Current Alzheimer Research, 2012, 9, 5-17
1567-2050/12 $58.00+.00 © 2012 Bentham Science Publishers
Metabolic Dysfunction in Alzheimer’s Disease and Related Neurodegen-
Huan Cai1,#, Wei-na Cong1,#, Sunggoan Ji1, Sarah Rothman2, Stuart Maudsley3 and
1Metabolism Unit, 2Cellular and Molecular Neurosciences Section, 3Receptor Pharmacology Unit, National Institute on
Aging, 251 Bayview Blvd., Suite 100, Baltimore, MD 21224, USA
Abstract: Alzheimer’s disease and other related neurodegenerative diseases are highly debilitating disorders that affect
millions of people worldwide. Efforts towards developing effective treatments for these disorders have shown limited ef-
ficacy at best, with no true cure to this day being present. Recent work, both clinical and experimental, indicates that many
neurodegenerative disorders often display a coexisting metabolic dysfunction which may exacerbate neurological symp-
toms. It stands to reason therefore that metabolic pathways may themselves contain promising therapeutic targets for ma-
jor neurodegenerative diseases. In this review, we provide an overview of some of the most recent evidence for metabolic
dysregulation in Alzheimer’s disease, Huntington’s disease, and Parkinson’s disease, and discuss several potential mecha-
nisms that may underlie the potential relationships between metabolic dysfunction and etiology of nervous system degen-
eration. We also highlight some prominent signaling pathways involved in the link between peripheral metabolism and the
central nervous system that are potential targets for future therapies, and we will review some of the clinical progress in
this field. It is likely that in the near future, therapeutics with combinatorial neuroprotective and ‘eumetabolic’ activities
may possess superior efficacies compared to less pluripotent remedies.
Keywords: Neurodegenerative diseases, metabolic dysfunction, bodyweight, diabetes, glucose homeostasis, insulin, leptin,
ghrelin, adiponectin, glucagon-like peptide 1, Alzheimer’s disease, Huntington’s disease, Parkinson’s disease.
process that is subject to modification by a myriad of genetic
and environmental factors. Aging can be defined as the pro-
gressive loss of an organism’s optimal function, which con-
tinues until its eventual failure and death. Aging and many
aging-associated disorders involve perturbed energy balance.
Metabolism, including glucose regulation and appetite bal-
ance, is controlled by both central regulatory inputs (primar-
ily via the hypothalamus) and peripheral signals such as in-
sulin, ghrelin, cholecystokinin, and adipokines (e.g. leptin,
adiponectin, resistin). Alzheimer’s
Huntington’s disease (HD), and Parkinson’s disease (PD) are
debilitating aging-related neurodegenerative disorders, with
severe cognitive and/or motor symptoms that progressively
worsen over time, causing reduced quality of life, increased
medical costs and eventual death. Neurodegenerative dis-
eases mainly affect the middle-aged and elderly and repre-
sent a significant burden on patients and healthcare systems
[1, 2]. Although AD, HD, and PD are neurodegenerative
disorders, current therapies designed to treat these disorders
that target the central nervous system often demonstrate lim-
ited efficacy. Increasing evidence suggests a link between
the incidence and progression of some neurodegenerative
disorders and metabolic dysfunction. Some recent data has
Aging is a highly complex, evolutionarily conserved
*Address correspondence to this author at the Metabolism Unit, National
Institute on Aging, 251 Bayview Blvd., Suite 100, Baltimore, MD 21224,
USA; Tel: (410) 558-8652; E-mail: email@example.com
#These authors contributed equally to the work.
demonstrated that therapies targeted at restoring metabolic
homeostasis may improve cognitive and motor function as
well as increase lifespan in neurodegenerative diseases [3,
4]. Uncontrolled, progressive weight loss and abnormal glu-
cose tolerance are common metabolic dysfunctions observed
in AD, HD, and PD, which appear to negatively impact
overall prognosis through an, as of yet, poorly defined series
of mechanisms [5, 6]. Whether alterations in systemic me-
tabolism are etiologically linked to AD, HD, and PD, or are a
consequence of the disease processes itself is still presently
unclear. However, it is noteworthy that the disease loci of
AD, HD, and PD often involve the hypothalamus, a key
regulatory brain region for global energy homeostasis .
This review will focus on the multiple metabolic risk factors
and disruptions associated with AD, HD, and PD, the
mechanisms of abnormal energy balance in these disorders,
and potential available therapies that could target metabolic
pathways (‘eumetabolic’ agents) to treat neurodegeneration
(see Fig. 1 for overview).
ALZHEIMER’S DISEASE (AD)
