Brain Health Services

Daniele Altomare, José Luis Molinuevo, Craig Ritchie, Federica Ribaldi,
Emmanuel Carrera, Bruno Dubois, Frank Jessen, Laura Mcwhirter, Philip
Scheltens, Wiesje M van der Flier, et al.

► To cite this version:

Daniele Altomare, José Luis Molinuevo, Craig Ritchie, Federica Ribaldi, Emmanuel Carrera, et al. Brain Health Services. Alzheimer's Research and Therapy, 2021, 13 (1), pp.168. 10.1186/s13195-021-00827-2. hal-04487719

HAL Id: hal-04487719

https://ut3-toulouseinp.hal.science/hal-04487719v1

Submitted on 4 Mar 2024

HAL is a multi-disciplinary open access
archive for the deposit and dissemination of sci-
entific research documents, whether they are pub-
lished or not. The documents may come from
teaching and research institutions in France or
abroad, or from public or private research centers.

L'archive ouverte pluridisciplinaire HAL, est
destinée au dépôt et à la diffusion de documents
scientifiques de niveau recherche, publiés ou non,
émanant des établissements d'enseignement et de
recherche français ou étrangers, des laboratoires
publics ou privés.

<figure><img src="image_1.png" /></figure>

Distributed under a Creative Commons CC BY 4.0 - Attribution - International License
REVIEW

Open Access

<figure><img src="image_2.png" /></figure>

Check for
updates

# Brain Health Services: organization, structure, and challenges for implementation. A user manual for Brain Health Services—part 1 of 6

Daniele Altomare<fnref n="1" />,<fnref n="2" />*†, José Luis Molinuevo³†, Craig Ritchie⁴, Federica Ribaldi<fnref n="1" />,<fnref n="2" />,⁵,⁶, Emmanuel Carrera⁷, Bruno Dubois⁸, Frank Jessen⁹, Laura McWhirter⁴, Philip Scheltens¹⁰,¹¹, Wiesje M. van der Flier¹⁰,¹², Bruno Vellas¹³, Jean-François Démonet¹⁴†, Giovanni B. Frisoni<fnref n="1" />,<fnref n="2" />†, on behalf of the European Task Force for Brain Health Services

## Abstract

Dementia has a devastating impact on the quality of life of patients and families and comes with a huge cost to society. Dementia prevention is considered a public health priority by the World Health Organization. Delaying the onset of dementia by treating associated risk factors will bring huge individual and societal benefit. Empirical evidence suggests that, in higher-income countries, dementia incidence is decreasing as a result of healthier lifestyles. This observation supports the notion that preventing dementia is possible and that a certain degree of prevention is already in action. Further reduction of dementia incidence through deliberate prevention plans is needed to counteract its growing prevalence due to increasing life expectancy.

An increasing number of individuals with normal cognitive performance seek help in the current memory clinics asking an evaluation of their dementia risk, preventive interventions, or interventions to ameliorate their cognitive performance. Consistent evidence suggests that some of these individuals are indeed at increased risk of dementia. This new health demand asks for a shift of target population, from patients with cognitive impairment to worried but cognitively unimpaired individuals. However, current memory clinics do not have the programs and protocols in place to deal with this new population.

We envision the development of new services, henceforth called Brain Health Services, devoted to respond to demands from cognitively unimpaired individuals concerned about their risk of dementia. The missions of Brain Health Services will be (i) dementia risk profiling, (ii) dementia risk communication, (iii) dementia risk reduction, and (iv) cognitive enhancement. In this paper, we present the organizational and structural challenges associated with
(Continued on next page)

<footnote>* Correspondence: Daniele.Altomare@unige.ch</footnote>

<footnote>†Daniele Altomare and José Luis Molinuevo contributed equally to this work (shared first author).</footnote>

<footnote>‡Jean-François Démonet and Giovanni B. Frisoni contributed equally to this work (shared last author).</footnote>

<footnote n="1">¹Laboratory of Neuroimaging of Aging (LANVIE), University of Geneva, Geneva, Switzerland</footnote>

<footnote n="2">²Memory Clinic, Geneva University Hospitals, Rue Gabrielle-Perret-Gentil 6, 1205 Geneva, Switzerland</footnote>

<footnote>Full list of author information is available at the end of the article</footnote>
(Continued from previous page)
the set-up of Brain Health Services.

**Keywords:** Brain Health Services, Dementia, Aging, Alzheimer's disease, Prevention, Dementia risk, Risk communication, Risk reduction, Cognitive enhancement, Personalized medicine

**Background**

Dementia consists of the cognitive decline from a previous level of performance to such an extent that it interferes with independence in everyday activities [1]. It impacts patients and their families and comes with a huge cost to society. Dementia prevention therefore is considered a public health priority by the World Health Organization [2]. Delaying the onset of dementia by treating underlying diseases will bring huge individual and societal benefit. Empirical observations in cohorts born in more recent decades in high-income countries indicate a reduction of the age-specific incidence of dementia [3–14], suggesting that dementia prevention is possible and already in action. This is likely the unintended result of greater overall wealth and healthier lifestyles, including better control of cardiovascular risk factors. Epidemiological evidence allows to estimate that 40% of dementia cases are due to lifestyle and cardiovascular modifiable risk factors [15], while the remaining cases are largely explained by genetic (e.g., APOE ε4), biological (e.g., amyloid and tau), other unknown risk factors, and their interactions [16]. However, the bad news is that dementia prevalence is steadily increasing worldwide. This is due mainly to population aging in lower- and middle-income countries and to the increased life span of individuals with dementia in higher-income countries. Therefore, a further decrease of dementia incidence is needed to counteract the worldwide trend of increased dementia prevalence. We believe that, today, evidence is sufficient to set up evidence-based, effective, personalized, and equitable dementia prevention plans in persons at risk of dementia.

The current memory clinics have been designed for the needs of patients with overt cognitive and/or behavioral disorders with the aim of reducing the burden of progressive decline (tertiary prevention). Nevertheless, a considerable number of cognitively unimpaired individuals believing that they may be at increased risk of dementia is seeking help in memory clinics, accounting for 20–30% of all patients [17–19]. Increasing and consistent evidence indicates that these have a mildly increased risk of dementia as compared to the general population [20]. These individuals present specific concerns, requests, expectations, and hopes different from those of the cognitively impaired ones, but they are usually discharged with generic recommendations and reassurance, and no really actionable and meaningful answers.

The development of new and innovative services, henceforth referred to as Brain Health Services (BHSs), is needed to provide specific answers to these individuals' unmet needs. The missions of BHSs consist of (i) dementia risk profiling, (ii) dementia risk communication, (iii) dementia risk reduction (primary and secondary prevention), and (iv) cognitive enhancement. BHSs will feature specific knowledge, skills, protocols, and technology to meet the challenges posed by this new demand. Some pilot experiences are ongoing at the time of the writing of this article (Q4 2020) in Barcelona, Edinburgh, and Paris and have provided ideas and tools for this article and the others of this series published in this issue of Alzheimer's Research & Therapy.

This is the first of six papers, which are part of a larger initiative of the European Task Force for Brain Health Services, aiming to draft the protocols of operations in the BHSs of the future. Here, we describe the organization, structure, and challenges for implementing BHSs, while the other papers focus on the four missions (mentioned above) and on the societal challenges.

**BHS organization**

In this section, we present how the novel BHS facilities might be structured at the time of writing of this article (Q4 2020). In Section 4.1, we envision how BHSs may look like in the upcoming years based on research advances and technological innovations.

