The utility of blood-based biomarkers for Alzheimer*s disease in memory Clinic

Alzheimer*s disease (AD) is one of the major healthcare challenges of this
century. In the Netherlands, an estimated >270,000 individuals suffer from
dementia, mostly the AD type. This number will continue to rise, exceeding half
a million by 2040. There is no cure for AD yet and the care given focuses on
the last stage of this disease, resulting in a compromised quality of life.

Research has shown that AD develops in the course of 20 to 30 years. Preventive
strategies are being developed to delay or stop progression to AD. In this
perspective, early stages of AD offer an opportunity for treatment and
prevention.

However, in patients, cognitive complains are usually present at least 1,5 year
before AD diagnosis. And commonly diagnosis is set in hospital using
neuropsychological test batteries and diagnostic tools (like MRI, CSF, or PET).
This results in delay and expensive care. To reduce healthcare costs the
diagnostic course need to be changed. As a consequence, there is an urgent need
for low*invasive and affordable techniques.

Blood biomarkers (BB) have been developed which can detect early AD
pathophysiological changes 5-9. Pathological, extracellular amyloid beta
(Abeta) and intracellular Tau are the hallmarks in brains of AD patients 4.
Individuals with these pathological changes are at increased risk to develop
dementia. For this reason, they are important to investigate. Can blood
biomarkers be used in the diagnostic process ?

Recently, Amyblood 4-plex is developed, an AD blood test. This is a fully
automated single molecule array (Simoa) digital immunoassay panel intended for
the quantitative measurement of amyloid-beta-40 (Aβ40), amyloid-beta-42 (Aβ42),
Glial Fibrillary Acidic Protein (GFAP) and Neurofilament Light (NfL). Together
with p-tau 181, these biomarkers combined are the most promising AD blood
biomarkers 11. Till now, these markers have being investigated only in tertiary
centres and are not yet in use in GP or MC.

These measurements are low invasive and affordable to pre-screen patients. We
hypothesise that if this method is implemented in the early diagnostic course,
fewer individuals will be forwarded toward memory clinics. This will eventually
result in fewer invasive and/or expensive testing and in an earlier diagnosis.
This delivers treatment opportunities in an early phase of the disease.

The goal of this study is to investigate the agreement between the blood test
and the clinical diagnosis (golden standaard). This will hopefully lead in
early identification of AD patients. Which will result in lower care costs, and
it will open opportunities for early diagnosis.

We aim to identify the utility of blood-based biomarkers for AD. Our first
objective is to determine percent agreement between plasma biomarkers and
clinical diagnosis set in a memory clinic.

In summary:
testing the agreement between plasma biomarkers and working diagnosis

Enrolment of subjects: Using digital referrals, GPs send patients with possibly
underlying cognitive problems to the memory clinic of the Medisch Centrum
Leeuwarden for further investigation. When a referral is received, patients
will be approached by phone to set an appointment at the memory clinic. This
moment will be used to ask an informed consent and to ask if the patient is
willing to participate with this study. After signing the informed consent,
blood biomarkers will be collected during routine blood drawn as part of
standard clinical care of patients visiting the memory clinic. The patients
will eventually be seen by the treating geriatrician/neurologists and care as
usual will be given. The results of the blood biomarkers will be blinded for
the treating geriatricians/neurologists. Patients will be enrolled for one year
(target is 400 samples) and will be followed up for at least 1 yar months.

Dementia assessment (care as usual): All participants will receive a dementia
screening/assessment at the Medisch Centrum Leeuwarden. It will include a
clinical history, a medical and neurological examination, and screening
laboratory tests. Screening using a neuropsychological assessment will be
performed by the geriatrician. If needed a magnetic resonance imaging (MRI) of
the brain or cerebrospinal fluid (CSF) will be performed. Diagnoses of probable
AD and MCI will be made according to the core clinical criteria of the National
Institute on Aging-Alzheimer*s Association (NIA-AA) workgroups. The
neuropsychological assessment consist of the MMSE, Clock drawing test
(Shulmanscore 1993), Informant Questionnaire on Cognitive Decline in the
Elderly (IQCODE-N), and the Zarit Burden Interview (ZBI).

Analysis of blood samples: Whole blood samples drawn following clinical best
practices, will be collected. Plasma samples will be stored and eventually
transported on dry ice for analysis at the Clinical Neurochemistry Laboratory,
AMC, location VUmc. AD biomarkers, amyloid-beta-40 (Aβ40), amyloid-beta-42
(Aβ42), Glial Fibrillary Acidic Protein (GFAP) and Neurofilament Light (NfL
will be measured on the Simoa HD-X instrument using in-house (Department
Clinical Chemistry, VUmc) developed and validated assay. Plasma p-tau181 is
measured using with the assay delivered by Simoa HD-X instrument (Quanterix) as
described bij Karikari, Lancet Neurology 2020.

We aim to make an AD diagnosis more reliable and easier. Members of the group
that is included in the current study will benefit from this research, but the
participants themselves will not. Risk on the other hand, is negligible. Blood
draw is already taking place for most participants and taking one additional
tube will not add to patient risk. Risk associated with blood draw itself is
minimal and consists of risk of a hematoma and a small infection risk at the
puncture site.