712442

review-article2017
TAJ0010.1177/2040622317712442Therapeutic Advances in Chronic DiseaseG. Rakesh et al.

Therapeutic Advances in Chronic Disease Review

Strategies for dementia prevention: latest

Ther Adv Chronic Dis

2017, Vol. 8(8-9) 121­–136

evidence and implications DOI: 10.1177/

https://doi.org/10.1177/2040622317712442
https://doi.org/10.1177/2040622317712442
2040622317712442

© The Author(s), 2017.

Reprints and permissions:
Gopalkumar Rakesh, Steven T. Szabo, George S. Alexopoulos and Anthony S. Zannas http://www.sagepub.co.uk/
journalsPermissions.nav

Abstract:  Dementia is a common and debilitating syndrome with enormous impact on

individuals and societies. Preventing disease onset or progression would translate to public
health and societal benefits. In this review, we discuss the latest evidence on interventions
that may show promise for the prevention of cognitive decline. We appraise existing evidence
primarily drawn from randomized controlled trials, systematic reviews, and meta-analyses,
but also highlight observational studies in humans and relevant work in model organisms.
Overall, there is currently limited evidence to support a cause–effect relationship between
any preventive strategy and the development or progression of dementia. However, studies to
date suggest that a multifactorial intervention comprising regular exercise and healthy diet,
along with the amelioration of vascular risk factors, psychosocial stress, and major depressive
episodes may be most promising for the prevention of cognitive decline. We discuss the
challenges, future directions, and implications of this line of research.

Keywords:  antidepressants, cognitive decline, dementia, exercise, immunomodulators, major

depression, meditation, mediterranean diet, mild cognitive impairment, psychosocial stress
Received: 16 November 2016; revised manuscript accepted: 24 April 2017

Introduction dementia prevention and treatment a public

Dementia encompasses a wide range of neu- health priority,5 and simulation studies suggest
ropsychiatric and medical conditions character- that even delaying disease onset by 2 years would
ized by cognitive deficits that interfere with daily have substantial public health, economic, and
life. The most common form of dementia is societal benefits.6,7
Correspondence to:
Alzheimer disease (AD), which accounts for Anthony S. Zannas
approximately two thirds of all cases.1 The In this article, we review and critically appraise Department of
Translational Research
remaining cases result from a number of condi- the latest evidence on interventions with potential in Psychiatry, Max Planck
tions with diverse etiologies.2 Importantly, the role in the prevention of cognitive syndromes. In Institute of Psychiatry,
Kraepelinstrasse 2-10,
pathological brain processes that underlie AD particular, we discuss strategies that target modi- 80804 Munich, Germany
and other dementias commence long before fiable risk factors that have the potential to act Division of Translational
clinical manifestation and progress slowly this before disease onset, increasing the cognitive Neuroscience, Department
of Psychiatry and
creates the prospect for developing interventions reserve of healthy individuals and delaying the Behavioral Sciences, Duke
that aim at early identification and treatment of development of neuropathological changes char- University Medical Center,
Durham, NC, USA
the preclinical stages of the disease. acteristic of dementia. Early prevention strate- aszannas@gmail.com
gies include lifestyle factors such as nutrition, Gopalkumar Rakesh
In 2015, 47 million people were estimated to be exercise, stress reduction, amelioration of vascu- Steven T. Szabo
Department of Psychiatry
living with dementia globally, and this number is lar risk factors like hypertension and diabetes and Behavioral Sciences,
projected to rapidly increase, reaching 75 mil- mellitus, treatment of major depressive disorder Duke University Medical
Center, Durham, NC, USA
lion by 2030 and 135 million by 2050.3 The esti- (MDD), and immunomodulators. The review Veteran Affairs Medical
mated global cost (direct and indirect financial also highlights the latest evidence on strategies Center, Durham, NC, USA
George S. Alexopoulos
burden on healthcare) for dementia is $818 bil- that examine later stages of cognitive syndromes, Department of Psychiatry,
lion and is expected to increase to $2 trillion by including interventions that aim at preventing the Weill Cornell Institute of
Geriatric Psychiatry, Weill
the year 2030.4 Recognizing this challenge, progression of mild cognitive impairment (MCI) Cornell Medical College,
the World Health Organization has declared to dementia. These include optimal control of White Plains, NY, USA

journals.sagepub.com/home/taj 121
Therapeutic Advances in Chronic Disease 8(8-9)
vascular risk factors, stress reduction, and treat-
ment of MDD, but also immunomodulators, vac-
cines, cognitive retraining, and non-invasive brain
stimulation. Lastly, we discuss the challenges,
future directions, and implications of this line of
research.
Review criteria
The aim of this article is not to comprehensively
review the entirety of the literature, but to high-
light and critically appraise studies examining
strategies that may hold promise for dementia
prevention. The included studies were identified
in Pubmed, EMBASE, and PsycINFO, using the
following combinations of search terms: demen-
tia, cognitive impairment, cognitive decline,
Alzheimer’s disease, diet, nutrition, exercise,
physical activity, vascular risk, hypertension, dia-
betes mellitus, cognitive training, stress reduc-
tion, MDD, antidepressants, immunomodulators.
Although we included studies from all time peri-
ods, particular emphasis was placed on high-
quality studies published in the last 5 years,
including randomized controlled trials (RCTs),
systematic reviews, and meta-analyses, but also
observational studies in humans and relevant
work in animal models.
Mild cognitive impairment and dementia:
strategies for prevention
Evidence supports the existence of prodromal
stages of dementia, including preclinical disease
and the early clinical stage of MCI.8,9 The hall-
mark of MCI is the presence of cognitive deficits
beyond what is expected for age but not severe
enough to cause disruption of daily life.10,11 MCI
represents a common prodrome of dementia
with an annual conversion rate to clinically definite
dementia of 10–15%.12,13 Given that different
stages and trajectories of cognitive decline may
vary in their response to distinct interventions,14
distinguishing the various stages of the disease
and the underlying pathogenic processes will be
essential for the development of personalized pre-
vention programs.
Epidemiological studies have highlighted the con-
cept of ‘cognitive reserve’: individuals with a
higher number of years of education and cogni-
tive functioning status show symptoms of
dementia later than those with lower educational
status. However, once individuals with higher
cognitive reserve exhibit symptoms of dementia,
122 journals.sagepub.com/home/taj
they show more rapid disease progression than
individuals at the other end of the spectrum.
This observation speaks to the complex relation
between cognitive reserve and cognitive
deterioration.15
Existing literature, including the World Alzheimer
Report, advocates for a multipronged approach to
dementia prevention, given the role played by
multiple risk factors for the disease. A total of
48.4% of dementia cases can be attributed to
seven modifiable lifestyle risk factors: smoking,
midlife obesity, physical inactivity, low educa-
tional attainment, diabetes mellitus, hypertension
and MDD.16 The World Alzheimer Report 2014
details an inverse relationship between physical
activity and dementia, with pooled relative risk
(RR) for dementia of 0.66 when comparing high
versus low physical activity, whereas the pooled
RR for AD is 1.52 when comparing smokers
versus nonsmokers. The report also summarized
benefits for cognitive stimulation on improve-
ment in several cognitive domains, including
executive function, attention and processing
speed, and memory; but not working memory.17
Nutrition and prevention of dementia
Evidence suggests that diet interventions may
show promise for the prevention of cognitive
decline. A recent systematic review that included
18 studies, 5 of which were RCTs showed that
Mediterranean diet, a nutritional style based on
fruits, vegetables, and fish can delay cognitive
decline, as measured across multiple domains of
memory and executive function.18 These findings
were consistent with an independent review that
included only RCTs and found beneficial effects
of Mediterranean diet on both global cognitive
functioning, as well as memory, language, and
domains of executive function.19 Despite these
effects on neuropsychological outcomes, how-
ever, there was overall no significant impact of
Mediterranean diet on incident dementia and
controversial impact on incident MCI.19 Notably,
the beneficial impact of the Mediterranean diet
on cognition may be enhanced when combining
this dietary style with the Dietary Approach to
Systolic Hypertension (DASH) diet. Studies sug-
gest that this hybrid diet is associated with delayed
age-related cognitive decline and decreased risk
for incident AD.20,21
Other nutritional components examined to date
include omega-3 fatty acids, vitamins of the B

