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Alzheimer's disease prevention: From risk factors to early intervention


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Due to the progressive aging of the population, Alzheimer’s disease (AD) is becoming a healthcare burden of epidemic proportions for which there is currently no cure. Disappointing results from clinical trials performed in mild–moderate AD dementia combined with clear epidemiological evidence on AD risk factors are contributing to the development of primary prevention initiatives. In addition, the characterization of the long asymptomatic stage of AD is allowing the development of intervention studies and secondary prevention programmes on asymptomatic at-risk individuals, before substantial irreversible neuronal dysfunction and loss have occurred, an approach that emerges as highly relevant. In this manuscript, we review current strategies for AD prevention, from primary prevention strategies based on identifying risk factors and risk reduction, to secondary prevention initiatives based on the early detection of the pathophysiological hallmarks and intervention at the preclinical stage of the disease. Firstly, we summarize the evidence on several AD risk factors, which are the rationale for the establishment of primary prevention programmes as well as revising current primary prevention strategies. Secondly, we review the development of public–private partnerships for disease prevention that aim to characterize the AD continuum as well as serving as platforms for secondary prevention trials. Finally, we summarize currently ongoing clinical trials recruiting participants with preclinical AD or a higher risk for the onset of AD-related cognitive impairment. The growing body of research on the risk factors for AD and its preclinical stage is favouring the development of AD prevention programmes that, by delaying the onset of Alzheimer’s dementia for only a few years, would have a huge impact on public health.
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R E V I E W Open Access
Alzheimers disease prevention: from risk
factors to early intervention
Marta Crous-Bou
, Carolina Minguillón
, Nina Gramunt
and José Luis Molinuevo
Due to the progressive aging of the population, Alzheimers disease (AD) is becoming a healthcare burden of
epidemic proportions for which there is currently no cure. Disappointing results from clinical trials performed in
mildmoderate AD dementia combined with clear epidemiological evidence on AD risk factors are contributing to the
development of primary prevention initiatives. In addition, the characterization of the long asymptomatic stage of AD
is allowing the development of intervention studies and secondary prevention programmes on asymptomatic at-risk
individuals, before substantial irreversible neuronal dysfunction and loss have occurred, an approach that emerges as
highly relevant.
In this manuscript, we review current strategies for AD prevention, from primary prevention strategies based on
identifying risk factors and risk reduction, to secondary prevention initiatives based on the early detection of the
pathophysiological hallmarks and intervention at the preclinical stage of the disease. Firstly, we summarize the evidence
on several AD risk factors, which are the rationale for the establishment of primary prevention programmes as well as
revising current primary prevention strategies. Secondly, we review the development of publicprivate partnerships for
disease prevention that aim to characterize the AD continuum as well as serving as platforms for secondary prevention
trials. Finally, we summarize currently ongoing clinical trials recruiting participants with preclinical AD or a higher risk for
the onset of AD-related cognitive impairment.
The growing body of research on the risk factors for AD and its preclinical stage is favouring the development of AD
prevention programmes that, by delaying the onset of Alzheimers dementia for only a few years, would have a huge
impact on public health.
Keywords: Alzheimers disease, Amyloid beta, Prevention, Risk factors, Susceptibility, Early intervention, Clinical trials
The prevalence of dementia worldwide is estimated to
be over 45 million people [1] and is predicted to triple
by 2050 as a consequence of increased life expectancy,
establishing dementia as one of the biggest global public
health challenges. Alzheimers disease (AD) is the most
common form of dementia and accounts for 6080% of
cases [1]. AD is a progressive neurodegenerative disease,
irreversible and disabling, causing a large socioeconomic
burden [2].
The criteria for AD diagnosis have been revised exten-
sively, and experts agree that the hallmark pathological
criteria include increased levels of amyloid-beta (Aβ)
peptide, which is deposited extracellularly in diffuse and
neuritic plaques, and hyperphosphorylated tau (p-tau), a
microtubule assembly protein that accumulates intracel-
lularly as neurofibrillary tangles [3]. Initial diagnostic
efforts focused on patients at the dementia stage of the
disease and, only recently, the importance of a long
pre-dementia stage, preceding the clinical onset of the
disease symptoms, has been recognized. As the disease pro-
gresses, the subjects cognition changes from an initial
phase where it is fully preserved to a final stage character-
ized by dementia [4]. The initial silent and asymptomatic
stage, referred to as preclinical AD, is characterized by a
sequence of pathophysiological hallmarks that start to
appear about 20 years before the onset of symptoms [5].
Unfortunately, none of the drugs tested to date in clinical
trials in order to change the course of the disease have
shown effective results in AD dementia [6]. Therefore,
* Correspondence:
Barcelonaβeta Brain Research CenterPasqual Maragall Foundation, C/
Wellington, 30, 08005 Barcelona, Spain
CIBER Fragilidad y Envejecimiento Saludable (CIBERFES), Madrid, Spain
© The Author(s). 2017 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0
International License (, which permits unrestricted use, distribution, and
reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to
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( applies to the data made available in this article, unless otherwise stated.
Crous-Bou et al. Alzheimer's Research & Therapy (2017) 9:71
DOI 10.1186/s13195-017-0297-z
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many interventional studies are currently moving their
focus to cognitively healthy individuals at risk of devel-
oping AD (before substantial irreversible neuronal
network dysfunction and loss, associated with overt
clinical symptoms, have occurred) as the best strategy
to reduce AD incidence and prevalence.
In this review, we will summarize current strategies
for AD prevention, from primary prevention strategies
based on identifying risk factors and risk reduction, to
secondary prevention based on early detection of the
pathophysiological hallmarks and intervention at the
preclinical stage. Furthermore, we will discuss a number
of selected environmental risk factors for AD, and we
will describe currently ongoing interventional initiatives
focused on primary prevention of AD, as well as some
of the publicprivate partnerships (PPPs) for disease
prevention that are setting up a framework to identify
and select individuals for clinical trials focused on
preclinical stages.
Primary prevention
Modifiable risk factors for AD
Since AD develops over a long preclinical stage that can
last for several decades, the extent to which risk factors
assessed in late life or shortly before the onset of clinical
symptoms are a result of pathological changes rather
than having a causal relationship has been discussed
intensively. Longitudinal studies that include participants
in early mid-life have been crucial to assess the relation-
ship between early or mid-life exposures and cognitive
decline or AD later in life [7].
Observational studies have identified several modifiable
risk factors for AD. Based on a comprehensive systematic
review of the evidence related to risk factors for cognitive
decline and AD, the US National Institutes of Health
highlighted diabetes mellitus, smoking, depression, mental
inactivity, physical inactivity and poor diet as being associ-
ated with increased risk of cognitive decline, AD, or both
[8]. Later on, this list was further extended to include
hypertension, obesity and low educational attainment [9].
Recently, an association was demonstrated between the
presence of vascular risk factors in mid-life and amyloid
deposition later in life [10], even though some of these
factors are still under debate. It has been estimated that
up to a third of AD cases are potentially attributed to
these factors and, consequently, could be prevented [11].
Modifiable risk factors for AD are mostly related to
either cardiovascular risk factors (diabetes, hypertension
and obesity) or lifestyle habits (e.g. smoking, physical
activity, diet, mental and social activity). Diabetes has been
associated with an increased risk of AD (RR = 1.39). It has
been suggested that diabetes could increase the risk by
directly affecting Aβaccumulation in the brain since hyper-
insulinemia disrupts brain Aβclearance by competing for
the insulin-degrading enzyme [12, 13]. In contrast, other
studies suggest that diabetes might increase the risk of
cerebrovascular but not AD pathology, and that at least
part of the relationship between diabetes and cognitive
impairment may be modified by neuropathology [14]. Even
though the association between high blood pressure and
AD risk is complex and age related, evidence suggest that
mid-life, and not late-life, hypertension is associated with a
50% increased risk of AD and dementia in later life.
