Serum ceramides increase the risk of
The Women’s Health and Aging Study II
Veera Vankata Ratnam
Jin Xia, MS
Linda P. Fried, MD,
Sevil Yasar, MD, PhD
Marilyn Albert, PhD
Greg Harris, BS
Eric B. Schneider, PhD
Peter V. Rabins, MD,
Constantine G. Lyketsos,
Objectives: Previous studies have shown that high serum ceramides are associated with memory
impairment and hippocampal volume loss, but have not examined dementia as an outcome. The
aim of this study was to examine whether serum ceramides and sphingomyelins (SM) were asso-
ciated with an increased risk of all-cause dementia and Alzheimer disease (AD).
Methods: Participants included 99 women without dementia aged 70–79, with baseline serum
SM and ceramides, enrolled in a longitudinal population-based study and followed for up to 6
visits over 9 years. Baseline lipids, in tertiles, were examined in relation to all-cause dementia and
AD using discrete time Cox proportional survival analysis. Lipids were analyzed using electros-
pray ionization tandem mass spectrometry.
Results: Twenty-seven (27.3%) of the 99 women developed incident dementia. Of these, 18
(66.7%) were diagnosed with probable AD. Higher baseline serum ceramides, but not SM, were
associated with an increased risk of AD; these relationships were stronger than with all-cause
dementia. Compared to the lowest tertile, the middle and highest tertiles of ceramide d18:1–
C16:0 were associated with a 10-fold (95% confidence interval [CI] 1.2–85.1) and 7.6-fold in-
creased risk of AD (95% CI 0.9–62.1), respectively. The highest tertiles of ceramide d18:1–
C24:0 (hazard ratio [HR] ? 5.1, 95% CI 1.1–23.6) and lactosylceramide (HR ? 9.8, 95% CI
1.2–80.1) were also associated with risk of AD. Total and high-density lipoprotein cholesterol and
triglycerides were not associated with dementia or AD.
Conclusions: Results from this preliminary study suggest that particular species of serum
ceramides are associated with incident AD and warrant continued examination in larger stud-
A? ? amyloid-?; AD ? Alzheimer disease; amu ? atomic mass units; APP ? amyloid precursor protein; BACE-1 ? ?-site APP
cleaving enzyme 1; BMI ? body mass index; CI ? confidence interval; DSM-IV ? Diagnostic and Statistical Manual of Mental
Disorders, 4th edition; ESI-MS/MS ? electrospray ionization tandem mass spectrometry; HDL ? high-density lipoprotein;
HR ? hazard ratio; MCI ? mild cognitive impairment; MMSE ? Mini-Mental State Examination; SM ? sphingomyelin; WHAS
II ? Women’s Health and Aging Study II.
Lipidomic, metabolomic, and targeted approaches have identified pathways and products of
sphingolipid metabolism that are altered early in the course of Alzheimer disease (AD).1–5
Ceramides facilitate the regulation of ?-site APP cleaving enzyme 1 (BACE-1) and ?-secretase
activity and amyloid precursor protein (APP) processing and trafficking. Evidence also suggests
that glycosphingolipids bind amyloid-? (A?) at the cell surface and form domains that facili-
tate the oligomerization and fibril formation of A?.6–10In addition to these roles, ceramide is a
From the Division of Epidemiology (M.M.M.), Department of Health Sciences Research, College of Medicine, Mayo Clinic, Rochester, MN;
Department of Psychiatry, Division of Geriatric Psychiatry and Neuropsychiatry (N.J.H., P.V.R., C.G.L.), Department of Neurology (V.V.R.B.,
N.J.H., M.A.), Center on Aging and Health (J.X., S.Y., V.V., G.H., M.C.C.), Department of Medicine, Division of Geriatric Medicine &
Gerontology (S.Y.), and Department of Surgical Trials and Outcomes Research (E.B.S.), Johns Hopkins University School of Medicine, Baltimore,
MD; Mailman School of Public Health (L.P.F.), Columbia University, New York, NY; and Departments of Mental Health (V.V., M.C.C.) and
Biostatistics (K.B.-R.), Johns Hopkins University Bloomberg School of Public Health, Baltimore, MD.
