Clinical Trial Summary
Alzheimer's disease (AD) is the leading cause of dementia and its prevalence is estimated to
exceed 100 million affects by 2050, becoming the main public health problem worldwide.
Classically, AD has been considered a clinicopathological entity characterized by a
progressive cognitive decline with early memory impairment followed by other cognitive
domains, and an underlying neuropathological pattern characterized by extracellular
accumulation of β-amyloid protein (Aβ) in the form of neuritic plaques, intracellular
deposits of tau protein in the form of neuritic strands and neurofibrillary tangles, neuronal
and synaptic loss and glial proliferation. In this context, a "probable" AD diagnosis was
based on determining the presence of dementia and ruling out other potential aetiologies
while a definite one required confirmation by post-mortem examination. In the last 15 to 25
years, progress in imaging and cerebrospinal fluid (CSF) biomarkers has enabled a change of
the AD conceptualization from a clinical-pathological entity to a clinical-biological one.
These new diagnostic criteria also divides the course of AD into 3 stages: (1) a preclinical
phase, which would include persons with positive AD biomarkers and normal cognitive
performance (the subjective perception of cognitive decline [SCD] is also part of this
stage); (2) a phase of mild cognitive impairment (MCI), characterized by cognitive
performance lower than expected by age and educational level; and (3) a dementia phase, once
cognitive deficits interfere with the activities of daily living. This new conceptualization
brings the opportunity of identifying the disease in very early symptomatic pre-dementia
stages or even before symptoms appear, creating a window of opportunity for dementia
prevention.
The lack of positive results in the different clinical trials performed to date in patients
with AD dementia has redirected the focus of therapeutic strategies towards preventing the
development of dementia. For this reason, a detailed characterization of risk factors is of
vital importance for identifying the persons who could benefit from a possible preventive
strategy, as well as the optimal moment to carry out the intervention. A recent effort by the
Lancet Commission on Dementia Prevention, Intervention, and Care reported the relative risk
for incident dementia of the main modifiable risk factors (low education in early life;
hypertension, obesity, and hearing loss in midlife; smoking, depression, physical inactivity,
social isolation, and diabetes in late life). In addition, the Framingham Heart Study has
shown that age, marital status, BMI, stroke, diabetes, ischemic attacks, and cancer are
independent predictors of event risk in the final multivariate model and were used to
construct a risk algorithm. These set of risk factors associated with an increased risk of
incident dementia can be coupled with well-known genetic risk factors such as APOE genotype
and with the presence of very mild symptoms, like self-perception of cognitive decline to
create individual estimates of risk for dementia, taking also into account the presence of
cognitive decline or impairment.
The possibility of creating individual estimates of risk of dementia implies a personalised
medicine approach and results in a change from the traditional diagnostic paradigm to a new
one in which people at risk are attended in order to disclose risk factor estimates and offer
them personalised solutions. This paradigm shift brings important consequences. On one hand,
disclosing medical information may potentially generate emotional impact, psychological
burden or harm. Although current experience with both disclosing APOE-e4 genetic status and
amyloid status reveals that it is safe, one still needs to understand the potential risks and
benefits of disclosing risk estimates for developing dementia. On the other hand, newly
designed infrastructures that are focused in the assessment and follow-up of pre-dementia
patients at high risk to develop dementia are needed, since they clearly represent a distinct
population from the one attending dementia clinics. These "prevention infrastructures" would
offer individual risk profiling accompanied by personalised risk reduction plans including,
but not limited to, primary prevention advice and secondary prevention approaches (e.g.
inclusion in prevention clinical trials).
With the ultimate aim of assessing and understanding the value of these "dementia prevention
infrastructures", several research questions need to be beforehand addressed such as the
following:
- Is disclosing risk factor estimates safe from the emotional and psychological point of
view?
- Is there any benefits derived from the personalised plans received by subjects?
- Would the creation of Dementia Prevention Clinics be cost efficient? The
BBRC-DevPrev-2018 study aims at answering the questions stated above.
