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Alzheimer’s Disease and Diabetes: New Insights and Unifying Therapies
Current Diabetes Reviews, 2013, 9, 000-000 1
1573-3998/13 $58.00+.00 © 2013 Bentham Science Publishers
Arianna Vignini#, Alessia Giulietti#, Laura Nanetti, Francesca Raffaelli, Lucia Giusti, Laura
Mazzanti* and 1Leandro Provinciali
Department of Clinical Science, Section of Biochemistry, and 1Department of Experimental and Clinical Medicine,
Università Politecnica delle Marche, Ancona, Italy
Abstract: Several research groups have begun to associate the Alzheimer Disease (AD) to Diabetes Mellitus (DM), obe-
sity and cardiovascular disease. This relationship is so close that some authors have defined Alzheimer Disease as Type 3
Diabetes. Numerous studies have shown that people with type 2 diabetes have twice the incidence of sporadic AD.
Insulin deficiency or insulin resistance facilitates cerebral ?-amyloidogenesis in murine model of AD, accompanied by a
significant elevation in APP (Amyloid Precursor Protein) and BACE1 (?-site APP Cleaving Enzime 1). Similarly, depos-
its of A? produce a loss of neuronal surface insulin receptors and directly interfere with the insulin signaling pathway.
Furthermore, as it is well known, these disorders are both associated to an increased cardiovascular risk and an altered
cholesterol metabolism, so we have analyzed several therapies which recently have been suggested as a remedy to treat
together AD and DM.
The aim of the present review is to better understand the strengths and drawbacks of these therapies.
Keywords: Type 2 Diabetes, Alzheimer’s disease, Statins, Liraglutide, Metformin.
Diabetes Mellitus (DM)
Diabetes is one of the fastest growing epidemics of mod-
ern times. It represents a group of metabolic diseases charac-
terized by hyperglycaemia resulting from defects in insulin
secretion, insulin action, or both. The American Diabetes
Association currently defines diabetes as a fasting glucose
elevation > 126 mg/dl, and glucose intolerance as an eleva-
tion of glucose between 110 and 126 mg/dl .
DM currently affects 250 million people worldwide, with
6 million new cases reported each year. Moreover, it is the
fourth leading cause of mortality in the world, accounting for
3 million deaths annually. In 2010, DM (type 1 or 2) was
estimated to affect nearly 30% (10.9 million) of people 65
years and older and 215,000 of those younger than 20 years
. In particular, people with T2DM are more likely to de-
velop hearth disease and kidney failure, and recent evidence
suggests that T2DM also increase the risk of developing de-
mentias, such as Alzheimer’s disease .
The development of these complications is dependent on
the duration of diabetes and the quality of metabolic control,
and can be only partially prevented by intensive insulin
Insulin exerts its action through the binding with the in-
sulin receptor (IR). The IR is present in all vertebrate tissues,
although the concentration varies from as few as 40 recep-
*Address correspondence to this author at the Department of Clinical Sci-
ence, Section of Biochemistry, School of Medicine. Università Politecnica
delle Marche, Via Tronto 10 A, 60020 Ancona, Italy; Tel: +390712204675
– 6014; Fax: +390712206058; E-mail: firstname.lastname@example.org
#these authors equally contributed to the work
tors on circulating erythrocytes to more than 200,000 recep-
tors on adipocytes and hepatocytes . The ? and ? IR
subunits seem to have distinct functions such that ? appears
to bind hormone whereas ? appears to possess intrinsic tyro-
sine kinase activity .
Upon binding of insulin, the IR undergoes autophos-
phorylation which enables the receptor to have a kinase ac-
tivity and phosphorylates various cytoplasmatic IR substrates
(IRSs) . From this point, signalling proceeds via a variety
of signalling pathways (e.g. PI-3K signalling pathway, Ras
and MAP kinase cascade) that are responsible for the meta-
bolic, growth-promoting and mitogenic effects of insulin ,
that will be discussed in the following paragraphs.
Alzheimer’s Disease (AD)
AD is the most common form and cause of dementia .
It is characterized by progressive cognitive impairment, loss
of memory and abnormal behaviour [8, 9].
Among the pathological features of AD the presence of
neurofibrillary tangles (NFT) consisting of hyperphosphory-
lated microtubule-associated tau protein, neuron loss in the
hippocampus and cortex regions , and high density of
neuritic plaques, mainly consisting of ?-amyloid (A?) pep-
tide, are the most common one. In particular, A? is believed
to play a crucial role in the pathogenesis of AD, and it is the
cleavage product derived from the transmembrane domain of
Amyloid Precursor Protein (APP)  (Fig. 1). Among the
various A? peptides generated by the multiple-site cleavages
of secretase, A? 42 has proved to be more hydrophobic and
amyloidogenic than others , and probably provides the
core for oligomerization, fibrillation and amyloid plaque
generation [13, 14].