**What is in a name?**

Equally tenable denominations could be proposed, emphasizing different aspects: i) the biomedical domains (e.g., brain, dementia, Alzheimer's disease, memory), (ii) the clinical mission (e.g., health, prevention), and (iii) the organizational structure (e.g., clinic, service, unit). The end result would be labels such as "brain health clinics," "dementia prevention services," etc.

We propose "Brain Health Services" for the following reasons: (i) the concept of "brain health" is more comprehensive than "dementia prevention," opening to cognitive enhancement which, by definition, aims to improve cognitive functions rather than preventing dementia, and is one of people's demands and (ii) the terms "clinic" and "unit" imply that the services would be delivered in structures independent of other services, while we believe that BHSs can be implemented either within the current memory clinics or as distributed and
interconnected services (see the “Context for BHS im-
plementation” section). Whatever the label, its semantic
should match the content of the health offer.

Users

The target population of BHSs will consist of older or
middle-aged adults who wish to check their risk of de-
mentia, preserve cognitive functions, or enhance their
cognitive performance. This population includes individ-
uals with subjective cognitive decline (SCD) [21], func-
tional cognitive disorders [19], and the “worried wells.”

Individuals with SCD experience persistent cognitive
decline which is not detected by the standard clinical
and neuropsychological batteries used to detect mild
cognitive impairment and dementia and, although cogni-
tively unimpaired, have an increased risk of dementia as
compared to the general population (incidence of 20.1/
1000 person-year vs 14.2/1000 person-year [20]). Func-
tional cognitive disorders consist of a range of overlap-
ping conditions in which cognitive symptoms, usually of
attentional nature, present characteristic internal incon-
sistency as the result of reversible changes in brain func-
tion rather than damage or disease [19]. Functional
cognitive disorders may present as an isolated syndrome,
or in the context of anxiety or depression, or alongside
other functional or somatoform symptoms such as
chronic pain [19]. Some individuals with functional cog-
nitive disorders may perform in the mildly impaired
range on cognitive tests [19]. Where a positive diagnosis
of functional cognitive disorders is made, appropriate
treatment should include a clear explanation of the diag-
nosis using supportive written material (for example,
“Functional Neurological Disorder (FND): a patient’s
guide” [22]). Worried wells do not have any specific cogni-
tive complaint, but they claim concern of declining cogni-
tion in the future, and strive to preserve it as long as
possible or even enhance it. Worried wells frequently re-
port a family history of dementia or Alzheimer’s disease.

Clearly, the target population of BHSs is remarkably
different from that of current memory clinics. The above
case-mix suggests not to refer to them as “patients,” but
to rather prefer a more neutral term such as “users.”

It is worth noting that the definition and identification
of the ideal target population might not always be clear-
cut, especially when it comes to individuals with border-
line or inconclusive cognitive testing or very mild cogni-
tive or executive dysfunctions who might still benefit of
the BHS offers. Moreover, while we expect that a larger
share of users might be classified as SCD, functional
cognitive disorders or worried wells, other groups might
access BHSs. These groups might include individuals
with mild forms of mood, anxiety, sleep, attention-
deficit/hyperactivity, or other disorders. Some of these
individuals might be eligible to enter a BHS journey

depending on BHS personnel and facilities (e.g., a psych-
iatrist or psychotherapist with experience in mood dis-
ders), while others should be referred to external
specialists. Individuals with severe psychiatric or physical
comorbidity (e.g., cardiovascular/cerebrovascular dis-
eases) will not represent the target population of BHSs.

In the perspective of growing demand and growing
offer, in the early years of BHSs, users will be referred by
memory clinics. At a later stage, as BHSs catch up, they
will consolidate their own user flow consisting of people
who spontaneously show up directly to BHSs. The im-
plementation of educational programs (e.g., awareness
campaigns on brain health for the general population)
and other initiatives [23] might increase the BHSs visi-
bility and reputation.

Missions

The four main missions of BHS are as follows: (i) dementia risk profiling, (ii) dementia risk communication, (iii) dementia risk reduction (*primary and secondary prevention*), and (iv) cognitive enhancement. These topics are exhaustively discussed in the pertinent papers [24–27], and briefly summarized below.

Education of the general public and health care pro-
viders might be a mission of BHSs in academic settings.
This will not be addressed in this paper as it will be of
interest to a minority of academic BHSs and is beyond
the scope of this initiative.

Dementia risk profiling

The very first step of assessment in BHSs will be un-
derstanding the user’s request. Anecdotal observations
indicate that a number of individuals with SCD, func-
tional cognitive disorders, or worried wells look for
reassurance. Indeed, malaises such as psychological/
psychiatric (e.g., depression, trauma, affective issues)
or personal issues (e.g., divorce, violent spouse, un-
employment, societal issues) are sometimes presented
in disguise as “memory” concerns. A careful history
collection, carried out with tact and empathy, can be
revealing. In such cases, a “blind” offer of dementia
risk assessment would be a clinical misstep. The BHS
clinician should here refer the user to the appropriate
specialist.

The following step to the implementation of personal-
ized prevention plans is to identify users’ risk factors for
dementia. The relative risk of modifiable dementia risk
factors varies widely between 1.1 for air pollution to 1.9
for hearing loss and depression [15] and dramatically in-
creases for genetic (*APOE ε4* genotype) and biological
(amyloid and tau deposition) risk factors [16]. BHSs
must be able to comprehensively assess, combine (e.g.,
through composite dementia risk scores such as the
Cardiovascular Risk Factors, Aging, and Incidence of Dementia (CAIDE) Dementia Risk Score [28]; the Brief Dementia Screening Indicator [29]; and the Australian National University Alzheimer's Disease Risk Index [30, 31]), and interpret all these risk factors together with protective factors, and to finally profile and categorize the user's specific risk into strata (e.g., high, moderate, or low risk of developing dementia in the following 5, 10, or 15 years). A basic level of assessment should include sociodemographic, lifestyle, and health risk factors, followed by APOE status and biomarkers if resources allow. Importantly, risk profiling should take into account other demographic variables such as age, gender, and ethnicity which might influence the interpretation of risk factors (e.g., APOE ε4 is associated with a higher risk of AD in individuals aged 65–70 years [32], in women as compared to men [33, 34], and in Japanese and Caucasian individuals as compared to African Americans and Hispanics [35]).

Further research is still needed to estimate the relative risk of each risk factor adjusted for communality with other factors; develop composite risk scores combining modifiable, biological (e.g., amyloid and tau), and genetic (e.g., APOE) risk factors; and develop cost-effective screening protocols [24].

## Dementia risk communication

We recommend disclosing the risk of dementia, whether based only on lifestyles or also on genetic or biomarker status, to users, providing expert counseling if necessary. However, this decision should be taken on an individual basis and taking into account user's cultural, societal, and economic backgrounds, belief system, and expectations.

The communication of the concept of risk to the general public is challenging, especially in the context of untreatable and stigmatized neurodegenerative diseases leading to dementia. Evidence on how to communicate dementia risk is scarce. Nevertheless, the available literature allows to put in place some practical recommendation [25]. These recommendations are inspired from other fields with more experience on this topic (e.g., oncology [36–38]) and from existing research disclosure protocols of genetic (e.g., APOE genotype [39–42]) and biomarker (e.g., amyloid-PET [43–47]) results that proved to have a well-tolerated psychological impact in the short term. Nevertheless, we acknowledge that these disclosure protocols are limited to explaining that genes or biomarkers are risk factors for dementia, but do not actually communicate the risk of developing dementia in the next few years.

