Review

Changes in insulin and insulin signaling in Alzheimer’s

disease: cause or consequence?
Molly Stanley, Shannon L. Macauley, and David M. Holtzman

Department of Neurology, Hope Center for Neurological Disorders, Charles F. and Joanne Knight Alzheimer’s Disease Research Center, Washington University School
of Medicine, St. Louis, MO

I ndividuals with type 2 diabetes have an increased risk for developing Alzheimer’s disease (AD), although the causal relation-
ship remains poorly understood. Alterations in insulin signaling (IS) are reported in the AD brain. Moreover, oligomers/fibrils
of amyloid-β (Aβ) can lead to neuronal insulin resistance and intranasal insulin is being explored as a potential therapy for

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AD. Conversely, elevated insulin levels (ins) are found in AD patients and high insulin has been reported to increase Aβ levels
and tau phosphorylation, which could exacerbate AD pathology. Herein, we explore whether changes in ins and IS are a cause
or consequence of AD.
The Journal of Experimental Medicine

Alzheimer’s disease (AD) is a devastating neurodegenera- One such risk factor for LOAD, which has received
tive disorder affecting roughly 30 million people worldwide. considerable attention is type 2 diabetes (T2D), which in-
Although some cases of AD (<1%) are caused by autoso- creases AD risk by at least twofold (Sims-Robinson et al.,
mal-dominant inherited mutations that typically lead to clin- 2010). Also a disease of aging, T2D is characterized by hy-
ical disease onset before the age of 60, the majority of AD is perglycemia, hyperinsulinemia, and insulin resistance (a lack
late-onset AD (LOAD) where age, genetics, environment, and of response in the insulin signaling [IS] pathway). Normally,
other diseases likely play a role (Holtzman et al., 2011; Musiek insulin binds to the insulin receptor (IR) which phosphor-
and Holtzman, 2015). AD is characterized by a cascade of ylates IR substrate (IRS) on a tyrosine residue, leading to
pathological events, including the formation of amyloid activation of the canonical signaling cascade (Fig. 1). In pe-
plaques (made up of aggregated forms of Aβ), neurofibril- ripheral tissues, such as muscle, fat, and liver, this signaling
lary tangles (composed of aggregated, hyperphosphorylated ultimately leads to the uptake and sequestration of glucose
tau), synapse loss, brain hypometabolism, neuroimflammation, to satisfy cellular energy requirements and plays a key role
and brain atrophy that is accompanied by severe and pro- in lipid metabolism (Dimitriadis et al., 2011). Contrary to
gressive cognitive impairment. Amyloid plaques, consisting of the periphery, where glucose uptake is largely insulin depen-
aggregated forms of Aβ in the extracellular space, are gen- dent, the brain uses nearly 20% of all glucose in the body in
erated in a concentration-dependent manner. The buildup a process that is largely insulin independent. However, brain
of hyperphosphorylated and aggregated tau protein leads to IS is robust and has pleotropic effects due to the widespread
the development of intracellular neurofibrillary tangles. Ac- distribution of IRs throughout the brain and the complexity
cumulation of Aβ occurs ∼15 yr before patients experience of IR signaling. For example, hippocampal activation of IR
cognitive decline, whereas tau begins to accumulate in the signaling can modulate memory (McNay et al., 2010) and
neocortex later but before the onset of dementia, adding to IR signaling in the hypothalamus can affect feeding behavior
the complexity of this disease. Many risk factors for LOAD, and peripheral metabolism (Brief and Davis, 1984). Similar
both genetic and nongenetic, have been identified. Apart from to AD, pathological changes in insulin occur years before pa-
aging, the strongest known risk factor for LOAD is genetic tients receive a diagnosis of T2D, which typically occurs once
variation in the apolipoprotein E (APOE) gene. The APOE4 pancreatic β cell dysfunction and insulin resistance produce
allele increases AD risk by 12-fold (two copies) or 3.7-fold chronic hyperglycemia (Dankner et al., 2009). Interestingly,
(one copy) in part by influencing Aβ accumulation. However, T2D alone has been associated with cognitive decline (Allen
APOE4 is only present in ∼50–60% of individuals with AD, et al., 2004), brain hypometabolism (Roberts et al., 2014), and
suggesting that other factors are involved in AD pathogenesis regional brain atrophy (Last et al., 2007). The cognitive defi-
(Holtzman et al., 2011). cits in T2D are proposed to be mediated by changes in brain
IS (McNay and Recknagel, 2011), although there is little data
from T2D patients measuring insulin/IS in the CNS to sup-
Correspondence to David M. Holtzman: holtzman@neuro.wustl.edu port this assertion (Liu et al., 2011).
Abbreviations used: Aβ, amyloid β; AD, Alzheimer’s disease; APOE, apolipoprotein E;
© 2016 Stanley et al. This article is distributed under the terms of an Attribution–Noncommercial–Share
APP, amyloid precursor protein; CSF, cerebrospinal fluid; GSK3, glycogen synthase
Alike–No Mirror Sites license for the first six months after the publication date (see http​://www​.rupress​.org​
kinase 3; ins, insulin level; IR, insulin receptor; IRS1, IR substrate 1; IS, insulin signaling; /terms). After six months it is available under a Creative Commons License (Attribution–Noncommercial–
LOAD, late-onset AD; p-tau, phosphorylated tau; T2D, type 2 diabetes. Share Alike 3.0 Unported license, as described at http​://creativecommons​.org​/licenses​/by​-nc​-sa​/3​.0​/).