complex, and vitamin E. However, a systematic
review and meta-analysis, which included 24
RCTs, found no significant effects for any of
these nutrients on cognitive function.22 Beneficial
effects have been reported by isolated studies for
other nutrients, including green tea extract,23
concord grape juice,24 chromium picolinate,25
vitamin D,26,27 and beta carotene.28 The effect of
vitamin B supplementation on progression of
MCI to dementia was assessed by the VITACOG
study. Significant delay of brain atrophy was
observed with a combination of vitamin B12,
folate, and pyridoxine compared with placebo,
especially in people with high homocysteine lev-
els.29 In the Finnish Diabetes Prevention Study,
lower intake of saturated fatty acids, as well as fre-
quent physical activity, correlated with better
cognitive performance measured over a period of
13 years.30,31 This preliminary evidence requires
further examination by future studies.
In summary, Mediterranean diet, both alone and
in combination with DASH, may be beneficial for
the prevention of cognitive decline. Future stud-
ies will need to rule out potential confounders
and better characterize the mechanisms underly-
ing the role of nutrition in cognitive outcomes.
For example, it will be important to characterize
whether dietary modifications may influence
dementia risk via effects on biological processes
relevant for neuronal function, including the
amelioration of oxidative stress and the mainte-
nance of neuronal membrane integrity,32 or to
what extent this influence results indirectly from
the attenuation of other risk factors for dementia,
such as hypertension or excessive body weight.33
Physical exercise and dementia prevention
Association between physical activity/exercise
and cognition
Evidence suggests that physical exercise may
improve cognition in older adults with normal
cognitive function, but also in individuals with
different levels of cognitive impairment. Beneficial
effects on cognition have been shown for aerobic
and resistance exercise in both humans and
rodent studies.34–37 Multiple long-term follow-up
studies have explored the connection between
physical activity and dementia, including the
LADIS study,38 the Rotterdam Study,39 and the
Caerphilly Prospective study.40 In a landmark
trial evaluating the usefulness of combining phys-
ical exercise and cognitive training in adults with
journals.sagepub.com/home/taj 123
G Rakesh, ST Szabo et al.
cognitive impairment [Mental Activity and eXer-
cise (MAX) trial], all participant groups showed
cognitive improvement. The study lacked a pure
control group and all participants received some
form of physical and mental stimulatory exercise
(mental activity and exercise for 60 min/day for 3
days/week for 12 weeks). The study found that
the amount of activity is more important than the
type of activity.41,42 In another study, exercise
was found to be more effective in slowing down
cognitive decline than was cognitive training.43
In accordance, older adults with normal cognitive
functioning who engaged in 3–4 instances of
moderate-to-vigorous-intensity exercise of at least
30 min duration every week showed lower risk for
cognitive decline over the course of 8 years.44 In
individuals with MCI, physical exercise can
improve several cognitive domains, including ver-
bal and spatial memory,45 and even delay progres-
sion to dementia.46 In patients with dementia,
evidence from 18 RCTs, recently synthesized in a
meta-analysis, showed that aerobic exercise alone
or in combination with nonaerobic exercise may
improve cognitive function.47
Mechanisms by which physical activity/exercise
may aid cognition
Postulated mechanisms for the beneficial effects
of exercise on cognition include the enhance-
ment of neurotrophin production and signal-
ing,48–50 the induction of angiogenesis and blood
flow in the brain,51,52 the amelioration of inflam-
matory processes,53 and the induction of epige-
netic modifications in brain regions relevant for
cognition.54
Recent studies and ongoing trials
Recent studies have also coupled physical exer-
cise with other interventions. The Life
Randomized Trial (Lifestyle Interventions and
Independence for Elders) recruited 1635 com-
munity-living participants at risk for cognitive
impairment at eight US centers from February
2010 until December 2011. The interventions
comprised either a structured, moderate-intensity
physical activity program, which included walk-
ing, resistance training, and flexibility exercises,
or a health education program of educational
workshops and upper-extremity stretching. No
differences in executive function were observed
between the two interventions over a period of 24
months when comparing adults over 80 years of
age or those with lower baseline physical activity
Therapeutic Advances in Chronic Disease 8(8-9)
performance who did benefit with the physical
activity intervention.55
Several ongoing trials seek to better characterize the
effect of physical exercise on cognitive decline. The
Finnish Geriatric Intervention Study to Prevent
Cognitive Impairment and Disability (FINGER) is
an ongoing trial recruiting individuals whose cogni-
tive performance is lower than average to partici-
pate in a multidomain intervention trial over a
2-year period. Interventions comprise nutritional
guidance, exercise, education on vascular risk fac-
tors and cognitive retraining. Nutritional interven-
tions comprise a diet low in carbohydrates and salt,
and with adequate amounts of unsaturated fatty
acids (from fish). Exercise consists of weekly physi-
cal activity encompassing both aerobic exercise and
muscle-strength training ranging from 30 to 60
min. Preliminary results suggest some beneficial
effect on cognitive domains assessed with a neu-
ropsychological battery for the intervention group
as compared with the control group.56 Another
ongoing trial will examine the combination of lean
red meat consumption and exercise (220 g of lean
red meat cooked and divided into two 80 g serv-
ings on each of the 3 days that they complete their
exercise session) in the form of progressive resist-
ance training (PRT) in community-dwelling indi-
viduals aged > 65 years for a duration of 48 weeks.
In this trial, PRT comprises a detailed exercise
regimen that occurs in 3 consecutive days of a week
ranging a duration of 30–75 min. Outcomes include
muscle mass, cognitive performance and inflam-
matory serum markers.57 The Australian Imaging
Biomarkers and Lifestyle Flagship Study of Aging
(AIBL) will examine if a combination of moderate
home-based physical activity (150 min every
week) and behavioral interventions over a period
of 24 weeks in patients with MCI and vascular
risk factors would cause changes in white matter
hyperintensities on magnetic resonance imaging
(MRI), changes in cognition, and positron emis-
sion tomography (PET)-measured amyloid–beta
(Aβ) burden.58 The Multidomain Alzheimer
Preventive Trial (MAPT study) aims at assessing
the effect of a combined approach with omega-3
fatty acids, physical activity, nutritional coun-
seling, and cognitive training in a group of adults
with cognitive impairment over a period of 3
years.59
Future directions
Challenges faced by studies examining the
impact of physical exercise on dementia
124 journals.sagepub.com/home/taj
prevention include the interindividual variability
in response to these interventions, differences
between physical activity and exercise, the diffi-
culty in quantifying benefits, and the heteroge-
neity of interventions across studies, which
overall impede replication efforts. Although
physical activity has moderate effect size in the
World Alzheimer’s Disease Report,17 more
RCTs are required to validate its recommenda-
tion as a lifestyle intervention.
Vascular risk factors and dementia
prevention
Vascular disease can predispose to the develop-
ment of dementia syndromes, including vascular
dementia and AD.60–62 Therefore, the ameliora-
tion of predisposing conditions for vascular
pathology, such as hypertension, dyslipidemia,
and diabetes, may be an important target for
dementia prevention.
The relationship of antihypertensive treatment
and risk for dementia has been examined by both
observational studies and RCTs. A recent sys-
tematic review found that antihypertensive medi-
cations may result in 19–55% reduced risk of
cognitive decline, vascular dementia, and AD.63
Nonetheless, the effect of antihypertensive treat-
ment on dementia risk is weaker when consider-
ing only RCTs,64 suggesting the presence of
confounding factors. A previous meta-analysis
concluded that antihypertensive treatment could
only decrease the risk of vascular dementia but
not Alzheimer dementia or cognitive decline.65 In
addition, negative results have been reported when
examining subjects without vascular disease,66,67
indicating that antihypertensive medications may
be more effective as a prevention strategy if tar-
geted at individuals with high risk for vascular dis-
ease. Among the classes of antihypertensive
medications, the strongest effect has been observed
for modulators of the renin–angiotensin system
(RAS), which may decrease the risk for cognitive
decline and dementia and slow conversion of
MCI to dementia.63,68,69 The effect of RAS mod-
ulators may be to an extent explained by their
actions in brain regions relevant for cognition that
are independent of effects in the vasculature.70
Supporting this hypothesis, polymorphisms of
RAS genes were associated with hippocampal
volume loss and longitudinal decline in the epi-
sodic memory performance of older adults.71,72
These findings also raise the possibility that tar-
geting carriers of these polymorphisms with RAS