Elevated blood pressure might increase the risk of AD by
decreasing the vascular integrity of the bloodbrain barrier,
resulting in protein extravasation into brain tissue, which
can consequently lead to cell damage, apoptosis and an
increase in Aβaccumulation [15]. However, the direction
of a possible causal relationship between hypertension and
subsequent cognitive decline is under debate since there is
also increasing evidence that hypertension may be a
protective response to cerebral hypoperfusion, which is
demonstrable 10 years prior to AD onset [16, 17]. Observa-
tional studies have shown a U-shaped relationship between
weight and cognitive performance: both low and high body
weight have been associated with increased risk of AD and
cognitive impairment. This association might also have an
age-dependent component. Data also exist for reverse
causation in the years preceding disease onset; that is, loss
of body weight might be caused by cognitive impairment
during the pre-dementia phase of AD. Consequently, the
relationship between body weight and AD seems to be a
consequence of mid-life obesity, which could increase the
risk of AD by 60%. Even though the underlying mecha-
nisms of this association remain unknown, studies suggest
that insulin resistance and co-incidence with diabetes mel-
litus may play a role [18].
With regards to lifestyle-related factors, the association
between smoking and AD risk has been controversial and
remains unclear. Most observational studies show an
association between current smoking and increased risk of
dementia, AD and cognitive decline. Even though relative
risks for AD are relatively small (RR = 1.201.60), nearly
14% of AD cases are estimated to be potentially attribut-
able to smoking due to its high prevalence [9]. Smoking
may increase AD risk through several mechanisms, mostly
related to oxidative stress and inflammatory responses
[19]. Epidemiological studies have shown that physical
activity has a beneficial effect on brain health, which
could be explained through multiple mechanisms
including activation of brain plasticity, promotion of
brain vascularization, stimulation of neurogenesis,
reduction of inflammation levels or even by decreasing
the rate of amyloid plaque formation. In comparison
with sedentary behaviours, individuals with high levels
of physical activity have been shown to reduce their AD
risk by half (RR = 0.72 for all causes of dementia; RR = 0.55
for AD) [20, 21]. Involvement in exercise programmes has
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been shown to significantly improve cognitive function in
healthy older people. In contrast, physical inactivity has
been associated with an increased risk of cognitive impair-
ment in most longitudinal studies. However, whilst there is
convincing evidence of an association between physical
activity and subsequent cognitive decline, the direction of
a possible causal relationship is still debatable. In their
recent study, Sabia et al. [22] did not find evidence of a
neuroprotective effect of physical activity and suggest that
previous findings showing a lower risk of dementia in
physically active people may be attributable to reverse
causation (i.e. due to a decline in physical activity levels in
the preclinical phase of dementia). The Mediterranean diet
(MD) [23] may also protect against cognitive decline, AD
and all-cause dementia [24, 25]. Observational studies have
shown that higher adherence to a MD is associated with
slower rates of cognitive decline, reduced progression to
AD and improvements in cognitive function. Specifically,
it has been shown that adherence to a MD might have a
beneficial effect on memory, executive function and visual
constructs [25]. A recent intervention study, PREDIMED,
has shown that a MD supplemented with olive oil or nuts
is associated with improved cognitive function [26].
Cognitive, social and intellectual activity jointly with
higher education and occupational attainment have been
shown to decrease risk of cognitive decline and demen-
tia by increasing cognitive reserve, the capacity of the
brain to resist the effects of neuropathological damage
[27]. Observational studies consistently show that people
who engage in mentally stimulating activities are less
likely to develop AD (RR = 0.54). About 19% of AD cases
worldwide are potentially attributable to low education
attainment, making it the risk factor that contributes to
the largest proportion of AD cases [9]. Helping to build
a cognitive reserve that enables individuals to continue
functioning at a normal level despite experiencing
neurodegenerative changes seems to have a high impact
on disease onset. The beneficial impact of bilingualism on
brain reserve and consequently on AD risk and cognition
has been highlighted recently [28, 29]. Studies suggest that
lifelong bilingualism may delay the onset of dementia by
about 4.5 years by contributing to cognitive reserve and,
consequently, protecting against neurodegeneration.
The fact that a third of AD cases are potentially attrib-
utable to modifiable risk factors highlights the potential
of risk factor reduction for disease prevention. However,
the need for therapeutic strategies for the remaining
two-thirds of cases is still urgent.
Primary prevention strategies
Intervention strategies focused on modifiable risk factors
for the disease are becoming a realistic and relevant
therapeutic strategy for disease prevention. Interestingly,
large epidemiological cohort studies suggest that the
incidence of age-specific dementia is decreasing, prob-
ably due to a better control of cardiovascular risk
factors [30, 31].
As an example, several intervention studies focused on
primary prevention of dementias are currently ongoing,
mainly in Europe, with the aim of reducing disease inci-
dence. It is worth mentioning the Finnish Geriatric
Intervention Study to Prevent Cognitive Impairment and
Disability (FINGER) study [32] which aimed to investi-
gate whether a multidomain intervention could prevent
cognitive decline among older people. Additionally,
investigators aimed to assess the effect of this multido-
main intervention on disability, quality of life, depressive
symptoms, the use of health care services and vascular
risk factors. The 1200 participants of the FINGER study
had an increased risk of cognitive decline. To date,
results from this large, long-term, randomized controlled
trial (RCT) have demonstrated that a multidomain inter-
vention including diet, exercise, cognitive training and
monitoring vascular risk can improve or maintain cogni-
tive functioning in older people (6077 years old) from
the general population at risk of dementia [33].
The Prevention of Vascular Dementia by Intensive
Care (PreDIVA) trial aimed to determine whether the
control of cardiovascular risk factors could reduce
dementia incidence. PreDIVA tested whether a multi-
component intervention targeting vascular risk factors
could prevent new cases of dementia [34]. Researchers
conducted a 6-year, open cluster RCT in primary care
with over 3500 cognitively healthy participants aged
7078. Results showed that this multidomain intervention
focused on vascular care did not result in a reduced inci-
dence of all-cause dementia in an unselected population
of older people and did not have an effect on mortality,
cardiovascular disease or disability, despite a greater
improvement in systolic blood pressure in the interven-
tion group compared with the control. Investigators
suggested that the absence of effect might have been
caused by modest baseline cardiovascular risks and high
standards of usual care received by the control group.
Hence, these results do not rule out the potential benefit
of a better management of cardiovascular risk factors on
brain health [35].
Another relevant study is the Multidomain Alzheimer
Preventive Trial (MAPT) which aimed to evaluate the
efficacy of a single multidomain intervention including
nutritional counselling, physical exercise and cognitive
training, the efficacy of an isolated omega 3 fatty acid
supplementation and the efficacy of a combination of
the two previously mentioned interventions on the
prevention of cognitive decline in frail older participants
aged 70 years or older [36]. A total of 1680 participants
were followed for a period of 3 years; the study also
collected imaging and biological data to be potentially
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used in future AD prevention and treatment trials. Both
the multidomain intervention and polyunsaturated fatty
acids, either individually or in combination, had no
significant effects on cognitive decline over 3 years in
older people with memory complaints. Particularly, the
fact that participants had subjective memory complaints
at enrolment, their mean age was 75 years and that
almost half of participants showed a clinical dementia
rating of 0.5 might have been important methodological
limitations of the study. It might have been too late for
the preventive intervention to show its potential efficacy.
However, a post-hoc analysis performed on those partici-
pants with a positive amyloid scan showed a significant
benefit in favour of the intervention [37].
Recently, a new study based on an eHealth intervention
has been presented. Healthy Ageing Through Internet
Counselling in the Elderly (HATICE) aims to investigate
whether a multidomain intervention to optimize self-
management of lifestyle-related risk factors for cardiovas-
cular disease in older individuals, delivered through a
coach-supported interactive platform, can improve the
cardiovascular risk profile and reduce the risk of cardio-
vascular disease and cognitive decline [38]. The study has
recruited 2600 people older than 65 years at increased risk
of cardiovascular disease. Investigators developed an intui-
tive, easy-to-use platform, allowing for widespread use
among older adults with only limited computer skills.
Results from this study are expected in 2017.
Based on experiences and data from the intervention
studies on AD prevention described (summarized in
Table 1), investigators from the European Dementia
Prevention Initiative (EPDI) have recently launched the
Multimodal Preventive Trials for AD (MIND-AD) pro-
ject. While all trials described previously are testing the
effects of multimodal interventions targeting vascular,
dietary and lifestyle-related risk factors in older adults
not suffering with dementia, the aim of the MIND-AD
project is to identify effective prevention strategies for
AD and dementia tailored to different at-riskgroups.