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www.jem.org/cgi/doi/10.1084/jem.20160493
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Figure 1. Canonical IR signaling cascade. Insulin binds to the insulin receptor (IR), a receptor tyrosine kinase, which autophosphorylates and activates a
cascade of phosphorylation events. IRS1 is phosphorylated on a tyrosine residue to activate further signaling, which ultimately leads to the translocation of
glucose transporter 4 (GLUT4) to the membrane and uptake of glucose for energy in peripheral tissues. Solid arrows represent activation upon insulin stim-
ulation. Blocked arrows represent inhibition. Glycogen synthase kinase 3 (GSK3) is serine phosphorylated and inhibited in response to insulin stimulation.
Dashed arrows represent downstream effectors that have been found to phosphorylate IRS1 on a serine residue (p(Ser)-IRS1), which is thought to lead to
less activation of the signaling cascade through negative feedback (dashed blocked arrow). p(Ser)-IRS1 is a marker of insulin resistance.

There are two broad ways in which T2D could influ- treatment may lead to modest cognitive improvement in AD
ence the risk of AD: (1) T2D can lead to small vessel disease, patients, it could also worsen underlying pathology. In this
which can cause or contribute to dementia, independent of review, we will analyze the changes in ins/IS that have been
or together with AD pathology, by disrupting proper function reported in AD and speculate if they are a cause or conse-
of the brain vasculature (Biessels and Reijmer, 2014), and (2) quence of disease based on experimental evidence and the
T2D can result in changes of brain function directly or in- timeline of AD progression. Critical evaluation of this liter-
teract with key proteins or pathways involved in AD pathol- ature as well as a determination of essential future experi-
ogy, such as Aβ or tau. This review will focus on mechanisms ments is crucial, as rates of both T2D and AD are on the rise
specific to AD pathology, but acknowledges the significant and insulin therapy is actively being pursued worldwide in
impact that vascular alterations may have on the brain in older adults and patients.
AD and other dementias.
Over the past 15 yr, many studies have reported changes INS​ULIN-REL​ATED CHA​NGES IN AD
in insulin levels (ins) or IS (ins/IS) in LOAD patients (Table 1), Brain insulin.Many groups have analyzed postmortem brain
suggesting that individuals with AD experience hyperinsulin- tissue from AD patients of varying severity and controls to
emia and brain insulin resistance. One interpretation is that look for alterations in Ins/IS through changes in mRNA,
the brain becomes insulin resistant as a consequence of AD protein, or phosphorylation (Table 1). Insulin has been mea-
pathology and hyperinsulinemia is compensatory, producing sured in relatively low levels in brain tissue of humans and ro-
what has been termed type 3 diabetes (Steen et al., 2005). dents (Banks et al., 1997; Frölich et al., 1998). Only one study
Insulin resistance in the AD brain may lead to cognitive im- reports insulin levels in the AD brain. They found that brain
pairment, similar to that observed in T2D patients, therefore insulin was equally reduced in AD patients and age-matched
treating individuals with AD with intranasal insulin to im- controls, indicating that reductions in brain insulin are likely a
prove memory is currently under investigation in clinical result of age, not AD (Frölich et al., 1998).Two other groups
trials (Reger et al., 2008; Craft et al., 2012; Wadman, 2012). report reductions in insulin mRNA in AD (Rivera et al.,
Conversely, hyperinsulinemia and insulin resistance can mod- 2005; Steen et al., 2005), yet questions remain as to whether
ulate Aβ and tau in ways that can put the brain at risk to insulin is synthesized in the brain to an appreciable level be-
develop further AD pathology, so that changes in the ins/IS cause there is evidence that a majority of brain insulin comes
in AD patients may represent a contributor/cause of disease from the blood (Banks, 2004). Specifically, one study could
progression (Fig. 2). If so, increasing brain insulin could ex- not detect insulin mRNA in the cortex (Steen et al., 2005)
acerbate AD pathology and cognitive decline over time. This but another did (Rivera et al., 2005), making this mRNA
proposes a unique problem as it relates to AD; whereas insulin data difficult to interpret. Ultimately, a greater understand-