Study funding: Supported in part by grants from the National Institute on Aging R37 AG19905, R01 AG19825–01, R03 AG032427–01A1, P50
AG005146–27, and U01 AG037526–01, the National Institute of Neurological Disorders and Stroke grant R21 NS060271, and the Johns Hopkins
Older Americans Independence Center (1 P30 AG021334–01).
Go to Neurology.org for full disclosures. Disclosures deemed relevant by the authors, if any, are provided at the end of this article.
Correspondence & reprint
requests to Dr. Mielke:
Copyright © 2012 by AAN Enterprises, Inc.
potent regulator of cell survival. Upon activa-
tion, ceramide-associated protein kinases and
phosphatases evoke proapoptotic signaling
pathways,11–15leading to neurodegeneration.
Despite the abundant laboratory and ani-
mal findings linking sphingolipids and AD
pathology, little research has extended these
findings to examine the role of sphingolipids
in AD pathogenesis among humans. The few
postmortem, and 1 CSF, studies suggest cer-
amide and SM levels, and gene expression
patterns of enzymes participating in the sph-
ingolipid pathway, vary by AD severity.1–3,16,17
We have shown that blood ceramide levels
vary by cognitive status, and that elevations of
ceramides in subjects with amnestic mild cog-
nitive impairment (MCI) predict cognitive
decline and hippocampal volume loss.18In a
separate study we also found that high blood
ceramides in cognitively normal women pre-
dicted memory impairment.19However, not
all individuals with memory impairment
progress to dementia or AD.20Therefore, we
were unable to determine whether increased
blood ceramides predicted dementia or AD,
or were a general indicator of cognitive im-
pairment. The goal of the present pilot study
was to determine whether serum ceramides
predicted all-cause dementia or were specifi-
cally associated with AD.
METHODS Study sample. The Women’s Health and Ag-
ing Study II (WHAS II) is a prospective study of physical func-
tioning among the two-thirds least disabled 70- to 79-year-old
community-dwelling women in Baltimore, MD. The sampling
and recruitment of this cohort have been previously de-
scribed.21,22Using the Health Care Financing Administration’s
Medicare eligibility lists for 12 zip code areas in Eastern Balti-
more City and County, age-stratified (70–74, 75–79) random
samples were drawn by Westat, Inc. in 1994–1995. Trained
interviewers screened 1,630 women and determined eligibility
according to whether women 1) were aged 70 to 79 years; 2) had
sufficient hearing and English proficiency to be interviewed; 3)
could be contacted by telephone; 4) had a Mini-Mental State
Examination score ?24; and 5) reported no, or limited, diffi-
culty in only 1 of the following 4 domains: mobility and exercise
tolerance, upper extremity function, high-functioning tasks, and
basic self-care. Of 880 women screened eligible, 436 (49.5%)
agreed to participate in the baseline examination at the Johns
Hopkins Hospital and to prospective follow-up. Those agreeing
to participate were more educated and had more diseases than
those who refused, but did not differ on other characteristics.21,22
For the present study, 223 women had adequate serum baseline
samples remaining in storage. Due to the limited blood reserved,
we randomly selected 100 participants’ serum samples for the
lipid assays. Follow-ups were conducted 1.5, 3, 6, 7.5, and 9
years after baseline. Each examination consisted of a comprehen-
sive medical history, medication inventory, physical and neuro-
logic examination, neuropsychological battery, and blood draw.