2 Current Diabetes Reviews, 2013, Vol. 9, No. 3 Vignini et al.
Intraneuronal accumulation of A? has been proposed as
an initiating event in the pathogenesis of AD. It plays a cen-
tral role in triggering a cascade ultimately leading to pro-
found neuronal death and memory defects [15, 16]. Confirm-
ing this, in transgenic mouse models of AD, an induced
cerebral insulin depletion aggravated AD-like traits such as
amyloid plaques, tau phosphorylation, neurofibrillary tan-
gles, and spatial memory deficits [17, 18].
Moreover, it is highly reported in literature the role of A?
in inducing oxidative stress . Cell metabolism generates
potentially harmful reactive oxygen species (ROS). At mod-
erate levels, ROS act as second messenger for different cel-
lular functions. At the same time, a variety of mechanisms
protect cell against ROS excess. But chronic increases in
ROS levels above a physiological threshold may trigger cell
death by interfering with normal cellular mechanism .
Oxidative stress, in fact, elicits the disruption of mitochon-
drial integrity through the opening of a large channel which
produces mitochondrial depolarization, a key event to initiate
cell death cascade .
Although drugs for AD can temporarily improve mem-
ory, at present, there are no treatments available to stop or
reverse the inexorable neurodegenerative process .
The Relationship Between Alzheimer’s Disease and
Diabetes: the Insulin Signalling Pathway
A number of well-designed epidemiological studies have
linked T2DM to an increased risk of AD.
The relationship between AD and T2DM was hypothe-
sized for the first time in 90’s, when Ott et al., through the
Rotterdam study, based on previous observational study
which underlined the high frequency of both dementia and
diabetes in elderly people, developed a cohort study where
they showed that DM almost doubled the risk of dementia,
particularly AD .
Some years later, similarly, Xu et al. found that uncon-
trolled diabetes increases the risk of AD, suggesting a direct
link between glucose dysregulation and neurodegeneration
In 2008 Rönnema et coll., investigating the associations
between midlife insulin secretion, glucose metabolism, and
the subsequent development of AD and dementia, found a
low insulin response at baseline that was associated with a
higher risk of AD also after adjustment for age, systolic
blood pressure, body mass index, serum cholesterol, smok-
ing, education level, and insulin resistance. Impaired insulin
Fig. (1). Non-amyloidogenic and amyloidogenic APP processing pathways. A) The non-amyloidogenic pathway consists in the cleavage of
APP within the A? sequence by ?-secretase followed by ?-secretase cleavage and results in the production of a short, possibly innocuous
APP fragment. B) The amyloidogenic pathway consists in the cleavage of APP within the A? sequence, firstly, by the BACE1, which liber-
ates its soluble ectodomain into the extracellular space. The resulting cell-associated C-terminal fragments, which can be either 99 or 89
amino acids in length, are subjected to intramembrane proteolysis mediated by ?-secretase, which generates a spectrum of A? peptides of
varying length at the COOH terminus. The predominant species of A? is 40 amino acids long (A?40), but the less abundant 42-amino-acid
variant (A?42) is more amyloidogenic and is the initial A? species that deposits into amyloid plaques in all forms of AD.
Alzheimer Disease and Diabetes Current Diabetes Reviews, 2013, Vol. 9, No. 3 3
secretion, glucose intolerance, and estimates of insulin resis-
tance were all associated with higher risk of any dementia
and cognitive impairment . In the same period, the Car-
diovascular Health Study Cognition Study (1992-2000) sug-
gested that having both diabetes and APOE ?4 increases the
risk of dementia, especially for AD .
Consistent with these epidemiological investigations
showing that diabetes is an important risk factor for sporadic
AD, a growing body of evidence indicates defective insulin
signalling in AD brains [23-26].
Early observations that many AD patients had impaired
glucose tolerance were typically attributed to low physical
activity or dietary differences. For instance, it was recently
demonstrated that aerobic exercise enhances cognition in
older glucose intolerant adults . Specifically, a substan-
tial proportion of adults with AD had high insulin concentra-
tions in response to glucose challenge and reduced insulin-
mediated glucose uptake . This pattern is characteristic
of insulin resistance, in which more insulin is required to
accomplish physiological functions. Further inquiry estab-
lished that this pattern characterised patients at very early
stages of disease, who did not differ from healthy similarly
aged adults on indices of physical inactivity or dietary com-
position . An interesting pattern was observed, in that
high insulin concentrations and reduced insulin-mediated
glucose uptake characterised patients with AD without the
ApoE ?4 allele, and suggested that hyperinsulinaemia and
insulin resistance may be a new class of risk factors for this
group of patients, who comprise adults with late onset AD
Recently it was demonstrated that insulin metabolism is
not only impaired in peripheral tissues, but also in the brain
of individuals with AD . It has to be noticed that neurons
themselves express insulin [31, 32], but the majority of the
brain insulin originates from the periphery through the
blood-brain barrier via a saturable transport mechanism .