modulators may be a promising strategy for the
prevention of dementia.
Studies have also examined the potential role of
interventions for dyslipidemia, but there is cur-
rently limited evidence to support their role in
dementia prevention. Prospective studies have
found an association of lipid-lowering drugs, and
in particular statins, with decreased risk for MCI
and dementia,73–75 and this association may be
independent of other vascular risk factors.74
Despite these encouraging reports, RCTs to date
have shown contradictory results and a recent
systematic review reported no significant effect of
statins on risk for cognitive decline or demen-
tia.76,77 Further studies that control for concomi-
tant vascular risk factors and other potential
confounders will need to delineate the potential
role of lipid-lowering interventions for dementia
prevention.
Lastly, studies have examined the potential to
prevent dementia by treating diabetes mellitus.
Association studies suggest that patients with dia-
betes have up to three times higher risk for the
development of dementia,78–80 and this risk
remains significant after adjusting for other vas-
cular risk factors.81 Notably, diabetes may confer
greater risk for vascular dementia in women than
in men,82 suggesting that vascular risk factors
for dementia may have sex-specific effects.
Longitudinal studies have also observed increased
incidence of dementia in patients with diabetes.83
However, negative findings are also reported,84
and a systematic review of RCTs found no effect
of treatment of diabetes mellitus on cognitive
decline.85 Potential explanations for these dis-
crepancies include the heterogeneity in the popu-
lations studied and the inadequate adjustment for
potential confounders. Beyond the acceleration
of microvascular pathology in the brains of dia-
betic patients, diabetes may confer risk for cogni-
tive impairment through other end-organ damage,
such as diabetic retinopathy, and through fluctua-
tions in blood glucose and insulin levels that
could influence clearance of Aβ.86–88
Major depressive disorder and risk for
cognitive decline
Neurobiological mechanisms
MDD is strongly associated with increased risk
for cognitive decline,80,89,90 but the causal direc-
tion of this association remains unclear. Most
journals.sagepub.com/home/taj 125
G Rakesh, ST Szabo et al.
studies have examined MDD occurring in late
life, proposing that depressive syndromes could
be a sequela, prodrome, or risk factor for demen-
tia.91 Depressive episodes have been associated
with persistent deficits in select cognitive
domains, including psychomotor retardation and
executive function,92 which may in turn predict
worse antidepressant treatment outcomes.93
Notably, the increasing burden of depressive ill-
ness, manifested by earlier onset, repetitive
MDD episodes, and greater illness severity and
duration, may cumulatively increase the risk for
dementia94–96 and predict structural brain
changes that are associated with higher risk for
cognitive decline, such as hippocampal and corti-
cal atrophy.97–99 MDD may further accelerate the
progression of MCI to dementia.100,101 Beyond
the MDD-related hippocampal and brain atro-
phy, other plausible neurobiological substrates
linking MDD and cognitive decline include the
downregulation of neurotrophins, the accumula-
tion of Aβ, and the accentuation of age-related
vascular changes and inflammatory processes in
brain circuits with critical roles in mood and
cognition.102–104 Furthermore, MDD throughout
life contributes to higher risk for cerebrovascu-
lar disease in a dose–effect manner,105–108 thus
increasing the likelihood for the clinical expres-
sion of dementia as amyloid and other brain
pathologies progress.109
Evidence linking major depressive disorder and
cognitive decline
While the sequence and exact role of these path-
ogenic events remain to be determined, the find-
ings to date suggest that timely identification
and treatment of MDD, which is a highly preva-
lent disorder impacting every age and popula-
tion, may substantially influence cognitive
functioning in late life. RCTs examining this
question show that effective treatment of MDD
may result in improvements across several cog-
nitive domains, including attention, psychomo-
tor speed, and executive function.110–112 Most
RCTs reporting beneficial effects have utilized
selective serotonin reuptake inhibitors,110,111,113
whereas negative findings have been reported in
observational studies114,115 and studies utilizing
tricyclic antidepressants.116 The identification
and treatment of MDD may be more effective
when targeted at high-risk subjects; for example,
untreated depression has been shown to increase
risk for negative cognitive outcomes following
stressful life experiences.117
Therapeutic Advances in Chronic Disease 8(8-9)
Despite these observations, there is a paucity of
studies examining the long-term impact of MDD
treatment on incident dementia. Furthermore,
several challenges are involved in the selection of
antidepressant strategies, particularly in patients
with cerebrovascular disease. Antidepressants are
the most commonly used treatment for MDD but
their efficacy is modest, at best helping 50% of
patients. The efficacy of antidepressants is even
lower in older patients, and their use has been
linked to cerebrovascular stigmata. Complicating
the picture further, recent studies have reported
an association of antidepressants with increased
risk for ischemic and hemorrhagic stroke. The
Women’s Health Initiative reported a 45%
increase in the risk of stroke.118 A large case-con-
trol study also found antidepressants to be linked
with a 20–40% increase in the risk of stroke,119
but disagreement on this association exists.120,121
Nonpharmacological, behavioral interventions
are a reasonable intervention for MDD without
the risk of increasing vascular pathology. An addi-
tional advantage of nonpharmacological therapies
is that they can target both depression and poor
health behaviors that increase the risk of stroke.
However, most nonpharmacological therapies are
complex, are rarely implemented in the commu-
nity correctly, and have limited scalability and
reach. We have proposed that neurobiological
concepts can be used to identify distinct behavio-
ral targets and use them, as simplification rules to
streamline behavioral interventions to enable
their use by community clinicians. We used con-
cepts of the Research Domain Criteria project
and our findings to develop a neurobiological
model of depression and utilized it in a simplified
behavioral intervention (Engage),122 which
appears to have similar efficacy to problem-solv-
ing therapy.123
Treatment of major depressive disorder to
prevent cognitive decline
Antidepressant and mood-stabilizing strategies
have also been examined in patients who already
have some degree of cognitive impairment. In a
group of healthy subjects, 60 mg of citalopram
given in divided doses of 30 mg reduced (Aβ) pro-
duction by 38% compared with placebo.124 In a
group of 45 patients with MCI treated with lithium
versus placebo, treatment with lithium titrated to a
blood level of 0.25–0.5 mEq/l for a year slowed
down cognitive deterioration compared with
placebo, as measured with the Alzheimer’s Disease
126 journals.sagepub.com/home/taj
Assessment Scale-Cognitive subscale. Lithium
also decreased the level of phosphorylated tau in
patients with MCI.125 In a study examining the
association between amyloid pathology and
remission of depressive symptoms with electro-
convulsive therapy (ECT), remitters showed sig-
nificantly lower Aβ40/Aβ42 than nonremitters.126
In a group of patients with MDD receiving ECT,
there were changes in levels of CSF Aβ1-42,
the (Aβ) isoform with highest amyloidogenic
potential.127 RCTs examining dementia pre-
vention as a result of ECT are lacking; however,
evidence points to an increase in hippocampal
volume with ECT,128,129 thus providing a patho-
physiological basis for the potential role of severe
MDD treatment in dementia prevention.130,131
The role of pharmacological and nonpharmaco-
logical antidepressant strategies in preventing
dementia onset and progression warrants further
examination by future studies.
Stress reduction as a dementia prevention
strategy: role of meditation
Psychosocial stressors, most notably chronic and
perceived stress, have been associated with lower
levels of cognitive performance across several
domains and with faster cognitive decline in both
healthy adults and subjects with MCI.132–137
Furthermore, chronic stress may indirectly influ-
ence cognitive function by moderating the impact
of other risk factors on cognitive function; for
example, metabolic risk factors strongly acceler-
ate the 8-year cognitive decline in chronically
stressed caregivers of a relative with dementia.138
These observations in human studies are congru-
ent with a large body of evidence in rodent and
other vertebrate models indicating that chronic
stress can impair cognitive performance.139–141
Notably, this negative influence is observed when
stressors are unpredictable, whereas mild pre-
dictable stress may actually enhance cognitive
performance.142 Furthermore, the impact of
chronic stress can manifest long after stressor
cessation; for instance, stress exposure during
adolescence may impair spatial memory when
mice age.143 The effects of stress on cognitive
function may be mediated by several mecha-
nisms, including the accumulation of Aβ in the
brain,144,145 the induction of brain inflamma-
tion,146 epigenetic modifications mediated by
stress-induced glucocorticoid deregulation,147–149
and changes in brain structures with central roles
in cognition, such as the hippocampus.150–152

Some of these effects, however, may vary depend-
ing on the timing and duration of stress
exposure.148,153
The negative impact of chronic and perceived
stress on cognition suggests that interventions aim-
ing at controlling stress levels may be beneficial for
dementia prevention. Supporting this notion, reg-
ular meditation may improve cognitive function of
healthy individuals.154,155 Furthermore, prelimi-
nary evidence suggests that long-term meditation
may delay age-related decline of several cognitive
functions156,157 and improve some neuropsycho-
logical outcomes in subjects with MCI.158 A rand-
omized trial which employed mindfulness-based
stress reduction (MBSR) found that MBSR-
treated patients with MCI showed improved cog-
nitive performance compared with the those
who received usual care.159 Furthermore, MBSR
increased functional connectivity between the pos-
terior cingulate cortex and bilateral medial pre-
frontal cortex and left hippocampus in adults with
MCI.160 Although these findings are encouraging,
the small sample sizes and potential confounders
of studies to date limit conclusions and call for
confirmation by larger RCTs.
Prevention by addressing other lifestyle
parameters
Several other lifestyle parameters, including the
level of education, smoking, and alcohol con-
sumption may influence the incidence of demen-
tia.87,161,162 Given that such factors frequently
coexist within individuals and synergize to influ-
ence the risk for cognitive decline, interventions
that address multiple risk factors in a coordinated
manner are more likely to prove beneficial for the
early prevention of dementia.
Cognitive retraining and dementia
Cognitive interventions for dementia syndromes
encompass a wide range of modalities, including
cognitive training that targets one domain and
increasing task difficulty as expertise develops,
cognitive stimulation targeting multiple domains
with emphasis on social interaction, and cognitive
rehabilitation tailored at improving activities of
daily living. These interventions aim at enhancing
cognitive reserve, that is, the structural and
dynamic capacities of brain circuits that compen-
sate when one or more brain regions do not func-
tion adequately, thus increasing resilience against
the neuropathological changes of dementia.15,163
journals.sagepub.com/home/taj 127
G Rakesh, ST Szabo et al.
Several long-term follow-up studies have looked
at trajectories of cognitive impairment and the
effect of cognitive stimulation, including the
German Interdisciplinary Longitudinal Study on
Adult Development and Aging Study, the
Minority Aging Research Study, the Memory and
Ageing Project, the Chicago Health and Ageing
Project, and the Betula prospective cohort study.
The PACE study was an RCT designed to study
the effect of cognitive interventions on the pro-
gression of MCI. The intervention group received
supervised education on cognitive retraining
strategies. Over a period of 2 years, there was no
significant effect on progression to dementia;164
however, a limitation of the trial was the lack of
active supervised task engagement for the partici-
pants of the intervention group beyond the 5-week
intervention period.
Non-invasive brain stimulation to modify the
course of dementia
A recent meta-analysis showed that non-invasive
modalities of brain stimulation (including repeti-
tive transcranial magnetic stimulation and tran-
scranial direct current stimulation) may
significantly improve cognitive function in both
healthy older adults and patients with AD.165
Notably, multiple sessions of brain stimulation
were twice as effective in improving cognition
than were single sessions, suggesting that a sus-
tained treatment effect is needed to modify brain
function. However, studies to date are limited by
the short duration of the follow-up after the inter-
vention,166–169 not allowing conclusions about the
long-term impact of brain stimulation on the
development and course of dementia. Notably,
preliminary evidence suggests that the lack of
neuropsychological and electrophysiological
response to brain stimulation may represent a
biomarker of increased risk for progression of
MCI to dementia.131 These findings and the role
of brain stimulation in dementia prevention war-
rant further examination by longitudinal RCTs
with long duration of follow up.
Immunomodulators to prevent dementia
The effect of immunomodulators, including active
immunization using vaccines and passive immuni-
zation with chimeric antibodies, have also been
evaluated as a therapeutic strategy in AD.170 Active
immunization to date includes either the use of tau
peptide conjugates or the use of prefibrillized syn-
thetic (Aβ1–42). Tau is a phosphoprotein with 85
Therapeutic Advances in Chronic Disease 8(8-9)