Standard protocol approvals, registrations, and patient
consent. The study was approved by The Johns Hopkins Uni-
versity institutional review board. Written informed consent was
obtained for all participants who were examined as part of the
Dementia adjudication. The pool of WHAS II participants
for dementia adjudication was chosen from the larger WHAS II
cohort (n ? 436) based on 3 criteria: Mini-Mental State Exami-
nation (MMSE) score ?24, history of stroke (either self-report
or diagnosed), or a decrease in MMSE score of ?2 points be-
tween 2 consecutive rounds (with the exception of the extended
3-year window between visits 3 and 4). A total of 239 WHAS II
participants met these criteria. These participants were adjudi-
cated through a consensus conference in collaboration with the
Johns Hopkins AD Research Center and included neuropsy-
chologists, geriatric psychiatrists, geriatricians, epidemiologists,
and faculty and staff involved in WHAS II. During each adjudi-
cation session, all available information on each participant was
reviewed, including up to 9 years of medical and neurologic his-
tory, cognitive test performance, and proxy reports of daily func-
tioning and cognitive problems. Consensus conferences
diagnosed mild cognitive impairment, dementia, and dementia
type using the National Alzheimer’s Coordinating Center ap-
proach, which is used in all AD Research Centers. Dementia was
initially diagnosed according to DSM-IV criteria23at each
WHAS II visit. The age at onset was assigned as the age when
each participant unambiguously met DSM-IV criteria for de-
mentia. Possible and probable AD were diagnosed according to
National Institute of Neurological and Communicative Disor-
ders and Stroke and Alzheimer’s Disease and Related Disorders
Association criteria.24In order to account for the differences in
the adjudication process over time, 20% (approximately 50 par-
ticipants) were adjudicated twice in a masked fashion. There was
85% agreement (? ? 0.68) between adjudication sessions.
Cholesterol and triglyceride assays. Nonfasting blood was
drawn at baseline and serum was frozen at ?80°C until process-
ing. Total and high-density lipoprotein (HDL) cholesterol and
triglycerides were determined using standard enzymatic tech-
niques at Quest Diagnostics.
Sphingolipid assays. A crude lipid extract was performed us-
ing previously published methods.25In brief, methanol contain-
ing 30 mM ammonium acetate (3 volumes/weight) was added to
each serum sample containing internal standards ceramide d18:
1–C12:0 and sphingomyelin d18:1–C12:0 (1.3 ?g/mL of ex-
Table 1 Baseline characteristics of participants without dementia, with any
dementia type, and with Alzheimer disease
(n ? 72), mean (SD)
Any dementia type
(n ? 27), mean (SD)
(n ? 18), mean (SD)
74.01 (2.41)74.19 (2.62) 73.97 (2.65)
White, n (%)
58 (80.56%) 18 (66.67%)14 (77.78%)
12.96 (2.93)11.85 (3.71) 12 (3.80)
Body mass index
27.06 (5.34)26.43 (5.61) 25.42 (5.32)
110.21 (40.91)104.00 (31.28)108.33 (36.52)
Systolic blood pressure
147.06 (19.11) 153.3 (27.46)155.61 (22.60)
Neurology 79 August 14, 2012
traction solvent) and the mixture was vortexed. Chloroform (4
volumes/weight) was added and the mixture was vortexed and
centrifuged at 1,000 g for 10 minutes. The chloroform layer was
removed and dried in a vacuum oven. Dried samples were resus-
pended in 100% methanol (200 ?L) just prior to analysis by
high-pressure liquid chromatography coupled tandem mass
Samples were injected using a Harvard Apparatus pump at
the rate of 15 ?L/min into a Sciex API3000 electrospray ioniza-
tion triple stage quadruple tandem mass spectrometer (ESI-MS/
MS; Thornhill, Ontario, Canada) operated in the positive mode.
The ESI-MS/MS scanned from 300 to 1,000 atomic mass units
(amu) per second at a step of 0.1 amu. Each lipid species was
initially identified by a Q1 mass scan, then by precursor ion
scanning or neutral loss scanning of a purified standard. Samples
were injected into the ESI-MS/MS for 3 minutes, where the
mass counts accumulate and the sum of the total counts under
each peak were used to quantitate each analyte. SM and cer-
amide reference standards were purchased from Avanti Polar
Lipids (Alabaster, AL).
Covariates. To examine whether sphingolipids levels varied by
demographic and health-related characteristics, we first assessed
the association between these variables and tertiles of SM and
ceramide species using analysis of variance for continuous vari-
ables and Fisher exact test for dichotomous variables. Potential
covariates included baseline age, race, education, smoking status,
and minutes of exercise per week; medical conditions and symp-
toms such as systolic and diastolic blood pressure, diabetes, myo-
cardial infarction, stroke, angina, peripheral artery disease, and
depression; statins and other medications; and serum total
and HDL cholesterol, triglycerides, blood glucose, creatinine,
and albumin levels. Of these variables, blood glucose was consis-
tently higher and body mass index (BMI) lower in the highest
tertile of all sphingolipids. Multivariable analyses controlled for
baseline blood glucose levels, BMI, and age.