In particular, the insulin signalling pathway components are
down-regulated in AD . In the same way, analyses of
human brain tissue deriving from T2DM patients showed
decreased levels of the insulin signalling pathway compo-
nents also in T2DM patients, suggesting that brain insulin
resistance in T2DM is similar to that in AD .
Decreased brain glucose metabolism in AD brains 
leads to down-regulation of tau O-GlcNAcylation. This
modification regulates phosphorylation of tau inversely ,
therefore it causes hyperphosphorylation of tau. The abnor-
mal hyperphosphorylation of tau leads to the formation of
NFT in the AD brain and promotes neurodegeneration .
Thus, it could be hypothesized that decreased brain glucose
metabolism contributes to neurodegeneration by facilitating
abnormal hyperphosphorylation of tau via down-regulation
of tau O-GlcNacylation in AD . All these findings sug-
gest that T2DM may increase the risk for AD through brain
insulin resistance that induces abnormal hyperphosphoryla-
tion of tau.
Moreover, hyperphosphorylation of tau have also been
observed in the brains of a T1DM mouse model .
T2DM, as mentioned above, is characterized by insulin
resistance . Insulin resistance is characterized by reduced
responsiveness of insulin receptors and decreased down-
stream signalling for the purpose of insulin stimulation. To
compensate for these dysfunctions, the islet ?-cells of the
pancreas secrete more insulin, thereby creating a state of
hyperinsulinaemia . Insulin resistance with hyperinsu-
linaemia constitutes the core feature of T2DM and is fre-
quently also observed in AD patients . Peripheral hyper-
insulinaemia may invoke a signal that inhibits synthesis of
insulin in the brain . It is hypothesized that low concen-
trations of insulin in the brain could reduce the release of A?
from intracellular compartments into extracellular compart-
ments for clearance, leading to its accumulation.
Different are the hypothesis reported to explain the pro-
tective role played by insulin in neuron’s impairment pro-
duced by A? oligomers.
In vitro studies provide the evidence that insulin can pro-
tect cells against damage induced by A? oligomers avoiding
the apoptosis program caused by its accumulation. It has
been demonstrated that, in the presence of A?, insulin pre-
vents the decline in mitochondrial oxidative phosphorilation
efficiency and avoids an increase in oxidative stress .
According to these findings, Di Carlo et al., in an in vitro
study, showed that the impairment of mitochondrial activity
as a result of the treatment with A? oligomers is recovered
after the treatment with insulin  (Fig. 2B).
Another hypothesis involves the insulin signalling path-
way (Fig. 2A). As mentioned above, insulin exerts its effect
by binding to the cell surface receptor IR. Binding of insulin
to IR activates the intrinsic tyrosine kinase activity of the
cytoplasmatic domain of IR, leading to autophosphorilation
on several tyrosine residues. These phosphotyrosine residues
provide docking sites for a number of adaptor proteins, such
as insulin receptor substrate (IRS) 1 and 2 , which recruit
and activate multiple proteins, thereby initiating several sig-
nalling cascades . In particular, the most involved in the
process is the lipid kinase phosphatidylinositol 3-kinase
(PI3K), which in turn, activates the Ser/Thr-kinase Akt .
The PI3K-Akt signalling pathway is responsive to trophic
factors, metabolic signals and environmental stress and regu-
lates survival, growth, differentiation and other homeostatic
functions. For instance, A? specifically inhibits the activa-
tion of Akt through a mechanism preventing its direct inter-
action . One of the actions of Akt is to inactivate pro-
apoptotic mediators which play a key role in cell death/life
pathways . For this reason the inhibition of Akt by A?
could be one of the causes of neuronal cells suffering and
death in AD patients.
The PI3K activation by insulin, furthermore, elicits
Hsp70 activation, protein involved in preventing protein ag-
gregation and degradation [43, 44], which therefore could
prevent A? oligomers by successive aggregation steps or
promote oligomers degradation.
Another possible mechanism through which the deficient
insulin signalling is an event triggering AD, involves
BACE1. BACE1 is the key enzyme that initiates the produc-
tion of A? peptides from their parent molecule APP. This
enzyme seems in fact to be up regulated in AD, involving the
acceleration of ?-amyloidogenesis and consequently A? ac-
cumulation, emphasizing the progression of the disease .