The novel approach of this project consists of multido-
main interventions, inclusion of novel models of delivery
(e.g. computer-based cognitive training, medical food),
critical feedback from trial participants and synergistic
use of data from several European countries with over
10,000 participants. Furthermore, a pilot study in which
a multimodal preventive intervention will be tested
for the first time in prodromal AD will be conducted
In the USA, an example of a cognitive-related interven-
tion is the ACTIVE study, the biggest RCT on cognitive
training in healthy older adults [39]. The ACTIVE study
included over 2800 cognitively healthy participants older
than 65 years who attended 10 group sessions during a
6-week period where, according to the intervention arm,
they received specific training in either memory, reasoning
or speed of processing. A subgroup of participants in each
arm received a few booster sessions just before the first
and third years post intervention. The intervention groups
were compared among them, and with a non-intervention
control group. Results confirmed that domain-specific
training was beneficial for maintaining cognition in the
targeted domain. Two years later, the intervention showed
modest benefits for cognitive training in cognitive per-
formance, which were maintained at the 5-year follow-up
[40], and slight benefits in self-reported function in daily
living activities [41]. After the 10-year follow-up investiga-
tors concluded that those who received any intervention
showed less functional decline in daily living activities,
and those trained in reasoning and speed of processing
also showed better performance in the targeted abilities
[42]. Dementia rates at 10 years were significantly lower
in participants in the speed of processing intervention
group [43].
Results from intervention studies highlight the meth-
odological limitations underlying the design and imple-
mentation of effective preventive strategies. Studies should
take into account that AD is multifactorial and, conse-
quently, interventions should be specific to risk profiles.
Small long-term effects on cognition, as those shown by
FINGER, are of high relevance for public health, since
they may significantly contribute to the reduction of the
overall burden of AD. An effective strategy for AD pre-
vention could start with recommendations addressed to
the general population (particularly to cognitively healthy
subjects older than 50 years) on how to manage lifestyle
and cardiovascular risk factors. In parallel, a multidomain
long-term intervention could be offered to individuals
identified as being at increased risk of developing AD (e.g.
subjects with subjective memory concerns or a family
history of dementia).
Secondary prevention
New consensus diagnostic criteria for preclinical AD,
together with the identification of at-risk individuals
through the use of biomarkers that are altered before
clinical decline (i.e. amyloid deposition in the brain), are
key for identifying at-risk asymptomatic individuals who
are ideal candidates to participate in secondary preven-
tion trials. Cerebral Aβdeposition is considered a neces-
sary, but not sufficient, step on the path towards AD
development [44].
Furthermore, results from most trials focused on Aβ-
centric approaches at the dementia stage of AD have
been disappointing, suggesting that those participants
have already surpassed the optimal therapeutic window
for intervention [6]. The preclinical stage might offer the
optimal window for therapeutic success and the oppor-
tunity to intervene at earlier stages of the continuum,
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Table 1 Description of randomized controlled trials of multidomain interventions for prevention of cognitive impairment, dementia or AD
Study population 1260 community dwellers from previous
population-based non-intervention studies
3526 community dwellers 1680 community dwellers 2600 community dwellers
Main inclusion
CAIDE Dementia Risk Score i6 and
cognitive performance at the mean level
or slightly lower than expected for age
assessed with the Consortium to Establish
a Registry for Alzheimers Disease
neuropsychological battery
All community-dwelling older people
without dementia registered with a
participating general practice
Frail older people: spontaneous memory complaint,
limitation in one instrumental activity of daily living
and slow walking speed (i.e. lower than 0.8 m/s)
Older adults without dementia at
increased risk of cardiovascular disease
Age at
6077 years 7078 years 70 years 65 years
Study design Multicentre, randomized
controlled trial
Multicentre, cluster randomized
controlled trial
Multicentre, randomized controlled trial Multicentre, randomized controlled trial
Intervention Multidomain: (1) nutritional guidance; (2)
physical exercise; (3) cognitive training
and social activity; and (4) intensive
monitoring and management of
metabolic and vascular risk factors
Multidomain: (1) nutritional
advice; (2) physical activity advice;
and (3) vascular care including
medical treatment of risk factors
Multidomain: (1) nutritional advice; (2) physical
activity advice; (3) cognitive training; and (4) vascular
care, and/or 800 mg docosahexaenoic acid per day
e-health: multidomain interactive Internet
platform, stimulating self-management of
vascular risk factors, with remote support
Control group General health advice Usual care Placebo alone Static Internet platform with basic health
Duration 2 years plus 5-year follow-up 6 years 3 years plus 2-year follow-up 18 months
Outcomes Primary: change in cognitive performance.
Secondary: dementia; disability; depression;
vascular risk factors and outcomes; quality
of life; utilization of health resources; and
neuroimaging biomarkers.
Primary: cumulative incidence of
dementia and disability score
(ALDS) at 6 years of follow-up.
Secondary: incident cardiovascular
disease and cardiovascular and
all-cause mortality. Other secondary:
cognitive decline, depression, blood
lipid concentrations, and glucose
Primary: change in memory function. Secondary:
cognitive performance, functional status,
depression, cost-effectiveness
Primary: outcome is a composite score
based on the average z-score of the
difference between baseline and
18-month follow-up values of systolic
blood pressure, low-density-lipoprotein
and body mass index. Secondary: include
the effect on the individual components
of the primary outcome, the effect on
lifestyle-related risk factors, incident
cardiovascular disease, mortality,
cognitive functioning, mood and
Status Completed in 2014 Completed in 2015 Completed in 2014 Due to finish in 2017
Findings (if available) The multidomain intervention could
improve or maintain cognitive
functioning [24]
The intervention did not result in a
reduced incidence of all-cause
dementia and did not have an effect
on mortality, cardiovascular disease
or disability [26]
The multidomain intervention and polyunsaturated
fatty acids, either alone or in combination, had no
significant effects on cognitive decline. Post-hoc
data showed that the combination of polyunsaturated
fatty acids and multidomain intervention had potential
beneficial effects in participants with CAIDE scores 6
or higher or evidence of brain amyloid pathology,
suggesting that people with increased risk of dementia
might benefit most from the intervention [28]
Reference [23][25][27][29]
AD Alzheimers disease, ALDS Academic Medical Center Linear Disability Score, CAIDE Cardiovascular Risk Factors, Aging, and Incidence of Dementia, FINGER Finnish Geriatric Intervention Study to Prevent Cognitive
Impairment and Disability, HATICE Healthy Ageing Through Internet Counselling in the Elderly, MAPT Multidomain Alzheimer Preventive Trial, PreDIVA Prevention of Vascular Dementia by Intensive Care
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arresting or delaying the onset of cognitive decline and
ultimately dementia.
This approach is also supported by studies showing
that biomarker abnormality in preclinical AD occurs in
a temporal manner: low Aβ42 in cerebrospinal fluid
(CSF) and cerebral amyloid deposits precede elevated
CSF tau, topographical cerebral injury and cognitive
decline [45, 46]. These pathologic changes may start de-
cades before the onset of symptoms: in pre-symptomatic
PSEN mutation carriers, CSF Aβ42 decline has been
observed 25 years before clinical symptoms, whilst brain
Aβdeposition and elevated CSF tau have been detected
15 years before symptom onset [47]. Observational studies
have shown that cognitively normal individuals with
abnormal levels of AD biomarkers exhibit longitudinal
cognitive decline [48, 49], suggesting that they are at
increased risk of progressing to cognitive impairment and,
consequently, to dementia.
Several PPPs for disease prevention are currently
ongoing, setting up a framework to identify and select
individuals to be included in trials focused on the AD
preclinical stage. These initiatives also aim to maximize
efficiency to obtain a clinical signal and develop sensi-
tive outcomes for detecting early decline, through new
trial designs.
The Dominantly Inherited Alzheimer Network (DIAN)
is an international PPP determined to understand a rare
form of AD that is dominantly inherited, caused by a
genetic mutation in presenilin 1 (PSEN1), presenilin 2
(PSEN2) or amyloid precursor protein (APP) [50]. The
DIAN pioneers observational studies in pre-symptomatic
individuals based on the hypothesis that understanding
this form of AD may provide insight into the more com-
mon form of the disease. DIAN is enrolling participants
who are adult children of a parent with a mutated gene
known to cause dominantly inherited AD. Participants
may or may not carry the gene, and may or may not have
disease symptoms. The DIAN is developing an expanded
registry to enable trials for research-neglected individuals
such as familial early-onset AD, to increase the power for
successful trials and to test more drugs. Moreover, the
project supports studies related to autosomal dominant
AD to increase the chance of success of treatment trials.