States and is the most common form of dementia and cogni-
tive impairment [8-10]. Symptoms of AD include progres-
sive cognitive decline and memory loss, as well as an inabil-
ity to perform routine daily activities. AD progression has
been demonstrated to involve the intricate alterations of
complex protein networks that still need further elucidation
. It is estimated that < 1% of AD cases are caused by rare
genetic variations found in a small number of families, in-
AD is the sixth leading cause of death in the United
6 Current Alzheimer Research, 2012, Vol. 9, No. 1 Cai et al.
volving chromosome 21 on the gene for amyloid precursor
protein (APP), chromosome 14 on the gene for the preseni-
lin-1 (PS-1), and chromosome 1 on the gene for presenilin-2
(PS-2) . In these inherited forms of AD, often referred to
as ‘early-onset’ AD, symptoms tend to develop before the
age of 65. The vast majority of AD cases however are spo-
radic and therefore lack a simple genetic cause, although
both early-onset and sporadic AD share similar behavioral
symptoms and pathophysiological mechanisms. Progressive
memory loss and reduced cognitive function are associated
with two primary neurodegenerative lesions, accumulations
of beta-amyloid (A?) known as plaques and neurofibrillary
tangles (NFTs) composed of the microtubule protein tau [13-
15]. The generation and accumulation of A? is considered
pivotal for the development of AD , because A? accu-
mulation can set forth a cascade of events, including hyper-
phosphorylation of tau, which in turn results in the formation
of neurofibrillary tangles. Although most cases of AD are
sporadic, alterations in the expression of the lipid-trafficking
molecule, apolipoprotein E4 (ApoE4), has also been demon-
strated to be a genetic risk factor for AD [16, 17]. Interest-
ingly, ApoE4 alterations have also been suggested to be a
risk factor for diabetes and hyperinsulinemia . Despite a
wealth of information concerning AD pathophysiology, the
initial events that trigger A? plaque formation are unclear
and there are currently no effective treatments that can stop
or reverse the AD-related neurodegeneration. The currently
available treatments for AD are only modestly effective, and
some recent clinical trials in AD patients have failed to dem-
onstrate benefit for current medications, or have even indi-
cated harm. Failure to treat AD effectively may be due to the
fact that the mechanisms that cause the disease are not fully
understood, or that existing diagnostic criteria exclude fac-
tors of etiologic importance. It is now clear that disruptions
in metabolism are present in AD and a greater understanding
of these disrupted metabolic pathways may offer new in-
sights into more efficacious treatments for AD.
AD AND BODY WEIGHT
during middle-age is linked to an increased risk of develop-
ing AD. Clinically, obesity (Body Mass Index - BMI greater
than 30) at 40-45 years of age is associated with a 3-fold
increase in the risk of developing AD, while being over-
weight (BMI between 25 and 30) is associated with a 2-fold
increase in AD risk, compared to individuals with a normal
BMI . The Baltimore Longitudinal Study of Aging, a
landmark study of aging and age-related disorders, demon-
strated that among women, being obese in midlife was asso-
ciated with a hazard ratio of 6.57 for AD and among men,
weight gain resulting in a BMI greater than the 90th percen-
tile, between ages 30 and 50, was associated with an in-
creased AD risk . Kivipelto et al. also found similar re-
sults in a cohort of 1449 individuals followed for approxi-
mately 21 years, and midlife obesity was a significant risk
factor for developing AD .
Numerous studies have shown that excess body weight
associated with an increased risk of developing AD. In a
cohort of 299 men and women aged 50-79 years old, in
High BMI and obesity are not the only weight changes
Fig. (1). An overview of some of the relationships between metabolic dysfunction, neurodegenerative disorders, and potential therapies.
Metabolic dysfunction including impaired glucose metabolism, insulin resistance and abnormal appetite regulation are now known to be
comorbid with AD and some other chronic neurodegenerative disorders, such as HD and PD. Treatments that target metabolic malfunctions
may be effective for modifying neurodegenerative-disease pathology and symptoms. IGF-1 (insulin-like growth factor-1); PPARs (perox-
isome proliferator-activated receptors); DPP-4 (dipeptidyl peptidase-4); APP (amyloid precursor protein); PS 1 (presenilin 1); PS 2 (preseni-
lin 2); APOE (apolipoprotein E); ?-SYN (?-synuclein); LRRK2 (leucine-rich repeat kinase 2); UCHL1 (ubiquitin carboxy-terminal hydro-
lase L1) [202, 203].
Metabolic Dysfunction in Alzheimer’s Disease Current Alzheimer Research, 2012, Vol. 9, No. 1 7
which 60 individuals developed AD after 20 years of follow-
up, weight loss of 5 kg or more reliably predicted AD devel-
opment . In contrast, Hughes et al. demonstrated that a
higher baseline BMI and a slower rate of BMI decline were
protective against dementia . It is unclear exactly why
excess body weight in midlife represents a risk factor for
developing AD later in life, whereas in old age it appears to
be protective. It must be noted however, that most studies
use non-specific measures of body composition, such as total
body weight and BMI (calculated as weight in kilograms
divided by height in meters squared), rather than specific
measures of body fat and muscle mass composition. Normal
aging is associated with increases in body fat and decreases
in lean muscle mass, therefore non-specific adiposity meas-
ures, such as BMI, may have limited accuracy when describ-
ing the relationship between body weight and the risk of de-
veloping AD. Yet, the studies summarized previously still
strongly suggest a link between obesity, global energy regu-
lation, and AD pathogenesis, which needs to be further elu-
cidated in order to fully understand AD pathology.
ALTERATIONS IN BRAIN GLUCOSE METABOLISM
of developing AD and excess body weight in midlife reflects
a diet high in simple sugars and fats and a sedentary lifestyle.
A recent study showed that adherence to a ‘Mediterranean
diet’ and intense physical exercise can be protective against
AD . Similarly, reducing caloric intake increases health-
span, reduces damage in the brain due to aging, and provides
greater maintenance of various brain functions, potentially
through ‘hormetic’ mechanisms [25-28]. Experimental re-
sults indeed can corroborate clinical findings, as it has been
shown that rats fed a high-fat/glucose diet, to induce insulin
resistance, were found to exhibit impaired spatial learning
ability, reduced hippocampal dendritic spine density, and
reduced long-term potentiation in the CA1 region . Glu-
cotoxicity, or disrupted insulin signaling, are two of the po-
tential mechanisms thought to mediate changes in hippo-
campal function observed from a high-fat diet, implying that
diet-induced insulin resistance/ hyperinsulinemia may be one
of the links between obesity and AD. Epidemiological stud-
ies have indicated an association between type 2 diabetes
mellitus (DM) and an increased risk of developing AD. The
Rotterdam study, the first of its kind to probe for a connec-
tion between type 2 DM and AD, revealed an approximate
two-fold increase in risk of developing AD in patients with
diabetes, compared to patients without the condition .