We underline that the use of standardized communication protocols on an individual level is challenging and

might require a certain degree of adaptation and clinical sensitivity. Further research is needed to develop communication protocols delivering quantitative information about individual risk, and scalable tools suitable to users with different socio-demographic and cultural features (including educational background). BHSs will represent the ideal context for this research.

Finally, BHSs will need to deal with the ethics regulations and potential regulatory hurdles associated with the communication of risk (mainly so if based on genetics) to the users, their families, and other actors (e.g., healthcare insurances, employers). Informed consent should be given before entering a BHS journey, and confidentiality should be enforced at all levels of the BHS journey.

## Dementia risk reduction

Risk reduction interventions aim to reduce the likelihood of long-term cognitive decline or dementia onset in at-risk individuals. Among all the randomized trials on multi-domain interventions, only the FINGER study met its primary outcome, showing greater cognitive improvement in participants of the experimental group versus controls [48]. On the contrary, other randomized trials on multi-domain interventions such as MAPT [49], preDIVA [50], Look AHEAD [51], and DO-HEAL TH [52] failed to meet their primary outcomes.

Interestingly, subsample analyses of the FINGER and MAPT studies showed that interventions were more effective in patients at increased risk for dementia based on genetic (APOE ε4) [53] or biological (amyloid positivity) [49] risk factors. This suggests that personalized multi-domain interventions, tailored to the individual's specific risk factors (reflecting the risk reduction potential), are likely associated to the highest clinical benefit.

Even though preliminary evidence is now available and allows to provide recommendations for practical implementation of precision dementia risk reduction interventions [26], long-term multi-domain randomized controlled trials are needed to provide definitive evidence on their efficacy. The World Wide-FINGERS, the first network for multimodal dementia prevention trials, aims to fill this evidence gap by adapting and optimizing the FINGER operational model for dementia risk reduction in different populations, and geographic and economic settings [54].

Translation of experimental risk reduction interventions to the clinical setting will not be straightforward. Possible interventions that can be offered to BHS users today or in the next few years might cover one of more of the following areas: diet, exercise, cognitive training, and vascular risk monitoring (inspired by current cardiovascular prevention programs) [26].
Finally, we underline the importance of correcting sensory impairment or emotional disorders (e.g., anxiety or depression) as a prerequisite for the implementation of effective dementia risk reduction intervention.

## Cognitive enhancement

Cognitive enhancement interventions aim to improve the individual's performance and abilities. These interventions are typically performed over a time span of a few days/weeks. Cognitive enhancement interventions include cognitive, mental, and physical training (including mindfulness); non-invasive brain stimulation; and cognitive-enhancement drugs. To date, currently available evidence supporting the efficacy of cognitive training is limited and heterogeneous but generally positive, while that supporting the efficacy of mindfulness and tDCS interventions might possibly increase in the next few years. Evidence on cognitive-enhancing drugs is poor and inconclusive [27].

## Personnel and expertise

The dementia domain is largely interdisciplinary and spans neurology, geriatrics, psychiatry, cognitive psychology, neuropsychology, nursing, and social sciences. Indeed, BHSs should be led by multidisciplinary teams to cover all these areas. Expertise in psychology and/or neuropsychology is necessary for the initial (and potential follow-up) clinical and cognitive evaluations, to communicate the risk, and to implement cognitive interventions. Medical expertise (e.g., in neurology, geriatrics, psychiatry) is necessary to define indications for entering the BHS track, carry out exams, interpret biological and genetic risk factors, prioritize risk, set risk reduction interventions, and propose follow-up if needed. Nursing competences might be necessary to collect samples and measures for risk factor assessment (e.g., biological samples, blood pressure). Further expertise, such as nutrition or a physical training, might be useful to cover some specific areas of prevention.

BHSs will wish to recruit personnel based on the required expertise rather than on a priori defined professional categories. For example, although current job descriptions usually suggest that dementia risk communication should be done by a physician, we believe that a psychologist with appropriate training, empathy, and communication skills can safely perform this task. Postgraduate courses on the care of persons with cognitive disorders that are active or being launched in Europe will help educate BHS professionals [55].

## Basic vs advanced BHSs

Not all BHSs will need to cover the whole range of potential health offer. We envision at least two levels, basic and advanced, depending on resources and available

facilities. Basic services may consist of (i) standardized risk assessment based on lifestyles, vascular and basic genetic risk factors (e.g., APOE), and possibly measures reflecting structural brain health (e.g., qualitative or quantitative measures of atrophy and vascular changes), implementing low-level composite dementia risk scores (e.g., the CAIDE Dementia Risk Score); (ii) adaptation and use of current practices for dementia risk communication; (iii) implementation of standardized non-pharmacological primary prevention protocols (e.g., FINGER and MAPT interventions) and pharmacological and non-pharmacological control of cardiovascular risk factors; and (iv) cognitive enhancement using cognitive training.

An advanced version of BHSs may expand the basic services with one or more of the following: (i) molecular imaging biomarkers (e.g., amyloid-PET, tau-PET, MRI with automated image post-processing) and/or CSF biomarkers (e.g., Aβ₄₂, phosphorylated tau, neurofilament light), (ii) use of structured personalized dementia risk communication protocols taking into account user's specific features (e.g., educational background), (iii) implementation of personalized primary and secondary prevention protocols tailored to the user's molecular risk profile including biomarker derived information, and (iv) combination of sophisticated and personalized cognitive enhancement techniques (e.g., cognitive training and non-invasive brain stimulation).

As of today, some of basic BHSs' activities (e.g., primary prevention) could be absorbed by general practice depending on the structure of local healthcare provision and local opportunities. On the contrary, at the current state of science and technology, most of the advanced BHSs' activities (e.g., secondary prevention) cannot take place in the general practice. The availability of blood-based biomarkers may change the scenario only if shown to be sufficiently specific and in the presence of a well-tolerated preventive drug.

## Facilities

The main technological facilities needed in BHSs are largely the same of a traditional memory clinic and might include MRI, PET, and fully automated CSF analysis platforms (e.g., Elecsys, Lumipulse).

Other facilities will be specific to BHSs and may include tablets for computerized cognitive training, physical activity monitors, and fitness trackers.

As is the case of current memory clinics, local factors such as availability of technology or expertise, or idiosyncrasies towards a given diagnostic or intervention technology will give individual BHSs their specificity.
## Context for BHS implementation

BHSs can be either hybrid or stand-alone services. In the first case, BHSs can leverage on the current memory clinics' structure and ongoing collaborations (with nuclear medicine, radiology, biochemistry laboratories, etc.). BHS-specific expertise and technology will need to be integrated, since some personnel and facilities are often lacking in memory clinics such as psychotherapists, nutrition experts, physical trainers, and devices for transcranial stimulation. The investment in this case would be relatively modest. In the second case, stand-alone BHSs will need new personnel and facilities and to build collaborations with other services. The investment in this case would obviously be significantly higher. In either case, since stroke centers are already dealing with the implementation of cardiovascular prevention programs and the promotion of awareness-rising campaigns (both key aspects of BHSs), BHSs can partner with them and leverage on their longstanding expertise.

Whatever the setup, a tight collaboration between BHSs and memory clinics is strongly encouraged by this working group. Indeed, memory clinics can refer cognitively unimpaired patients to BHSs in order to investigate their request and provide meaningful answers. Conversely, BHSs can refer cognitively impaired users to memory clinics in order to start proper diagnostic workup and treatment.