1376 Insulin signaling in Alzheimer’s disease | Stanley et al.

ing of insulin in the brain relative to the severity of AD and found no differences (Moloney et al., 2010; Liu et al., 2011;
age-matched controls needs to be obtained in order to fully Ho et al., 2012; Talbot et al., 2012). The most convincing,
comprehend insulin’s function in healthy and diseased brains. consistent change in IS is a lower level of IR substrate 1
(IRS1) and higher p(Ser)-IRS1, a marker of insulin resistance,
Brain IS.IRs are widely distributed throughout the brain, in AD brains (Steen et al., 2005; Moloney et al., 2010; Bom-
with relatively high concentrations in the olfactory bulb, hy- fim et al., 2012; Talbot et al., 2012; Yarchoan et al., 2014).
pothalamus, and hippocampus (Fernandez and Torres-Alemán, Higher p-JNK, which can lead to p(Ser)-IRS1, has also been
2012). IRs are largely localized to neurons (Unger et al., found in AD brains (Bomfim et al., 2012; Talbot et al., 2012),
1989), although IR mRNA is present in glia and endothelial suggesting some level of insulin resistance in AD. Questions
cells (Zhang et al., 2014). Although alterations in IR levels still remain as to what are the physiological and pathological
(Frölich et al., 1998; Steen et al., 2005) and its phosphoryla- implications of increased markers such as p(Ser)-IRS1 and
tion (Steen et al., 2005) are reported in AD, other studies p-JNK and how that relates to AD pathology and brain function.

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Table 1. Insulin-related changes in AD
Parameter AD ↑ ↓ Study Details

Blood insulin ↑ Bucht et al., 1983; Fujisawa et al., -Fasting or after glucose tolerance test -In women only (1 study) -Only in non-APOE4 and
1991; Stolk et al., 1997; Craft moderate/severe AD (1 study) -Meta-analysis of 11 studies: 5 report overall ↑, 1 ↑ in
et al., 1998; Ma et al., 2016 women, 1 ↑ with advanced stage (Ma et al., 2016)
CSF insulin ↑ Fujisawa et al., 1991 -Also found small increase with vascular dementia
↓ Craft et al., 1998; Gil-Bea et al., -Only in non-APOE4 and moderate/severe AD -No relationship to APOE or AD severity
2010
No change Molina et al., 2002 -No relationship with AD severity or cognition
Brain insulin No change Frölich et al., 1998 -Comparing controls >65 y/o and AD patients
↓ Frölich et al., 1998; Rivera et al., -Comparing controls <65 y/o and AD patients -mRNA: in hippocampus and hypothalamus
2005; Steen et al., 2005 -mRNA: progressive reduction with Braak stage
Brain IR (total) ↓ Frölich et al., 1998; Rivera et al., -Comparing controls <65 y/o and AD patients -mRNA and protein -mRNA: progressive
2005; Steen et al., 2005 reduction with Braak stage
↑ Frölich et al., 1998 -Comparing controls >65 y/o and AD patients
No change Moloney et al., 2010; Liu et al., -Potential changes in cellular distribution -Also no change in p-IR -Only reduced in patients
2011; Ho et al., 2012; Talbot et with T2D and AD
al., 2012
Brain p-IR and activity ↓ Frölich et al., 1998; Rivera et al., -In hippocampus -Reduced insulin binding -TK activity reduced compared to all controls
2005; Steen et al., 2005
Brain IRS1 (total) ↓ Steen et al., 2005; Moloney et -mRNA in 3 regions -Also reductions in IRS2
al., 2010
No change Liu et al., 2011; Talbot et al., 2012 -Also no change in IRS2 -Only reduced in patients with T2D and AD
Brain p(Ser)-IRS1 ↑ Moloney et al., 2010 Talbot et -Regardless of APOE status and reduced ex vivo insulin stimulation -Highest in AD, but also
al., 2012 Bomfim et al., 2012 elevated in some tauopathies
Yarchoan et al., 2014
Brain AKT (total) ↓ Griffin et al., 2005; Liu et al., 2011 -Reduced in AD and in patients with T2D and AD
No change Steen et al., 2005; Talbot et al.,
2012
Brain p-AKT ↑ Pei et al., 2003; Griffin et al., -Associated with tangles
2005; Talbot et al., 2012;
Yarchoan et al., 2014
↓ Steen et al., 2005 -In hippocampus
No change Liu et al., 2011 -Only reduced in patients with T2D and AD
Brain GSK3 (total) ↓ Ho et al., 2012 -With advanced AD
No change Steen et al., 2005; Liu et al., 2011; -Only reduced in patients with T2D or T2D and AD
Talbot et al., 2012
Brain p(Ser)-GSK3 ↓ Steen et al., 2005 Griffin et al., -In hippocampus
2005
No change Liu et al., 2011 -Only reduced in patients with T2D or T2D and AD
Brain p-GSK3 ↑ Pei et al., 2003 -Associated with tangles
Brain p-JNK ↑ Bomfim et al., 2012; Talbot et
al., 2012
Other IR signaling ↓ Griffin et al., 2005; Liu et al., 2011; -PDK1, p-PDK1 and p-PI3K -PIP3, PKC, p-mTOR, p-ERK2 -PTEN
molecules Talbot et al., 2012