Furthermore, in the same study, DM requiring insulin treat-
ment was associated with a four-fold increase in incidence of
AD. The presence of type 2 DM and the ApoE4 allele to-
gether has also been shown to increase the risk of developing
AD, to more than five-fold, compared to individuals without
those two conditions . Additionally, Luchsinger et al.
demonstrated that hyperinsulinemia is associated with a dou-
bled risk of developing AD . Moreover, a thorough re-
view of a registry of AD patients revealed that 80% had ei-
ther type 2 DM or impaired fasting glucose measurements
Abnormal glucose homeostasis is linked to cognitive
dysfunction in such that patients with either type 1 or type 2
It is possible that the association between increased risk
DM display significant memory impairment and attention
deficits on cognitive testing compared to control subjects
. Hyperglycemia increases the number of mental subtrac-
tion errors in individuals with diabetes  and poor glyce-
mic control (as evidenced by high hemoglobin A1C levels),
has been associated with low scores on neuropsychological
testing . There are a number of mechanisms through
which dysglycemia can lead to cognitive dysfunction. Hy-
perglycemia can lead to the activation of the polyol pathway,
formation of advanced glycation end products, activation of
protein kinase C, increased glucose shunting in the hexosa-
mine pathway, and it is also possible that the increase in re-
active oxygen species (ROS) associated with these mecha-
nisms are then, in-part, responsible for altered brain function
[36-38]. In animal models, global alterations in functional
neurotransmission have also been linked to hyperglycemia,
including abnormal N-methyl-D-aspartate (NMDA), acetyl-
choline, serotonin, dopamine and norepinephrine neuro-
transmission [39-42]. Whether these abnormalities lead to
irreversible neuronal damage is presently unclear. There is
also evidence that hyperglycemia may directly contribute to
the pathophysiology of AD. Administration of high amounts
of glucose can induce tau cleavage and apoptosis, and db/db
mice, which are commonly used to model DM, exhibit an
increase in tau phosphorylation compared to controls .
Although the exact mechanism is not entirely known, nu-
merous reports therefore support the notion that metabolic
dysfunction may worsen neurodegeneration in AD patients.
METABOLIC HORMONES AND THEIR THERA-
PEUTIC POTENTIAL IN AD
Insulin and AD
signaling dysfunction in AD. Insulin receptors are abundant
in many brain regions, including the hippocampus, although
the physiological role of insulin in the brain is not fully un-
derstood [44, 45]. Insulin is now believed to influence re-
gional glucose metabolism, as evidenced by rodent studies
and one human study utilizing PET imaging [46-49]. Many
studies have also shown that insulin plays a role in regulating
learning and memory processes [50-52]. Clinically, there is a
higher density of insulin receptors in the brain of AD pa-
tients compared to control subjects, possibly reflecting
upregulation of the receptor in an attempt to compensate for
the decreased functionality of insulin . Furthermore, hy-
perinsulinemia (a marker of insulin resistance in the meta-
bolic disease spectrum) can decrease the availability of insu-
lin degrading enzyme (IDE), which is essential for the deg-
radation and clearance of A? in the brain . Additionally,
mouse models of type 1 and type 2 DM are associated with
increased tau phosphorylation, which is likely secondary to
It is therefore likely that therapies that manipulate insulin
signaling may be beneficial for treating the neurological
symptoms of AD. Peroxisome proliferator-activated recep-
tors (PPARs), which belong to the steroid, thyroid and reti-
noid receptor superfamily, are ligand-inducible transcription
factors. The PPARs subfamily is comprised of three iso-
forms: PPAR?, PPAR?/? and PPAR?. Two PPAR? agonists,
pioglitazone and rosiglitazone, are currently widely pre-
Recent work has begun to outline the presence of insulin
8 Current Alzheimer Research, 2012, Vol. 9, No. 1 Cai et al.
scribed for the treatment of type 2 DM. PPAR? agonists im-
prove both lipid and glucose metabolism, mainly by increas-
ing peripheral insulin sensitivity, which ameliorates the
metabolic dysfunction brought on by the diabetic patho-
physiology . There is increasing evidence demonstrating
the efficacy of PPAR? agonists for the treatment of AD.
PPAR? activation suppresses the expression of inflammatory
genes, which, clinically, has been shown to ameliorate neu-
rodegeneration . Experimentally, treatment with PPAR?
agonists has been associated with both reduced A? plaque
load and improved behavioral outcomes in an animal model
of AD . Clinical studies have corroborated this finding;
i.e. treatment with a PPAR? agonist reduces disease-related
pathology, improves learning and memory, and enhances
attention in AD patients . The cyclooxygenase inhibitor
Ibuprofen (iso-butyl-propanoic-phenolic acid), which can
activate PPAR?, has been demonstrated to significantly re-
duce amyloid pathology and reduce microglial-mediated
inflammation in a mouse model of AD, potentially via
PPAR? signaling [58, 59]. In addition, PPAR? agonists have
been shown to reduce A? plaque burden and A?42 (a specifi-
cally toxic form of A?) levels in the brain by approximately
20-25%, restore insulin responsiveness and lower glucocorti-
coid levels in mouse models of AD [60, 61]. These results
suggest that PPAR? agonists may be useful for the treatment
of AD, a hypothesis greatly strengthened by both experimen-
tal and clinical studies demonstrating that rosiglitazone can
attenuate learning and memory deficits in AD [3, 61, 62]. It
is worth noting that PPAR? also transcriptionally induces
IDE expression, which could explain the effectiveness of
PPAR? agonists in treating both type 2 DM and AD .
