Alzheimers Disease Clinical Trial
Official title:
Neurodegenerative Changes in Alzheimer's Disease: Identifying Potential Effects of Liraglutide on Degenerative Changes
Today Alzheimers disease can not be cured. Animal experiments have shown that the hormone
GLP-1 can improve memory in Alzheimer-prone mice.
The investigators hypothesis is that a 6-month treatment with the GLP-1 receptor stimulating
drug liraglutide will reduce the intracerebral amyloid deposition in the central nervous
system (CNS) in patients with Alzheimer's disease (AD) and thereby reduce the clinical
symptoms of the disease.
The incidences of both type 2 diabetes (DM-2) and Alzheimer's disease (AD) have increased
during the last years, resulting in an increase in morbidity and mortality. DM-2 is a risk
factor for both AD and vascular dementia. In addition, an increased incidence of DM-2 in
Alzheimer's patients has been observed. The understanding of the underlying mechanism behind
this linkage is so far very sparse.
In both diseases premature cell degeneration develops. DM-2 is characterized by a loss of
β-cell function and β cell mass in the pancreas, whereas AD shows a loss of neuronal
function as well as neuronal cell death. General metabolic risk factors such as
hyperglycemia and hypercholesterolemia are evident in both diseases.
Glucagon-like-peptide-1 (GLP-1) is an incretin hormone with numerous documented effects on
the glycaemic response. It is released as a response to food ingestion and consequently
exerts a glucose-dependent stimulation of insulin secretion while inhibiting glucagon
secretion. In animal experiments as well as cell experiments β-cell neogenesis, growth and
differentiation are stimulated by GLP-1, and inhibition of β-cell apoptosis has been
demonstrated in cell studies. In addition to α- and β-cells of the pancreas, GLP-1 receptors
(GLP-1R) have been localized to the CNS, where GLP-1R are distributed corresponding to the
hypothalamus and hippocampus. Experimental investigations on mice where GLP-1 was given
intra-cerebroventricularly, GLP-1R stimulation reduced nerve cell damage caused by
neurotoxic stimuli. Furthermore, GLP-1R stimulation in hippocampus induced learning ability
and memory and it has been shown that GLP-1R stimulation leeds to neurite outgrowth and
protects against nerve cell apoptosis.
In connection with hyperinsulinaemia in early stages of DM-2, studies suggest that
stimulation of insulin receptors represented in the brain produce an increased level of
β-amyloid and an increased number of neurofibrillary tangles. AD is pathologically
characterized by an increased level of β-amyloid as well as an increased number of
neurofibrillar tangles. Accumulation of β-amyloid in the brain is localized to areas with
cognitive functions. A recent animal experimental work has shown reduced memory in GLP-1
receptor KO mice and mentions the lack of a possible neuroprotective effect as a potential
explanation for the observation. In studies of humans a worsening of the cognitive functions
has been shown to be associated with dementia and DM-2, even though an actual causal
relation has not yet been found. The investigators have recently shown that GLP-1 has a
neuroprotective function in patients with DM-2.
Positron emission tomography (PET) scanning has been well evaluated in clinical
demonstration of CNS changes following AD including changes in amyloid deposits.
Presently there are no registered drugs which change the deposition of amyloid and there are
no drugs with convincing effect on the progression of the disease in patients with
Alzheimer's. Moreover the drugs which have been marketed for treatment have a
disadvantageous side effect profile. Besides insulin, β-cells secrete amylin, amyloid or
IAPP (islet amyloid polypeptide) and these thus share certain characteristics with
β-amyloid. Previously IAPP was considered to be non-toxic but recent studies have indicated
a possible conversion to toxic β-amyloid.
The insulin-producing β-cells have been found to be characterized by accumulation of amyloid
in several DM-2 models. A recent study with treatment with DPP-4 inhibitors (increasing
endogenous GLP-1) improved glucose tolerance, increased GLP-1 levels and normalized the
topography of the islets of Langerhans in a mouse model with β cell specific over expression
of human amyloid.
The investigators hypothesis is that a 26 week treatment with the GLP-1 receptor stimulating
pharmaceutical liraglutide will reduce the intracerebral amyloid deposition in the CNS in
patients with Alzheimer's disease, as demonstrated by PET.
The investigators aim is that this clinical study will be able to give new information about
the effect of the GLP-1 axis in the CNS and explore the potential for treatment of large
groups of patients who cannot be offered effective drugs today. Altogether the results from
the studies will contribute to the development of future treatment options for AD.
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Allocation: Randomized, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Primary Purpose: Treatment
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