## Similar initiatives

The BHS initiative has some similarities with previous initiatives. For example, a similar approach has been previously adopted by two Alzheimer's Prevention Clinics whose mission is to provide personalized therapeutic interventions, based on the individual risk profile, in patients at risk for AD [56]. This approach was clearly presented in a paper describing in detail the supporting methodology as well as the proposed risk reduction interventions and the associated challenges [56]. Briefly, patients entering the Alzheimer's Prevention Clinics undergo a basic assessment of genetic, lifestyle, and cardiovascular risk factors followed by personalized therapeutic interventions. We acknowledge that the basic BHSs (as described in the "Basic vs advanced BHSs" section) might resemble, at least in some aspects, the Alzheimer's Prevention Clinics. Nevertheless, the advanced BHSs will allow to take a step forward towards a more comprehensive and accurate risk profiling by assessing molecular biomarkers, and more effective risk reduction interventions tailored to the user's molecular risk profile.

In the last few years, several "trial-ready" cohort projects have been launched, the most relevant of which are EPAD [57] and TRC-PAD [58]. Such projects aim to recruit and screen participants in order to assemble deeply phenotyped cohorts which provide a pool of participants

to clinical trials. Indeed, the only offer of "trial-ready" projects is inclusion in clinical trial, and their target population most of the times consists only of amyloid-positive individuals. Differently, BHSs will deliver multiple pharmaceutical and non-pharmaceutical risk reduction interventions and their target population in broader covering older or middle-aged adults with variable risk profiles. These differences make the BHS initiative unique of its kind.

## BHS challenges

### Equity and societal challenges

One of the main challenges will consist in making BHSs equitable, i.e., accessible to the general population regardless of their economic status. Most interventions potentially offered by BHSs are not reimbursed in any Western country; they may take place in for-profit enterprises where users pay interventions with out-of-pocket money. Indeed, BHSs, at least at their first development stages, will thrive mainly in higher-income countries for the greater social awareness of cognitive diseases. As a consequence, access may be limited to the more affluent and more highly educated members of society. Paradoxically, the population that would benefit the most from the BHSs is the one likely to be excluded (at least initially). Indeed, individuals with disadvantaged conditions, lower education, and lower socioeconomic status are likely those with higher risk of dementia and who might benefit the most from risk reduction and cognitive enhancement interventions. See Milne et al. [59] for a deeper discussion on this topic. The affiliation to an existing memory clinic or stroke center might facilitate the coverage at least some procedures by healthcare insurances.

### Individual interventions vs large-scale population interventions

The European Task Force for Brain Health Services is largely made of clinicians and clinical researchers who are by mission focused on individuals rather than on society as a whole. Indeed, even though BHSs can sporadically touch the general population (e.g., by awareness promoting campaigns on brain health), their mission is the implementation of personalized prevention plans tailored to the individual's risk profile. This is the so-called "high-risk approach" that has contributed to dramatically decrease stroke morbidity and mortality over the past decades [60].

Nevertheless, the authors acknowledge that well-designed and implemented prevention initiatives at the population level might be associated with great societal benefit, if only in the long term. Such interventions require the direct engagement of healthcare systems and payers and strong evidence supporting the efficacy of
interventions [61]. BHSs may contribute to the produc-
tion of this evidence, while they may or may not be the
hubs of prevention initiatives at the population level.

Sustainability

Depending on the context (see the “Context for BHS im-
plementation” section), a BHSs will require variable
amount of funding to be financially sustainable. It is
likely that business models for BHSs will develop
through several stages. Initial resources may come from
grants, philanthropy, and channeling research income/
overheads into the establishment of innovator sites that
will by necessity be located in university teaching hospi-
tals. Such settings will not need to invest heavily in up-
front capital costs for, e.g., MRI scanners. These settings
must commit to generating substantial evidence on ac-
cess and health outcomes to deliver both short- and
long- term health economic analysis. These will be lo-
cally derived to take to the local health care funders and
will be nuanced to reflect the needs/motivations of the
purchaser.

The purchasing by the extant health providers has to
be the exit strategy for the reactive initial funding. One
could argue that a 5-year period of funding for “pilot or
innovator” sites is sufficient to make the argument to
transition to centralized funding by, e.g., Healthcare
Commissioners in the NHS. This will be supported by,
e.g., NICE guidance and other clinical policy documents
that will support individual practitioners in making their
business case. Reports from advocacy groups whilst
helpful are no replacement for policy documents gener-
ated in an unbiased fashion by organizations like NICE.
Finally, the patient perspectives on the service can act as a
powerful motivator for change. Collecting data on their ex-
perience will help the development of services as well as
their extension to other regions of the country in question.

Of course, investors in the market of private health-
care may also wish to seize the opportunity of investing
in this growing market. The setups of BHSs in already
existing structures (e.g., memory clinics or stroke cen-
ters) will minimize the amount of the investment.

Research

In order to promote equity and sustainability, BHSs
should integrate their offer with continuing research activ-
ity. Sound evidence produced by BHSs research activity
might contribute to (i) identifying the trajectories of the
underlying pathologies by the follow-up of individuals at a
preclinical stage, (ii) selecting individuals at high risk for
the inclusion in clinical trials aimed at studying the effi-
cacy of disease-modifying therapies at a preclinical asymp-
tomatic stage of the disease, (iii) producing strong
scientific evidence on the efficacy of interventions (or lack
thereof), (iv) making structural efforts to access more

marginalized communities by design, and (v) drawing at-
tention of healthcare systems and persuade them to pro-
vide coverage, making BHS sustainable and equitable.

Discussion

The increasing prevalence of dementia, the awareness of the
general population on brain health, recent advancements in
technology and knowledge of neurodegenerative diseases,
and preliminary evidence of effective risk reduction interven-
tions constitute the rationale behind the development of
BHSs. BHSs will focus on a new target population (cogni-
tively unimpaired individuals concerned with the preserva-
tion or improvement of their cognitive abilities); have specific
missions (dementia risk profiling, dementia risk communica-
tion, dementia risk reduction, and cognitive enhancement);
face relevant challenges (demonstrating efficacy, equity and
sustainability of the services); and require high-level expertise,
facilities, and personnel. BHSs might rely on the current
memory clinics or be independent services.

The current aim of this BHS initiative is to raise
awareness on the need for new services aimed at cur-
rently underserved group individuals and provide a large
set of recommended interventions which should be lo-
cally adapted by healthcare providers based on local
needs and resources.

The future of BHSs

We envision that BHSs might change in the upcoming
years thanks to research advances and novel
technologies.

Dementia risk profiling

The clinical validation of blood-based biomarkers of
amyloid [62], tau [63], and neurodegeneration (e.g., neu-
rofilament light [64]) will radically change the way indi-
vidual risk is assessed. Indeed, blood-based biomarkers
are much cheaper than molecular imaging and much
more accessible. We envision a scenario where blood-
based biomarkers with high sensitivity for abnormality
will be used for large-scale dementia screening, thus re-
ducing the number of users requiring more expensive
testing. Polygenic risk scores may also make the transi-
tion to clinical fruition in the coming years. The wide-
spread use of calculators (e.g., ADappt [65]) will allow a
comprehensive interpretation of multiple risk factors
and the quantification of the user's risk. Finally, the use
of brain health registries [66, 67] and digital tools will fa-
cilitate the access of users to BHSs.

