Clinical Implementation of Amyloid Neurodegeneration and Tau testing in Primary Care.

Cognitive complaints have a broad differential diagnosis. The challenge for the
general practitioner or elderly care physician is to facilitate an optimal
diagnostic trajectory, treatment and management for each patient. Blood-based
biomarkers for Alzheimer*s disease and neurocognitive disorders in general may
aid in this process. For example, Alzheimer*s disease (AD) is the most common
form of dementia with roughly 200.000 persons suffering from the disease in the
Netherlands. An accurate diagnosis improves action ability for patients and
caregivers and is therefore highly important. With the first disease-modifying
therapy available in the United States and other treatments in the pipeline,
the need for accurate and cost-effective detection of AD becomes critical.

Unfortunately, an accurate diagnosis in primary care is difficult. Early and
atypical signs of AD often remain unrecognized by the GP or elderly care
physician and other diseases may be mistaken for AD. The pathological hallmarks
of the disease - amyloid and tau - are traditionally detected using either
cerebrospinal fluid (CSF) or PET imaging techniques. These methods are invasive
or very expensive and cannot be utilized in primary care. Moreover, in view of
the foreseen increased demand for AD diagnostic testing, such testing in
primary care is critical to meet the demand in a cost-effective way. This
leaves a need for biomarkers that are both accurate and can be easily obtained.
Based on well-defined recent prospective and retrospective cohort studies
several blood-based biomarkers are on the brink of being able to fulfill this
need.

The AD blood test is a fully automated singlemolecule array (Simoa) digital
immunoassay panel intended for the quantitative measurement of biomarkers for
AD, astrocyte dysfunction and neurodegeneration (for example Amyloid-Beta-40
(Aβ40), Amyloid-Beta-42 (Aβ42), Glial Fibrillary Acidic Protein (GFAP) and
Neurofilament Light (NfL)). In addition, recent evidence from multiple cohorts
suggests that p-tau isoforms are highly accurate detectors of AD pathology.
Together, these markers combine the most promising blood biomarkers that is
specific for AD and other neurodegenerative causes of cognitive complaints with
the most sensitive immunoassay technology.

Clinically, the combination of Aβ42/40 and GFAP predict amyloid PET positivity
with an area under the ROC curve of 88% (95% confidence interval 83-93%) when
APOE*4 and age were included in the model. This is similar to the performance
of combinations between Aβ42/40 and p-tau. In addition, NfL is increased in all
forms of dementia, especially in frontotemporal dementia, thus enabling us to
detect other forms of dementia than AD. Cut-points and their according
sensitivity and specificity have recently been defined for the aforementioned
AD plasma biomarker panel (Aβ40, Aβ42, GFAP, NfL and pTau-181) by Verberk et al
(in preparation). Also, age and disease specific reference values for NfL have
been defined in studies before. Precision results of these biomarkers are
acceptable with average intra-assay CV*s ranging from 6-15% and average
reproducibility between runs between 6.5 % CV and 16% CV for Aβ40, Aβ42, GFAP
and NfL.

Current evidence is restricted to highly selected cohorts. The aim of this
study is to take first steps towards development of a prediction model based on
blood-based biomarkers for AD in primary care, tailored to the specific needs
of this setting.

The objective of this study is, to detect potential uses of plasma biomarkers
in primary care, by
(a) To investigate if plasma biomarkers are associated with working diagnosis
in primary care.
(b) To ascertain if diagnosis and patient management differ between patients
with and without plasma evidence of underlying AD.
(c) To explore associations between plasma biomarkers and (1) the nature and
severity of cognitive complaints, (2) global cognitive performance and (3)
functioning in iADL.
(d) To qualitatively identify scenarios in which plasma biomarkers can improve
current care.

Observational study with a single invasive measurement (venipuncture).

The benefit for participating in this study is the contribution to making the
diagnostic process of AD and other neurocognitive disorders in primary care
more reliable, cost-effective and easier. Eventually, this study will
contribute to improvement of patient care, diagnostics and prognostics.
Moreover, improvement of diagnostics can benefit patients with AD receiving
accurate treatment without delay and in the future, receiving disease modifying
therapy.We aim to make the diagnostic process of neurocognitive disorders more
reliable and easier in primary care and thereby intent to contribute to
limiting the healthcare costs in the course of this disease. The group of
patients with cognitive complaints who present to primary care stand to benefit
from this research, but the participants themselves will not. Risk on the other
hand, is negligible. Risk associated with blood draw is minimal and consists of
risk of a hematoma and a small infection risk at the puncture site. The
CANTATE-PC test Battery consists of clinical and tests and questionnaires that
have been widely implemented in the AD research field. Each researcher that
visits participants has the experience and knowledge on how to conduct these
test with minimal risks.