The ultimate objective of DIAN is a successful prevention
trial that yields the approval of the first disease-modifying
drug, bolsters interest in developing improved drugs and
demonstrates a clear pathway to prevent AD in the
general population.
The Alzheimers Prevention Initiative (API) is an inter-
national collaborative initiative established to provide an
innovative approach to Alzheimers prevention research
by evaluating the most promising therapies in cognitively
normal people who, based on their age and genetic back-
ground, are at the highest imminent risk of developing
AD symptoms [51]. The API is focused on prevention and
treatment trials, biomarker studies and registries, with the
ultimate goal being to delay, reduce the risk or prevent
AD clinical onset. The API has set up a robust registry
where members receive regular informational materials
including new trials.
A major European PPP, the European Prevention of
Alzheimers Dementia (EPAD) project, funded by the
Innovative Medicines Initiative, is designed to increase
the likelihood of the successful development of new
treatments for the secondary prevention of Alzheimers
dementia by creating a novel environment for testing
numerous interventions [52]. EPAD aims to create the
necessary infrastructure, including a registry and a longi-
tudinal cohort study, for delivering an adaptive trial for
secondary prevention of AD. EPAD will test different
agents in pre-dementia AD participants through an
infrastructure providing: improvement of access to exist-
ing cohorts and registries; development of a registry of
approximately 24,000 individuals who might be at
increased risk of developing AD; establishment of a lon-
gitudinal cohort study of 6000 subjects; and establish-
ment of an adaptive, proof-of-concept trial including
1500 participants at any given time.
In the USA, the Global Alzheimers Platform (GAP)
has already been launched, while Canada and Japan are
about to promote similar sister initiatives. There are
several projects under the GAP umbrella: GAP-track is
establishing a global standing, trial-ready platform to
reduce clinical testing cycle times by 2 years or more
and achieve greater efficiency and uniformity in trial
populations through large, well-characterized trial-ready
cohorts, certified clinical trial sites and an adaptive
proof-of-concept trial mechanism. This will enable the
delivery of efficient and effective proof-of-concept and
confirmatory trials and ultimately a more rapid delivery
of effective therapies to patients or persons at risk. GAP-
net is creating a trial-ready network of sites all over the
USA for the prevention and treatment of AD [53].
Secondary prevention trials in asymptomatic partici-
pants with preclinical AD who are amyloid positive are
already ongoing. Some of these trials are summarized in
Table 2. In the context of the dominantly inherited form
of AD, the DIAN-TU trial targets cognitively normal
individuals, participants with mild cognitive impairment
or mild dementia who are either known to have an AD-
causing mutation or at risk for such a mutation. The
aim is to assess the efficacy of gantenerumab and solane-
zumab by determining whether treatment improves
cognitive outcomes and disease-related biomarkers. The
API-ADAD (for Autosomal Dominant AD) trial will
recruit preclinical members of the PSEN1 E280A muta-
tion carrier kindred. It will evaluate the efficacy of crene-
zumab in 200 cognitively normal individuals who carry
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Table 2 Description of currently ongoing AD prevention clinical trials
210 300 1150 3494 1340 1650
Target population/
specific characteristics
Autosomal dominant Alzheimers
disease (ADAD) mutation carriers or
persons that have a 50% chance of
carrying an ADAD mutation
Membership in PSEN1
E280A mutation carrier
Cognitively normal,
positive brain amyloid
Cognitively normal with
genetic risk (TOMM40 and
APOE genotype)
Cognitively normal APOE-ε4
Cognitively normal
positive amyloid
Age 1880 years 3060 years 6585 years 6583 years 6075 years 6085 years
Phase Phase II/III Phase II Phase III Phase III Phase II/III Phase II/III
Compound Gantenerumab
Crenezumab Solanezumab Pioglitazone CAD106
Mechanism Anti-Aβantibodies Anti-Aβantibody Anti-Aβantibody PPAR-γagonist Aβvaccine
BACE inhibitor
BACE inhibitor
Status Ongoing, not recruiting Active, not recruiting Recruiting Active, not recruiting Recruiting Recruiting
Primary outcome Composite Cognitive Test Score Composite Cognitive
Test Score
Composite Cognitive
Test Score
Time to diagnosis of mild
cognitive impairment (MCI)
due to AD
Time to diagnosis of MCI
or dementia due to AD
Composite Cognitive Test
Composite Cognitive
Test Score
Study duration 4 years 5 years 3 years 5 years 5 years 4.5 years
Trial identifier NCT01760005 NCT01998841 NCT02008357 NCT01931566 NCT02565511 NCT02569398
Expected completion December 2019 September 2020 October 2020 July 2019 August 2023 May 2023
Source: (accessed May 2017) [45]
A4 Anti-Amyloid Treatment in Asymptomatic Alzheimers study, Aβamyloid beta, AD Alzheimers disease, API-ADAD Alzheimers Prevention Initiative for Autosomal Dominant Alzheimers Disease, API-GENERATION A
Study of CAD106 and CNP520 Versus Placebo in Participants at Risk for the Onset of Clinical Symptoms of Alzheimer's Disease, BACE Beta-secretase, DIAN Dominantly Inherited Alzheimer Network, EARLY An Efficacy
and Safety Study of JNJ-54861911 in Participants Who Are Asymptomatic at Risk for Developing Alzheimer's Dementia, PET Positron Emission Tomography, PPAR Peroxisome proliferator activated receptor, PSEN1
presenilin 1, TOMMORROW Biomarker Qualification for Risk of Mild Cognitive Impairment (MCI) Due to Alzheimer's Disease (AD) and Safety and Efficacy Evaluation of Pioglitazone in Delaying Its Onset
Crous-Bou et al. Alzheimer's Research & Therapy (2017) 9:71 Page 7 of 9
Content courtesy of Springer Nature, terms of use apply. Rights reserved.
the PSEN1 E280A mutation. The study will also include
100 PSEN1 E280A mutation non-carriers who will
receive placebo only.
Regarding sporadic AD, the Anti-Amyloid Treatment
in Asymptomatic Alzheimers (A4) study aims to test
whether an anti-amyloid antibody, solanezumab, can
slow cognitive loss caused by AD. The overall goal is to
test whether solanezumab can help slow the cognitive
loss associated with amyloid build-up. The study plans
to enrol 1150 cognitively healthy adults with a positive
amyloid scan who are randomly assigned to receive the
investigational drug or placebo. New studies with a
similar approach, such as the EARLY study, are cur-
rently ongoing. The purpose of EARLY is to evaluate
whether treatment with the BACE inhibitor JNJ-
54861911 slows cognitive decline, as measured by a
composite cognitive measure, the Preclinical Alzheimer
Cognitive Composite (PACC), in cognitively healthy
amyloid-positive participants.
Other studies employ a different approach, selecting
participants through a genetic risk profile. The TOM-
MORROW study will use a genetic risk assignment
algorithm (BRAA) to determine the 5-year risk of
developing MCI due to AD. The efficacy of low-dose
pioglitazone to delay the onset of MCI due to AD will
be tested in cognitively normal, high-risk individuals, as
identified by the BRAA. The study uses TOMM40 and
APOE genotype and age to identify individuals who
may be at a high or low risk of developing MCI in the
following 5 years. High-risk individuals will be ran-
domly assigned to the active or placebo arms. A small
group of low-risk individuals will receive placebo. The
API-GENERATION study, a randomized, double-blind,
placebo-controlled, two-cohort parallel group study,
aims to evaluate the efficacy of CAD106 and CNP520
in participants at risk for the onset of AD symptoms.
The purpose is to determine the effects of each of the
two therapies given separately, on cognition, global
clinical status and underlying pathology. Cognitively
unimpaired individuals, homozygotes for APOE-ε4aged
6075 years, were selected as a high-risk population for
progression to MCI due to AD and/or dementia.
Epidemiological evidence of AD risk factors is con-
tributing and encouraging the development of primary
prevention initiatives. Current trials and strategies are
necessary steps whose results are helping to improve
future designs, bringing some post-hoc analysis on
the potential benefits of risk factor reduction on
disease incidence. Identifying individuals at risk of
developing the disease might be the key to success of
intervention studies.