Figure 1.  Schematic summary of the strategies that may show promise for the prevention of dementia at
different stages of the disease. Details for each intervention are provided in the text. Overall, the evidence for
preventing dementia is, to date, limited, and the exact role of these interventions warrants further examination
by future studies.
DASH, Dietary Approach to Systolic Hypertension diet; MDD, major depressive disorder.

phosphorylation sites. Selective targeting of indi- was recently terminated (NCT01850238,

vidual sites with engineered tau peptide conjugate
is one way of active immunization. In rodent mod-
els, active vaccination has achieved a striking
decrease in tau oligomer aggregation, tau hyper-
phosphorylation, and neurofibrillary burden.171 In
humans, however, the initial vaccine used, AN1972
(combination of prefibrillized synthetic Aβ and
adjuvant), had modest efficacy on cognitive func-
tioning, and clinical trials were halted due to the
adverse effect of subacute meningoencephalitis.172
Newer vaccines, such as ACC-001 (also known as
Vanutide cridificar), containing multiple short Aβ
fragments linked to a carrier made of inactivated
diphtheria toxin demonstrated a safer profile in
phase II trials,173 but did not prove to be effica-
cious and trials were discontinued.174 AADvac-1 is
a vaccine which is currently in a phase II trial and
consists of modified tau protein (synthetic peptide
derived from amino acids 294–305 of the tau
sequence, coupled with hemocyanin). Passive
immunization, using agents such as bapineuzumab
and solanezumab, has been tested in phase III
trials. Patients with mild or moderate dementia
treated with bapineuzumab showed no substantial
improvement in any primary cognitive outcome,
and the main adverse effect related to the drug was
vasogenic cerebral edema.175 Trials with solane-
zumab (EXPEDITION 1, 2 and 3 and
EXPEDITION-PRO) did not show robust
changes in cognition, and a phase III trial
NCT02031198). Other immunomodulators being
tested include intravenous immunoglobulin
infusions and passive immunization with gan-
tenerumab, BAN2401, aducanumab, and crene-
zumab. The potential role of these approaches in
preventing dementia remains to be determined.
Conclusion and future directions
As summarized in Figure 1 and Table 1, several
preventive strategies have been examined to date,
but there is currently limited evidence to support
a cause–effect relationship between any strategy
and the development or progression of dementia.
Most animal studies have targeted the amyloid
cascade in the pathogenesis of dementia, showing
encouraging or even enthusiastic results in model
organisms; however, therapeutic interventions
derived from these studies have not been able to
meaningfully impact disease course. This lack of
therapeutic translation calls for animal models
that target novel mechanisms and encapsulate the
multifactorial processes implicated in the patho-
genesis and progression of dementia. Studies in
humans face major challenges, including the mul-
tiple confounding factors, the clinical heterogene-
ity of dementia syndromes, and the need to
properly randomize and follow subjects over the
long term. Keeping these limitations in mind,
studies to date indicate that a multifactorial