Reported alterations in ins and brain IS in AD are categorized by the specific component measured, whether there have been reports of an increase, decrease (up and down arrows), or no
change in individuals with AD, the studies that report this specific alteration, and important details. For blood and CSF insulin, AD diagnosis was based on clinical criteria. For postmortem
analysis of brain insulin and IS components, AD was confirmed by clinical diagnosis and histological analyses. All reported changes were at the protein level unless mRNA is specified in the
details. Overall, data from this table supports a higher level of blood insulin in individuals with AD and some degree of brain insulin resistance.

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Figure 2. Connections between T2D and AD: cause or consequence? Big picture questions that need to be addressed to determine if insulin-related
changes represent a cause or consequence of AD. In regards to the evidence that T2D increases the risk of AD, answering the questions in the top arrow
will determine how and why T2D is a risk factor and the potentially causal role of insulin/IS. In regards to the idea that AD progression may lead to a dia-
betic phenotype, answering the questions in the bottom arrow will determine if and how AD pathology may affect insulin homeostasis and the potential
consequences of these changes on cognition.

Canonical IS posits that, upon activation of AKT by in- brain are seen as detrimental, mouse studies have paradoxi-
sulin, glycogen synthase kinase 3 (GSK3) is serine phosphor- cally shown that deleting IRs or IGF1 receptors in the brain
ylated to reduce its activity. Active GSK3 phosphorylates tau is protective against amyloid plaque deposition (Freude et al.,
among other substrates, suggesting that overly active GSK3 2009; Stöhr et al., 2013) and improves survival (Freude et
may exacerbate tau phosphorylation and, ultimately, its aggre- al., 2009), demonstrating that there is much left to elucidate
gation. In postmortem brain samples, there are reductions in about the physiological consequences of reduced insulin or
p-AKT and p(Ser)-GSK3, suggesting increased GSK3 activity, IGF1 signaling in the brain.
which can lead to tau phosphorylation (Steen et al., 2005;
Liu et al., 2011). In contrast, other groups report increases in Blood and cerebrospinal fluid (CSF) insulin.Studies reported
p-AKT and p(Ser)-GSK3, even in the presence of elevated alterations in blood insulin in AD as early as 1983 (Table 1).
phosphorylated tau (p-tau) and tangles (Pei et al., 2003; Grif- Fasted blood insulin or insulin in response to a glucose chal-
fin et al., 2005; Yarchoan et al., 2014), making this particular lenge are higher in AD patients (Bucht et al., 1983; Fujisawa
signaling component difficult to interpret. Reductions in the et al., 1991; Stolk et al., 1997; Craft et al., 1998; Ma et al.,
level or phosphorylation of other IS molecules are reported 2016). The transport of insulin from blood to brain and CSF
in AD brains (Liu et al., 2011; Talbot et al., 2012) and ex vivo is a receptor-mediated process. This transport is saturable
activity assays have shown that tyrosine kinase activity, insu- within physiological levels and is affected by numerous vari-
lin binding, and insulin stimulation are reduced in AD brains ables (Banks, 2004).The CSF/serum insulin ratio is subtly de-
(Frölich et al., 1998; Rivera et al., 2005; Talbot et al., 2012). creased with age (Sartorius et al., 2015). Craft and colleagues
Overall, there does appear to be some level of insulin re- also found the CSF/serum insulin ratio to be lower in AD,
sistance in the AD brain. However, this is not specific to insu- where higher blood and lower CSF insulin was more prom-
lin, as there are also reductions in both the levels and signaling inent with disease progression. Interestingly, they only found
of insulin-like growth factor (IGF) I and II (Steen et al., 2005; this change in AD patients without an APOE4 allele (Craft et
Moloney et al., 2010) and leptin signaling (Maioli et al., 2015). al., 1998). Other groups who measured CSF insulin reported
Although brain insulin and IGF resistance in the human AD reductions but no difference with APOE4 (Gil-Bea et al.,