Dementia risk communication

Large-scale education programs will result in increased
awareness of the general population on brain health. A
more educated and aware population has a better predis-
position to understand the concept of risk. Nevertheless,
further research is needed to develop and implement
proper communication strategies on an individual level.

## Dementia risk reduction

Aducanumab [68, 69] might be the very first disease-
modifying therapy approved by the FDA for clinical use
in patients with prodromal Alzheimer's disease or mild
Alzheimer's disease dementia. Several phase 3 clinical
trials on anti-amyloid drugs in cognitively healthy indi-
viduals are currently ongoing, and their results are ex-
pected between 2021 and 2025 [70]. If they prove to be
effective, disease-modifying therapies will be the main
weapon to prevent cognitive deterioration in cognitively
unimpaired biomarker-positive individuals. In the opti-
mistic scenario of an effective disease-modifying therapy,

BHSs will play a key role in screening the population
and delivering such therapies.

However, whether disease-modifying therapies will be
available or not, more targeted personalized multido-
main interventions will be increasingly fine-tuned and
implemented in BHSs [54].

## Cognitive enhancement

In the next few years, protocols combining cognitive
training, mindfulness, and non-invasive brain stimula-
tion might be available, although the timelines are even
harder to predict than for industry-sponsored pharmaco-
logical clinical trials.

This provides an example of how BHSs might operate
when blood-based biomarkers are available. In this

<figure><img src="image_3.png" /></figure>
scenario, users undergo screening including assessment of APOE genotype and lifestyle risk factors as well as high-sensitivity blood-based biomarkers. Those users with positive or borderline blood-based biomarkers might also undergo a second-level assessment with molecular imaging (e.g., amyloid-PET, tau-PET), even if this might be not necessary if blood-based biomarkers prove to be highly accurate (in terms of both high sensitivity and specificity). Taken together, this information allows to profile the user's risk and classify it (e.g., as "low," "moderate," or "high" based on a composite relative risk). Afterward, the risk is communicated to the user. Finally, the intervention is chosen accordingly: users with low risk might start personalized cognitive enhancement interventions, while users with moderate or high risk should undergo personalized risk reduction interventions possibly including disease-modifying therapies. This is a purely indicative scenario and can vary based on the context of BHS implementation. CT, computerized tomography; MRI, magnetic resonance imaging; FDG, fluorodeoxyglucose; PET, positron emission tomography; APOE, apolipoprotein E; RR, relative risk; BBB, blood-based biomarkers; DMT, disease-modifying therapies. The risk operationalization of "low" (RR = 1–2), "moderate" (RR = 2–4), and "high" (RR > 4) intended to be indicative and is used for illustrative purposes only.

Figure 1 provides an example of how BHSs might operate.

## Conclusion

Despite the many organizational and structural challenges to be faced, we envision that the development of BHSs will play a key role in the fight against the increasing dementia prevalence by embracing the needs of cognitively unimpaired individuals who wish to preserve or improve their cognitive abilities.

## Abbreviations

BHS: Brain Health Services; CAIDE: Cardiovascular Risk Factors, Aging, and Incidence of Dementia; MRI: Magnetic resonance imaging; SCD: Subjective cognitive decline

## Acknowledgments

European Task Force for Brain Health Services (in alphabetical order): Marc ABRAMOWICZ, Daniele ALTOMARE, Frederik BARKHOF, Marcelo BERTHIER, Melanie BIELER, Kaj BLENNOW, Carol BRAYNE, Andrea BRIOSCHI, Emmanuel CARRERA, Gael CHÉTELAT, Chantal CSAJKA, Jean-François DEMONET, Alessandra DODICH, Bruno DUBOIS, Giovanni B. FRISONI, Valentina GARIBOTTO, Jean GEORGES, Samia HURST, Frank JESSEN, Miia KIVIPELTO, David LLEWELLYN, Laura McWHIRTER, Richard MILNE, Carolina MINGUILLÓN, Carlo MINIUSSI, José Luis MOLINUEVO, Peter M NILSSON, Janice RANSON, Federica RIBALDI, Craig RITCHIE, Philip SCHELΤENS, Alina SOLOMON, Wiesje VAN DER FLIER, Cornelia VAN DUIJN, Bruno VELLAS, Leonie VISSER.

## Authors' contributions

Daniele Altomare and José Luis Molinuevo conceptualized this Paper, drafted the manuscript for intellectual content, and approved the manuscript.

Jean-François Démonet conceptualized this Paper, revised the manuscript for intellectual content, and approved the manuscript.

Craig Ritchie, Bruno Dubois, and Laura McWhirter drafted specific parts of the manuscript, revised the manuscript for intellectual content, and approved the manuscript.

Emmanuel Carrera, Frank Jessen, Philip Scheltens, Wiesje M. van der Flier, and Bruno Vellas revised the manuscript for intellectual content, and approved the manuscript.

Daniele Altomare, Giovanni B. Frisoni, and Federica Ribaldi conceived and organized the workshop whence the Papers of the BHS series in this issue of Alzheimer's Research & Therapy originated, conceived the related editorial initiative, revised this manuscript for intellectual content, harmonized the manuscript with the other Papers of the BHS series, and approved the manuscript.

## Funding

This paper was the product of a workshop funded by the Swiss National Science Foundation entitled "Dementia Prevention Services" (grant number: IZSEZ0_193593).

GBF received funding by: the EU-EFPIA Innovative Medicines Initiatives 2 Joint Undertaking (IMI 2 JU) "European Prevention of Alzheimer's Dementia consortium" (EPAD, grant agreement number: 115736) and "Amyloid Imaging to Prevent Alzheimer's Disease" (AMYPAD, grant agreement number: 115952); the Swiss National Science Foundation: "Brain connectivity and metacognition in persons with subjective cognitive decline (COSCODE): correlation with clinical features and in vivo neuropathology" (grant number: 320030_182772).

WMvdF holds the Pasman chair.

## Availability of data and materials

Data sharing is not applicable to this article as no datasets were generated or analyzed during the current study.

## Declarations

### Ethics approval and consent to participate

Not applicable.

### Consent for publication

Not applicable.

## Competing interests

JLM is currently a full-time employee of Lundbeck and has previously served as a consultant or at advisory boards for the following for-profit companies, or has given lectures in symposia sponsored by the following for-profit companies: Roche Diagnostics, Genentech, Novartis, Lundbeck, Oryzon, Biogen, Lilly, Janssen, Green Valley, MSD, Eisai, Alector, BioCross, GE Healthcare, ProMIS Neurosciences.

BD has received research funding (paid to the institution) from Merck-Avenir Foundation, Roche and consultancy fees from Biogen, Neurodiem, Green Valley, Cytox, Brainstorm. He is PI of clinical trials with EISAI, Genentech, Novartis, Biogen, Roche.

PS has received consultancy fees (paid to the institution) from AC Immune, Alkermes, Alnylam, Anavex, Biogen, Brainstorm Cell, Cortexyme, Denali, EIP, ImmunoBrain Checkpoint, GemVax, Genentech, Green Valley, Novartis, Novo Noridisk, PeopleBio, Renew LLC, Roche. He is PI of studies with AC Immune, CogRx, FUJI-film/Toyama, IONIS, UCB, Vivoryon. He serves on the board of the Brain Research Center.