4 Current Diabetes Reviews, 2013, Vol. 9, No. 3 Vignini et al.
In a recent study, Devi et al., demonstrated that streptozoto-
cin induced insulin-deficient diabetes exacerbates A? accu-
mulation by elevating expression levels of ?-secretase en-
zyme BACE1 and its substrate APP in a transgenic mouse
model of AD .
All these findings support the hypothesis that deficient
insulin signalling may represent a critical contributing factor
in the acceleration of ?-amyloidogenesis during the progres-
sion of sporadic AD and thus be an important therapeutic
target in AD treatments.
Several studies utilizing intravenous  or intranasal
administration [47, 48] of insulin demonstrated in fact an
improvement in cognition.
Recently a nasal spray has been tested that delivers insu-
lin quickly and directly to the brain, in order to test its effi-
cacy in slowing or stopping the progression of AD. In the
small study, 104 people with Alzheimer or mild cognitive
impairment were enrolled. The participants were given 20 IU
(international units) of insulin, 40 IU of insulin or a saline
placebo. Adults treated with 20 IU of the insulin nasal spray
experienced improved memory and both doses of insulin
protected general cognition and ability to function. But the
study lasted only four months. No harmful side effects, such
as increased insulin levels throughout the whole body, were
detected. To make these findings more than just hopeful,
researchers must carry out a much larger and longer study.
Insulin, in addition to its critical role in controlling me-
tabolism in peripheral tissues, has been found to have
profound effects in the central nervous system (CNS), where
it enters through the blood-brain barrier . It regulates
many key processes in CNS such as food intake, energy ho-
meostasis, reproductive endocrinology, sympathetic activity,
peripheral insulin actions, and even learning and memory
[50, 51]. Insulin also regulates neuronal proliferation, apop-
tosis, and synaptic transmission. Thus, any disturbance in the
metabolism of insulin in the CNS may put unfavourable ef-
fects, such as the insurgence of AD. Hence investigating the
role of pharmacological agents that could ameliorate neu-
ronal insulin resistance merit attention in AD therapeutics
Given the increasingly stronger evidence showing the
link between onset brain insulin-resistance and onset and
progression of AD, an effective therapy is necessary to ame-
liorate or contrast neuronal insulin resistance.
The most used drug against peripheral insulin resistance
is metformin, an FDA-approved biguanide, molecule already
known for the treatment of diabetes. It works by suppressing
glucose production by the liver but its precise mechanism of
action remains unclear. Recently, it was demonstrated that
this compound is also active in the brain. Kickstein et coll.
has found that metformin would include features to counter-
act the evolving of AD . Their study shows that this anti-
diabetes drug is able to regulate the functioning of the pro-
tein PP2A. PP2A is the major tau-phosphatase in the brain,
and it is responsible for removing phosphate groups from tau
protein. In AD patients this enzyme is less active and the
metformin could enhance the functioning, preventing the
accumulation of phosphate groups in tau-protein and, thus,
the accumulation of tau-protein in neurofibrillary tangles,
which have a crucial role in the onset of the disease .
Moreover, recently growing evidence for beneficial effect of
Fig. (2). The protective role of insulin in neuron impairment produced by A? oligomers. A) Insulin protective action against apoptotic cell-
death promoted by A? oligomers. Binding of insulin to insulin receptor (IR) in the ? domain, activates the intrinsic tyrosine kinase activity of
the cytoplasmatic domain (?), leading to autophosphorilation on several tyrosine residues which in turn provide dicking sites for insulin re-
ceptor substrate (IRS 1-2). IRS 1-2 recruit kinase phosphatidylinositol 3-kinase (PI3K), which in turn activates the Ser/Thr-kinase Akt and
Hsp 70. Akt regulates survival, growth, differentiation and homeostatic functions. Hsp 70 is instead involved in preventing protein aggrega-
tion and degradation. A? oligomers prevents the activation of Akt, thus causing neuronal cell death, and inducing aggreagation and degrada-
tion of A?. B) Insulin protective action against neuron apoptosis through the inhibition of A? oligomer’s on mitochondrial oxidative phos-
phorylation and oxidative stress.
Alzheimer Disease and Diabetes Current Diabetes Reviews, 2013, Vol. 9, No. 3 5
metformin on disease other than diabetes has been presented.
Particularly, metformin long-term use is associated with
lower risk of certain cancers [53, 54]. In contrast to such
beneficial effects, metformin has been found to induce
BACE1 transcription and to increase A? production in neu-
ronal cell lines and primary neurons in the absence of insulin
. However, these effects can be inverted by the addition
of insulin: metformin in fact appears to be able to enhance
insulin’s anti-A? effect, and thus reducing A? generation
. It remains an interesting question how metformin spe-
cifically sensitizes insulin’s effect, when used together.