Ongoing clinical trials in asymptomatic participants
with either a positive amyloid biomarker or at increased
genetic risk of AD will help ascertain whether secondary
prevention initiatives are valid strategies and whether
clinical trials of 35 years are sufficient for delaying cog-
nitive decline, and consequently the onset of Alzheimers
The implementation of effective prevention strategies
is not free from challenges since they require the iden-
tification, characterization and participation of asymp-
tomatic individuals, developing new primary endpoints,
implementing the use of AD biomarkers in cognitively
healthy people, disclosing these results and performing
long trials, whose optimal length is yet to be deter-
mined. The incorporation of biomarkers to identify
individuals at risk of developing AD dementia is a key
step for the identification of ideal candidates to partici-
pate in trials and secondary prevention initiatives.
Clinical trials focused on the preclinical stage of AD
might help to maximize the possibility of obtaining a
clinical signal as well as developing sensitive methods
for detecting early decline through new trial designs.
A4: Anti-Amyloid Treatment in Asymptomatic Alzheimers study; AD: Alzheimers
disease; API: Alzheimers Prevention Initiative; API-ADAD: Alzheimers Prevention
Initiative for Autosomal Dominant AlzheimersDisease;Aβ: Amyloid beta;
CSF: Cerebrospinal fluid; DIAN: Dominantly Inherited Alzheimer Network;
EPAD: European Prevention of Alzheimers Dementia; FINGER: Finnish Geriatric
Intervention Study to Prevent Cognitive Impairment and Disability; GAP: Global
Alzheimers Prevention; HATICE: Healthy Ageing Through Internet Counselling in
the Elderly; MAPT: Multidomain Alzheimer Preventive Trial; MD: Mediterranean
diet; MIND-AD: Multimodal Preventive Trials for Alzheimers Disease; PPP: Public
private partnership; PreDIVA: Prevention of Vascular Dementia by Intensive Care;
RCT: Randomized controlled trial; RR: Relative risk
The authors acknowledge fellow colleagues at the Barcelonaβeta Brain
Research Center for their stimulating and inspiring discussions. They apologize
to colleagues whose studies were not cited due to space constraints.
Research conducted by JLM receives support from: the EU/EFPIA Innovative
Medicines Initiative Joint Undertaking AMYPAD grant agreement no. 115952;
the EU/EFPIA Innovative Medicines Initiative Joint Undertaking EPAD grant
agreement no. 115736; the EU/EFPIA Innovative Medicines Initiative Joint
Undertaking AETIONOMY grant no. 115568; and la CaixaFoundation. CM is
supported by the Spanish Ministry of Economy and Competitiveness (grant
no. IEDI-2016-00690).
Availability of data and materials
Not applicable.
MC-B, CM, NG, and JLM reviewed the literature and were involved in manuscript
preparation and revision. All authors read and approved the final manuscript.
Ethics approval and consent to participate
Not applicable.
Consent for publication
Not applicable.
Crous-Bou et al. Alzheimer's Research & Therapy (2017) 9:71 Page 8 of 9
Content courtesy of Springer Nature, terms of use apply. Rights reserved.
Competing interests
The authors declare that they have no competing interests.
Springer Nature remains neutral with regard to jurisdictional claims in
published maps and institutional affiliations.
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... Alzheimer's disease is the most common type of dementia [1][2][3]. Studies have shown that many patients with Alzheimer's disease (AD) have reading difficulties resulting from line skipping, mainly because of degeneration in fixation, saccadic pursuit, or vergence capabilities [4,5]. Although such changes are usually subtle in the early stages of dementia, or mild cognitive impairment (MCI), they can still be detected through a functional vision assessment [5]. ...
Full-text available
The transition of Taiwan from an aging to a super-aging society has come with a cost as more elderly now suffer from cognitive impairment. The main purpose of our study was to investigate if early detection can be developed so that timely intervention can be instituted. We analyzed the correlation of cognitive function with ocular physiology and visual functions between senior citizens aged 60 years or older in Taiwan. Methods: Thirty-six healthy subjects were recruited for the study. Addenbrooke’s cognitive examination III (ACE-III), binocular functions (including objective and subjective refraction, distance and near dissociated phoria, stereopsis, contrast sensitivity, adult developmental eye movement (ADEM), and ocular physiology (by using optical coherence tomography, OCT, and macular pigment measurement, MPS) were performed, and the data were analyzed via independent t-test, chi-square test, Pearson correlation, linear regression, and ROC (receiver operating characteristic) curve. Results: Data analysis showed that (1) patients with poor eye movement had a strong correlation with the total score and all dimensions of cognitive functions, (2) the thickness of the macula had a strong correlation with attention and memory, and (3) patients with poor eye movement and poor stereopsis in combination with thinner inferior macula appeared to have lower cognitive abilities. Discussion and Conclusions: Cognitive dysfunction is not readily identified during the early stage of cognitive decline. The use of simple and inexpensive ADEM or stereopsis test and comparing the OCT results that are popular in optometry clinics for reference can be diagnostic in identifying patients with mild cognitive impairments. With the combined use of macular pigment density or retinal thickness measurements, it was possible to effectively predict the early degradation of cognition.
... This finding is particularly important given that executive function deficits are associated with a high risk of dementia in later life (Rouch et al., 2020;Shepherd et al., 2021). Allied to this, effective intervention for Alzheimer's disease comes at the stage prior to mild cognitive impairment (Crous-Bou et al., 2017;Kivipelto et al., 2018). ...
Full-text available
Emerging evidence indicates that acute exercise improves executive function, but its effects on higher-order executive functioning skills among people with a risk of Alzheimer’s disease are not well understood. This study addressed the effects of acute exercise on the planning dimension of executive function among late middle-age adults who carried Apolipoprotein (APOE)-ɛ4. Exercise volume was kept constant, but exercise intensity and duration were manipulated. Eighteen adults in the age range 55–70 years who carried APOE-ɛ4 were recruited for a laboratory-based study set in a within-subjects, counterbalanced design. There was a reading control condition along with three exercise conditions: Acute cycle exercise at a moderate intensity for 30 min (MI-30); higher intensity exercise of a shorter duration (16 min); and lower intensity exercise of a longer duration (40 min). Exercise volume was set with reference to energy expenditure in MI-30. The Tower of London Test was administered at the end of each condition. Acute aerobic exercise improved cognitive performance in regard to move-related scores and time-related scores, but not violation-related scores, when compared to the control condition. There was no difference in terms of the facilitation effect among the three exercise conditions. The present findings indicate that acute aerobic exercise, regardless of intensity/duration manipulation, facilitates higher-order executive function in late middle-aged APOE-ɛ4 carriers. Practitioners should, accordingly, consider exercise as a suitable intervention for those at risk of Alzheimer’s disease.
... Alzheimer's disease (AD) is a progressive neurodegenerative disorder that commonly affects the elderly [1], accounting for up to 80% of dementias, [2] with a heavy socio-economic burden [3,4]. The diagnosis of AD at preclinical stages is critical, because treatment after the onset of clinical symptoms cannot halt or reverse disease progression. ...
Full-text available
With emerging amyloid therapies, documentation of the patient’s amyloid status to confirm the etiology of a clinical diagnosis is warranted prior to instituting amyloid-based therapy. The Multimer Detection System-Oligomeric Amyloid-β (MDS-OAβ) is a noninvasive blood-based biomarker utilized to measure Aβ oligomerization tendency. We determined the difference in MDS-OAβ ratio across the groups: (a) no cognitive impairment or subjective cognitive impairment (NCI/SCI), (b) Alzheimer’s disease (AD), (c) non-AD, and (d) mixed Alzheimer’s disease-Vascular dementia (AD-VaD). MDS-OAβ level was not significantly different between AD and mixed AD-VaD, but both groups were significantly different from the NCI/SCI and from the non-AD group. An MDS-OAβ level of >1 could potentially indicate clinical variants of AD or mixed pathology (AD-VaD).