1378 Insulin signaling in Alzheimer’s disease | Stanley et al.

 Figure 3. Where and when do changes
in ins and IS affect AD? Colored lines
represent our current understanding of the
pathological timeline in AD. It is currently
unclear when and where changes in ins/IS
occur in this timeline. If changes in ins/
IS happen early, (1) they could initiate or
potentiate amyloid accumulation to casu-
ally influence AD. If ins/IS changes appear
around the time of symptoms (4), this
could be a consequence of years of patho-
logical changes and may be directly related
to cognitive decline. If changes in ins/
IS occur in the presymptomatic period (2

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and 3), they could be interacting with Aβ,
tau, or metabolism to contribute to disease
progression. Conversely, presymptomatic
changes could be a result of tau or Aβ
accumulation or metabolic perturbation.
Additionally, it is possible that changes in
ins/IS could simply push the symptomatic
period to the left (earlier) without directly
interacting with these pathologies.

2010), no difference (Molina et al., 2002), or increases with ins/IS is a primary instigator of disease. In contrast, amyloid
higher CSF/plasma ratios (Fujisawa et al., 1991), making in- accumulation which begins ∼15 yr before cognitive decline
terpretations of this data difficult.While reports of CSF insulin could lead to brain insulin resistance, with hyperinsulinemia
are variable, current data suggests that AD patients are likely to acting as a secondary indicator of underlying pathology in
experience higher blood insulin. When trying to determine AD, and contribute to cognitive decline. To properly clarify
if this hyperinsulinemia could be a cause or consequence of whether insulin is a cause or consequence of disease, blood
disease, it is important to consider when hyperinsulinemia and CSF insulin should be tracked longitudinally, beginning
occurs in relation to the development of AD. Table 1 demon- before the onset of AD pathology, during AD pathology
strates that blood insulin is higher in AD patients, and it may accumulation while individuals are still normal (preclinical
increase with disease progression (Craft et al., 1998), but other AD), and then during the clinical stage of AD. To date, no
studies suggest that higher blood insulin, before diagnosis, such study has been reported. Recent studies have started to
may be present and influencing disease progression. analyze the relationship between insulin resistance and AD
biomarkers during the asymptomatic, preclinical stage in at-
Changes in ins and IS: cause of AD? risk populations. In asymptomatic middle-age adults, insulin
A longitudinal study found that fasting hyperinsulinemia, resistance was associated with higher CSF tau, p-tau (Starks
even without T2D, doubled the risk of developing AD et al., 2015) and Aβ42 (Hoscheidt et al., 2016). CSF insulin
(Luchsinger et al., 2004). A cross-sectional study found that was not measured, but baseline levels of blood glucose, insu-
in AD patients without an APOE4 allele, hyperinsulinemia lin, and insulin resistance were no different between APOE4
was also associated with an increased risk of AD (Kuusisto carriers and noncarriers at this early stage of disease (Starks
et al., 1997) and higher insulin was associated with amyloid et al., 2015). Additional studies of this type, measuring CSF
deposition, visualized by amyloid imaging on positron emis- insulin in addition to traditional AD biomarkers, will help
sion tomography (PET) scans, before symptom onset (Wil- to determine the temporal relationship between insulin dys-
lette et al., 2015). Taken together, these studies suggest that regulation and AD progression.
high insulin could play a causative role in AD, although the
AD population can be heterogeneous and it is possible that Ins, IS, and Aβ.There are many studies suggesting that hyper-
causal mechanisms differ across subgroups of patients. Since insulinemia may be directly influencing the risk of AD by
Aβ and tau deposition begin to occur ∼15 yr before symp- modulating Aβ. In vitro studies demonstrate that high insulin
tom onset, these studies are difficult to interpret (Fig. 3). For can lead to higher extracellular Aβ by affecting clearance
example, high blood insulin before the onset of AD pathol- mechanisms and Aβ degrading enzymes. Both insulin and Aβ
ogy could increase the risk of Aβ/tau deposition because are degraded by insulin degrading enzyme (IDE), and in the

