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ABBREVIATIONS
Aβ
42
Amyloid beta (42 amino acid variant)
AD
Alzheimer’s disease
AGER
Advanced glycation end-products receptor
AMD
Age-related macular degeneration
AMPAR
α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid
receptor
AUC
Area under the curve
C1q
Complement component 1 q
C2
Complement component 2
C3
Complement component 3
C4
Complement component 4
CFB
Complement factor B
CFH
Complement factor H
CNS
Central nervous system
CR1
Complement receptor 1
CSF
Cerebrospinal fluid
EPSP
Excitatory postsynaptic potential
FAD
Familiar Alzheimer’s disease
LTP
Long-term potentiation
MCI
Mild
cognitive impairment
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MMSE
Mini mental state examination
MRI
Magnetic resonance imaging
n
Number of synapses or release sites
NMDAR
N-methyl-D-aspartate receptor
NP
Neuronal pentraxine
NPR
Neuronal pentraxine receptor
OR
Odds ratio
p
Release probability
PPR
Paired pulse ratio
q
Quantal content
RAGE
Receptor for advanced glycation end-products
ROC
Receiver operating characteristic
SAD
Sporadic Alzheimer’s disease
SNP
Single nucleotide polymorphism
TACE
Tumor necrosis factor-alpha converting enzyme
VIP
Variable in the projection
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1
INTRODUCTION
1.1
Alzheimer’s disease
Alzheimer’s disease (AD) was first described by Alois Alzheimer in 1906
(Maurer et al. 1997). It is the most common form of dementia, and it is
characterized by a progressive decline in cognitive ability. This can be
attributed to the progressive loss of synapses and neurons seen in patients. At
least two forms of AD are recognized; early onset familial AD (FAD), where
a single mutation in a key AD gene causes AD in an autosomal dominant,
fully penetrant manner, and sporadic AD (SAD) where several risk factors,
both genetic and environmental, are thought to contribute to the disease.
1.1.1
Diagnosis
Clinically, the disease is foremost characterized by amnesia - beginning as
anterograde amnesia, and as the disease progresses this is followed by a
retrograde amnesia (Salmon and Bondi 2009). Other psychiatric symptoms
are common, and include emotional and attention deficits (Salmon and Bondi
2009). Several tests are used to assess cognitive function when trying to
determine diagnosis. One of the simplest and most frequently used is mini
mental state examination (MMSE) (Tombaugh and McIntyre 1992; Folstein
et al. 1975).
Traditionally, AD has been a post mortem diagnosis. Aside from progressive
cognitive deterioration, the patient also has to show some specific
pathological changes. These hallmarks of the disease were described as
plaques and tangles by Alois Alzheimer over a century ago. In the eighties
the plaques were shown to consist mainly of the 42 amino acid long β-
amyloid peptide (Aβ
42
) (Glenner and Wong 1984; Masters et al. 1985; Wong
et al. 1985), whereas the tangles were shown to be made up of hyper-
phosphorylated tau protein (Grundke-Iqbal et al. 1986). These two molecules
now constitute the core cerebrospinal fluid (CSF) biomarkers for AD
(Blennow et al. 2010). Diagnosis is chiefly based on clinical assessments, but
in recently revised diagnostic criteria biomarkers have entered as important
adjuncts
(http://www.alzheimersanddementia.org/content/ncg).
Other
methods utilised include different brain
imaging techniques, such as magnetic
resonance imaging (MRI).
In the present thesis AD subjects fulfilled the DSM-IIIR criteria of dementia
(Spitzer et al. 1987) and were either pathologically confirmed or fulfilled the
Synaptic elimination and the complement system in Alzheimer’s disease
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criteria of probable AD defined by NINCDS-ADRDA (McKhann et al. 1984)
which was further supported by CSF biomarkers.
MCI is defined as not normal but not demented. Cognitive impairment can be
reported by the patient him- or herself, but is preferably also confirmed by an
informant, and in objective neuropsychological tests. An alternative criterion
is evidence of cognitive decline over time. Otherwise the patient should be
able to lead an ordinary life with only minimal impairment in complex
instrumental functions (Winblad et al. 2004). Around 50% of MCI patients
eventually develop AD, whereas the remaining 50% have benign cognitive
impairment or suffer from other neurodegenerative conditions.
Although there is no cure for AD, a correct diagnosis is important to exclude
other diagnoses for which treatment might be available. It is also important in
order to provide the patient and relatives with correct information and a
reasonable prognosis so they know what to expect of the future, enabling
them to make arrangements and plans in good time. Lastly, efforts in making
accurate early diagnoses will hopefully pay off when treatments become
available.
1.1.2
Epidemiology
In 2011 AD had a prevalence of about 34 million cases worldwide (Barnes
and Yaffe 2011). The incidence is approximately 1% and increases
exponentially with age (Reitz et al. 2011). Due to increased life expectancies,
the prevalence has been estimated to triple over the next 40 years (Barnes and
Yaffe 2011). The suffering and economic impact cannot be overstated.
Age is the major risk factor for AD. FAD has a marked earlier onset than
SAD; typically it starts in the late 40’s or early 50’s and has an absolute
genetic aetiology. Although the present thesis only concerns the more
common SAD, it is important to note that FAD and SAD are clinically and
neuropathologically similar, and since all known FAD mutations are located
in genes involved in Aβ processing, a common conclusion is that Aβ should
play a central role in AD.
SAD, in contrast to FAD, has a later onset, and a more complicated
aetiology, where several risk factors are thought to contribute. Twin studies
have shown that as much as 60-80% of the risk is of hereditary origin (Gatz
et al. 2006). The only confirmed susceptibility gene is the ε4 allele of the
apolipoprotein E gene (APOE ε4) (Corder et al. 1993; Kurz et al. 1996;
Poirier et al. 1993). Although APOE ε4 has been suggested to account for 20-
30% of the risk (Reitz et al. 2011), it is neither necessary nor sufficient for