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Age-related Neurodegenerative Disease Alzheimer’s Disease
Blood Biomarkers for Alzheimer’s Disease
a report by
Bengt Winblad
1
and Anders Lönneborg
2
1. Professor of Geriatric Medicine, Karolinska Institute; 2. Research Director, DiaGenic ASA
Alzheimer’s disease (AD) is a multifactorial and heterogeneous disease oxidative stress, inflammation and lipid dysregulation. NFTs and senile
in both its clinical and histopathological appearance. In more than plaques are the neuropathological hallmarks of AD and were described
99% of cases the cause of the disease is not understood. Independent by Alois Alzheimer as early as 1906. Senile plaques and NFTs, although
of its cause, AD is clinically characterised by a developing dementia not individually unique to AD, have a characteristic spreading and
and histopathologically characterised by neuronal degeneration. density in the diseased brain.
7
The plaque is an extracellular lesion
Although the presence of neurofibrillary tangles (NFTs) and neurotic composed mainly of amyloid peptides with 40 or 42 amino acids,
(senile) plaques are the characteristic hallmarks in the AD brain, AD designated as Aβ40 or Aβ42. Aβ42 is the initial and more toxic species
histopathology shows considerable qualitative and quantitative deposited in the brain and is also fibrillogenic in vitro.
8–10
Conversely,
heterogeneity. A definitive diagnosis has to await a post mortem NFTs are intracellular lesions composed mainly of paired helical
biopsy, when a histopathological examination can be performed. fragments of highly phosphorylated and aggregated tau protein.
11
The
Therefore, the clinical diagnosis today is made primarily by excluding tau protein is a normal and essential component of neurons and it is
other causes of dementia.
1
the incorporation of excess phosphate groups that leads to the
formation of the aggregated tau protein.
11
AD is becoming a major health problem in the developed world as life
expectancy increases, and the disease affects about 15 million people The development of biomarkers for AD is challenging as it is complicated
worldwide today.
2,3
The prevalence of AD is expected to rise dramatically by several factors. In addition to the variability in clinical features and
in the next few decades and it is estimated that 20–30 million people multiple molecular aetiologies, the development of AD biomarkers is
just in the US will be living with the disease by 2030.
4
Concentrated burdened with a diagnostic imprecision as confirmation of the disease
efforts are under way to identify reliable cures or preventative measures preferentially has to await a post mortem histopathological examination.
for the disease. To facilitate these investigations, biomarkers are critically The long asymptomatic prodromal stages, rates of progression and
needed that can reliably detect the disease at the earliest possible stage.
5
complex disease genetics complicate the situation further. In this article
we will review the current developments in the field of biomarkers for the
In AD, the main cause of dementia is assumed to result from the detection of AD in blood.
progressive loss of synaptic function and neurological degeneration.
6
The disease is associated with profound biochemical and pathological Single-component Biomarkers
alterations in the brain, including aberrant amyloid precursor protein The physiology of the blood–brain barrier limits potential biomarkers that
(APP), amyloid β-protein (Aβ) metabolism, tau protein phosphorylation, are closely associated to brain pathophysiology to small molecules,
lipophilic molecules and molecules with specific transporters.
12
Brain-
derived proteins and metabolites that pass into the plasma will also
Bengt Winblad is a Professor of Geriatric Medicine at the
Karolinska Institute and Chief Physician at Karolinska
become markedly diluted in a biochemically complex medium.
12
University in Huddinge. He is a member of the Nobel
Moreover, it is not known whether there are any direct patho-
Assembly for the Prize of Medicine and Physiology and is
physiological processes associated with AD in blood cells. The traditional
Head of the KI–Alzheimer Disease Research Centre in
Huddinge, as well as Director of the Swedish Brain Power approach of using one or a few closely related molecules as a biomarker,
Research Network. Professor Winblad has been a Guest
a single-component biomarker, in plasma, serum or blood has been
Professor at the Department of Psychiatry in Frankfurt and
an Honorary Professor at Beijing University, Wuhan
utilised since the late 1990s.
13–15
However, their usefulness has been
University and Shanghai University in China. He is Co-Chair of the European Alzheimer limited, mainly due to discrepant results between studies.
Disease Consortium (EADC) and Chair of the Medical Scientific Advisory Panel of the
Alzheimer Disease International (ADI).
Amyloid β-protein
Aβ can be detected in plasma and is thus a compelling candidate
Anders Lönneborg is Research Director of DiaGenic ASA, of
biomarker for AD. The plasma total Aβ or Aβ42 was increased in familial
which he is also Co-Founder. His research focus is the
development of gene expression technology to be used as a
AD with presenilin or APP mutations
16,17
and in Down’s syndrome with
tool for the early diagnosis of important diseases such as
APP triplication,
18
which raises the possibility that sporadic AD may also
Alzheimer’s disease, breast cancer and Parkinson’s disease.
He has received funding for his work several times from the
be associated with detectable and diagnostic changes in Aβ plasma
Norwegian Research Council and from the Michael J Fox levels. Animal models suggest that Aβ can pass between cerebrospinal
Foundation in 2007.
fluid (CSF) and plasma compartments,
19,20
but this has yet to be
E:
anders.lonneborg@diagenic.com
confirmed in humans. APP is also produced by platelets and is, therefore,
an alternative source for the APP and Aβ pools found in plasma.
28 © TOUCH BRIEFINGS 2008
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