128 journals.sagepub.com/home/taj

Table 1.  Overall appraisal of existing strategies for
the prevention of cognitive decline (rating is based on
the GRADE system).176
Intervention Strength of
evidence
Physical activity +++
Treatment of vascular risk factors +++
Dietary modification ++
Treatment of MDD ++
Cognitive retraining ++
Stress reduction ++
Immunomodulators + computer model of dementia prevalence in
Brain stimulation
+
+++, moderate; ++, low; +, very low; MDD, major
depressive disorder.
intervention approach characterized by regular
exercise and healthy diet, along with the amelio-
ration of vascular risk factors, psychosocial stress,
and major depressive episodes, may be most
promising for the prevention of cognitive decline.
Future studies may help to determine the exact
role of these interventions and to identify novel
modalities with therapeutic benefit for the differ-
ent stages of cognitive decline.
Funding
This research received no specific grant from any
funding agency in the public, commercial, or not-
for-profit sectors.
Conflict of interest statement
The authors declare that there is no conflict of
interest.
References
1. Winblad B, Amouyel P, Andrieu S, et al.
Defeating Alzheimer’s disease and other
dementias: a priority for European science and
society. Lancet Neurol 2016; 15: 455–532.
2. Small GW. Detection and prevention of
cognitive decline. Am J Geriatr Psychiatry 2016;
24: 1142–1150.
3. Prince M, Ali GC, Guerchet M, et al. Recent
global trends in the prevalence and incidence
of dementia, and survival with dementia.
Alzheimers Res Ther 2016; 8: 23.
4. Prince M, Comas-Herrera A, Knapp M,
et al. World Alzheimer report 2016: improving
journals.sagepub.com/home/taj 129
G Rakesh, ST Szabo et al.
healthcare for people living with dementia: coverage,
quality and costs now and in the future. London,
UK: Alzheimer’s Disease International,
2016, https://www.alz.co.uk/research/
WorldAlzheimerReport2016.pdf2016.
5. Wortmann M. Dementia: a global health
priority – highlights from an ADI and World
Health Organization report. Alzheimers Res Ther
2012; 4: 40.
6. Brodaty H, Breteler MM, Dekosky ST, et al.
The world of dementia beyond 2020. J Am
Geriatr Soc 2011; 59: 923–927.
7. Vickland V, McDonnell G, Werner J, et al. A
Australia: foreseeing outcomes of delaying
dementia onset, slowing disease progression,
and eradicating dementia types. Dement
Geriatr Cogn Disord 2010; 29: 123–130.
8. Mufson EJ, Binder L, Counts SE, et al.
Mild cognitive impairment: pathology and
mechanisms. Acta Neuropathol 2012; 123:
13–30.
9. Ismail Z, Smith EE, Geda Y, et al.
Neuropsychiatric symptoms as early
manifestations of emergent dementia:
provisional diagnostic criteria for mild
behavioral impairment. Alzheimers Dement 2016;
12: 195–202.
10. Langa KM and Levine DA. The diagnosis and
management of mild cognitive impairment:
a clinical review. JAMA 2014; 312: 2551–
2561.
11. Apostolo J, Holland C, O’Connell MD, et al.
Mild cognitive decline. A position statement
of the Cognitive Decline Group of the
European Innovation Partnership for Active
and Healthy Ageing (EIPAHA). Maturitas
2016; 83: 83–93.
12. Espinosa A, Alegret M, Valero S, et al. A
longitudinal follow-up of 550 mild cognitive
impairment patients: evidence for large
conversion to dementia rates and detection of
major risk factors involved. J Alzheimers Dis
2013; 34: 769–780.
13. Taragano FE, Allegri RF, Krupitzki H, et al.
Mild behavioral impairment and risk of
dementia: a prospective cohort study of 358
patients. J Clin Psychiatry 2009; 70: 584–592.
14. Leoutsakos JM, Muthen BO, Breitner JC, et al.
Effects of non-steroidal anti-inflammatory drug
treatments on cognitive decline vary by phase
of pre-clinical Alzheimer disease: findings from
the randomized controlled Alzheimer’s Disease
Anti-Inflammatory Prevention Trial. Int J
Geriatr Psychiatry 2012; 27: 364–374.
Therapeutic Advances in Chronic Disease 8(8-9)
15. Stern Y. Cognitive reserve in ageing and
Alzheimer’s disease. Lancet Neurol 2012; 11:
1006–1012.
16. Ashby-Mitchell K, Burns R, Shaw J, et al.
Proportion of dementia in Australia explained
by common modifiable risk factors. Alzheimers
Res Ther 2017; 9: 11.
17. Prince M, Albanese E, Guerchet M, et al.
World Alzheimer’s Dementia Report 2014.
2014; 9. Available at: https://www.alz.co.uk/
research/WorldAlzheimerReport2014.pdf
18. Hardman RJ, Kennedy G, Macpherson H,
et al. Adherence to a Mediterranean-style diet
and effects on cognition in adults: a qualitative
evaluation and systematic review of longitudinal
and prospective trials. Front Nutr 2016; 3: 22.
19. Canevelli M, Lucchini F, Quarata F, et al.
Nutrition and dementia: evidence for preventive
approaches? Nutrients 2016; 8: 144.
20. Morris MC, Tangney CC, Wang Y, et al.
MIND diet associated with reduced incidence
of Alzheimer’s disease. Alzheimers Dement 2015;
11: 1007–1014.
21. Morris MC, Tangney CC, Wang Y, et al.
MIND diet slows cognitive decline with aging.
Alzheimers Dement 2015; 11: 1015–1022.
22. Forbes SC, Holroyd-Leduc JM, Poulin MJ,
et al. Effect of nutrients, dietary supplements
and vitamins on cognition: a systematic review
and meta-analysis of randomized controlled
trials. Can Geriatr J 2015; 18: 231–245.
23. Park SK, Jung IC, Lee WK, et al. A combination
of green tea extract and l-theanine improves
memory and attention in subjects with mild
cognitive impairment: a double-blind placebo-
controlled study. J Med Food 2011; 14: 334–343.
24. Krikorian R, Nash TA, Shidler MD, et al.
Concord grape juice supplementation improves
memory function in older adults with mild
cognitive impairment. Br J Nutr 2010; 103:
730–734.
25. Krikorian R, Eliassen JC, Boespflug EL, et al.
Improved cognitive-cerebral function in older
adults with chromium supplementation. Nutr
Neurosci 2010; 13: 116–122.
26. Balion C, Griffith LE, Strifler L, et al. Vitamin
D, cognition, and dementia: a systematic review
and meta-analysis. Neurology 2012; 79: 1397–
1405.
27. Andreeva VA, Whegang-Youdom S, Touvier
M, et al. Midlife dietary vitamin D intake and
subsequent performance in different cognitive
domains. Ann Nutr Metab 2014; 65: 81–89.
130 journals.sagepub.com/home/taj
28. Grodstein F, Kang JH, Glynn RJ, et al.
A randomized trial of beta carotene
supplementation and cognitive function in men:
the Physicians’ Health Study II. Arch Intern Med
2007; 167: 2184–2190.
29. De Jager CA, Oulhaj A, Jacoby R, et al.
Cognitive and clinical outcomes of
homocysteine-lowering B-vitamin treatment
in mild cognitive impairment: a randomized
controlled trial. Int J Geriatr Psychiatry 2012;
27: 592–600.
30. Lehtisalo J, Lindstrom J, Ngandu T, et al.
Association of long-term dietary fat intake,
exercise, and weight with later cognitive
function in the Finnish Diabetes Prevention
Study. J Nutr Health Aging 2016; 20: 146–
154.
31. Lindstrom J, Louheranta A, Mannelin M, et al.
The Finnish Diabetes Prevention Study (DPS):
lifestyle intervention and 3-year results on diet
and physical activity. Diabetes Care 2003; 26:
3230–3236.
32. Gustafson DR, Clare Morris M, Scarmeas N,
et al. New perspectives on Alzheimer’s disease
and nutrition. J Alzheimers Dis 2015; 46:
1111–1127.
33. Xu WL, Atti AR, Gatz M, et al. Midlife
overweight and obesity increase late-life
dementia risk: a population-based twin study.
Neurology 2011; 76: 1568–1574.
34. Dustman RE, Ruhling RO, Russell EM,
et al. Aerobic exercise training and improved
neuropsychological function of older
individuals. Neurobiol Aging 1984; 5: 35–42.
35. Antunes HK, De Mello MT, de Aquino Lemos
V, et al. Aerobic physical exercise improved the
cognitive function of elderly males but did not
modify their blood homocysteine levels. Dement
Geriatr Cogn Dis Extra 2015; 5: 13–24.
36. Suijo K, Inoue S, Ohya Y, et al. Resistance
exercise enhances cognitive function in mouse.
Int J Sports Med 2013; 34: 368–375.
37. Siette J, Westbrook RF, Cotman C, et al. Age-
specific effects of voluntary exercise on memory
and the older brain. Biol Psychiatry 2013; 73:
435–442.
38. Verdelho A, Madureira S, Ferro JM, et al.
Physical activity prevents progression for
cognitive impairment and vascular dementia:
results from the LADIS (Leukoaraiosis and
Disability) study. Stroke 2012; 43: 3331–3335.
39. De Bruijn RF, Schrijvers EM, de Groot KA,
et al. The association between physical activity
and dementia in an elderly population: the