PPAR?, which is expressed at higher levels in the brain than
PPAR?, also plays a role in regulating lipid and glucose me-
tabolism. In a recent study, treatment with the PPAR? ago-
nist, GW742, reduced amyloid burden, an effect thought to
be mediated by alterations in amyloid clearance . Current
data suggest that insulin and its downstream signaling cas-
cades play an important role in AD pathogenesis. It is un-
clear whether treatments that target insulin signaling demon-
strate efficacy due to direct or indirect mechanisms, because
insulin directly affects the brain and a systemic metabolic
dysfunction is often co-morbid with AD. Nevertheless, these
studies provide convincing evidence that the insulin signal-
ing pathway may be a novel therapeutic target for the treat-
ment of AD.
Leptin and AD
plays a pivotal role in the control of food intake, body
weight, fat storage, immune system function, reproductive
function, insulin sensitivity, and neuronal protection [65-67].
Obesity is associated with leptin resistance/hyperleptinemia
in addition to insulin resistance. Within the central nervous
system, leptin crosses the blood-brain-barrier to bind to spe-
cific receptors in the hypothalamus to mediate food intake,
body weight and energy expenditure . A small number of
studies have begun to outline a potential connection between
abnormal leptin levels and AD. AD patients with significant
weight loss display lower plasma leptin levels than weight-
stable AD patients, and disruption of homeostasis between
Leptin, which is primarily synthesized in adipose tissue,
leptin and cortisol is also observed in some AD patients [69,
70]. In the Framingham study, a landmark longitudinal
study, lower plasma leptin levels were associated with a
higher risk of incident AD, corresponding to an absolute risk
over a 12-year follow-up of 25% for persons in the lowest
quartile versus 6% in the highest . Leptin may be directly
involved in the development of AD symptoms by exerting
effects on the brain, as high expression of leptin receptors are
found in the hippocampus, suggesting that leptin plays a role
in controlling learning and memory. Indeed, leptin has been
shown to be crucial for the maintenance of normal hippo-
campal synaptic plasticity [72, 73]. Impairments in long-term
potentiation in the CA1 region of the hippocampus and poor
spatial memory compared to controls, are noted in leptin
receptor-deficient rodent models, implying an involvement
of leptin and/or its receptor in normal memory function .
If leptin is indeed required for normal hippocampal function,
it stands to reason that it may represent a reasonable thera-
peutic target for AD, a disease in which the hippocampus is
particularly vulnerable. These data indicate that leptin - be-
sides its role in energy regulation - may directly regulate the
behavioral and pathological progression of AD. Leptin is
structurally and functionally similar to a class of signaling
molecules known as proinflammatory cytokines, and it plays
a regulatory role in innate and adaptive immunity . AD
pathogenesis in the brain includes overexpression of cytoki-
nes and upregulation of the innate immune system. Multiple
studies have shown that manipulating leptin levels can ame-
liorate AD pathology by affecting A? plaques. Leptin treat-
ment can promote A? clearance by reducing ?-secretase ac-
tivity and increasing ApoE-dependent A? uptake , and it
also improves memory performance in AD animal models.
Leptin can also reduce tau phosphorylation through inactiva-
tion of GSK-3? . AMP-activated protein kinase (AMPK)
is emerging as a central modulator of the major pathological
hallmarks of AD in the brain, and leptin deficiency in AD
can contribute to down-regulation of the AMPK system,
causing increases in A? and phosphorylated tau [78, 79]. As
leptin appears to play a significant functional role in the pro-
gression of AD, a growing body of evidence supports the use
of leptin-modifying drugs to treat AD. Leptin administration
improves memory in SAMP-8 mice, an accelerated senes-
cence rodent model that develops amyloid plaques .
Chronic leptin treatment has also been shown to significantly
reduce the levels of A? and phosphorylated tau without an
untoward inflammatory reaction in two different transgenic
models of AD [76, 81]. These biochemical and pathological
changes were also correlated with behavioral improvements,
suggesting that leptin not only reduces AD pathology but
also ameliorates cognitive symptoms . Direct administra-
tion of leptin into the brain has been observed to facilitate
hippocampal long-term potentiation and improve memory
performance in mice . Thus, abnormal leptin signaling -
either as a consequence of leptin resistance or secondary to
reduced leptin levels - may be one of the primary mecha-
nisms underlying hippocampal dysfunction in AD. The stud-
ies summarized here suggest that leptin could also serve as a
therapy that increases learning and memory capacity in AD
patients and reduces A? plaques in the brain, while helping
maintain adequate metabolic control.
Metabolic Dysfunction in Alzheimer’s Disease Current Alzheimer Research, 2012, Vol. 9, No. 1 9
Ghrelin and AD
assists in the promotion of sensations of hunger . While
its interactions with the neurons of lateral, paraventricular,
and arcuate nuclei of the hypothalamus to regulate energy
balance and growth hormone release have been well docu-
mented , recent evidence suggests that ghrelin also binds
to and activates the ghrelin receptors expressed on the py-
ramidal neurons of layer V in the sensorimotor area and in
the cingulate gyrus of the cerebral cortex . Furthermore,
studies have demonstrated that ghrelin, in addition to its role
in promoting energy intake, may also affect cognition as
well. Carlini et al. demonstrated that intracerebroventricular
(i.c.v.) injections of ghrelin increased memory retention in
rats . This group also showed that ghrelin potentiates a
dose-dependent increase in memory retention, with the
maximal effect occurring in the hippocampus . It was
recently shown that circulating ghrelin binds to neurons of
the hippocampal formation, promoting dendritic spine for-
mation and generation of long-term potentiation (LTP) .