Some authors suggest that the combinatory effect of met-
formin and insulin involves the interplay of their antagoniz-
ing effects on BACE1 transcription and on APP processing
and trafficking. This, however, leaves the question open of
what effects metformin would cause on BACE1 expression
and A? production in an individual with normal insulin lev-
els. This must be tested in the next future in animal models
of sporadic AD. In case of success of these studies, the com-
bination metformin/insulin may result in a beneficial effect
in treating both T2DM and mitigating AD progression.
As described so far, a contributing factor of the link be-
tween AD and T2DM is the desensitisation of insulin recep-
tors in the brains of patients with Alzheimer’s disease .
Building on this, a new strategy is being developed to nor-
malise insulin signalling in the brain, such as the use of the
incretin hormone glucagon-like peptide-1 (GLP-1) as a new
treatment for Alzheimer’s disease. GLP-1 is an incretin hor-
mone which regulates postprandial glucose levels through
glucose-dependent insulin secretion . Interestingly, GLP-
1 also plays an important role in the brain, it is expressed in
neurons and acts as a neurotransmitter . GLP-1 has
growth factor-like properties and protects neurons from neu-
rotoxic influences, reduces the induction of apoptosis of hip-
pocampal neurons (the brain area that is involved in memory
formation) and improves spatial associative learning .
In particular, GLP-1 carries out its action through the ac-
tivation of the specific receptor GLP-1R. In a recent study, in
fact, has been shown that the lack of GLP-1R function in the
brain affects synaptic plasticity and cognitive processes ,
thus demonstrating its specific role in neuronal activity and
brain function, and explaining the mechanisms via which, in
mouse models of Alzheimer’s disease, GLP-1R agonists
exert neuroprotective effects on neurons and synapses [60,
For these interesting properties, GLP-1 analogues have
recently been developed, substituting amino acids in the na-
tive GLP-1 peptide position, where the endogenous protease
dipeptidyl-peptidase IV (DPP-IV) degrades native GLP-1.
Natural GLP-1, in fact, is rapidly degraded by this enzyme
and its half-life is only 2-3 minutes in blood plasma , and
is, accordingly, unsuitable as therapeutic agent. Among these
molecules we can mention liraglutide, a modified form of
human GLP-1 which has been released on the market in
Europe as a once-daily subcutaneous treatment for type 2
diabetes . Clinical trials in T2DM patients demonstrated
an improved glycaemic control and a reduction in body
weight . The liraglutide molecule can cross the blood-
brain barrier  and has a fatty acid (C-16 palmitoyl) con-
jugated to the side-chain of Lys26 and an Arg for Ser amino
acid substitution at position 34. Together, these modifica-
tions result in a significantly prolonged circulating biological
half-life in vivo, primarily due to binding to serum albumin
and resistance to DPP-IV . This implies that diabetic
patients only need one injection per day independent of
In a recent study, the pre-exposure effects of liraglutide
were observed to examine its protective effects against A?-
induced impairments in behaviour, a pre-exposure protective
effect that might be of great significance in the prevention of
T2DM developed to AD. Authors found that the GLP-1
analogous significantly protected against the A?-induced
impairment of learning and memory; in fact, the intrahippo-
campal injection of liraglutide dose-dependently prevented
the A?-induced deficits in spatial cognition of rats .
These findings are also supported by McClean’s study in
which liraglutide administration induced a reduction of A?
plaques and an increase in neurogenesis in a mouse model of
AD . These results suggest that liraglutide could play an
important role in the prevention or treatment of memory loss
in AD patients. Since liraglutide is already marketed for the
treatment of T2DM, and that T2DM is considered a risk fac-
tor for the development of AD, the drug could be a great
treatment to counteract the onset and evolution of the dis-
ease. However, clinical trials are required to test this hy-
Cholesterol, in particular Low Density Lipoprotein-
cholesterol (LDL), is considered one of the most significant
risk factors for the occurrence of cardiovascular events. In
around 360000 men who were screened for the Multiple
Risk Factor Intervention Trial (MRFIT), every 1 mmol/L
lower blood total cholesterol was associated with about a
50% lower risk of death from coronary heart disease, irre-
spective of blood cholesterol at baseline. In the 5000 men
who had reported a history of diabetes at the baseline as-
sessment for MRFIT, the relation between blood cholesterol
and risk of coronary mortality was of similar magnitude, but
the absolute risk of coronary mortality was three to five
times higher than it was in those without diabetes .