WMvdF has received consultancy fees (paid to the institution) from Oxford Health Policy Forum CIC, Roche BV. She has been an invited speaker at Boehringer Ingelheim, Biogen MA Inc., and WebMD Neurology (Medscape). She has performed contract research for Biogen MA Inc. and Boehringer Ingelheim. All funding is paid to her institution. WF is associate editor at Alzheimer's Research & Therapy.

JFD has received consultancy fees from Biogen and OM Pharma; unrestricted grants from OM Pharma; and has collaboration agreements with Siemens and MindMaze.

GBF reports grants from Alzheimer Forum Suisse, Académie Suisse des Sciences Médicales, Avid Radiopharmaceuticals, Biogen, GE International, Guerbert, Association Suisse pour la Recherche sur l'Alzheimer, IXICO, Merz Pharma, Nestlé, Novartis, Piramal, Roche, Siemens, Teva Pharmaceutical
Industries, Vifor Pharma, and Alzheimer's Association; he has received personal fees from AstraZeneca, Avid Radiopharmaceuticals, Elan Pharmaceuticals, GE International, Lundbeck, Pfizer, and TauRx Therapeutics. The other coauthors declare that they have no competing interests.

## Author details

¹Laboratory of Neuroimaging of Aging (LANVIE), University of Geneva, Geneva, Switzerland. ²Memory Clinic, Geneva University Hospitals, Rue Gabrielle-Perret-Gentil 6, 1205 Geneva, Switzerland. ³Barcelonaßeta Brain Research Center, Pasqual Maragall Foundation, Barcelona, Spain. ⁴Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh, UK. ⁵Laboratory of Alzheimer's Neuroimaging and Epidemiology (LANE), Saint John of God Clinical Research Centre, Brescia, Italy. ⁶Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy. ⁷Department of Neurology, Stroke Center, University Hospitals and University of Geneva, Geneva, Switzerland. ⁸Institut de la Mémoire et de la Maladie d'Alzheimer, IM2A, INSERM, Institut du Cerveau et de la Moelle Épinière, UMR-S975, Groupe Hospitalier Pitié-Salpêtrière, AP-HP, Sorbonne Université, Paris, France. ⁹Department of Psychiatry and Psychotherapy, Medical Faculty, University of Cologne, Cologne, Germany. ¹⁰Department of Neurology, Alzheimer Center Amsterdam, Amsterdam Neuroscience, Vrije Universiteit Amsterdam, Amsterdam UMC, Amsterdam, The Netherlands. ¹¹Life Science Partners, Amsterdam, The Netherlands. ¹²Department of Epidemiology and Biostatistics, Vrije Universiteit Amsterdam, Amsterdam UMC, Amsterdam, The Netherlands. ¹³Gérontopole of Toulouse, University Hospital of Toulouse (CHU-Toulouse), Toulouse, France. ¹⁴Centre Leenaards de la Mémoire, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland.

Received: 14 January 2021 Accepted: 12 April 2021

Published online: 11 October 2021

## References

1. APA. Diagnostic and statistical manual of mental disorders (DSM-5): American Psychiatric Pub; 2013. https://en.wikipedia.org/wiki/DSM-5.

2. WHO | Dementia: a public health priority. https://www.who.int/mental_health/publications/dementia_report_2012/en/. Accessed 27 Dec 2020.

3. Schrijvers EMC, Verhaaren BFJ, Koudstaal PJ, Hofman A, Ikram MA, Breteler MMB. Is dementia incidence declining? Trends in dementia incidence since 1990 in the Rotterdam Study. Neurology. 2012;78(19):1456–63. https://doi.org/10.1212/WNL.0b013e3182553be6.

4. Langa KM. Is the risk of Alzheimer's disease and dementia declining? in Alzheimer's Research and Therapy vol. 7 (BioMed Central Ltd., 2015).

5. Knopman DS. The enigma of decreasing dementia incidence. JAMA Netw Open. 2020;3:e2011199. https://doi.org/10.1001/jamanetworkopen.2020.11199.

6. Wolters FJ, Chibnik LB, Wazir Y, Anderson R, Berr C, Beiser A, et al. Twenty-seven-year time trends in dementia incidence in Europe and the United States: the Alzheimer Cohorts Consortium. Neurology. 2020;95(5):e519–31. https://doi.org/10.1212/WNL.0000000000010022.

7. Wu YT, Fratiglioni L, Matthews FE, Lobo A, Breteler MMB, Skoog I, et al. Dementia in western Europe: epidemiological evidence and implications for policy making. Lancet Neurol. 2016;15(1):116–24. https://doi.org/10.1016/S1474-4422(15)00092-7.

8. Satizabal CL, Beiser AS, Chouraki V, Chêne G, Dufouil C, Seshadri S. Incidence of dementia over three decades in the Framingham Heart Study. N Engl J Med. 2016;374(6):523–32. https://doi.org/10.1056/NEJMoa1504327.

9. Matthews FE, et al. A two decade dementia incidence comparison from the Cognitive Function and Ageing Studies I and II. Nat Commun. 2016;7(1). https://doi.org/10.1038/ncomms11398.

10. Prince M, Ali GC, Guerchet M, Prina AM, Albanese E, Wu YT. Recent global trends in the prevalence and incidence of dementia, and survival with dementia. Alzheimers Res Ther. 2016;8(1):23. https://doi.org/10.1186/s13195-016-0188-8.

11. Wu YT, Beiser AS, Breteler MMB, Fratiglioni L, Helmer C, Hendrie HC, et al. The changing prevalence and incidence of dementia over time-current evidence. Nat Rev Neurol. 2017;13(6):327–39. https://doi.org/10.1038/nrneurol.2017.63.

12. Derby CA, Katz MJ, Lipton RB, Hall CB. Trends in dementia incidence in a birth cohort analysis of the Einstein Aging Study. JAMA Neurol. 2017;74(11): 1345–51. https://doi.org/10.1001/jamaneurol.2017.1964.

13. Roehr S, Pabst A, Luck T, Riedel-Heller SG. Is dementia incidence declining in high-income countries? A systematic review and meta-analysis. Clin Epidemiol. 2018;10:1233–47.

14. Tom SE, Phadke M, Hubbard RA, Crane PK, Stern Y, Larson EB. Association of demographic and early-life socioeconomic factors by birth cohort with dementia incidence among US adults born between 1893 and 1949. JAMA Netw Open. 2020;3:e2011094. https://doi.org/10.1001/jamanetworkopen.2020.11094.

15. Livingston G, Huntley J, Sommerlad A, Ames D, Ballard C, Banerjee S, et al. Dementia prevention, intervention, and care: 2020 report of the Lancet Commission. Lancet. 2020;396(10248):413–46. https://doi.org/10.1016/S0140-6736(20)30367-6.

16. Frisoni GB, Molinuevo JL, Altomare D, Carrera E, Barkhof F, Berkhof J, et al. Precision prevention of Alzheimer's and other dementias: anticipating future needs in the control of risk factors and implementation of disease-modifying therapies. Alzheimers Dement. 2020;16(10):1457–68. https://doi.org/10.1002/alz.12132.

17. Van Dier Fler WM, et al. Optimizing patient care and research: the Amsterdam dementia cohort. J Alzheimers Dis. 2014;41(1):313–27. https://doi.org/10.3233/JAD-132306.

18. Hejl A, Høgh P, Waldemar G. Potentially reversible conditions in 1000 consecutive memory clinic patients. J Neurol Neurosurg Psychiatry. 2002; 73(4):390–4. https://doi.org/10.1136/jnnp.73.4.390.