Targeted disruption of ghrelin signaling resulted in a de-
creased number of spine synapses in the stratum radiatum
and impaired performance in behavioral memory testing,
both of which were rapidly restored by ghrelin administra-
tion . These data strongly support a role for ghrelin sig-
naling in maintaining normal memory function and provide a
motivation for the study of ghrelin regulation in AD. Clinical
studies have indicated a role for ghrelin in various metabolic
disorders as well as AD [88, 89]. Ghrelin levels in the brain
are altered in some Alzheimer’s patients, suggesting that
changes to the ghrelin signaling system may indeed contrib-
ute to AD pathophysiology . Recently, two non-peptide
ghrelin receptor agonists (GSK894490A and CP-464709-18)
were shown to significantly improve performance in the
novel object recognition and modified water maze tests in
male Lister hooded rats, indicating the potential of ghrelin
for treating cognitive dysfunction . These studies suggest
that ghrelin plays a vital role in not only regulating metabolic
control, but also in regulating cognitive function and mem-
ory capacity, and that abnormal ghrelin signaling could be
caused by, and/or worsen AD and its symptomology [92,
Ghrelin is a hormone produced by the stomach which
Adiponectin and AD
by adipose tissue, is a hormone that plays a role in regulating
insulin sensitivity and energy expenditure . Targeted
deletion of the adiponectin gene can lead to insulin resistance
, and continuous systemic infusion of adiponectin can
enhance insulin sensitivity in type 2 diabetic mice . Adi-
ponectin abnormalities have been implicated in various
metabolic disorders [97-99], all of which could also act as
risk factors for the development of AD . Recent studies
have shown that the adiponectin receptors AdipoR1 and
AdipoR2 are expressed throughout the central nervous sys-
tem (CNS) . However, there is still some debate about
whether adiponectin crosses the blood-brain-barrier or not
[102, 103]. Few studies to date have focused on a potential
correlation between adiponectin and AD. Recently, one
clinical study demonstrated that some AD patients have ele-
vated levels of adiponectin in both plasma and cerebrospinal
Adiponectin, the most abundant adipocytokine secreted
fluid (CSF) , suggesting that it may play a role in medi-
ating AD progression, possibly through its effects on periph-
eral or brain metabolism. It is also noteworthy that elevated
interleukin-6 has been detected in the brains of some AD
patients [105, 106], and that treatment with adiponectin can
reduce the secretion of the centrally active interleukin-6 from
brain endothelial cells . Due to its relatively recent dis-
covery, there are currently no known clinical trials of adi-
ponectin modifying drugs related to AD therapy. However, it
is likely that adiponectin system-targeted compounds could
offer potential as therapeutic targets for the metabolic com-
ponent of AD due to its well documented role in diabetes and
other metabolic disorders [99, 107].
Glucagon-Like Peptide 1 and AD
islet beta-cell proliferation and glucose-dependent insulin
secretion, lowers blood glucose and food intake, and is an
effective incretin-based therapy for type 2 DM . GLP-1
and its cognate receptor are both expressed throughout the
brain and stimulation of this system appears to be neuropro-
tective and can reduce neuronal degeneration in various ani-
mal models [4, 109, 110]. A body of literature suggests the
potential therapeutic relevance of GLP-1 to CNS disorders
such as AD . GLP-1 and exendin-4, a natural and stable
long-acting analogue of GLP-1, possess neurotrophic proper-
ties and protect neurons against A? and oxidative insults
. GLP-1 can reduce amyloid-beta peptide levels in vivo
and decreases levels of amyloid precursor protein in cultured
neuronal cells, implying that GLP-1 could be effective at
reducing plaque load in AD . In addition, GLP-1 recep-
tor agonists protect neurons against A? and glutamate-
induced apoptosis in cells and attenuate cholinergic neuron
atrophy in the basal forebrain of the rat following an excito-
toxic lesion . A recent study using GLP-1 receptor
knock-out mice demonstrated that GLP-1 receptor signaling
can play an important role in the control of synaptic plastic-
ity . The novel GLP-1 analogue (Val8(GLP-1)) has also
been shown to enhance synaptic plasticity and to reverse the
impairment of long-term potentiation (LTP) induced by A?
fragments, further strengthening the hypothesis that GLP-1
may be useful for treating AD . Other stable GLP-1
analogues such as Liraglutide, Asp7GLP-1, N-glyc-GLP-1,
and Pro9GLP-1 were recently found to have facillitatory ef-
fects on LTP by the same group . Additionally, the
novel long-acting GLP-1 analogue GLP-1/Tf (GLP-1 fused
to transferrin) potentially also shows promise for the treat-
ment of metabolic dysfunction in AD . Attenuation of
the activity levels of dipeptidyl peptidase 4 (DPP-4, the en-
zyme that cleaves and inactivates GLP-1), can stabilize the
plasma levels of the bioactive GLP-1. A recent study has
demonstrated that sitagliptin, a DPP-4 inhibitor, could sig-
nificantly delay some forms of AD pathology, including
amyloid deposition, when administrated early in the disease
course in a mouse model of AD .