... Given the absence of effective AD treatments, the current consensus is that, if diseasemodifying therapy is to be effective, the drug or treatment intervention must occur during AD's preclinical stage when pathophysiological processes are present but have not yet produced identifiable cognitive impairments. Coincident with the current shift in AD research from treatment and cure to prevention and risk reduction, research objectives too are shifting toward identifying novel techniques to screen more carefully those individuals who are cognitively normal but display underlying evidence of AD pathology so that available therapeutic interventions can be begun promptly to delay, or even prevent, debilitating neural deterioration [9,10]. ...
Full-text available
The present study investigated whether defective affordance perception capacity underpins tool use deficits in patients with Alzheimer’s disease (AD). An affordance, a concept James Gibson introduced, scales environmental objects to an animal’s action capabilities, thus offering opportunities for action. Each man-made artifact carries both a primary affordance (its designed function) and secondary affordances. In Experiment 1, participants identified secondary affordances of objects as a measure of their ability to identify alternative uses of familiar tools. A single response Go/No-Go task was administered to 4 groups: AD, mild cognitive impairment (MCI), Parkinson’s disease (PD), and elderly controls (EC). Groups were matched for age and years of education. The AD group performed poorest, followed by MCI, and PD and EC. EC and PD groups’ results failed to reach statistical significance, and the AD group performed at chance. In Experiment 2, participants judged the physical properties of the same objects used in Experiment 1. Even AD patients performed reliably, ruling out a visual processing deficit as the basis for their poor performance in Experiment 1. Results suggest that degraded affordance detection capacity can differentiate AD from normal aging and other neurodegenerative disorders and could be an affordable marker for AD, even in the early stages of AD.
Growing evidence suggests that impairment in rest‐activity rhythms may be a risk factor for cognitive decline and impairment in the aging population. However, previous studies included only a limited set of rest‐activity metrics and produced mixed findings. We studied a comprehensive set of parametric and nonparametric characteristics of rest‐activity rhythms in relation to mild cognitive impairment (MCI) and probable dementia in a cohort of older women. The prospective analysis included 763 women enrolled in two ancillary studies of the Women's Health Initiative (WHI): the WHI Memory Study‐Epidemiology of Cognitive Health Outcomes and Objective Physical Activity and Cardiovascular Health studies. The association between accelerometry‐based rest‐activity parameters and centrally adjudicated MCI and probable dementia were determined using Cox regression models adjusted for sociodemographic characteristics, lifestyle factors, and comorbidities. Overall, the results support a prospective association between weakened rest‐activity rhythms (e.g., reduced amplitude and overall rhythmicity) and adverse cognitive outcomes. Specifically, reduced overall rhythmicity (pseudo F statistic), lower amplitude and activity level (amplitude/relative amplitude, mesor, and activity level during active periods of the day [M10]), and later activity timing (acrophase and midpoint of M10) were associated with a higher risk for MCI and probable dementia. Women with lower amplitude and mesor also exhibited faster cognitive decline over follow‐up. Weakened rest‐activity rhythms may be predictive markers for cognitive decline, MCI, and dementia among older women.
Acetylcholine (ACh) is one of the most important neurotransmitters in the central cholinergic system; it specifically binds to muscarinic and nicotinic receptors and is degraded by acetylcholinesterase (AChE). ACh plays a crucial role in learning and memory. It is generally believed that, in the central nervous system, ACh promotes the conduction of brain nerves and accelerates information transmission. Besides, increasing central ACh levels can enhance memory ability and comprehensively improve brain function. Thus, AChE inhibitors (AChEI), which inhibit the degradation of ACh by AChE, have been used to treat Alzheimer's disease (AD) and Parkinson's disease dementia (PDD). However, recent studies have shown that excessive ACh in the central nervous system impairs learning and memory. Here we review the roles of ACh in learning and memory; we focus on the adverse effects of excessive ACh, the possible mechanisms, and the bidirectional role of ACh in the pathology and cure of AD and PDD. We conclude that the timing and dose of ACh administration should be carefully prescreened when using it to alleviate learning and memory in dementia patients.
Full-text available
Olfactory dysfunction is one of the biomarkers for Alzheimer’s disease (AD) diagnosis and progression. Deficits with odor identification and discrimination are common symptoms of pre-clinical AD, preceding severe memory disorder observed in advanced stages. As a result, understanding mechanisms of olfactory impairment is a major focus in both human studies and animal models of AD. Pretangle tau, a precursor to tau tangles, is first observed in the locus coeruleus (LC). In a recent animal model, LC pretangle tau leads to LC fiber degeneration in the piriform cortex (PC), a cortical area associated with olfactory dysfunction in both human AD and rodent models. Here, we review the role of LC-sourced NE in modulation of PC activity and suggest mechanisms by which pretangle tau-mediated LC dysfunction may impact olfactory processing in preclinical stage of AD. Understanding mechanisms of early olfactory impairment in AD may provide a critical window for detection and intervention of disease progression.
Background: Disease-modifying treatments for Alzheimer's disease (AD) may be more successful if interventions occur early, prior to significant neurodegeneration and subsequent to the onset of clinical symptoms, potentially during middle age. Polymorphisms within BDNF, COMT, and KIBRA have been implicated in AD and relate to episodic memory and executive functioning, two domains that decline early in AD. Objective: The purpose of the current study was to use an endophenotype approach to examine in healthy, non-demented middle-aged adults the association between polymorphisms in BDNF, COMT, and KIBRA and functional connectivity within networks related to episodic memory and executive function (i.e., default mode network (DMN), executive control network (ECN), and frontoparietal network (FPN)). Methods: Resting state networks were identified using independent component analysis and spatial maps with associated time courses were extracted using a dual regression approach. Results: Functional connectivity within the DMN was associated with polymorphisms in BDNF (rs11030096, rs1491850) and KIBRA (rs1030182, rs6555791, rs6555802) (ps < 0.05), ECN connectivity was associated with polymorphisms in KIBRA (rs10475878, rs6555791) (ps < 0.05), and FPN connectivity was associated with KIBRA rs6555791 (p < 0.05). There were no COMT-related differences in functional connectivity of any of the three networks investigated (ps > 0.05). Conclusion: Our study demonstrates that in middle age, polymorphisms in BDNF and KIBRA are associated with altered functional connectivity in networks that are affected early in AD. Future preclinical work should consider these polymorphisms to further elucidate their role in pathological aging and to aid in the identification of biomarkers.
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BACKGROUND: This study aimed to investigate the associations between secondhand smoke exposure and dementia, Alzheimer's disease (AD) and stroke. METHODS: This prospective study analyzed Framingham Offspring (FHS-OS) cohort participants with parents in the original Framingham Heart Study (FHS) cohort with known smoking status during offspring childhood. Surveillance for incident events, including dementia and stroke, among offspring participants exposed to parental smoking up to the age of 18 years commenced at examination 9 through 2014 and continued for approximately 30 years. RESULTS: At baseline, a total of 1683 (56.2%) subjects were not exposed to any secondhand smoke, whereas 670 (22.4%) subjects were exposed to 0-1 packs (20 cigarettes)/day, and 640 (21.4%) were exposed to over 1 pack/day. On follow-up (median: 31 years), 2993 patients developed dementia, including 103 with AD dementia and 315 with stroke. After adjusting for a wide range of established risk factors, participants with the highest exposure to secondhand smoke exhibited increased risks of all dementia, AD dementia and stroke compared with individuals with no exposure [HR 2.86 (2.00-4.09) for dementia; HR 3.13 (1.80-5.42) for AD dementia; HR 1.89 (1.37-2.61) for stroke]. The results remained comparable in the subgroup for individuals with median exposure to secondhand smoke. CONCLUSION: Exposure to secondhand smoke may be associated with increased risks of dementia, AD dementia and stroke.
