Subjective Cognitive Impairment Cohort, a focus on the earliest changes leading to Alzheimer*s disease.

Background
Alzheimer*s disease (AD) is the most common cause of dementia and has been
coined one of the grand challenges of this century. There is no curative
therapy available. This may have several causes. First, AD is a complex
disease. A narrow focus on one aspect of the disease will not result in an
answer. In addition to addressing the roles of amyloid-beta and tau, the main
pathological hallmarks of AD, we must also take into account other factors,
such as lifestyle factors and brain connectivity. Second, when patients have
reached the clinical stage of dementia, the disease process has gradually
unfolded in the course of 15 to 20 years.1 Even when we would be able to stop
or modify the disease process, this would hardly help, as the damage in the
brain is already irreversible in the dementia stage. In other words, to find an
effective therapy, we have to focus on the very earliest stages of the disease.

In vivo measurement of AD pathology
The amyloid cascade hypothesis, the most prominent hypothesis concerning the
etiology of AD, is built around the assumption that deposition of the protein
amyloid-beta 1-42 (A*42) in so-called plaques is among the initial brain
changes associated with AD. The deposition of amyloid-beta subsequently
triggers a cascade of events, including development of tau inclusions
(tangles), synaptic loss, neurodegeneration, cognitive decline and eventually
dementia due to AD. For a long time, amyloid-beta and tau could only be
demonstrated at autopsy, hampering progress in AD research. The novel
techniques to measure Alzheimer pathology in vivo (using CSF biomarkers or
PET-scan) have opened op new avenues for Alzheimer research. Both CSF
biomarkers and amyloid PET-tracers distinguish AD patients from controls with
relatively good accuracy. In addition, both types of markers have prognostic
value for the development of dementia in patients with MCI. These developments
have led to the inclusion of these markers in the new research criteria for
diagnosis of both dementia and MCI due to AD.

The primary objective of the SCIENCe project is to establish a prospective
cohort of patients with subjective complaints, to study the earliest brain
changes ultimately leading to cognitive decline and dementia due to AD.

Specific research questions which will be addressed include:
In patients with subjective complaints,
1. What are the trajectories of cognitive decline?
2. Do the known Alzheimer markers amyloid-PET and CSF biomarkers predict
clinical progression?
3. Which (combinations of) imaging markers predict clinical progression?
4. Can we identify genetic markers that predict clinical progression?
5. Can we identify new markers in CSF and/or blood that predict clinical
progression?
6. Is the immunophenotype isolated from blood predictive for clinical
progression?
7. Is the gut microbiome predictive for clinical progression?
8. Do lifestyle factors (including physical and mental activity, smoking
and diet) predict clinical progression?
Newly identified imaging, genetic and CSF/blood/microbiome markers (question
3-7) will be studied taking into account preclinical AD stages as defined by
amyloid-PET or CSF biomarkers.

SCIENCe is a prospective cohort study. We will include patients who have
visited our diagnostic screening and subjects with memory complaints from the
register www.hersenonderzoek.nl. The duration of follow up will initially be
twelve years. A schematic overview of the study is provided in Figure 1 (see
page 10 of the protocol v1.9, November 2021).

The value of the cohort lies in the extensive phenotyping of participants and
the long duration of follow-up. The current protocol will serve as an *umbrella
protocol*. We hope and expect that in time we will obtain funding for enlarging
the cohort and extending follow-up. In addition, we expect additional
sub-studies to be added in the future. These studies will share the well
characterized SCIENCe cohort as a constant factor.

When patients participate in SCIENCe, they will undergo an additional
neuropsychological test battery focusing on memory function and a series of
questionnaires focusing on behavioural symptoms and lifestyle factors
(estimated time: one hour), additional blood will be drawn (paxgene tube, for
RNA; 10 min, under protocol P2017.315), and they will be offered the
possibility to participate in the PET sub study (separate protocol; P13-256).
In addition, patients will be invited for an annual follow-up visit (visit
medical doctor, neuropsychologist and research nurse; 2.5 hours). The risks
associated with participation are negligible and follow-up is organized in much
the same way as our clinical follow-up. When there is clinical progression,
patients have the benefit of the possibility to re-enter clinical follow-up.