Statistical analysis. SM species were highly correlated (p ?
0.0001) after Bonferroni correction. We therefore summed all
SM species to create a single (total) SM variable. Individual cer-
amides species were less correlated so these species were exam-
ined separately. SM and ceramides were analyzed in tertiles
because they were highly skewed to the right. t Tests and Fisher
exact tests were used to compare the 100 randomly selected
women with available baseline samples and the 123 women with
available samples who were not selected. Differences between the
100 women with assayed lipids and the rest of the population
(n ? 336), regardless of sample availability, were also examined.
Among the 100 participants with assayed serum sphingolip-
ids, 1 person with prevalent dementia at baseline was excluded
from the analysis, leaving a total of 99 individuals. Additionally,
9 participants developed non-AD dementia, and were therefore
excluded from the analysis examining SM and ceramides as a risk
factor for AD. Due to the time interval feature of WHAS II data,
the discrete time Cox proportional hazards model with a com-
plementary log-log link was used to assess the effect of baseline
lipid levels on the risk of developing all-cause dementia or AD.26
Exponentiated coefficients from the model can be interpreted as
hazard ratios (HRs). Participants were included in longitudinal
analyses if they received a baseline evaluation and at least 1 addi-
tional follow-up. For each outcome, participants contributed in-
formation up to the examination at which they first developed
dementia, died, or were lost to follow-up and therefore censored.
Multivariate models controlled for age, blood glucose, and BMI.
Baseline serum lipids, in tertiles, predict incident dementiaa
Lipids in tertiles
HR (95% CI)
HR (95% CI)
HR (95% CI)
Abbreviations: BMI ? body mass index; CI ? confidence interval; HDL ? high-density lipoprotein; HR ? hazard ratio.
aControlling for age, BMI, and blood glucose at baseline.
bp ? 0.05.
Neurology 79 August 14, 2012
The a priori p value was p ? 0.05. Analyses were conducted
using SAS version 9.2 (SAS Institute Inc., Cary, NC).
RESULTS The 100 participants with SM and cer-
amide assays were slightly younger (74.0 vs 74.7; p ?
0.036) and had lower baseline systolic blood pressure
(148.6 vs 153.5; p ? 0.047) compared to the rest of
the sample (n ? 336). No other health or demo-
graphic characteristics differed between the 2 groups,
including baseline cognitive test scores. Among the
223 women with available baseline serum samples,
there were no differences between the 100 women
randomly selected for the study and the 123 women
with available stored bloods but who were not ran-
domly selected. Of the 99 women in the all-cause
dementia analyses, 27 (27.3%) developed incident
dementia over the 9-year follow-up (this percentage
is similar to the 24.8% that developed dementia in
the full cohort); 18 of the 27 (66.7%) dementia cases
were diagnosed with probable AD. There were no
baseline demographic or health-related differences
between those who did and those who did not de-
velop all-cause dementia or AD (table 1). The aver-
age participant follow-up time in our study sample
was 8.2 years (SD ? 2.4) with a mean of 5.3 study
visits (SD ? 1.2) for individuals without dementia
and 6 years (SD ? 2.5) and 4.1 study visits (SD ?
1.2) for those with incident dementia. Total risk
time evaluated was 755.1 risk years for all-cause de-
mentia vs no dementia analyses and 710.4 risk years
for AD vs no dementia analyses.
The number of events in each lipid tertile and
corresponding incidence rates for all-cause dementia
and AD are shown in tables 2 and 3, respectively.
Using multivariable discrete time survival analysis to
examine serum lipids as predictors of incident de-
mentia (table 2), the highest tertile of lactosylcer-
amide was associated with an increased risk of all-
cause dementia (HR ? 4.3; 95% confidence interval
[CI] 1.1–16.1). Additionally, compared to the lowest
tertile, the middle tertile of ceramide d18:1–C16:0
(HR ? 3.8; 95% CI 1.2–12.5) was associated with
an increased risk of all-cause dementia, while the ef-
fect of the highest tertile was attenuated and not sig-
nificantly different from the lowest tertile (p ?