Glucagon-like peptide 1 (GLP-1) enhances pancreatic
Brain-Derived Neurotrophic Factor and AD
tein, is a member of the family of neutrophins . Besides
its well-established roles in neuronal development, neuronal
maintenance and survival as well as promoting synaptic plas-
Brain-derived neurotrophic factor (BDNF) a 13-kDa pro-
10 Current Alzheimer Research, 2012, Vol. 9, No. 1 Cai et al.
ticity, BDNF also plays a considerable role in regulating
global metabolic function. BDNF deficiency in rodents leads
to hyperphagia, obesity, hyperinsulinemia, and hyperlepti-
nemia [120, 121]. There is also evidence that BDNF defi-
ciency in humans can lead to metabolic dysfunction .
BDNF signaling has been shown to be impaired in AD,
which could be relevant considering the neurological and
metabolic abnormalities noted in AD. Studies have demon-
strated low brain BDNF mRNA expression in patients with
AD, including the hippocampus , neocortex and in the
nucleus basalis of Meynert [124-126]. A recent study on the
role of BDNF in AD investigated the sorting protein-related
receptor with A-type repeats (SORLA). SORLA regulates
APP intracellular trafficking and processing into A?, and
when overexpressed, can reduce amyloid plaque formation
[127, 128]. BDNF was found to be a major inducer of
SORLA gene transcription through the extracellular regu-
lated kinase (ERK) pathway . Circulating plasma
BDNF levels have been shown to associate with multiple
cardiovascular markers of age-related pathophysiology and
also to significantly decrease with age , and it is there-
fore possible that a gradual decrease in BDNF levels may
contribute to the increase in the risk of developing AD with
METABOLIC DYSFUNCTION IN HUNTINGTON’S
disorder that affects approximately 5-7 individuals per
100,000 . The disease is characterized by progressive
chorea, dystonia, cognitive dysfunction and psychiatric and
behavioral symptoms . Individuals with HD usually
become symptomatic between the fourth and fifth decades of
life and invariably die from complications of the disease
within one to two decades after initial diagnosis . The
neuropathologic hallmarks of HD include severe cell loss
and atrophy in the caudate and putamen . The underly-
ing genetic defect in HD is the presence of expanded repeats
of the trinucleotide CAG in exon 1 of the HD gene, which
encodes for the protein huntingtin . Huntingtin (htt) is
expressed ubiquitously in mammalian cells but its specific
functions are not fully understood. Htt is believed to influ-
ence a number of cellular functions, including BDNF expres-
sion, vesicle trafficking, axonal transport and transcriptional
regulation [136-139]. The genetic defect that leads to the
development of HD causes the formation of a mutant form of
huntingtin, which contains polyglutamine expansions that
make the protein more susceptible to a pathological prote-
olysis process that generates cytotoxic amino-terminal htt
fragments and also promotes subsequent aggregation of the
remaining htt protein . Aggregates of mutant huntingtin
appear to be neurotoxic, as they interfere with the normal
function of several nuclear and cytoplasmic proteins that
regulate transcription, apoptosis, mitochondrial function and
axonal transport [141-144]. Postmortem brains of HD pa-
tients demonstrate reduced BDNF levels in the caudate and
putamen, whereas wild-type htt stimulates BDNF gene tran-
scription through promoter II activation [145-147]. In the
presence of mutant htt, a transcriptional repressor inhibits
BDNF gene transcription [146, 148]. In addition, as men-
tioned above, mutant htt may also interfere with BDNF vesi-
Huntington’s disease is an autosomal dominant genetic
cle transport . Mutant htt aggregates are also found out-
side of the central nervous system, and animal studies sug-
gest that these aggregates can cause cell toxicity in periph-
eral organs as well. For example, in the R6/2 and N171-82Q
mouse models of HD, mutant htt aggregates are present in
pancreatic islet cells [150, 4], and these HD mice display
decreased pancreatic beta-cell mass and exhibit impaired
HD and Body Weight
[151-153]. Patients with clinical HD and presymptomatic
gene carriers typically have a lower BMI than control sub-
jects . Although poor dietary intake from severe
dysphagia can occur in HD, weight loss is common in pa-
tients who have an intact appetite and high caloric intake
[155, 156]. Total energy expenditure is higher in HD patients
compared to controls, which in part reflects their present
hyperkinetic state (chorea and dystonia) [157-159]. While
hyperkinesis appears to be an important contributing factor,
it does not entirely account for all weight loss observed in
HD. A cross-sectional study of individuals with early-stage
HD showed that BMI was significantly lower in HD patients
than control subjects and that neither disease duration,
dystonia, nor chorea scores were significantly associated
with BMI . If indeed hyperkinesis is not a sine qua non
for weight loss in HD, it has been speculated that HD pa-
tients experience increased energy expenditure, secondary to
a hypermetabolic state. A recent study demonstrated that
clinically unaffected individuals with a CAG repeat length
greater or equal to 37 required an increased caloric intake to
maintain their BMI compared to individuals with less than
37 CAG repeats , suggesting a deficit in energy homeo-
stasis not accounted for by excessive motor activity. In addi-
tion, among a group of 517 patients with early stage HD fol-
lowed for 3 years, a higher CAG repeat number was associ-
ated with a lower initial mean BMI and faster rate of BMI
decline . Increasing numbers of CAG repeats correspond
to increased disease severity, indicating more substantial
aggregation of mutant htt in central and peripheral organs
involved in energy regulation. Post-mortem studies in HD
patients have demonstrated neuronal loss in regions of the
hypothalamus involved in energy balance, including both the
paraventricular and ventromedial nuclei. Although the hypo-
thalamus plays an important role in energy regulation, attrib-
uting a high rate of energy expenditure to the presence of
aggregates in the hypothalamus is too simplistic. Direct dele-
terious effects of mutant htt on peripheral tissues are likely to
contribute to the dysregulation of the energy balance system.