Rotterdam Study. Eur J Epidemiol 2013; 28:
277–283.
40. Morgan GS, Gallacher J, Bayer A, et al. Physical
activity in middle-age and dementia in later life:
findings from a prospective cohort of men in
Caerphilly, South Wales and a meta-analysis. J
Alzheimers Dis 2012; 31: 569–580.
41. Lautenschlager NT and Cox KL. Can
participation in mental and physical activity
protect cognition in old age?: Comment on ‘The
Mental Activity and eXercise (MAX) trial: a
randomized controlled trial to enhance cognitive
function in older adults.’ JAMA Intern Med
2013; 173: 805–806.
42. Barnes DE, Santos-Modesitt W, Poelke G,
et al. The Mental Activity and eXercise (MAX)
trial: a randomized controlled trial to enhance
cognitive function in older adults. JAMA Intern
Med 2013; 173: 797–804.
43. Law LL, Barnett F, Yau MK, et al. Effects of
functional tasks exercise on older adults with
cognitive impairment at risk of Alzheimer’s
disease: a randomised controlled trial. Age
Ageing 2014; 43: 813–820.
44. Chu DC, Fox KR, Chen LJ, et al. Components
of late-life exercise and cognitive function: an
8-year longitudinal study. Prev Sci 2015; 16:
568–577.
45. Nagamatsu LS, Chan A, Davis JC, et al. Physical
activity improves verbal and spatial memory
in older adults with probable mild cognitive
impairment: a 6-month randomized controlled
trial. J Aging Res 2013; 2013: 861893.
46. Lam LC, Chau RC, Wong BM, et al. Interim
follow-up of a randomized controlled trial
comparing Chinese style mind body (Tai Chi)
and stretching exercises on cognitive function in
subjects at risk of progressive cognitive decline.
Int J Geriatr Psychiatry 2011; 26: 733–740.
47. Groot C, Hooghiemstra AM, Raijmakers PG,
et al. The effect of physical activity on cognitive
function in patients with dementia: a meta-
analysis of randomized control trials. Ageing Res
Rev 2016; 25: 13–23.
48. Berchtold NC, Kesslak JP, Pike CJ, et al.
Estrogen and exercise interact to regulate brain-
derived neurotrophic factor mRNA and protein
expression in the hippocampus. Eur J Neurosci
2001; 14: 1992–2002.
49. Hakansson K, Ledreux A, Daffner K, et al. BDNF
responses in healthy older persons to 35 minutes
of physical exercise, cognitive training, and
mindfulness: associations with working memory
function. J Alzheimers Dis 2017; 55(2): 645–657.
journals.sagepub.com/home/taj 131
G Rakesh, ST Szabo et al.
50. Fahimi A, Baktir MA, Moghadam S, et al.
Physical exercise induces structural alterations
in the hippocampal astrocytes: exploring the
role of BDNF-TrkB signaling. Brain Struct
Funct. Epub ahead of print 29 September 2016.
DOI: 10.1007/s00429-016-1308-8.
51. Isaacs KR, Anderson BJ, Alcantara AA, et al.
Exercise and the brain: angiogenesis in the adult
rat cerebellum after vigorous physical activity
and motor skill learning. J Cereb Blood Flow
Metab 1992; 12: 110–119.
52. Swain RA, Harris AB, Wiener EC, et al.
Prolonged exercise induces angiogenesis and
increases cerebral blood volume in primary
motor cortex of the rat. Neuroscience 2003; 117:
1037–1046.
53. Nascimento CM, Pereira JR, de Andrade LP,
et al. Physical exercise in MCI elderly promotes
reduction of pro-inflammatory cytokines
and improvements on cognition and BDNF
peripheral levels. Curr Alzheimer Res 2014; 11:
799–805.
54. De Meireles LC, Bertoldi K, Cechinel LR, et al.
Treadmill exercise induces selective changes
in hippocampal histone acetylation during the
aging process in rats. Neurosci Lett 2016; 634:
19–24.
55. Sink KM, Espeland MA, Castro CM,
et al. Effect of a 24-month physical activity
intervention vs health education on cognitive
outcomes in sedentary older adults: the LIFE
randomized trial. JAMA 2015; 314: 781–790.
56. Ngandu T, Lehtisalo J, Solomon A, et al. A 2
year multidomain intervention of diet, exercise,
cognitive training, and vascular risk monitoring
versus control to prevent cognitive decline in
at-risk elderly people (FINGER): a randomised
controlled trial. Lancet 2015; 385: 2255–2263.
57. Daly RM, Gianoudis J, Prosser M, et al. The
effects of a protein enriched diet with lean red
meat combined with a multi-modal exercise
program on muscle and cognitive health and
function in older adults: study protocol for a
randomised controlled trial. Trials 2015; 16: 339.
58. Cyarto EV, Lautenschlager NT, Desmond
PM, et al. Protocol for a randomized controlled
trial evaluating the effect of physical activity on
delaying the progression of white matter changes
on MRI in older adults with memory complaints
and mild cognitive impairment: the AIBL Active
trial. BMC Psychiatry 2012; 12: 167.
59. Vellas B, Carrie I, Gillette-Guyonnet S, et al.
MAPT study: a multidomain approach for
preventing Alzheimer’s disease: design and
Therapeutic Advances in Chronic Disease 8(8-9)
baseline data. J Prev Alzheimers Dis 2014; 1:
13–22.
60. Hughes TM and Sink KM. Hypertension and
its role in cognitive function: current evidence
and challenges for the future. Am J Hypertens
2016; 29: 149–157.
61. Love S and Miners JS. Cerebrovascular
disease in ageing and Alzheimer’s disease. Acta
Neuropathol 2016; 131: 645–658.
62. Kling MA, Trojanowski JQ, Wolk DA, et al.
Vascular disease and dementias: paradigm shifts
to drive research in new directions. Alzheimers
Dement 2013; 9: 76–92.
63. Rouch L, Cestac P, Hanon O, et al.
Antihypertensive drugs, prevention of cognitive
decline and dementia: a systematic review of
observational studies, randomized controlled
trials and meta-analyses, with discussion of
potential mechanisms. CNS Drugs 2015; 29:
113–130.
64. Levi Marpillat N, Macquin-Mavier I, Tropeano
AI, et al. Antihypertensive classes, cognitive
decline and incidence of dementia: a network
meta-analysis. J Hypertens 2013; 31: 1073–
1082.
65. Chang-Quan H, Hui W, Chao-Min W, et al.
The association of antihypertensive medication
use with risk of cognitive decline and dementia:
a meta-analysis of longitudinal studies. Int J Clin
Pract 2011; 65: 1295–1305.
66. McGuinness B, Todd S, Passmore P, et al.
Blood pressure lowering in patients without
prior cerebrovascular disease for prevention of
cognitive impairment and dementia. Cochrane
Database Syst Rev 2009; 4: CD004034.
67. Feigin V, Ratnasabapathy Y and Anderson C.
Does blood pressure lowering treatment prevent
dementia or cognitive decline in patients with
cardiovascular and cerebrovascular disease? J
Neurol Sci 2005; 229–230: 151–155.
68. Wharton W, Goldstein FC, Zhao L, et al.
Modulation of renin-angiotensin system may
slow conversion from mild cognitive impairment
to Alzheimer’s disease. J Am Geriatr Soc 2015;
63: 1749–1756.
69. Zhuang S, Wang HF, Wang X, et al. The
association of renin-angiotensin system
blockade use with the risks of cognitive
impairment of aging and Alzheimer’s disease: a
meta-analysis. J Clin Neurosci 2016; 33: 32–38.
70. Zhuang S, Wang HF, Li J, et al. Renin-
angiotensin system blockade use and risks of
cognitive decline and dementia: a meta-analysis.
Neurosci Lett 2016; 624: 53–61.
132 journals.sagepub.com/home/taj
71. Zannas AS, McQuoid DR, Payne ME,
et al. Association of gene variants of the
renin-angiotensin system with accelerated
hippocampal volume loss and cognitive decline
in old age. Am J Psychiatry 2014; 171: 1214–
1221.
72. Taylor WD, Benjamin S, McQuoid DR,
et al. AGTR1 gene variation: association with
depression and frontotemporal morphology.
Psychiatry Res 2012; 202: 104–109.
73. Haag MD, Hofman A, Koudstaal PJ, et al.
Statins are associated with a reduced risk of
Alzheimer disease regardless of lipophilicity.
The Rotterdam Study. J Neurol Neurosurg
Psychiatry 2009; 80: 13–17.
74. Cramer C, Haan MN, Galea S, et al. Use of
statins and incidence of dementia and cognitive
impairment without dementia in a cohort study.
Neurology 2008; 71: 344–350.
75. Song Y, Nie H, Xu Y, et al. Association of statin
use with risk of dementia: a meta-analysis of
prospective cohort studies. Geriatr Gerontol Int
2013; 13: 817–824.
76. McGuinness B, Craig D, Bullock R, et al.
Statins for the prevention of dementia. Cochrane
Database Syst Rev 2016; 1: CD003160.
77. Swiger KJ, Manalac RJ, Blumenthal RS, et al.
Statins and cognition: a systematic review and
meta-analysis of short- and long-term cognitive
effects. Mayo Clinic Proc 2013; 88: 1213–1221.
78. Ott A, Stolk RP, van Harskamp F, et al.
Diabetes mellitus and the risk of dementia: The
Rotterdam Study. Neurology 1999; 53: 1937–
1942.
79. Ninomiya T. Diabetes mellitus and dementia.
Curr Diab Rep 2014; 14: 487.
80. Katon W, Pedersen HS, Ribe AR, et al. Effect
of depression and diabetes mellitus on the
risk for dementia: a national population-based
cohort study. JAMA Psychiatry 2015; 72:
612–619.
81. Ott A, Stolk RP, Hofman A, et al. Association of
diabetes mellitus and dementia: the Rotterdam
Study. Diabetologia 1996; 39: 1392–1397.
82. Chatterjee S, Peters SA, Woodward M, et al.
Type 2 diabetes as a risk factor for dementia in
women compared with men: a pooled analysis
of 2.3 million people comprising more than
100,000 cases of dementia. Diabetes Care 2016;
39: 300–307.
83. Biessels GJ, Staekenborg S, Brunner E,
et al. Risk of dementia in diabetes mellitus: a
systematic review. Lancet Neurol 2006; 5: 64–74.

84. Akomolafe A, Beiser A, Meigs JB, et al.
Diabetes mellitus and risk of developing
Alzheimer disease: results from the
Framingham Study. Arch Neurol 2006; 63:
1551–1555.
85. Areosa SA and Grimley EV. Effect of the
treatment of type II diabetes mellitus on the
development of cognitive impairment and
dementia. Cochrane Database Syst Rev 2002; 4:
CD003804.
86. Bruce DG, Harrington N, Davis WA, et al.;
Fremantle Diabetes Study. Dementia and its
associations in type 2 diabetes mellitus: the
Fremantle Diabetes Study. Diabetes Res Clin
Pract 2001; 53: 165–172.
87. Bruce DG, Davis WA, Starkstein SE, et al.
Mid-life predictors of cognitive impairment
and dementia in type 2 diabetes mellitus: the
Fremantle Diabetes Study. J Alzheimers Dis
2014; 42(Suppl. 3): S63–S70.
88. Ojo O and Brooke J. Evaluating the association
between diabetes, cognitive decline and
dementia. Int J Environ Res Public Health 2015;
12: 8281–8294.
89. Ownby RL, Crocco E, Acevedo A, et al.
Depression and risk for Alzheimer disease:
systematic review, meta-analysis, and
metaregression analysis. Arch Gen Psychiatry
2006; 63: 530–538.
90. Da Silva J, Goncalves-Pereira M, Xavier M,
et al. Affective disorders and risk of developing
dementia: systematic review. Br J Psychiatry
2013; 202: 177–186.
91. Byers AL and Yaffe K. Depression and risk of
developing dementia. Nat Rev Neurol 2011; 7:
323–331.
92. Gorwood P, Richard-Devantoy S, Bayle F,
et al. Psychomotor retardation is a scar of
past depressive episodes, revealed by simple
cognitive tests. Eur Neuropsychopharmacol 2014;
24: 1630–1640.
93. Alexopoulos GS, Meyers BS, Young RC, et al.
Executive dysfunction and long-term outcomes
of geriatric depression. Arch Gen Psychiatry
2000; 57: 285–290.
94. Dotson VM, Beydoun MA and Zonderman
AB. Recurrent depressive symptoms and the
incidence of dementia and mild cognitive
impairment. Neurology 2010; 75: 27–34.
95. Geerlings MI, den Heijer T, Koudstaal PJ, et al.
History of depression, depressive symptoms,
and medial temporal lobe atrophy and the
risk of Alzheimer disease. Neurology 2008; 70:
1258–1264.
journals.sagepub.com/home/taj 133
G Rakesh, ST Szabo et al.
96. Chen R, Hu Z, Wei L, et al. Severity of
depression and risk for subsequent dementia:
cohort studies in China and the UK. Br J
Psychiatry 2008; 193: 373–377.
97. Sheline YI, Gado MH and Kraemer HC.
Untreated depression and hippocampal volume
loss. Am J Psychiatry 2003; 160: 1516–1518.
98. Schmaal L, Veltman DJ, van Erp TG, et al.
Subcortical brain alterations in major depressive
disorder: findings from the ENIGMA Major
Depressive Disorder working group. Mol
Psychiatry 2016; 21: 806–812.
99. Schmaal L, Hibar DP, Samann PG, et al.
Cortical abnormalities in adults and adolescents
with major depression based on brain scans
from 20 cohorts worldwide in the ENIGMA
Major Depressive Disorder Working Group.
Mol Psychiatry. Epub ahead of print 3 May
2016. DOI: 10.1038/mp.2016.60.
100. Richard E, Reitz C, Honig LH, et al. Late-life
depression, mild cognitive impairment, and
dementia. JAMA Neurol 2013; 70: 374–382.
101. Mourao RJ, Mansur G, Malloy-Diniz LF,
et al. Depressive symptoms increase the risk of
progression to dementia in subjects with mild
cognitive impairment: systematic review and
meta-analysis. Int J Geriatr Psychiatry 2016; 31:
905–911.
102. Leyhe T, Reynolds CF III, Melcher T,
et al. A common challenge in older adults:
Classification, overlap, and therapy of
depression and dementia. Alzheimers Dement.
Epub ahead of print 28 September 2016. DOI:
10.1016/j.jalz.2016.08.007.
103. Alexopoulos GS and Morimoto SS. The
inflammation hypothesis in geriatric depression.
Int J Geriatr Psychiatry 2011; 26: 1109–1118.
104. Taylor WD, Aizenstein HJ and Alexopoulos
GS. The vascular depression hypothesis:
mechanisms linking vascular disease with
depression. Mol Psychiatry 2013; 18: 963–974.
105. Colloby SJ, Firbank MJ, He J, et al. Regional
cerebral blood flow in late-life depression:
arterial spin labelling magnetic resonance study.
Br J Psychiatry 2012; 200: 150–155.
106. Colloby SJ, Vasudev A, O’Brien JT, et al.
Relationship of orthostatic blood pressure to
white matter hyperintensities and subcortical
volumes in late-life depression. Br J Psychiatry
2011; 199: 404–410.
107. Vasudev A, O’Brien JT, Tan MP, et al. A study
of orthostatic hypotension, heart rate variability
and baroreflex sensitivity in late-life depression.
J Affect Disord 2011; 131: 374–378.
Therapeutic Advances in Chronic Disease 8(8-9)