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presence of high insulin, IDE will preferentially degrade insu- its GSK3 through canonical signaling which would suggest
lin over Aβ (Qiu et al., 1998). In vivo experiments corrobo- that adequate ins/IS may contain Aβ levels. So far, this has
rate in vitro findings where Aβ clearance is significantly not been validated experimentally. Lowering blood insulin by
reduced in rats in the presence of high insulin (Shiiki et al., destroying insulin-producing cells in a mouse model of AD
2004). In addition to affecting Aβ clearance, in vitro work reduces brain ins/IS and results in elevated Aβ levels (Wang
demonstrates that high insulin increases extracellular Aβ con- et al., 2010). While the authors conclude that insulin defi-
centrations by increasing production through IS (Gasparini et ciency raised Aβ, these mice also have extreme hyperglycemia
al., 2001). Conversely, inhibition of PI3K leads to reduced Aβ which we and others have recently shown can independently
production (Stöhr et al., 2013). Crossing neuronal IR knock- increase extracellular Aβ (Macauley et al., 2015; Chao et al.,
out mice to an APP transgenic mouse abolishes IR signaling 2016). Moreover, decreasing insulin production would lead
in the brain and leads to reduced Aβ levels and amyloid depo- to decreased IDE levels, which could affect Aβ since IDE is
sition, indicating that endogenous IS elevates Aβ in vivo an Aβ degrading enzyme.
(Stöhr et al., 2013). A recent study in mice found that injec- While hyperinisulinemia can initially increase brain

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tion of supraphysiological levels of insulin increased brain IS insulin and positively regulate Aβ acutely, chronic
and possibly Aβ (Sajan et al., 2016). In earlier work by Craft hyperinsulinemia can down-regulate transport leading to
and colleagues, intravenous infusion of insulin in healthy lower blood​:brain insulin (Banks et al., 1997).This decrease in
older adults by hyperinsulinemic-euglycemic clamps im- BBB transport may also increase Aβ, although there is no
proved performance on a declarative memory task, but in- direct experimental evidence supporting this claim. Since it is
creased CSF Aβ in ‘older’ participants (Watson et al., 2003). unclear whether chronic hyperinsulinemia (described in
These clamps also increased plasma and CSF Aβ in another Table 1) leads to increased brain insulin or to decreased insulin
cohort, and increased inflammatory markers in the CSF transport, additional experimental confirmation is required to
(Fishel et al., 2005). Collectively, data suggests that elevated ins identify a causal relationship with Aβ and AD.
can modulate Aβ, suggesting T2D could exacerbate AD
pathogenesis over time via this mechanism. Ins, IS, and tau phosphorylation.GSK3 activity is often con-
A crucial, remaining question is whether physiolog- nected to the phosphorylation of tau. Neuronal IR knockout
ical, peripheral hyperinsulinemia seen in AD or T2D raises mice have higher p-tau, presumably due to more active GSK3
brain insulin enough in vivo to actively compete with IDE, (Schubert et al., 2004). Interestingly, these IR knockout mice
activate IS, or increase Aβ since insulin transport across the do not have any memory deficits despite evidence that IS is
blood brain barrier (BBB) is saturable at normal physiologi- connected to cognition and p-tau is linked with memory
cal levels (Banks, 2004). A recent paper found that in several deficits in mice (Schindowski et al., 2006). Peripheral injec-
mouse models of T2D and in T2D monkeys, hyperinsulin- tion of supraphysiological insulin is capable of elevating IS in
emia was associated with higher brain IS and higher Aβ levels the mouse brain and increases p-tau even though GSK3 is
at baseline. Murine Aβ was reportedly measured by Western serine phosphorylated by p-AKT to reduce activity and pre-
blot in these experiments but the concentration is typically sumably p-tau (Freude et al., 2005). Hyperinsulinemia also
so low that this method may not be sufficient to detect small increases p-tau in aged, wild-type mice (Becker et al., 2012).
changes. Regardless, insulin injection did not further increase In vivo studies from mice agree with the complex findings
IS or Aβ, which could be due to transport or receptor satu- from AD brains (Table 1) which found GSK3 to be both
ration (Sajan et al., 2016). Overall, it still appears that hyper- more active and less active while p-tau was high. Overall,
insulinemia can positively regulate Aβ, though further studies these data suggest, again, that both high ins/IS (from hyperin-
are needed to clarify this. sulinemia) and low IS (from insulin resistance) may put the
While high blood insulin may indicate higher brain ins/ brain at risk to exacerbate AD.
IS, it is also possible that lower brain ins/IS leads to higher One study found that chronically raising blood insu-
blood insulin as an attempt to compensate for the reduction. lin in mice via a high fat diet had no effect on p-tau in the
A longitudinal study found that both the highest and lowest brain, but they also reported no change in brain IS (Becker
quartiles for fasting insulin were associated with the devel- et al., 2012). When injected peripherally with supraphysio-
opment of dementia (Peila et al., 2004). One mouse model logical insulin, p-tau was unchanged in mice with chronic
of AD was found to have reduced brain insulin and some hyperinsulinemia (Becker et al., 2012). Brain IS in response
changes in IS that preceded the deposition of Aβ (Chua et to the peripheral injection was not measured, but this likely
al., 2012). These results suggest that low brain ins/IS may also demonstrates that insulin transport is reduced with chronic
affect Aβ. Unfortunately, they did not measure blood or CSF hyperinsulinemia. Additional evidence from a study in mice
insulin to know how these measures fluctuate overtime in and monkeys demonstrates that chronic hyperinsulinemia re-
relation to amyloid deposition and brain ins/IS. sulted in higher brain IS and higher p-tau (Sajan et al., 2016).
GSK3 can increase Aβ levels in vitro and inhibition of They also found no further increase in IS with insulin injec-
GSK3 by lithium can reduce APP processing and Aβ levels tion, confirming that chronic hyperinsulinemia is most likely
(Phiel et al., 2003). As shown in Fig. 1, insulin also inhib- saturating BBB transport and/or IS. These studies highlight