Abnormalities in key metabolic tissues such as adipose tissue
[161, 162], pancreas [163, 164], and skeletal muscle [165,
166] have all been described in mouse models of HD. Fur-
thermore, Mochel et al. demonstrated that HD patients with
weight loss have lower levels of the branched chain amino
acids, valine, leucine, and isoleucine, suggesting a critical
need for Krebs cycle energy substrates , and reflecting
mitochondrial dysfunction. Additionally, Popovic et al.
found high plasma ghrelin and low plasma leptin in HD pa-
tients (~ 6 years of disease duration) compared with healthy
controls, indicating a state of negative energy balance .
Low leptin levels have also been noted in a mouse model of
Weight loss is a well-recognized manifestation of HD
Metabolic Dysfunction in Alzheimer’s Disease Current Alzheimer Research, 2012, Vol. 9, No. 1 11
HD , suggesting that metabolic hormones are an important
aspect of the energy dysregulation observed in HD.
HD and Altered Glucose Homeostasis
increased risk for the development of type 2 DM . In
one study, seven out of 14 patients with documented HD
demonstrated an abnormal response in standard glucose tol-
erance tests . Additionally, some HD patients with
normal glucose tolerance can still display an increase in insu-
lin resistance . Glycosuria and glucose intolerance de-
velop in mouse models of HD beginning as early as 9 weeks
and as mentioned above, these mice also express mutant htt
aggregates in the pancreas, implying that mutant htt pathol-
ogy can also mediate metabolic dysfunction . Therefore
it has been suggested that an effective treatment for HD
should target the symptoms that affect the entire body, in-
cluding the loss of motor coordination and dysglycemia
. In addition to directly impairing insulin secretion due
to the formation of aggregates in the pancreas, mutant htt
may also affect insulin resistance via pathophysiological
functionality of the hypothalamus . Blockade of hypotha-
lamic insulin receptors by phosphoinositide 3-kinase inhibi-
tors leads to hepatic insulin resistance and increased hepatic
glucose production, implying that the hypothalamus is nec-
essary for normal insulin signaling . Martin et al. dem-
onstrated that treatment with insulin failed to correct hyper-
glycemia, although treatment with exendin-4, a drug com-
monly used for the treatment of type 2 DM, improved the
glycemic profile and reduced mutant huntingtin aggregates
in both the brain and pancreas, while also prolonging
lifespan in a mouse model of HD . These findings suggest
that targeting the peripheral metabolic dysfunction observed
in HD could be beneficial for treating some aspects of this
disorder, and further support the notion that new treatments
that target the entire body - rather than just the CNS – are
likely to be more effective for treating HD.
Studies have found an association between HD and an
METABOLIC DYSFUNCTION IN PARKINSON’S
ment disorder, only slightly less prevalent than AD, that usu-
ally affects individuals in their sixth decade of life .
Classical PD symptoms include bradykinesia, resting tremor,
rigidity, and gait instability. Pathologically, PD is character-
ized by a profound neuronal loss in the pars-compacta of the
substantia nigra. In addition, in PD there is often an accumu-
lation of ubiquinated protein deposits in the cytoplasm of
neurons (Lewy bodies) and neurites (Lewy neurites), usually
containing aggregates of the protein ?-synuclein [175-177].
Low levels of BDNF have been observed in the substantia
nigra pars compacta of PD patients compared to controls and
experimentally, two pathogenic mutations linked to ?-
synuclein have been associated with a loss of BDNF synthe-
sis in rodents [124, 178]. Furthermore, mice with a condi-
tional deletion of BDNF in the midbrain and hindbrain have
been shown to exhibit reduced numbers of dopaminergic
neurons in the substantia nigra , indicating that BDNF
is necessary for normal development of those neurons.
