Supplementary Table 4 | Summary of observational studies that considered participants’ history of statin use during follow-up, and their cognitive outcomes
First
author
(year)
Cohort name
n
Age at
baseline
(years)
Exposure
(time of exposure:
classification of statin use)
Outcome
Follow-up
time
Statistical
methods
Summary of findings
Betterma
n (2012)1
Ginkgo
Evaluation of
Memory Study
(GEMS)
3,069
79
(mean)
Time-updated: never use of
3MSE (estimated from
TICS for non-clinic visit
participants), cognitive
scale of the ADAS-Cog,
administered every
6 months
6 years
(mean)
Linear mixed
effects
regression
models
Marginally significant
protective association with
time-updated ever statin
use; significant association
with time-updated current,
but not former, statin use
Bernick
(2005)2
Cardiovascular
Health Study
(CHS)
3,334
Rate of change on
3MSE, administered
annually
7 years
(mean)
Linear
regression
with annual
rate of
change as
the outcome
variable
Significant benefit of
>4 years of continuous
statin use during follow-up
compared with <2 years of
statin use, treatment not
recommended; marginally
significant benefit compared
with <2 years of statin use,
drug therapy recommended;
no results reported for other
comparisons, although
consideration of mean
change in cognitive score
according to group suggests
a similar benefit compared
with <2 years of statin use,
diet therapy recommended
and compared with the
attenuated benefit of
continuous treatment vs
intermittent treatment.
≥68
lipid-lowering medications,
statin use, non-statin lipidlowering medication use;
current, former, never use of
statins; ever use of lipophilic
vs non-lipophilic statins
Timing unclear: continuous
users (>4 years of
continuous statin use);
intermittent users (2–4 years
of continuous treatment or
3–5 years of nonconsecutive use); untreated
(<2 years of statin use),
which was further divided
into no treatment
recommended, diet therapy
recommended, and drug
therapy recommended
groups, based on the ATPIII guidelines; timing relative
to cognitive assessment is
unclear
Authors’
reported
direction of
association
between
statin use
and cognition
Protective
Protective
At the end of follow-up: non-
AD dementia (NINCDS–
ADRDA, n = 25; n = 20
statin non-users, n = 4
statin users, n = 1
mixed statin users, and
n = 0 other lipidlowering medication
users)
4 years
(maximum
)
Cox
proportional
hazards
model
Significant reduction in risk
of AD dementia with statin
use
Protective
73
(mean)
At the end of follow-up:
Change in performance
on 10
neuropsychological
tests and the CDR-SOB,
administered annually
3 years
(mean),
minimum
of 3 annual
visits
Linear mixed
effects
regression
model
Protective
478
11
(mean)
At the end of follow-up:
Difference in
performance on the
Moray House Test of
intelligence at age
11 years and age
80 years
69 years
(mean)
2,004,692*
30–84
At the end of follow-up:
Dementia (EMR codes)
7 years
(maximum
)
General
linear
modelling
using a
repeated
measures
design
(reported
F-test and
proportion of
variance
explained
quantified as
a partial η2)
Cox
proportional
hazards
model
Significant beneficial effect
of statin use on change in
the CDR-SOB, marginally
significant benefit of statin
use with respect to change
in MMSE scores, no
association between statin
use and change on the 10
other cognitive tests
Significant benefit of selfreported statin use at followup with respect to difference
in intelligence scores at age
11 years and age 80 years
Null overall, although
consideration of individual
statins suggested a
protective association of
simvastatin and atorvastatin
use in women
Null
Sparks
(2008)3
Alzheimer's
Disease Antiinflammatory
Prevention
Trial (ADAPT)
2,233
Steenland
(2013)4
Uniform Data
Set
maintained by
the National
Alzheimer’s
Coordinating
Center
3,607
Starr
(2004)5
Lothian Birth
Cohort followup of the
1932 Scottish
Mental Health
Survey
HippisleyCox
(2010)6
QResearch
≥70
users of lipid-lowering drugs
(never or early and
infrequent statin use); statin
users (report statin use at all
visits, excluding the 1 month
visit); non-statin lipidlowering drug users (nonstatin lipid lowering drug at
over half of study visits);
mixed statin users
(intermittent statin users,
with at least half of visits on
statin therapy)
always report statin use
versus never report statin
use
statin use (yes/no)
initiation of statin use during
follow-up vs never statin use
during follow-up
Protective
Chou
(2014)7
Longitudinal
Health
Insurance
Database
2000
16,699
statin users
and 16,699
matched
non-users
of statins
60–100
Beydoun
(2011)8
Baltimore
Longitudinal
Study of Aging
(BLSA)
1,604
≥50
(mean
58)
At the end of follow-up:
Dementia (ICD-9-CM
EMR codes)
5 years
(mean),
maximum
11 years
Cox
proportional
hazards
model
Time-updated: never or ever
use of statins; Defined at the
end of follow-up: never or
All-cause dementia
(DSM-III-R, n = 259),
AD dementia (NINCDS–
ADRDA, n = 182)
25 years
(median)
Not reported
initiation of statin use during
follow-up vs never statin use
during follow-up
ever use of statins
Significant benefit of statin
use during follow-up with
respect to incident dementia;
stronger associations with
higher-potency statins and
longer cumulative duration
of statins; no difference in
association by lipophilicity of
statins or age of participants,
authors conclude differences
in association by sex
Ever statin use defined at
the end of follow-up was
associated with a reduced
risk of dementia, AD
dementia and MCI.
Protective
Protective
*Prior to exclusion for pre-existing dementia code. Abbreviations: AD, Alzheimer disease; ADS-Cog, Alzheimer's Disease Assessment Scale, cognitive subscale; ATP-III, Third Adult Treatment
Panel of the National Cholesterol Education Program; CDR-SOB, Clinical Dementia Rating—Sum of Boxes; DSM-III-R, Diagnostic and Statistical Manual, 3rd Edition, Revised; EMR, electronic
medical records; ICD-9-CM, International Classification of Diseases, 9th Revision, Clinical Modification; MCI, mild cognitive impairment; MMSE, Mini-Mental State Examination; 3MSE, Modified
Mini-Mental State Examination; NINCDS–ADRDA, National Institute of Neurological and Communicable Disorders and Stroke—Alzheimer's Disease and Related Disorders Association; TICS,
Telephone Interview for Cognitive Status.
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Bernick, C. et al. Statins and cognitive function in the elderly: the Cardiovascular Health Study. Neurology 65, 1388–1394 (2005).
Sparks, D. L. et al. Reduced risk of incident AD with elective statin use in a clinical trial cohort. Curr. Alzheimer Res. 5, 416–421 (2008).
Steenland, K., Zhao, L., Goldstein, F. C. & Levey, A. I. Statins and cognitive decline in older adults with normal cognition or mild cognitive impairment. J. Am. Geriatr. Soc. 61, 1449–1455
(2013).
Starr, J. M. et al. Life long changes in cognitive ability are associated with prescribed medications in old age. Int. J. Geriatr. Psychiatry 19, 327–332 (2004).
Hippisley-Cox, J. & Coupland, C. Unintended effects of statins in men and women in England and Wales: population based cohort study using the QResearch database. BMJ 340, c2197
(2010).
Chou, C.-Y., Chou, Y.-C., Chou, Y.-J., Yang, Y.-F. & Huang, N. Statin use and incident dementia: a nationwide cohort study of Taiwan. Int. J. Cardiol. 173, 305–310 (2014).
Beydoun, M. A. et al. Statins and serum cholesterol’s associations with incident dementia and mild cognitive impairment. J. Epidemiol. Community Health 65, 949–957 (2011).