Background
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. Alzheimer’s disease (AD) is the most common form of dementia and accounts for 60–80% 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 extensively, 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 intracellularly 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 progresses, the subject’s cognition changes from an initial phase where it is fully preserved to a final stage characterized 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, many interventional studies are currently moving their focus to cognitively healthy individuals at risk of developing 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 public–private partnerships (PPPs) for disease prevention that are setting up a framework to identify and select individuals for clinical trials focused on preclinical stages.
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 prevention trials. Cerebral Aβ deposition is considered a necessary, 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 opportunity to intervene at earlier stages of the continuum, 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 decades before the onset of symptoms: in pre-symptomatic PSEN mutation carriers, CSF Aβ42 decline has been observed 25 years before clinical symptoms, whilst brain Aβ deposition 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 sensitive 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 common 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 Alzheimer’s Prevention Initiative (API) is an international collaborative initiative established to provide an innovative approach to Alzheimer’s prevention research by evaluating the most promising therapies in cognitively normal people who, based on their age and genetic background, 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 Alzheimer’s 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 Alzheimer’s dementia by creating a novel environment for testing numerous interventions [
52]. EPAD aims to create the necessary infrastructure, including a registry and a longitudinal 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 existing cohorts and registries; development of a registry of approximately 24,000 individuals who might be at increased risk of developing AD; establishment of a longitudinal cohort study of 6000 subjects; and establishment of an adaptive, proof-of-concept trial including 1500 participants at any given time.
In the USA, the Global Alzheimer’s 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 participants 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 solanezumab 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 mutation carrier kindred. It will evaluate the efficacy of crenezumab in 200 cognitively normal individuals who carry the
PSEN1 E280A mutation. The study will also include 100
PSEN1 E280A mutation non-carriers who will receive placebo only.
Table 2
Description of currently ongoing AD prevention clinical trials
Estimated enrolment | 210 | 300 | 1150 | 3494 | 1340 | 1650 |
Target population/specific characteristics | Autosomal dominant Alzheimer’s disease (ADAD) mutation carriers or persons that have a 50% chance of carrying an ADAD mutation | Membership in PSEN1 E280A mutation carrier kindred | Cognitively normal, positive brain amyloid PET | Cognitively normal with genetic risk (TOMM40 and APOE genotype) | Cognitively normal APOE-ε4 homozygous | Cognitively normal positive amyloid |
Age | 18–80 years | 30–60 years | 65–85 years | 65–83 years | 60–75 years | 60–85 years |
Phase | Phase II/III | Phase II | Phase III | Phase III | Phase II/III | Phase II/III |
Compound | Gantenerumab Solanezumab | Crenezumab | Solanezumab | Pioglitazone | CAD106 CNP520 | JNJ-54861911 |
Mechanism | Anti-Aβ antibodies | Anti-Aβ antibody | Anti-Aβ antibody | PPAR-γ agonist | Aβ vaccine 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 Score | 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 |
Regarding sporadic AD, the Anti-Amyloid Treatment in Asymptomatic Alzheimer’s (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 currently 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 TOMMORROW 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 randomly 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-ε4 aged 60–75 years, were selected as a high-risk population for progression to MCI due to AD and/or dementia.
Conclusions
Epidemiological evidence of AD risk factors is contributing 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 3–5 years are sufficient for delaying cognitive decline, and consequently the onset of Alzheimer’s dementia.
The implementation of effective prevention strategies is not free from challenges since they require the identification, characterization and participation of asymptomatic 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 determined. The incorporation of biomarkers to identify individuals at risk of developing AD dementia is a key step for the identification of ideal candidates to participate 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.