Parkinson’s disease (PD) is a neurodegenerative move-
PD and Body Weight
general, individuals with PD possess a lower BMI than age-
matched controls [180, 181]. PD patients lose weight in the
years preceding their diagnosis and continue to lose weight
thereafter . While impaired hand-mouth coordination,
dysphagia, and hyposmia have been listed as contributing
factors, there is some debate over whether decreased energy
intake is a significant contributor to the weight loss observed
in PD [182, 183]. Levi et al. and Markus et al. observed an
increased resting energy expenditure in PD patients, com-
pared to healthy controls, using indirect calorimetry [184,
185]. However Toth et al. reported a lower daily energy ex-
penditure in PD patients using double-labeled water tech-
nique . A recent study using double-labeled water to
measure daily energy expenditure in PD patients displaying
weight loss or a stable-weight found no significant energetic
difference between the two groups . Unlike AD, obesity
is not considered to be a risk factor for PD development
[187, 188]. However, at least one study reported that in a
cohort of over 10,000 men, subjects who lost at least 0.5
units of BMI in the decade following college entry had a
significantly increased risk of developing PD compared with
individuals with stable weight. It is unclear however if the
weight loss during young adulthood seen in the study repre-
sented an early manifestation of PD. Leptin tends to be low
in PD patients who experience weight loss, which may re-
flect a decrease in body fat. Evidente et al. found a trend
towards low plasma leptin levels in PD patients with unin-
tended weight loss . These results were corroborated by
another study that demonstrated that PD patients who lost
body weight possessed lower serum leptin levels than
weight-stable PD patients . In addition to lower plasma
leptin levels, lower plasma ghrelin levels were also noted in
PD patients who experienced weight loss . While low
plasma leptin is expected to accompany loss of body fat, the
finding of low plasma ghrelin is less intuitive and warrants
further investigation. A recent study showed that peripheral
ghrelin is neuroprotective for nigrostriatal dopamine function
through activation of UCP2-dependent alterations in mito-
chondrial respiration . Additionally, ghrelin or ghrelin
receptor knockout mice are more susceptible to dopaminer-
gic neuron loss in the substantia nigra and striatum after
MPTP treatment, suggesting that abnormal ghrelin signaling
may represent a predisposing factor for nigrostriatal dopa-
Weight loss is a well-recognized manifestation of PD. In
PD and Altered Glucose Homeostasis
glycemia and abnormal glucose tolerance in patients with PD
[193, 194]. However, there is some debate regarding a direct
association between PD and type 2 DM. One large epidemi-
ologic study, which utilized the UK-based General Practice
Research Database (GPRD) which contains computerized
medical records of over 5 million people, found that the
prevalence of diabetes was similar in patients with and with-
out PD. Furthermore, the study concluded that the risk of
developing diabetes was lower in PD patients than in sub-
jects without PD . A second major epidemiological
Recent studies have demonstrated the presence of dys-
12 Current Alzheimer Research, 2012, Vol. 9, No. 1 Cai et al.
study, the Physician’s Health Study, which includes a cohort
of U.S. male physicians, indicated that although individuals
with diabetes had an increased risk of developing PD, the
highest risk was found in individuals with short-duration,
older-onset diabetes without complications. Thus, it is pres-
ently unclear whether diabetes increases the likelihood of
developing PD and further studies are therefore needed to
investigate a potential link. There is also some evidence for
abnormal insulin signaling in PD. Although insulin receptors
are normally abundant in the substantia nigra, some PD pa-
tients display a loss of insulin receptors in this brain region
[196, 197]. In rat models with streptozotocin-induced diabe-
tes, low levels of insulin have been associated with de-
creased amounts of dopamine transporter mRNA and tyro-
sine hydroxylase mRNA in the substantia nigra .
Moreover, increased insulin receptor substrate-2 phosphory-
lation, a sign of insulin resistance, has been observed in the
dopamine-depleted striatum in PD .
age-dependent, but accelerated, manner. All of these disor-
ders display accumulation of products of oxidative reactions
which lead to wide-spread lipid and protein damage .
These neurodegenerative disorders mimic advanced aging on
multiple levels, including cognitive and motor decline as
well as molecular signaling defects such as impaired insulin
signaling. It is striking that all three disorders display a
metabolic dysfunction phenotype in conjunction with a neu-
rodegenerative pathology. While damage to the hypothala-
mus via abnormal protein aggregates, such as mutant htt or
A? plaques, may be part of the cause of energy dysregula-
tion, hypothalamic disease on its own does not explain the
whole process entirely. A more complete and acceptable
hypothesis that explains the metabolic changes combined
with neuronal damage in these diseases includes a descrip-
tion of a disrupted connection between peripheral organs that
manage energy regulation and the CNS through alterations in
leptin, ghrelin, GLP-1 and insulin signaling. Although these
metabolic hormones are traditionally thought to be involved
primarily in metabolic disorders, it is now clear, as discussed
above, that alterations in these hormones can have severe
implications for the etiology of several prominent neurode-
generative disorders. Furthermore, it is also clear that thera-
peutic targets that manipulate these metabolic factors are
showing promise for the treatment of neurodegenerative dis-
orders (see Fig. 1 for overview). Current research is starting
to suggest that successful treatments for neurodegenerative
disorders should ideally target the whole body, rather than
focusing on the CNS alone. It is likely that multiple endocri-
nological factors play a combinatorial role in facilitating AD,
HD, and PD pathophysiology; hence, studies that attempt to
understand the overall effects of the combination of these
hormones, rather than just the individual, are necessary
. It is important to note that many animal studies are
confounded by a series of factors, including housing condi-
tions and diet, that can make these subjects more prone to
developing metabolic dysfunctions and cause challenges in
ascertaining whether the metabolic phenotype is associated
with the disease progression or with the animal’s lifestyle
. In order to better understand disease processes and bet-
AD, PD and HD all represent diseases that progress in an
ter serve patients, we must attempt to design studies that look
into combinatorial effects of metabolic hormones and neu-
ronal signaling molecules in accurate animal models, allow-
ing us to characterize and discover the potential that meta-
bolic factors hold, in treating both metabolic disorders and
various neurodegenerative diseases.
CONFLICT OF INTEREST
Program of the National Institute on Aging, National Insti-
tutes of Health. The authors have no conflicts of scientific
interest with respect to the manuscript.
This research was supported by the Intramural Research
A? = Beta-amyloid
AD = Alzheimer’s disease
AMP-activated protein kinase
APP = Amyloid precursor protein
Brain-derived neurotrophic factor
Body Mass Index
CNS = Central nervous system
DPP4 = Dipeptidyl peptidase-4
Extracellular regulated kinase
Glucagon-like peptide 1
= General Practice Research Database
Glycogen synthase kinase-3?
Huntington’s disease =
htt = Huntingtin
Insulin degrading enzyme
Insulin-like growth factor-1
LRRK2 = Leucine-rich repeat kinase 2
NFTs = Neurofibrillary tangles
PPARs = Peroxisome proliferator-activated receptors
ROS = Reactive oxygen species
Metabolic Dysfunction in Alzheimer’s Disease Current Alzheimer Research, 2012, Vol. 9, No. 1 13
SORLA = Sorting protein-related receptor with A-type
Ubiquitin carboxy-terminal hydrolase L1
Uncoupling protein 2 =
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Received: February 07, 2011 Revised: July 17, 2011 Accepted: August 09, 2011