0.137). Figure 1 displays the Kaplan-Meier plots for
incident dementia by baseline tertiles of ceramide
d18:1–C16:0 and lactosylceramide.
Higher baseline serum ceramides were also associ-
ated with an increased risk of AD, and the relation-
ships were stronger than that seen when examining
all-cause dementia as the outcome (table 3). Notably,
there was only one case of AD in the lowest tertile of
ceramides d18:1–C16:0, d18:1–C22:0, and lactosyl-
ceramide. There was also a threshold effect for most
Baseline serum lipids, in tertiles, predict incident Alzheimer disease
Lipids in tertiles
HR (95% CI)
HR (95% CI)
HR (95% CI)
All models control for age, body mass index, and blood glucose at baseline.Abbreviations: CI ? confidence interval; HDL ? high-density lipoprotein; HR ? hazard ratio; SM ? sphingomyelin.
aOne case in lowest tertile.
bp ? 0.05.
Neurology 79August 14, 2012
ceramides such that both the second and third ter-
tiles exhibited an increased risk of AD, although the
results were not always significant at the p ? 0.05
level. For example, compared to the lowest tertile,
the second tertile of ceramide d18:1–C16:0 was asso-
ciated with a 10-fold increased risk of AD (95% CI
1.2–85.1) and the highest tertile was associated with
a 7.6-fold increased risk (95% CI 0.9–62.1). The
highest tertiles of ceramide d18:1–C24:0 (HR ?
5.1; 95% CI 1.1–23.6) and lactosylceramide (HR ?
9.8; 95% CI 1.2–80.1) were also associated with an
increased risk of AD. Figure 2 displays the Kaplan-
Meier plots for incident AD by baseline tertiles of
lactosylceramides and ceramides d18:0–C16:0, d18:
1–C22:0, and d18:1–C24:0.
To determine the specificity of the associations,
we also examined other baseline serum lipid levels,
including total and HDL cholesterol and triglycer-
ides, but did not find associations between these lip-
ids and incident all-cause dementia or AD (tables 2
and 3). In additional analyses, baseline SM and cer-
amide levels were not associated with loss to
follow-up (data not shown).
DISCUSSION In this population-based sample of
older women, high serum ceramide levels (especially
ceramides d18:1–C16:0, d18:1–C24:0, and lactosyl-
ceramide) were associated with an increased risk of
all-cause dementia independent of age, blood glu-
cose, and BMI. Importantly, the relationship be-
tween these lipids and AD was much stronger than
for all-cause dementia, with an HR of about 10 and
an apparent threshold effect. Only 1 person in the
lowest tertile of serum ceramides d18:1–C16:0 and
d18:1–C22:0 and lactosylceramide developed AD
dementia. These findings suggest that high levels of
serum ceramides increase the risk of developing AD.
Accumulating evidence suggests that ceramide
metabolism may be perturbed early in the pathogen-
esis of AD.2,16,17,27While the exact mechanisms by
which this happens is an active area of research, a
number of studies have identified pathogenic links
between ceramides and amyloid-? (A?). First, expo-
sure of cultured neurons to A?1–42directly increases
ceramide levels by activating neutral sphingomyeli-
nase28–30; inhibiting this ceramide production pro-
tects neurons from A?1–42-induced cell death.16
Second, A?1–42indirectly increases ceramide pro-
duction through an oxidative stress-mediated mecha-
nism.16,31Ceramides then increase inflammatory and
reactive oxygen species, further enhancing the pa-
thology in a self-sustaining way. Finally, increased
levels of ceramides accelerate the formation of patho-
genic forms of amyloid by increasing ?- and
?-cleavage of APP.32–35These results suggest that a
disruption of ceramide metabolism may be an early
and critical event involved in A? production and the
neuronal dysfunction associated with AD.4
We have previously reported that high blood cer-
amide levels varied by AD severity and were predic-
tive of cognitive decline and hippocampal volume
loss among clinically adjudicated patients with am-
nestic MCI.18The present study supports these find-
ings by showing that high ceramide levels,
particularly ceramides d18:1–C16:0, d18:1–C24:0,
and lactosylceramide, are most strongly associated
with an increased risk of AD dementia. Notably in
previous shotgun and targeted studies of blood and
brain ceramides,1,16,18,19the ceramide d18:1–C24:0
has consistently been altered.