108. Vasudev A, Saxby BK, O’Brien JT, et al. a population-based, nested case-control study.
Relationship between cognition, magnetic Ann Pharmacother 2008; 42: 177–184.
resonance white matter hyperintensities, and
120. Bak S, Tsiropoulos I, Kjaersgaard JO, et al.
cardiovascular autonomic changes in late-life
Selective serotonin reuptake inhibitors and the
depression. Am J Geriatr Psychiatry 2012; 20:
risk of stroke: a population-based case-control
691–699.
study. Stroke 2002; 33: 1465–1473.
109. Snowdon DA, Greiner LH, Mortimer JA, et al.
121. Kharofa J, Sekar P, Haverbusch M, et al.
Brain infarction and the clinical expression of
Selective serotonin reuptake inhibitors and
Alzheimer disease. The Nun Study. JAMA
risk of hemorrhagic stroke. Stroke 2007; 38:
1997; 277: 813–817.
3049–3051.
110. Devanand DP, Pelton GH, Marston K, et al.
122. Alexopoulos GS and Arean P. A model for
Sertraline treatment of elderly patients with
streamlining psychotherapy in the RDoC era:
depression and cognitive impairment. Int J
the example of ‘Engage.’ Mol Psychiatry 2014;
Geriatr Psychiatry 2003; 18: 123–130.
19: 14–19.
111. Culang ME, Sneed JR, Keilp JG, et al. Change
123. Alexopoulos GS, Raue PJ, Kiosses DN, et al.
in cognitive functioning following acute
Comparing Engage with PST in late-life major
antidepressant treatment in late-life depression.
depression: a preliminary report. Am J Geriatr
Am J Geriatr Psychiatry 2009; 17: 881–888.
Psychiatry 2015; 23: 506–513.
112. Butters MA, Becker JT, Nebes RD, et al.
124. Sheline YI, West T, Yarasheski K, et al. An
Changes in cognitive functioning following
antidepressant decreases CSF Aß production in
treatment of late-life depression. Am J
healthy individuals and in transgenic AD mice.
Psychiatry 2000; 157: 1949–1954.
Sci Transl Med 2014; 6: 236re4.
113. Barch DM, D’Angelo G, Pieper C, et al.
125. Forlenza OV, Diniz BS, Radanovic M, et al.
Cognitive improvement following treatment in
Disease-modifying properties of long-term
late-life depression: relationship to vascular risk
lithium treatment for amnestic mild cognitive
and age of onset. Am J Geriatr Psychiatry 2012;
impairment: randomised controlled trial. Br J
20: 682–690.
Psychiatry 2011; 198: 351–356.
114. Bali V, Holmes HM, Johnson ML, et al.
126. Piccinni A, Veltri A, Vizzaccaro C, et al.
Comparative effectiveness of second-generation
Plasma amyloid-beta levels in drug-resistant
antidepressants in reducing the risk of dementia
bipolar depressed patients receiving
in elderly nursing home residents with
electroconvulsive therapy. Neuropsychobiology
depression. Pharmacotherapy 2016; 36: 38–48.
2013; 67: 185–191.
115. Saczynski JS, Rosen AB, McCammon RJ, et al.
127. Kranaster L, Aksay SS, Bumb JM, et al.
Antidepressant use and cognitive decline: The
Electroconvulsive therapy selectively enhances
Health and Retirement Study. Am J Med 2015;
amyloid beta 1–42 in the cerebrospinal fluid of
128: 739–746.
patients with major depression: a prospective
116. Meyers BS, Mattis S, Gabriele M, et al. Effects pilot study. Eur Neuropsychopharmacol 2016; 26:
of nortriptyline on memory self-assessment and 1877–1884.
performance in recovered elderly depressives.
128. Cano M, Martinez-Zalacain I, Bernabeu-
Psychopharmacol Bull 1991; 27: 295–299.
Sanz A, et al. Brain volumetric and metabolic
117. Hatch DJ, Schwartz S and Norton MC. correlates of electroconvulsive therapy for
Depression and antidepressant use moderate treatment-resistant depression: a longitudinal
association between widowhood and neuroimaging study. Transl Psychiatry 2017; 7:
Alzheimer’s disease. Int J Geriatr Psychiatry e1023.
2015; 30: 292–299.
129. Steffens DC, McQuoid DR, Payne ME, et al.
118. Smoller JW, Allison M, Cochrane BB, et al. Change in hippocampal volume on magnetic
Antidepressant use and risk of incident resonance imaging and cognitive decline among
cardiovascular morbidity and mortality among older depressed and nondepressed subjects in
postmenopausal women in the Women’s Health the neurocognitive outcomes of depression in
Initiative study. Arch Intern Med 2009; 169: the elderly study. Am J Geriatr Psychiatry 2011;
2128–2139. 19: 4–12.
119. Chen Y, Guo JJ, Li H, et al. Risk of 130. McDonald WM. Neuromodulation treatments
cerebrovascular events associated with for geriatric mood and cognitive disorders. Am J
antidepressant use in patients with depression: Geriatr Psychiatry 2016; 24: 1130–1141.