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Amyloid-β (Aβ) and semen-derived enhancer of viral infection (SEVI) are considered as the two causative proteins for central pathogenic cause of Alzheimer’s disease (AD) and HIV/AIDS, respectively. Separately, Aβ-AD and SEVI-HIV/AIDS systems have been studied extensively both in fundamental research and in clinical trials. Despite significant differences between Aβ-AD and SEVI-HIV/AIDS systems, they share some commonalities on amyloid and antimicrobial characteristics between Aβ and SEVI, there are apparent overlaps in dysfunctional neurological symptoms between AD and HIV/AIDS. Few studies have reported a potential pathological link between Aβ-AD and SEVI-HIV/AIDS at a protein level. Here, we demonstrate the cross-seeding interactions between Aβ and SEVI proteins using in vitro and in vivo approaches. Cross-seeding of SEVI with Aβ enabled to completely prevent Aβ aggregation at sub-stoichiometric concentrations, disaggregate preformed Aβ fibrils, reduce Aβ-induced cell toxicity, and attenuate Aβ-accumulated paralysis in transgenic AD C. elegans. This work describes a potential crosstalk between AD and HIV/AIDS via the cross-seeding between Aβ and SEVI, identifies SEVI as Aβ inhibitor for possible treatment or prevention of AD, and explains the role of SEVI in the gender difference in AD. Cross-seeding of SEVI, a protein that enhances the infectivity of HIV virus, with Amyloid-β (Aβ) can prevent Aβ aggregation, disaggregate preformed Aβ fibrils, reduce Aβ-induced cell toxicity, and attenuate Aβ-accumulated paralysis in a transgenic C. elegans model of Alzheimer’s Disease.
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Objective To test the hypotheses that physical activity in midlife is not associated with a reduced risk of dementia and that the preclinical phase of dementia is characterised by a decline in physical activity. Design Prospective cohort study with a mean follow-up of 27 years. Setting Civil service departments in London (Whitehall II study). Participants 10 308 participants aged 35-55 years at study inception (1985-88). Exposures included time spent in mild, moderate to vigorous, and total physical activity assessed seven times between 1985 and 2013 and categorised as “recommended” if duration of moderate to vigorous physical activity was 2.5 hours/week or more. Main outcome measures A battery of cognitive tests was administered up to four times from 1997 to 2013, and incident dementia cases (n=329) were identified through linkage to hospital, mental health services, and mortality registers until 2015. Results Mixed effects models showed no association between physical activity and subsequent 15 year cognitive decline. Similarly, Cox regression showed no association between physical activity and risk of dementia over an average 27 year follow-up (hazard ratio in the “recommended” physical activity category 1.00, 95% confidence interval 0.80 to 1.24). For trajectories of hours/week of total, mild, and moderate to vigorous physical activity in people with dementia compared with those without dementia (all others), no differences were observed between 28 and 10 years before diagnosis of dementia. However, physical activity in people with dementia began to decline up to nine years before diagnosis (difference in moderate to vigorous physical activity −0.39 hours/week; P=0.05), and the difference became more pronounced (−1.03 hours/week; P=0.005) at diagnosis. Conclusion This study found no evidence of a neuroprotective effect of physical activity. Previous findings showing a lower risk of dementia in physically active people may be attributable to reverse causation—that is, due to a decline in physical activity levels in the preclinical phase of dementia.
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Alzheimer's disease (AD) drug development is costly, time-consuming, and inefficient. Trial site functions, trial design, and patient recruitment for trials all require improvement. The Global Alzheimer Platform (GAP) was initiated in response to these challenges. Four GAP work streams evolved in the US to address different trial challenges: 1) registry-to-cohort web-based recruitment; 2) clinical trial site activation and site network construction (GAP-NET); 3) adaptive proof-of-concept clinical trial design; and 4) finance and fund raising. GAP-NET proposes to establish a standardized network of continuously funded trial sites that are highly qualified to perform trials (with established clinical, biomarker, imaging capability; certified raters; sophisticated management system. GAP-NET will conduct trials for academic and biopharma industry partners using standardized instrument versions and administration. Collaboration with the Innovative Medicines Initiative (IMI) European Prevention of Alzheimer's Disease (EPAD) program, the Canadian Consortium on Neurodegeneration in Aging (CCNA) and other similar international initiatives will allow conduct of global trials. GAP-NET aims to increase trial efficiency and quality, decrease trial redundancy, accelerate cohort development and trial recruitment, and decrease trial costs. The value proposition for sites includes stable funding and uniform training and trial execution; the value to trial sponsors is decreased trial costs, reduced time to execute trials, and enhanced data quality. The value for patients and society is the more rapid availability of new treatments for AD.
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Cognitive reserve (CR) prevents cognitive decline and delays neurodegeneration. Recent epidemiological evidence suggests that lifelong bilingualism may act as CR delaying the onset of dementia by ∼4.5 y. Much controversy surrounds the issue of bilingualism and its putative neuroprotective effects. We studied brain metabolism, a direct index of synaptic function and density, and neural connectivity to shed light on the effects of bilingualism in vivo in Alzheimer’s dementia (AD). Eighty-five patients with probable AD and matched for disease duration (45 German-Italian bilingual speakers and 40 monolingual speakers) were included. Notably, bilingual individuals were on average 5 y older than their monolingual peers. In agreement with our predictions and with models of CR, cerebral hypometabolism was more severe in the group of bilingual individuals with AD. The metabolic connectivity analyses crucially supported the neuroprotective effect of bilingualism by showing an increased connectivity in the executive control and the default mode networks in the bilingual, compared with the monolingual, AD patients. Furthermore, the degree of lifelong bilingualism (i.e., high, moderate, or low use) was significantly correlated to functional modulations in crucial neural networks, suggesting both neural reserve and compensatory mechanisms. These findings indicate that lifelong bilingualism acts as a powerful CR proxy in dementia and exerts neuroprotective effects against neurodegeneration. Delaying the onset of dementia is a top priority of modern societies, and the present in vivo neurobiological evidence should stimulate social programs and interventions to support bilingual or multilingual education and the maintenance of the second language among senior citizens.
Dementia is an increasing focus for policymakers, civil organizations and multidisciplinary researchers. The most recent descriptive epidemiological research into dementia is enabling investigation into how the prevalence and incidence are changing over time. To establish clear trends, such comparisons need to be founded on population-based studies that use similar diagnostic and research methods consistently over time. This narrative Review synthesizes the findings from 14 studies that investigated trends in dementia prevalence (nine studies) and incidence (five studies) from Sweden, Spain, the UK, the Netherlands, France, the USA, Japan and Nigeria. Besides the Japanese study, these studies indicate stable or declining prevalence and incidence of dementia, and some provide evidence of sex-specific changes. No single risk or protective factor has been identified that fully explains the observed trends, but major societal changes and improvements in living conditions, education and healthcare might have favourably influenced physical, mental and cognitive health throughout an individual's life course, and could be responsible for a reduced risk of dementia in later life. Analytical epidemiological approaches combined with translational neuroscientific research could provide a unique opportunity to explore the neuropathology that underlies changing occurrence of dementia in the general population.
Background: Recently, the LIfestyle for BRAin health (LIBRA) index was developed to assess an individual's prevention potential for dementia. Objective: We investigated the predictive validity of the LIBRA index for incident dementia in midlife, late life, and the oldest-old. Methods: 9,387 non-demented individuals were recruited from the European population-based DESCRIPA study. An individual's LIBRA index was calculated solely based on modifiable risk factors: depression, diabetes, physical activity, hypertension, obesity, smoking, hypercholesterolemia, coronary heart disease, and mild/moderate alcohol use. Cox regression was used to test the predictive validity of LIBRA for dementia at follow-up (mean 7.2 y, range 1-16). Results: In midlife (55-69 y, n = 3,256) and late life (70-79 y, n = 4,320), the risk for dementia increased with higher LIBRA scores. Individuals in the intermediate- and high-risk groups had a higher risk of dementia than those in the low-risk group. In the oldest-old (80-97 y, n = 1,811), higher LIBRA scores did not increase the risk for dementia. Conclusion: LIBRA might be a useful tool to identify individuals for primary prevention interventions of dementia in midlife, and maybe in late life, but not in the oldest-old.