Also people with AD have an increased cardiovascular
risk. In AD patients the ATP Binding Cassette A1 and Scav-
enger Receptor-BI-mediated cholesterol efflux pathway from
macrophages (the principal constituent of atherosclerotic
plaque) is impaired , and the beneficial effect of High
Density Lipoprotein (HDL) on cholesterol metabolism and
inflammatory processes decreased with the severity of AD
, contributing to increase the cardiovascular risk. This
alteration in cholesterol metabolism by inefficient HDL from
AD patients seems to favour A? production through the
promotion of ?- and ?-secretase activities .
Therefore, alterations in lipid metabolism play an impor-
tant role in the pathogenesis of AD. Moreover, a significant
number of studies have shown that high serum total choles-
terol is a risk factor for mild cognitive impairment and de-
mentia [67, 68], and epidemiological  and experimental
 studies have shown that hypercholesterolemia is also an
early risk factor for AD, but the mechanism is less known.
6 Current Diabetes Reviews, 2013, Vol. 9, No. 3 Vignini et al.
Statins, as known, are a class of drugs used to lower cho-
lesterol levels by inhibiting the enzyme 3-hydroxy-3-
methylglutaryl-coenzyme A (HMG-CoA) reductase, which
plays a central role in the production of cholesterol in
the liver. For this property, as the close correlation between
cholesterol, diabetes and cardiovascular risk, statins are often
used in some diabetic patients. Recent trails of cholesterol-
lowering therapy, using statins, in people with established
coronary hearth disease (CHD) have reported clinically im-
portant treatment benefits in patient with diabetes. The
Scandinavian Simvastatin Survival Study reported a 42%
lower rate of major CHD events among patients with diabe-
tes treated with simvastatin than in those on matching pla-
cebo , in the Cholesterol and Recurrent Events trial
(CARE), which included 586 patients with diabetes, treat-
ment with pravastatin reduced the relative risk of coronary
events by 25% . Pravastatin was used also in the LIPID
(Long-term Intervention with Pravastatin in Ischemic Dis-
ease) trial, where the treatment with the drug conferred clini-
cal benefits in the groups studied (patients with only diabe-
tes, patients with only impaired fasting glucose (IFG), pa-
tients with both, and placebo), but in those with IFG or dia-
betes, the absolute risk reduction was greater . Taken
together these findings provide clear evidence for the bene-
fits of treatment with statins for secondary prevention of
CHD in patients with diabetes. These benefits, in addition to
the reduction of plasma levels of cholesterol, it is not ex-
cluded may be due to the pleiotropic effects of this class of
drugs , such as anti-inflammatory properties and endo-
In the brain, cholesterol of neuronal membranes induces
large changes in membrane fluidity, regulating the activity of
several membrane proteins. Although neurons produce
enough cholesterol to survive, the formation of new synapses
requires higher input of this lipid that is provided by glial
cells . Moreover HDLs are critical for maturation of syn-
apses and maintenance of synaptic plasticity . The per-
turbation of brain cholesterol homeostasis is involved in sev-
eral neurodegenerative diseases, including AD, and could
thus represent a major therapeutic target in common with the
treatment of diabetes .
The large body of literature on a putative connection be-
tween elevated cholesterol level and increased AD risk sug-
gests that lowering cholesterol level might be a viable strat-
egy for AD treatment or prevention. Numerous studies have
confirmed that cholesterol favours the processing of APP via
the ?-secretase instead of the ?-secretase pathway, resulting
in an increase in production of A? . Based on this evi-
dence, researchers have investigated the potential therapeutic
effects of lipid-lowering agents, with a focus on statins.
Results from several cell culture studies and animal stud-
ies have indicated that statins use results in decreased pro-
duction of A? levels , suggesting that cholesterol, some-
how, may increase production and accumulation of A?,
through a mechanism of action still unknown.
For instance, Kojro et al. reported that treatment of vari-
ous cell lines with lovastatin increased ?-secretase activity
and that treatment of human astroglioma cells with lovastatin
decreased A? production . In hippocampal or mixed cor-
tical neurons from rats, treatment with simvastatin or lovas-
tatin reduced levels of both intracellular and extracellular
A?40 and A?42 . This study also demonstrated that lo-
vastatin in primary neurons carrying the Swedish missense
mutation in APP had a stimulation of ?-secretase processing.
Statins moreover depleted membrane rafts of cholesterol and
reduced the production of A? [82, 83-86]. Together, the re-
sults of these in vitro studies suggest that statins use can
lower A? generation.