There was a threshold effect for both incident de-
mentia and AD such that the HR of the highest ter-
tile was similar or lower than the middle tertile.
Figure 1 Kaplan-Meier plot for incident dementia
Kaplan-Meier plot for incident dementia by (A) ceramide C16:0 tertiles and (B) glycosyl
Neurology 79 August 14, 2012
Thus, it is possible that low ceramide levels reduce
the risk of dementia/AD, rather than that high levels
are detrimental. Future studies with larger sample
sizes are needed to better determine this threshold
effect. Additionally, normal ceramide and SM levels
have not been adequately established. Thus, we used
tertiles because our data were in cycles per second,
and not in easily quantifiable clinical units. Ongoing
research is examining normal levels in the population
and will be essential to define abnormal values,
whether high or low, for risk of dementia and AD.
The exact mechanism by which blood ceramides
could contribute to AD is currently unknown, but
both direct and indirect mechanisms have been sug-
gested.4Among HIV-infected participants we have
found a significant correlation between plasma and
CSF ceramides,36suggesting that there is a relation
between blood measures of ceramides and brain lev-
els. As HIV disruptions of the blood–brain barrier
could be driving this association, additional research
examining the blood–CSF relationship of sphingo-
lipids in AD is ongoing. Indirect mechanisms may
also contribute. Both ceramides and SM increase the
risk of cardiovascular disease and insulin resis-
tance,37–39both of which are associated with an in-
creased risk of AD. In the present study, we
examined several vascular factors as mediators of the
ceramide–AD relationship and found no attenuation
of the relationship between serum ceramides and AD,
but additional examination is needed in a larger study.
Several limitations warrant consideration. First,
this sample was composed of women and may not be
generalizable to men. However, there are currently
no results from other studies to suggest the relation-
Figure 2Kaplan-Meier plot for incident Alzheimer disease (AD)
Kaplan-Meier plot for incident AD by (A) ceramide C16:0 tertiles, (B) ceramide C22:0 tertiles, (C) ceramide C24:0 tertiles,
(D) lactosyl C12:0 tertiles.
Neurology 79August 14, 2012
ship should be different among men. Second, serum
lipids were only assayed at baseline, leaving open the
possibility that change in these biomarkers may be a
better indicator of progression. Third, lipids were
nonfasting and the effect of fasting on SM and cer-
amides is not clear. Correcting for fasting status by
controlling for blood glucose had little effect on
point estimates. Finally, while there was a high reten-
tion rate in this cohort (55.7% of the 436 partici-
pants completed all 6 examinations), over 9 years 90
participants died21and some individuals were lost to
follow-up (n ? 103) and may have developed de-
mentia, leading to a potential underdetection of cases
and a conservative estimate of the lipid–dementia as-
sociations. The findings from this small study of
women warrant replication in a larger population-
based sample to verify the results.
Despite these limitations, there are several
strengths. WHAS II is a longitudinal, population-
based study that allowed us to examine the specificity
of associations between blood SM and ceramides and
incident dementia. Women had up to 6 examina-
tions, and 9 years of follow-up. Second, dementia
diagnoses were conducted via consensus conference
and in collaboration with the Johns Hopkins AD Re-
search Center. Finally, despite the small sample size,
effect sizes were quite large and specific to ceramides.
In this preliminary study, high serum ceramide
levels were associated with an increased risk of AD
and warrant replication in a larger study. Additional
research is also needed in larger studies to determine
whether there are mediating vascular factors or
whether the timing of the measurement (midlife vs
late life) is important. The present results, combined
with the current literature, call for additional exami-
nation into ceramide metabolites as potential new
targets for the prevention or treatment of AD.
Dr. Mielke: drafting/revising the manuscript for content, including med-
ical writing for content, study concept or design, analysis and interpreta-
tion of data, obtaining funding. Dr. Bandaru: drafting/revising the
manuscript for content, analysis or interpretation of data. Dr. Haughey:
drafting/revising the manuscript for content, including medical writing
for content, study concept or design, analysis or interpretation of data.