Importance Midlife vascular risk factors have been associated with late-life dementia. Whether these risk factors directly contribute to brain amyloid deposition is less well understood. Objective To determine if midlife vascular risk factors are associated with late-life brain amyloid deposition, measured using florbetapir positron emission tomography (PET). Design, Setting, and Participants The Atherosclerosis Risk in Communities (ARIC)–PET Amyloid Imaging Study, a prospective cohort study among 346 participants without dementia in 3 US communities (Washington County, Maryland; Forsyth County, North Carolina; and Jackson, Mississippi) who have been evaluated for vascular risk factors and markers since 1987-1989 with florbetapir PET scans in 2011-2013. Positron emission tomography image analysis was completed in 2015. Exposures Vascular risk factors at ARIC baseline (age 45-64 years; risk factors included body mass index ≥30, current smoking, hypertension, diabetes, and total cholesterol ≥200 mg/dL) were evaluated in multivariable models including age, sex, race, APOE genotype, and educational level. Main Outcomes and Measures Standardized uptake value ratios (SUVRs) were calculated from PET scans and a mean global cortical SUVR was calculated. Elevated florbetapir (defined as a SUVR >1.2) was the dependent variable. Results Among 322 participants without dementia and with nonmissing midlife vascular risk factors at baseline (mean age, 52 years; 58% female; 43% black), the SUVR (elevated in 164 [50.9%] participants) was measured more than 20 years later (median follow-up, 23.5 years; interquartile range, 23.0-24.3 years) when participants were between 67 and 88 (mean, 76) years old. Elevated body mass index in midlife was associated with elevated SUVR (odds ratio [OR], 2.06; 95% CI, 1.16-3.65). At baseline, 65 participants had no vascular risk factors, 123 had 1, and 134 had 2 or more; a higher number of midlife risk factors was associated with elevated amyloid SUVR at follow-up (30.8% [n = 20], 50.4% [n = 62], and 61.2% [n = 82], respectively). In adjusted models, compared with 0 midlife vascular risk factors, the OR for elevated SUVR associated with 1 vascular risk factor was 1.88 (95% CI, 0.95-3.72) and for 2 or more vascular risk factors was 2.88 (95% CI, 1.46-5.69). No significant race × risk factor interactions were found. Late-life vascular risk factors were not associated with late-life brain amyloid deposition (for ≥2 late-life vascular risk factors vs 0: OR, 1.66; 95% CI, 0.75-3.69). Conclusions and Relevance An increasing number of midlife vascular risk factors was significantly associated with elevated amyloid SUVR; this association was not significant for late-life risk factors. These findings are consistent with a role of vascular disease in the development of Alzheimer disease.
Background: No large trials have been done to investigate the efficacy of an intervention combining a specific compound and several lifestyle interventions compared with placebo for the prevention of cognitive decline. We tested the effect of omega 3 polyunsaturated fatty acid supplementation and a multidomain intervention (physical activity, cognitive training, and nutritional advice), alone or in combination, compared with placebo, on cognitive decline. Methods: The Multidomain Alzheimer Preventive Trial was a 3-year, multicentre, randomised, placebo-controlled superiority trial with four parallel groups at 13 memory centres in France and Monaco. Participants were non-demented, aged 70 years or older, and community-dwelling, and had either relayed a spontaneous memory complaint to their physician, limitations in one instrumental activity of daily living, or slow gait speed. They were randomly assigned (1:1:1:1) to either the multidomain intervention (43 group sessions integrating cognitive training, physical activity, and nutrition, and three preventive consultations) plus omega 3 polyunsaturated fatty acids (ie, two capsules a day providing a total daily dose of 800 mg docosahexaenoic acid and 225 mg eicosapentaenoic acid), the multidomain intervention plus placebo, omega 3 polyunsaturated fatty acids alone, or placebo alone. A computer-generated randomisation procedure was used to stratify patients by centre. All participants and study staff were blinded to polyunsaturated fatty acid or placebo assignment, but were unblinded to the multidomain intervention component. Assessment of cognitive outcomes was done by independent neuropsychologists blinded to group assignment. The primary outcome was change from baseline to 36 months on a composite Z score combining four cognitive tests (free and total recall of the Free and Cued Selective Reminding test, ten Mini-Mental State Examination orientation items, Digit Symbol Substitution Test, and Category Naming Test) in the modified intention-to-treat population. The trial was registered with (NCT00672685). Findings: 1680 participants were enrolled and randomly allocated between May 30, 2008, and Feb 24, 2011. In the modified intention-to-treat population (n=1525), there were no significant differences in 3-year cognitive decline between any of the three intervention groups and the placebo group. Between-group differences compared with placebo were 0?093 (95% CI 0?001 to 0?184; adjusted p=0?142) for the combined intervention group, 0?079 (-0?012 to 0?170; 0?179) for the multidomain intervention plus placebo group, and 0?011 (-0?081 to 0?103; 0?812) for the omega 3 polyunsaturated fatty acids group. 146 (36%) participants in the multidomain plus polyunsaturated fatty acids group, 142 (34%) in the multidomain plus placebo group, 134 (33%) in the polyunsaturated fatty acids group, and 133 (32%) in the placebo group had at least one serious emerging adverse event. Four treatment-related deaths were recorded (two in the multidomain plus placebo group and two in the placebo group). The interventions did not raise any safety concerns and there were no differences between groups in serious or other adverse events. Interpretation: The multidomain intervention and polyunsaturated fatty acids, either alone or in combination, had no significant effects on cognitive decline over 3 years in elderly people with memory complaints. An effective multidomain intervention strategy to prevent or delay cognitive impairment and the target population remain to be determined, particularly in real-world settings. Funding: French Ministry of Health, Pierre Fabre Research Institute, Gerontopole, Exhonit Therapeutics, Avid Radiopharmaceuticals.
Background: Epidemiological studies proposed a linear connection between developing dementia including Alzheimer's disease (AD) and obesity. Adiposity, insulin resistance and dementia indicated probable mechanistic links in this process. Indeed, it has been known that optimum insulin action in the brain plays critical role in cognitive function; whereas, insulin resistance in obese individuals finally leads to insulin deficiency in central nervous system (CNS) and down regulation of the efficiency of insulin uptake from periphery into CSF. In the current study, we aimed to assess correlation between increased body weight and insulin resistance with CSF to serum ratio of insulin and to evaluate the correlation between CSF to serum ratio of insulin with cognitive function in high fat diet induced obese rats. Methods and material: Twelve male Wister rats were randomly divided into two groups receiving Diet 1 (D1, 10% fat) and Diet 2 (D2, 59% fat) for 16 weeks. Weight was recorded weekly to assure body weight gain. Morris Water Maze (MWM) task was designed to assess spatial learning memory function. Finally, blood samples were collected for determining fasting serum glucose using enzymatic spectrophotometric method, insulin levels by ELISA kit and homeostasis model assessment of insulin resistance (HOMA-IR) was calculated. Fasting Cerebrospinal Fluid (CSF) insulin was also measured by ELISA kit. Result: D1 and D 2 groups both experienced weight gain but weight gain in D2 group was significantly higher. A significant correlation between CSF to serum ratio of insulin with weight (r=0.882, p=0.001) and HOMA-IR index (r=0.798, p=0.002) was reported. Moreover, the present study indicated significant correlations between CSF to serum ratio of insulin and escape latency time in first (r=0.631, p=0.028), second (r=0.716, p=0.009) and third (r=0.609, p=0.036) day of MWM test and probe time of MWM test (r=0.762, p=0.004). Conclusion: Increased body weight induced by high fat diet and insulin resistance in rats led to down regulation of CSF to serum ratio of insulin in the current research. Brain insulin deficiency may be responsible for possible decline of cognitive function in obesity. More researches are needed to better clarify the underlying mechanisms and also to confirm the similar findings in human studies.
Bilingualism as a component of cognitive reserve has been claimed to delay the onset of Alzheimer's disease (AD). However, its effect on cerebrospinal fluid (CSF) AD-biomarkers has not been investigated. We assessed cognitive performance and CSF AD-biomarkers, and potential moderation effect of bilingualism on the association between age, CSF AD-biomarkers, and cognition. Cognitively healthy middle-aged participants classified as monolinguals (n = 100, nCSF = 59), early (n = 81, nCSF = 55) and late bilinguals (n = 97, nCSF = 52) were evaluated. Models adjusted for confounders showed that bilinguals performed better than monolinguals on digits backwards (early-bilinguals p = 0.003), Judgment of Line Orientation (JLO) (early-bilinguals p = 0.018; late-bilinguals p = 0.004), and Trail Making Test-B (late-bilinguals p = 0.047). Early bilingualism was associated with lower CSF total-tau (p = 0.019) and lower prevalence of preclinical AD (NIA-AA classification) (p = 0.02). Bilingualism showed a moderation effect on the relationship between age and CSF AD-biomarkers and the relationship between age and executive function. We conclude that bilingualism contributes to cognitive reserve enhancing executive and visual-spatial functions. For the first time, this study reveals that early bilingualism is associated with more favorable CSF AD-biomarker profile.