Animal models of AD have generally complementary
findings. Administering simvastatin to guinea pigs for 3
weeks resulted in decreased brain and cerebrospinal fluid
levels of A?, an effect that was reversed by discontinuing the
treatment . In another study, Kurata et al. examined the
effects of atorvastatin and pitavastatin on senile plaque (SP)
size and inflammatory responses in the brain of an APP
transgenic mouse, and they found a reduction of SP and in-
flammatory response (markers: e.g. MCP-1, TNF-?) in the
mice treated, suggesting therefore a protective effect, prop-
erty which might be exploited for a preventative approach in
patients at risk of AD .
Despite the good results of in vitro and animal models,
nevertheless epidemiological studies reported contradictory
results concerning the role of cholesterol as a risk factor for
AD. In some, hypercholesterolemia enhances the risk to de-
velop AD. However, others did not find the same correlation
or found an opposite relationship .
Recently Sparks et al.  presents evidence that statins
may have a favourable impact in the treatment of AD. In a
double-blind study, controlled verso placebo, carried out by
Sparks, individuals with AD were treated with atorvastatin.
The results of Sparks underline benefits in cognition after the
treatment with atorvastatin which reached statistical signifi-
cance compared with placebo at six months. Although these
findings are provocative, tests are needed more and larger, to
search for the importance of statins as a treatment for AD.
On the contrary Sano et coll. made a double-blind pla-
cebo vs treated study, with 40mg/day simvastatin. Simvas-
tatin lowered plasmatic lipid level, but it was found neither
change in Alzheimer’s Disease Assessment Scale-cognitive
portion, nor clinical change, cognition, function and behav-
iour, thus providing that 40mg/day simvastatin does not slow
the disease .
The contradictory results in epidemiological studies
might be explained through different doses of statins that
may have opposite effects. Inhibiting cholesterol synthesis,
statins reduce in fact isoprenoids levels but in a different way
depending on the used doses . At low doses, statins have
no effects in membrane cholesterol levels and the reduction
of isoprenoid levels does not alter A? production. However,
these doses are neuroprotective and rescue neurons from A?-
induced cell death. At low doses, statins in fact significantly
decrease oxidative stress, cytosolic Ca2+ deregulation, hyper-
phosphorylation of tau, inflammation, and apoptotic cell
death triggered by A? due to inhibition of isoprenoid produc-
tion. High doses of statins, instead, can have opposite ef-
fects; in fact strongly reduce isoprenoid levels and conduct
to APP accumulation and inhibition of ?- and ?-secretases
activity, thus decreasing A? generation . Nevertheless
Alzheimer Disease and Diabetes Current Diabetes Reviews, 2013, Vol. 9, No. 3 7
the strong reduction of isoprenoid and high cholesterol levels
are toxic to cells.
In conclusion, more studies are needed to determine if
the lipid-lowering action and pleiotropic effects of statins
actually have a beneficial role in the treatment of AD. If so,
since the potential beneficial role of this class of drugs also
in diabetes, statins therapy may be shared between the two
diseases, or used as a preventive drug in diabetes patients to
counteract the onset of AD.
Both AD and DM are associated with increased oxidative
stress and production of Advanced Glycation End products
(AGEs). AGEs are formed by a sequence of events identified
as the end-products of the Maillard reaction, during which
reducing sugars can react with the amino groups of proteins
to produce cross-linked complexes and unstable compounds
. AGEs couple with free radicals and create oxidative
damage, which in turn leads to cell injury. In diabetic pa-
tients the presence of AGEs is demonstrated, especially in
kidney and CNS. For this reason this patients could have an
increase risk of AD via AGE production . Oxidative
stress on its own also causes AGEs, creating a vicious cycle
. On the other hand, immunohistochemical studies
showed the existence of AGEs in senile plaques and NTs
: accumulation of A? is increased by A? glycation, and
formation of NFTs from phosphorylated tau is accelerated by
glycation of tau protein . Krautwald and Münch pro-
posed that AGEs might contribute to the pathogenesis of AD
by two major mechanisms. Firstly, intracellular AGEs cross-
link cytoskeletal proteins and render them insoluble. These
intracellular aggregates might inhibit cellular functions in-
cluding transport processes and contribute to neural dysfunc-
tion and death. Secondly, they suggest that extracellular
AGEs accumulate in on long-lived protein deposits like the
senile plaques and thus chronically activate of astroglial cells
which constantly produce free radicals (superoxide and NO)
and neurotoxic cytokines . In addition, it is shown that
A?- and AGEs- positive granules were present in the peri-
karyon of hippocampal neurons in diabetic patients with AD
. Moreover, AGEs and A? are both signal transduction
ligands of RAGE, a specific surface receptor found in a vari-
ety of cells including neurons. This interaction ligand-
receptor elicits cell death, ROS generation, vascular inflam-
mation, and subsequently alters various gene expression in
numerous cell types, all of which could contribute to the
pathological changes of diabetic vascular complications and
All these findings suggest that AGEs could be and inter-
esting target to attend both diseases. Recently AGEs inhibi-
tors have been developed. AGEs inhibitors inhibit the cova-
lent cross linking of proteins and peptides by sugars or sugar
derived oxidation products. It contains a nucleophilic amino
group which competes with lysine in side chains of proteins
for reactive carbonyl groups present on proteins and in solu-
tion . Several natural and synthetic compounds have
been shown to inhibit AGE-formation in vivo and in vitro.