1380 Insulin signaling in Alzheimer’s disease | Stanley et al.

the complexity between acute and chronic changes in blood Aβ and brain insulin resistance.There is substantial evidence
insulin and insulin sensitivity in the brain that need to be from in vitro experiments that Aβ may directly contribute to
considered when trying to understand how hyperinsulinemia neuronal insulin resistance. Aβ can competitively inhibit the
and brain insulin resistance relate to each other and AD. binding of insulin to the IR (Xie et al., 2002). Aβ oligomers
(AβO) are thought to be the more toxic species of Aβ, and
Changes in ins and IS: consequence of AD? synthetic AβOs bind to and internalize IRs causing an in-
One AD population study found that up to 80% of AD pa- crease in neuronal p(Ser)-IRS1 and p-JNK, markers of insulin
tients had either T2D or insulin resistance, suggesting that resistance (Zhao et al., 2008; Bomfim et al., 2012). In vivo
AD may lead to a diabetic phenotype (Janson et al., 2004). experiments found higher p(Ser)-IRS1 and p-JNK in human
Unfortunately, there are no longitudinal studies showing AD brains (Table 1) and aged APP transgenic mice. They also
whether or not diabetic phenotypes occur after AD onset or found that intracerebroventricular injection of AβO’s into
precede AD diagnosis. Tissue analysis (Table 1) supports that monkeys elevated p(Ser)-IRS1 and p-JNK, demonstrating
brain insulin resistance worsens with advancing AD, but it that these AβO’s can cause resistance in vivo (Bomfim et al.,