19. McWhirter L, Ritchie C, Stone J, Carson A. Functional cognitive disorders: a systematic review. Lancet Psychiatry. 2020;7(2):191–207. https://doi.org/10.1016/S2215-0366(19)30405-5.

20. Slot RER, Sikkes SAM, Berkhof J, Brodaty H, Buckley R, Cavedo E, et al. Subjective cognitive decline and rates of incident Alzheimer's disease and non-Alzheimer's disease dementia. Alzheimers Dement. 2019;15(3):465–76. https://doi.org/10.1016/j.ialz.2018.10.003.

21. Jessen F, Amariglio RE, Buckley RF, van der Flier WM, Han Y, Molinuevo JL, et al. The characterisation of subjective cognitive decline. Lancet Neurol. 2020;19(3):271–8. https://doi.org/10.1016/S1474-4422(19)30368-0.

22. Memory Concentration - neurosymptoms.org. https://www.neurosymptoms.org/memory-concentration/4594358003. Accessed 27 Dec 2020.

23. Giovannoni G. et al. Brain diseases - time matters: a call to prioritize brain health. 2019. https://www.oxfordhealthpolicyforum.org/reports/brain-diseases/brain-diseases-report.

24. Ranson JM, Rittman T, Hayat S, Brayne C, Jessen F, Blennow K, van Duijn C, Barkhof F, Tang E, Mummery CJ, Stephan BCM, Altomare D, Frisoni GB, Ribaldi F, Molinuevo JL, Scheltens P, Llewellyn, DJ. Modifiable risk factors for dementia and dementia risk profiling. A user manual for Brain Health Services - Part 2 of 6. Alzheimer's Research & Therapy. 2021.

25. Visser LNC, Minguillon C, Sánchez-Benavides G, Abramowicz M, Altomare D, Fauria K, Frisoni GB, Georges J, Ribaldi F, Scheltens P, van der Schaar J, Zwan M, van der Flier WM, Molinuevo JL. Dementia risk communication. A user manual for Brain Health Services - Part 3 of 6. Alzheimer's Research & Therapy. 2021.

26. Solomon A, Stephen R, Altomare D, Carrera E, Frisoni GB, Kulmala J, Molinuevo JL, Nilsson P, Ngandu T, Ribaldi F, Vellas B, Scheltens P, Kivipelto M. Multidomain interventions: state-of-the-art and future directions for protocols to implement precision dementia risk reduction. A user manual for Brain Health Services - Part 4 of 6. Alzheimer's Research & Therapy. 2021.

27. Brioschi Guevara A, Bieler M, Altomare D, Berthier M, Csajka C, Dautricourt S, Démonet JF, Dodich A, Frisoni GB, Miniussi C, Molinuevo JL, Ribaldi F, Scheltens P, Chêtelat G. Protocols for cognitive enhancement. A user manual for Brain Health Services - Part 5 of 6. Alzheimer's Research & Therapy. 2021.

28. Kivipelto M, Ngandu T, Laatikainen T, Winblad B, Soininen H, Tuomilehto J. Risk score for the prediction of dementia risk in 20 years among middle aged people: a longitudinal, population-based study. Lancet Neurol. 2006; 5(9):735–41. https://doi.org/10.1016/S1474-4422(06)70537-3.

29. Barnes DE, et al. Development and validation of a brief dementia screening indicator for primary care. Alzheimers Dement. 2014;10:656–665.e1.

30. Anstey KJ, Cherbuin N, Herath PM. Development of a new method for assessing global risk of Alzheimer's disease for use in population health approaches to prevention. Prev Sci. 2013;14(4):411–21. https://doi.org/10.1007/s11121-012-0313-2.

31. Anstey KJ, Cherbuin N, Herath PM, Qiu C, Kuller LH, Lopez OL, et al. A self-report risk index to predict occurrence of dementia in three independent cohorts of older adults: the ANU-ADRI. Plos One. 2014;9(1):e86141. https://doi.org/10.1371/journal.pone.0086141.

32. Saddiki H, Fayosse A, Cognat E, Sabia S, Engelborghs S, Wallon D, et al. Age and the association between apolipoprotein E genotype and Alzheimer disease: a cerebrospinal fluid biomarker-based case-control study. PLoS Med. 2020;17(8):e1003289. https://doi.org/10.1371/journal.pmed.1003289.

33. Altmann A, Tian L, Henderson VW, Greicius MD. Sex modifies the APOE-related risk of developing Alzheimer disease. Ann Neurol. 2014;75(4):563–73. https://doi.org/10.1002/ana.24135.
34. Fisher DW, Bennett DA, Dong H. Sexual dimorphism in predisposition to Alzheimer's disease. Neurobiol Aging. 2018;70:308-24. https://doi.org/10.1016/j.neurobiolaging.2018.04.004.

35. Farrer L, Cupples LA, Haines JL, Hyman B, Kukull WA, Mayeux R, et al. Effects of age, sex, and ethnicity on the association between apolipoprotein E genotype and Alzheimer disease. A meta-analysis. APOE and Alzheimer Disease Meta Analysis Consortium. JAMA. 1997;278(16):1349-56.

36. Zipkin DA, Umscheid CA, Keating NL, Allen E, Aung KK, Beyth R, et al. Evidence-based risk communication: a systematic review. Ann Intern Med. 2014;161(4):270-80. https://doi.org/10.7326/M14-0295.

37. Fagerlin A, Zikmund-Fisher BJ, Ubel PA. Helping patients decide: ten steps to better risk communication. J Natl Cancer Inst. 2011;103(19):1436-43. https://doi.org/10.1093/jnci/djr318.

38. van de Water LF, van Kleef JJ, Dijksterhuis WPM, Henselmans J, van den Boorn HG, Vaarzon Morel NM, et al. Communicating treatment risks and benefits to cancer patients: a systematic review of communication methods. Qual Life Res. 2020;29(7):1747-66. https://doi.org/10.1007/s11136-020-02503-8.

39. Green RC, Roberts JS, Cupples LA, Relkin NR, Whitehouse PJ, Brown T, et al. Disclosure of APOE genotype for risk of Alzheimer's disease. N Engl J Med. 2009;361(3):245-54. https://doi.org/10.1056/NEJMoa0809578.

40. Chao S, Roberts JS, Marteau TM, Silliman R, Cupples LA, Green RC. Health behavior changes after genetic risk assessment for Alzheimer disease: the REVEAL study. Alzheimer Dis Assoc Disord. 2008;22(1):94-7. https://doi.org/10.1097/WAD.0b013e31815a9dcc.

41. Bemelmans SASA, et al. Psychological, behavioral and social effects of disclosing Alzheimer's disease biomarkers to research participants: a systematic review. Alzheimers Res Ther. 2016;8:1-17.

42. Langlois CM, Bradbury A, Wood EM, Roberts JS, Kim SYH, Riviere ME, et al. Alzheimer's Prevention Initiative Generation Program: development of an APOE genetic counseling and disclosure process in the context of clinical trials. Alzheimers Dement Transl Res Clin Interv. 2019;5(1):705-16. https://doi.org/10.1016/j.trci.2019.09.013.

43. Harkins K, Sankar P, Sperling R, Grill JD, Green RC, Johnson KA, et al. Development of a process to disclose amyloid imaging results to cognitively normal older adult research participants. Alzheimers Res Ther. 2015;7(1):26. https://doi.org/10.1186/s13195-015-0112-7.