Ms. Xia: drafting/revising the manuscript for content, statistical analysis,
Interpretation of the data. Dr. Fried: drafting/revising the manuscript for
content, including medical writing for content, study concept or design.
Dr. Yasar: drafting/revising the manuscript for content, including medical
writing for content, study concept or design, interpretation of data. Dr.
Albert: drafting/revising the manuscript for content, including medical
writing for content, interpretation of data. Mr. Varma: study concept or
design, drafting/revising the manuscript for content, including medical
writing for content. Mr. Harris: study concept or design, drafting/revising
the manuscript for content, including medical writing for content. Dr.
Schneider: study concept or design, drafting/revising the manuscript for
content, including medical writing for content. Dr. Rabins: drafting/
revising the manuscript for content, including medical writing for con-
tent, interpretation of data. Dr. Bandeen-Roche: analysis and
interpretation of data, drafting/revising the manuscript for content, in-
cluding medical writing for content. Dr. Lyketsos: drafting/revising the
manuscript for content, including medical writing for content, interpreta-
tion of the data. Dr. Carlson: drafting/revising the manuscript for con-
tent, including medical writing for content, study concept or design,
interpretation of the data, obtaining funding.
M. Mielke, V.V.R. Bandaru, N. Haughey, J. Xia, L. Fried, S. Yasar, M.
Albert, V. Varma, G. Harris, E. Schneider, P. Rabins, and K. Bandeen-
Roche report no disclosures. C. Lyketsos has received grant support (re-
search or CME) from the following organizations: NIMH, NIA,
Associated Jewish Federation of Baltimore, Weinberg Foundation, Forest,
GlaxoSmithKline, Eisai, Pfizer, Astra-Zeneca, Lilly, Ortho-McNeil,
Bristol-Myers, and Novartis. Dr. Lyketsos has served as a consultant/
advisor for Astra-Zeneca, GlaxoSmithKline, Eisai, Novartis, Forest, Su-
pernus, Adlyfe, Takeda, Wyeth, Lundbeck, Merz, Lilly, and Genentech.
Dr. Lyketsos has received honorarium or travel support from Pfizer,
Forest, GlaxoSmithKline, and Health Monitor. M. Carlson reports no
disclosures. Go to Neurology.org for full disclosures.
1. Han X, Rozen S, Boyle SH, et al. Metabolomics in early
Alzheimer’s disease: identification of altered plasma sphin-
golipidome using shotgun lipidomics. PLoS One 2011;6:
Serum ceramides—A new biomarker for preclinical AD?
Projections that the global prevalence of Alzheimer disease (AD) will double
every 20 years for the foreseeable future have increased the sense of urgency among
researchers and health care agencies to identify more effective screening,
prevention, and treatment strategies. In their prospective cohort study, Mielke et
al.1found a strong relationship between elevated blood ceramides at a baseline
examination and the subsequent risk of developing all-cause dementia and AD.
Previous laboratory and clinical studies had pointed to a role for sphingolipid
metabolism in the neuropathologic pathways leading to AD, but the study by
Mielke et al. is the first to demonstrate that a specific class of sphingolipids
measured in blood can predict the development of AD over a 9-year period. The
findings are noteworthy because identification of an accurate biomarker of
prodromal AD, which can be obtained with a minimum of cost and inconvenience
to the individual, would greatly facilitate the transition of AD therapeutics research
from the traditional model focused on treating established disease to a model
focused on preventing or delaying disease onset.2The study is compelling because
of its population-based prospective design, rigorous methods, and consistency with
preliminary research on the role of ceramides in cognitive decline. We must temper
our enthusiasm by recognizing the limitations of the study, which include a small
sample size of women only, and a single baseline measurement of the biomarker.
Much work must still be done to replicate the findings in larger, more diverse
samples, to determine which ceramide species are the most consistent predictors of
risk, to establish optimal thresholds for predicting the outcome, and most
importantly, to understand the relationship between longitudinal variations in
blood ceramide levels and the underlying pathologic processes of AD.
1. Mielke MM, Bandaru VVR, Haughey NJ, et al. Serum ceramides increase the
risk of Alzheimer disease: The Women’s Health and Aging Study II. Neurology
2. Golde TE, Schneider LS, Koo EH. Anti-a? therapeutics in Alzheimer’s disease:
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