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is unclear how early in disease progression insulin resistance 2012). AβO’s increase p-tau, which may result from activation
occurs (Fig. 3). If reduced brain IS is associated with cog- of GSK3 as a result of reductions in IS (Ma et al., 2009).Taken
nitive decline, one would expect changes to occur around together, these data suggest that Aβ has the ability to induce
the time that symptoms start to appear, which may be after insulin resistance in vitro and in vivo using several dif-
blood insulin is already high. In T2D patients, insulin resis- ferent model organisms.
tance is also associated with brain hypometabolism (Baker et
al., 2011). In AD, hypometabolism occurs before symptom Insulin treatment for brain insulin resistance.Craft et al.
onset and is likely related to synaptic dysfunction and neu- (1996, 1999, 2003, 2012) continue to demonstrate that insulin
ronal loss, and worsens with disease progression (Sperling et treatment, either by intravenous infusion or intranasal deliv-
al., 2011). It is unclear how hyperinsulinemia, insulin resis- ery, can modestly enhance performance on memory tasks in
tance, brain hypometabolism, and cognitive decline are tem- healthy adults and patients with AD or mild cognitive impair-
porally related in AD (Fig. 3). A recent study used plasma ment (MCI) at specific doses (Watson et al., 2003; Reger et
exosomes from neural sources to measure p(Ser)-IRS1, a al., 2008; Claxton et al., 2015). Gender and APOE4 modulate
marker of insulin resistance, longitudinally in individuals the beneficial effects of insulin (Craft et al., 2000, 2003; Reger
with AD, T2D, or healthy controls (Kapogiannis et al., 2015). et al., 2008; Claxton et al., 2013). In mice, intranasal adminis-
In these exosomes, p(Ser)-IRS1 was found to be higher in tration of insulin increases insulin in the cortex and hippo-
AD and T2D compared with controls, and was elevated up campus to some extent (Salameh et al., 2015), but whether or
to 1–10 yr before AD diagnosis. However, there was no not it increases IS and confers protection against neuronal
association of exosome p(Ser)-IRS1 with AD severity or damage is still unknown. In vitro studies show that synthetic
insulin resistance, which is contrary to results from postmor- AβOs co-cultured with neurons can bind to synapses and re-
tem brain tissue (Table 1). Determining which comes first, duce dendritic spines, an effect that is rescued when treated
hyperinsulinemia or brain insulin resistance, would be the with high insulin and IS is activated (De Felice et al., 2009).
key to understanding which is a cause or consequence of Increasing hippocampal insulin and IS in rats also enhances
AD and how they relate to AD pathogenesis. memory. However, rats with T2D induced by a high fat diet
In T2D, hyperinsulinemia is capable of leading to in- did not show improvement with insulin treatment (McNay et
sulin resistance through negative feedback at the IR (Fig. 1). al., 2010), suggesting that once brain insulin resistance has
Thus, it is possible that the hyperinsulinemia seen in AD pa- developed, insulin treatment may not be sufficient to over-
tients may lead to brain insulin resistance or reduced insulin come resistance at a cellular level. In a mouse model of AD,
transport, which can modulate both Aβ and p-tau to con- high fat diet led to insulin resistance and exacerbated amyloid
tribute to AD in a causal way. Although there is currently pathology and memory impairment. A single, supraphysio-
no longitudinal data demonstrating that hyperinsulinemia logical injection of insulin was found to improve IS in pe-
precedes the onset of AD pathology, there is mechanistic ev- ripheral tissues and reduce soluble Aβ in the brain, but brain
idence that it is possible for hyperinsulinemia to drive both IS was not measured (Vandal et al., 2014). If insulin resistance
insulin resistance and AD. Alternatively, insulin resistance in is severe and causing brain insulin to be too low, increasing
T2D can also be initiated by other processes, such as cellular insulin under these conditions may help mitigate Aβ levels;
stress and inflammation, which activate signaling molecules however, this hypothesis was not directly tested. If brain IS is
like p-JNK to increase p(Ser)-IRS1, causing hyperinsulin- within normal range, insulin injection can increase IS and
emia as a compensatory mechanism (Draznin, 2006). More- possibly Aβ levels (Sajan et al., 2016). Additionally, raising
over, oxidative stress and neuroinflammation are key features brain insulin by intranasal delivery appears to elevate brain
of the AD brain, which may promote brain insulin resistance, insulin high enough that it may increase Aβ or p-tau, al-
but most experiments have yet to explore these mecha- though this has not been addressed in studies to date. Prelim-
nisms in the context of AD. inary reports using intranasal insulin in mouse models suggests

JEM Vol. 213, No. 8 1381

that this treatment may have some positive effects on memory Denali. SML consults for Denali. The authors declare no additional competing fi-
nancial interests.
and pathology (Chen et al., 2014; Zhang et al., 2016). Exten-
din-4, an antidiabetic medication thought to enhance IS by
activating similar pathways, was able to prevent the develop- Submitted: 5 April 2016
ment of insulin resistance (p(Ser)-IRS1) in neuronal cultures Accepted: 20 June 2016
and APP transgenic mice (Bomfim et al., 2012). Insulin sensi-
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Acknowledgments in female AβPPsw/PS1ΔE9 mice. J. Alzheimers Dis. 29:783–791.
This work was supported by a National Science Foundation Graduate Research Fel- Claxton, A., L.D. Baker, C.W. Wilkinson, E.H. Trittschuh, D. Chapman, G.S.
lowship (DGE-1143954; M. Stanley), National Institute on Ageing grant K01 Watson, B. Cholerton, S.R. Plymate, M. Arbuckle, and S. Craft. 2013.
AG050719 (S.L. Macauley), National Institute of Neurological Disorders and Stroke Sex and ApoE genotype differences in treatment response to two
grants F32 NS080320 (S.L. Macauley) and P01 NS080675 (D.M. Holtzman), New Vi- doses of intranasal insulin in adults with mild cognitive impairment or
sion Award through Donors Cure Foundation (S.L. Macauley), and the JPB Founda- Alzheimer’s disease. J. Alzheimers Dis. 35:789–797. http​://dx​.doi​.org​/10​
tion (D.M. Holtzman). .3233​/JAD​-122308
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intranasal insulin detemir improves cognition for adults with mild

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