Among these, aminoguanidine was the first AGE-inhibitor
tested in vitro and in animal models . In the original
study, aminoguanidine inhibited the cross-linking and fluo-
rescence of aortic collagen in diabetic rats. Later studies by
several investigators demonstrated that aminoguanidine re-
tarded the development of diabetic complications including
nephropathy , neuropathy, and vasculopathy .
However, it had no effects on hyperglycaemia . Al-
though this compound showed pharmaceutical promise as an
AGE inhibitor, clinical trials showed high levels of toxicity.
Given the harmful side effects of AG, the search resumed for
other compounds that might inhibit protein modifications
and cross-links. Pyridoxamine (PM) is a vitamin B6 deriva-
tive, which is water-soluble and non-toxic in rats and hu-
mans. Studies in streptozotocin (STZ)-induced diabetic rats
revealed that AG and PM were comparable in their effects
on AGEs . In addition to lowering AGE levels, PM also
improved renal function, hypercholesterolemia and hyper-
triglyceridemia, and retarded the development of retinopathy
Another interesting compound is Tenilsetam, a cognition-
enhancing and anti dementia drug shown to be an effective
AGE-inhibitor without any radical scavenging properties
. It is effective also in AD patients and acts inhibiting
nucleation-dependent polymerization of A? peptide .
The positive effects of AGE-inhibitors with respect to the
reduction of A? toxicity may be attributable to the formation
of ‘masked’, less toxic and less cross linked AGE peptide
aggregates. Tenilsetam seems to be effective in diabetes as
well, particularly on its side effects. In fact it is reported in
literature its positive effects in preventing retinopathy thanks
to important rescue functions on endothelial cells .
Therefore, Tenilsetam might be an interesting candidate drug
for the treatment of AD and diabetes .
Growing evidences of epidemiological, in vitro and in
vivo studies have shown the close relationship between AD
and T2DM. In particular it is hypothesized that to be affected
by T2DM increase the risk of AD. This connection is attrib-
uted in part to the common impairment of insulin signalling
pathway in the brain of both pathologies. Insulin, in fact,
exerts a basic role in neuron survival. For this reason, the
neuron impairment of insulin signalling pathway in T2DM
patients might be the cause of triggering cognitive impair-
ment and AD. Thus, several research groups hypothesized
that drugs already used for T2DM treatment might be ex-
ploited for AD prevention and/or treatment. Among these,
the most promising are metformin and liraglutide. Prelimi-
nary studies show that metformin prevents the accumulation
of tau-protein in neurofibrillary tangles and reduce the risk
of certain cancers. Despite this, the drug increase BACE1
activity. This effect is suppresses by insulin treatment. As
regards liraglutide, recent studies demonstrate its capacity
for reduction of A? plaques, on the increase of neurogenesis,
and protective effect against A? induced deficits in spatial
cognition. These results suggest that metformin and liraglu-
tide could play an important role in the prevention or treat-
ment of memory loss in AD patients. Since these drugs are
already marketed for the treatment of T2DM, and that T2DM
is considered a risk factor for the development of AD, they
could be a great treatment to counteract the onset and evolu-
tion of the disease. Nevertheless more studied are needed.
8 Current Diabetes Reviews, 2013, Vol. 9, No. 3 Vignini et al.
In addition, both T2DM and AD patients have an in-
creased cardiovascular risk. Cholesterol enhances the risk of
cognitive impairment and dementia, and epidemiological and
experimental studies have shown that hypercholesterolemia
is also an early risk factor for AD. Since statins are used in
some T2DM patients for the secondary prevention of cardio-
vascular events, they are considered as another favourable
candidate for the treatment of both diseases, but also in this
case more studies are needed to determine if the lipid-
lowering action and pleiotropic effects of statins actually
have a beneficial role in the treatment of AD.
Finally, since the importance of AGEs in diabetes and
AD onset and development is well recognized, other interest-
ing candidates to be studied could be AGEs inhibitors.
CONFLICT OF INTEREST
The author(s) confirm that this article content has no con-
flicts of interest.
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Received: July 23, 2012
Revised: January 17, 2013 Accepted: January 18, 2013