 71 : 725 - 34 .
25. Mattsson N , Insel PS , Donohue M , Jagust W , Sperling R , Aisen P , Weiner MW . Predicting reduction of cerebrospinal fluid β-amyloid 42 in cognitively healthy controls . JAMA Neurol . 2015 ; 72 : 554 - 60 .
26. Caselli RJ , Dueck AC , Osborne D , Sabbagh MN , Connor DJ , Ahern GL , Baxter LC , Rapcsak SZ , Shi J , Woodruff BK , et al. Longitudinal modeling of age-related memory decline and the APOE ε4 effect . N Engl J Med . 2009 ; 361 : 255 - 63 .