44. Burns JM, Johnson DK, Liebmann EP, Bothwell RJ, Morris JK, Vidoni ED. Safety of disclosing amyloid status in cognitively normal older adults. Alzheimers Dement. 2017;13(9):1024-30. https://doi.org/10.1016/j.jalz.2017.01.022.

45. Largent EA, Harkins K, van Dyck CH, Hachey S, Sankar P, Karlawish J. Cognitively unimpaired adults' reactions to disclosure of amyloid PET scan results. Plos One. 2020;15(2):e0229137. https://doi.org/10.1371/journal.pone.0229137.

46. Grill JD, Raman R, Ernstrom K, Sultzer DL, Burns JM, Donohue MC, et al. Short-term psychological outcomes of disclosing amyloid imaging results to research participants who do not have cognitive impairment. JAMA Neurol. 2020;77(12):1504. https://doi.org/10.1001/jamaneurol.2020.2734.

47. De Wilde A, et al. Disclosure of amyloid positron emission tomography results to individuals without dementia: a systematic review. Alzheimers Res Ther. 2018;10(1):72. https://doi.org/10.1186/s13195-018-0398-3.

48. Ngandu T, Lehtisalo J, Solomon A, Levälähti E, Ahtiluoto S, Antikainen R, 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(9984):2255-63. https://doi.org/10.1016/S0140-6736(15)60461-5.

49. Andrieu S, Guyonnet S, Coley N, Cantet C, Bonnefoy M, Bordes S, et al. Effect of long-term omega 3 polyunsaturated fatty acid supplementation with or without multidomain intervention on cognitive function in elderly adults with memory complaints (MAPT): a randomised, placebo-controlled trial. Lancet Neurol. 2017;16(5):377-89. https://doi.org/10.1016/S1474-4422(17)30040-6.

50. van Charante EPM, Richard E, Eurelings LS, van Dalen JW, Ligthart SA, van Bussel EF, et al. Effectiveness of a 6-year multidomain vascular care intervention to prevent dementia (preDIVA): a cluster-randomised controlled trial. Lancet. 2016;388(10046):797-805. https://doi.org/10.1016/S0140-6736(16)30950-3.

51. Espeland MA, Carmichael O, Hayden K, Neiberg RH, Newman AB, Keller JN, et al. Long-term impact of weight loss intervention on changes in cognitive function: exploratory analyses from the action for health in diabetes randomized controlled clinical trial. J Gerontol A Biol Sci Med Sci. 2018;73(4):484-91. https://doi.org/10.1093/gerona/glx165.

52. Bischoff-Ferrari HA, Vellas B, Rizzoli R, Kressig RW, da Silva JAP, Blauth M, et al. Effect of vitamin D supplementation, omega-3 fatty acid supplementation, or a strength-training exercise program on clinical outcomes in older adults: the DO-HEALTH randomized clinical trial. JAMA. 2020;324(18):1855-68. https://doi.org/10.1001/jama.2020.16909.

53. Solomon A, Turunen H, Ngandu T, Peltonen M, Levälähti E, Helisalmi S, et al. Effect of the Apolipoprotein E genotype on cognitive change during a multidomain lifestyle intervention a subgroup analysis of a randomized clinical trial. JAMA Neurol. 2018;75(4):462-70. https://doi.org/10.1001/jama neurol.2017.4365.

54. Kivipelto M, Mangialasche F, Snyder HM, Allegri R, Andrieu S, Arai H, et al. World-Wide FINGERS Network: a global approach to risk reduction and prevention of dementia. Alzheimers Dement. 2020;16(7):1078-94. https:// doi.org/10.1002/alz.12123.

55. CAS HES-SO en Démences et troubles psychiques de la personne âgée 2020-2021 | HEoS. https://www.hesge.ch/heds/formation-continue/forma tions-postgrades/certificats-cas/cas-hes-so-en-demences-et-troubles. Accessed 27 Dec 2020.

56. Isaacson RS, Ganzer CA, Hristov H, Hackett K, Caesar E, Cohen R, et al. The clinical practice of risk reduction for Alzheimer's disease: a precision medicine approach. Alzheimers Dement. 2018;14(12):1663-73. https://doi. org/10.1016/j.jalz.2018.08.004.

57. Solomon A, Kivipelto M, Molinuevo JL, Tom B, Ritchie CW. European Prevention of Alzheimer's Dementia Longitudinal Cohort Study (EPAD LCS): study protocol. BMJ Open. 2018;8(12):e021017. https://doi.org/10.1136/ bmjopen-2017-021017.

58. Aisen PS, Sperling RA, Cummings J, Donohue MC, Langford O, Jimenez- Maggiora GA, et al. The trial-ready cohort for preclinical/prodromal Alzheimer's disease (TRC-PAD) project: an overview. J Prev Alzheimers Dis. 2020;7(4):208-12. https://doi.org/10.14283/jpad.2020.45.

59. Milne R, Altomare D, Ribaldi F, Molinuevo JL, Frisoni GB, Brayne C. Societal and equity challenges for Brain Health Services. A user manual for Brain Health Services - Part 6 of 6. Alzheimer's Research & Therapy. 2021

60. Elkind MSV. Implications of stroke prevention trials: treatment of global risk. Neurology. 2005;65(1):17-21. https://doi.org/10.1212/01.WNL.0000171745.13 592.cbp.

61. Brainin M, Feigin VL, Norrving B, Martins SCO, Hankey GJ, Hachinski V, et al. Global prevention of stroke and dementia: the WSO Declaration. Lancet Neurol. 2020;19(6):487-8. https://doi.org/10.1016/S1474-4422(20)30141-1.

62. Verberk IMW, Slot RE, Verfaillie SCJ, Heijst H, Prins ND, van Berckel BNM, et al. Plasma amyloid as prescreener for the earliest Alzheimer pathological changes. Ann Neurol. 2018;84(5):648-58. https://doi.org/10.1002/ana.25334.

63. Mattsson N, Zetterberg H, Janelidze S, Insel PS, Andreasson U, Stomrud E, et al. Plasma tau in Alzheimer disease. Neurology. 2016;87(17):1827-35. https://doi.org/10.1212/WNL.0000000000003246.

64. Mattsson N, Cullen NC, Andreasson U, Zetterberg H, Blennow K. Association between longitudinal plasma neurofilament light and neurodegeneration in patients with Alzheimer disease. JAMA Neurol. 2019;76(7):791-9. https://doi. org/10.1001/jamaneurol.2019.0765.

65. Van Maurik IS, et al. Development and usability of ADappt: web-based tool to support clinicians, patients, and caregivers in the diagnosis of mild cognitive impairment and Alzheimer disease. J Med Internet Res. 2019;21. Hersenonderzoek.nl. https://hersenonderzoek.nl/. Accessed 27 Dec 2020.

66. Brain Health Registry Switzerland. http://www.bhr-suisse.org/en. Accessed 27 Dec 2020.

67. Haeberlein S. B. et al. EMERGE and ENGAGE topline results: two phase 3 studies to evaluate aducanumab in patients with early Alzheimer's disease. 2019. https://investors.biogen.com/static-files/ddd45672-9c7e-4c99-8a06-3 b557697c06f.

68. Schneider L. A resurrection of aducanumab for Alzheimer's disease. Lancet Neurol. 2020;19(2):111-2. https://doi.org/10.1016/S1474-4422(19)30480-6.

69. NIA-funded active Alzheimer's and related dementias clinical trials and studies. https://www.nia.nih.gov/research/ongoing-AD-trials#section2. Accessed 27 Dec 2020.

## Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.