134 journals.sagepub.com/home/taj

131. Naro A, Corallo F, De Salvo S, et al. Promising
role of neuromodulation in predicting the
progression of mild cognitive impairment to
dementia. J Alzheimers Dis 2016; 53: 1375–
1388.
132. Peavy GM, Salmon DP, Jacobson MW, et al.
Effects of chronic stress on memory decline in
cognitively normal and mildly impaired older
adults. Am J Psychiatry 2009; 166: 1384–1391.
133. Aggarwal NT, Wilson RS, Beck TL, et al.
Perceived stress and change in cognitive
function among adults 65 years and older.
Psychosom Med 2014; 76: 80–85.
134. Ohman L, Nordin S, Bergdahl J, et al. Cognitive
function in outpatients with perceived chronic
stress. Scand J Work Environ Health 2007; 33:
223–232.
135. Xavier FM, Ferraz MP, Trentini CM, et al.
Bereavement-related cognitive impairment in
an oldest-old community-dwelling Brazilian
sample. J Clin Exp Neuropsychol 2002; 24:
294–301.
136. Teixeira RR, Diaz MM, Santos TV, et al.
Chronic stress induces a hyporeactivity of
the autonomic nervous system in response to
acute mental stressor and impairs cognitive
performance in business executives. PLoS One
2015; 10: e0119025.
137. Peavy GM, Jacobson MW, Salmon DP, et al.
The influence of chronic stress on dementia-
related diagnostic change in older adults.
Alzheimer Dis Assoc Disord 2012; 26: 260–266.
138. Brummett BH, Austin SB, Welsh-Bohmer
KA, et al. Long-term impact of caregiving and
metabolic syndrome with perceived decline
in cognitive function 8 years later: a pilot
study suggesting important avenues for future
research. Open J Med Psychol 2013; 2: 23–28.
139. Bondi CO, Rodriguez G, Gould GG, et al.
Chronic unpredictable stress induces a cognitive
deficit and anxiety-like behavior in rats that
is prevented by chronic antidepressant drug
treatment. Neuropsychopharmacology 2008; 33:
320–331.
140. Piato AL, Capiotti KM, Tamborski AR, et al.
Unpredictable chronic stress model in zebrafish
(Danio rerio): behavioral and physiological
responses. Prog Neuropsychopharmacol Biol
Psychiatry 2011; 35: 561–567.
141. Xie F, Zhao Y, Ma J, et al. The involvement of
homocysteine in stress-induced Aß precursor
protein misprocessing and related cognitive
decline in rats. Cell Stress Chaperones 2016; 21:
915–926.
journals.sagepub.com/home/taj 135
G Rakesh, ST Szabo et al.
142. Parihar VK, Hattiangady B, Kuruba R, et al.
Predictable chronic mild stress improves mood,
hippocampal neurogenesis and memory. Mol
Psychiatry 2011; 16: 171–183.
143. Sterlemann V, Rammes G, Wolf M, et al.
Chronic social stress during adolescence
induces cognitive impairment in aged mice.
Hippocampus 2010; 20: 540–549.
144. Green KN, Billings LM, Roozendaal B, et al.
Glucocorticoids increase amyloid-beta and tau
pathology in a mouse model of Alzheimer’s
disease. J Neurosci 2006; 26: 9047–9056.
145. Jeong YH, Park CH, Yoo J, et al. Chronic
stress accelerates learning and memory
impairments and increases amyloid deposition
in APPV717I-CT100 transgenic mice, an
Alzheimer’s disease model. FASEB J 2006; 20:
729–731.
146. Liu M, Li J, Dai P, et al. Microglia activation
regulates GluR1 phosphorylation in chronic
unpredictable stress-induced cognitive
dysfunction. Stress 2015; 18: 96–106.
147. Gassen NC, Chrousos GP, Binder EB, et al.
Life stress, glucocorticoid signaling, and the
aging epigenome: implications for aging-
related diseases. Neurosci Biobehav Rev. Epub
ahead of print 23 June 2016. DOI: 10.1016/j.
neubiorev.2016.06.003.
148. Zannas AS, Arloth J, Carrillo-Roa T, et al.
Lifetime stress accelerates epigenetic aging in an
urban, African American cohort: relevance of
glucocorticoid signaling. Genome Biol 2015; 16:
266.
149. Zannas AS and Chrousos GP. Epigenetic
programming by stress and glucocorticoids
along the human lifespan. Mol Psychiatry 2017;
22: 640–646.
150. Kitayama N, Vaccarino V, Kutner M,
et al. Magnetic resonance imaging (MRI)
measurement of hippocampal volume in
posttraumatic stress disorder: a meta-analysis. J
Affect Disord 2005; 88: 79–86.
151. McEwen BS and Sapolsky RM. Stress and
cognitive function. Curr Opin Neurobiol 1995; 5:
205–216.
152. Tata DA, Marciano VA and Anderson
BJ. Synapse loss from chronically elevated
glucocorticoids: relationship to neuropil volume
and cell number in hippocampal area CA3. J
Comp Neurol 2006; 498: 363–374.
153. Zannas AS, McQuoid DR, Payne ME,
et al. Negative life stress and longitudinal
hippocampal volume changes in older adults
Therapeutic Advances in Chronic Disease 8(8-9)
with and without depression. J Psychiatr Res
2013; 47: 829–834.
154. Singh Y, Sharma R and Talwar A. Immediate
and long-term effects of meditation on acute
stress reactivity, cognitive functions, and
intelligence. Altern Ther Health Med 2012; 18:
46–53.
155. Quach D, Jastrowski Mano KE and Alexander
K. A randomized controlled trial examining the
effect of mindfulness meditation on working
memory capacity in adolescents. J Adolesc
Health 2016; 58: 489–496.
156. Sperduti M, Makowski D and Piolino P. The
protective role of long-term meditation on the
decline of the executive component of attention
in aging: a preliminary cross-sectional study.
Neuropsychol Dev Cogn B Aging Neuropsychol
Cogn 2016; 23: 691–702.
157. Gard T, Holzel BK and Lazar SW. The
potential effects of meditation on age-related
cognitive decline: a systematic review. Ann N Y
Acad Sci 2014; 1307: 89–103.
158. Newberg AB, Wintering N, Khalsa DS, et al.
Meditation effects on cognitive function and
cerebral blood flow in subjects with memory
loss: a preliminary study. J Alzheimers Dis 2010;
20: 517–526.
159. Wells RE, Kerr CE, Wolkin J, et al. Meditation
for adults with mild cognitive impairment: a
pilot randomized trial. J Am Geriatr Soc 2013;
61: 642–645.
160. Wells RE, Yeh GY, Kerr CE, et al. Meditation’s
impact on default mode network and
hippocampus in mild cognitive impairment: a
pilot study. Neurosci Lett 2013; 556: 15–19.
161. De Bruijn RF, Bos MJ, Portegies ML, et al.
The potential for prevention of dementia
across two decades: the prospective,
population-based Rotterdam Study. BMC Med
2015; 13: 132.
162. Alonso A, Mosley TH Jr, Gottesman RF, et al.
Risk of dementia hospitalisation associated with
cardiovascular risk factors in midlife and older
age: the Atherosclerosis Risk in Communities
(ARIC) study. J Neurol Neurosurg Psychiatry
2009; 80: 1194–1201.
163. Cheng ST. Cognitive reserve and the prevention
of dementia: the role of physical and cognitive
activities. Curr Psychiatry Rep 2016; 18: 85.
164. Vidovich MR, Lautenschlager NT, Flicker L,
Visit SAGE journals online et al. The PACE study: a randomised clinical
journals.sagepub.com/ trial of cognitive activity (CA) for older adults
home/taj
with mild cognitive impairment (MCI). Trials
SAGE journals 2009; 10: 114.
136 journals.sagepub.com/home/taj
165. Hsu WY, Ku Y, Zanto TP, et al. Effects of
noninvasive brain stimulation on cognitive
function in healthy aging and Alzheimer’s
disease: a systematic review and meta-analysis.
Neurobiol Aging 2015; 36: 2348–2359.
166. Ahmed MA, Darwish ES, Khedr EM, et al.
Effects of low versus high frequencies of
repetitive transcranial magnetic stimulation
on cognitive function and cortical excitability
in Alzheimer’s dementia. J Neurol 2012; 259:
83–92.
167. Boggio PS, Ferrucci R, Mameli F, et al.
Prolonged visual memory enhancement after
direct current stimulation in Alzheimer’s
disease. Brain Stimul 2012; 5: 223–230.
168. Khedr EM, Gamal NF, El-Fetoh NA, et al. A
double-blind randomized clinical trial on the
efficacy of cortical direct current stimulation
for the treatment of Alzheimer’s disease. Front
Aging Neurosci 2014; 6: 275.
169. Cotelli M, Calabria M, Manenti R, et al.
Improved language performance in Alzheimer
disease following brain stimulation. J Neurol
Neurosurg Psychiatry 2011; 82: 794–797.
170. Wisniewski T and Goni F. Immunotherapeutic
approaches for Alzheimer’s disease. Neuron
2015; 85: 1162–1176.
171. Kontsekova E, Zilka N, Kovacech B, et al.
First-in-man tau vaccine targeting structural
determinants essential for pathological tau-tau
interaction reduces tau oligomerisation and
neurofibrillary degeneration in an Alzheimer’s
disease model. Alzheimers Res Ther 2014; 6: 44.
172. Orgogozo JM, Gilman S, Dartigues JF, et al.
Subacute meningoencephalitis in a subset of
patients with AD after Aß42 immunization.
Neurology 2003; 61: 46–54.
173. Arai H, Suzuki H and Yoshiyama T. Vanutide
cridificar and the QS-21 adjuvant in Japanese
subjects with mild to moderate Alzheimer’s
disease: results from two phase II studies. Curr
Alzheimer Res 2015; 12: 242–254.
174. Pasquier F, Sadowsky C, Holstein A, et al.
Two phase II multiple ascending-dose studies
of vanutide cridificar (ACC-001) and QS-21
adjuvant in mild-to-moderate Alzheimer’s
disease. J Alzheimers Dis 2016; 51: 1131–1143.
175. Salloway S, Sperling R, Fox NC, et al. Two
phase III trials of bapineuzumab in mild-to-
moderate Alzheimer’s disease. N Engl J Med
2014; 370: 322–333.
176. Atkins D, Best D, Briss PA, et al. Grading
quality of evidence and strength of
recommendations. BMJ 2004; 328: 1490.