7

DIABETICMedicine
DOI: 10.1111/j.1464-5491.2011.03464.x
Review Article
Insulin resistance and pathological brain ageing
B. Cholerton, L. D. Baker and S. Craft

Geriatric Research, Education and Clinical Center, Veterans Aairs Puget Sound Health Care System, Department of Psychiatry and Behavioral Sciences, University
of Washington School of Medicine, Seattle, WA, USA
Accepted 28 September 2011
Abstract
Sir Harold Himsworth’s prescient observations 75 years ago have recently been expanded to include a clear relationship
between insulin resistance and central nervous system function. Insulin is a master regulator of corporeal ageing in all known
species, determining the rate and expression of ageing in multiple body systems. Thus, it is not surprising that insulin also plays an
important role in brain ageing and cognitive decline that is associated with pathological brain ageing. Brain ageing is
accompanied by reduced insulin effectiveness, either by an inadequate cellular response to insulin or by insulin deficiency
attributable to reduced insulin transport across the blood–brain barrier. Age-associated brain insulin abnormalities may
contribute to cognitive decline in ageing, as have been documented in older adults with Type 2 diabetes mellitus and
hypertension. With more extreme pathology, brain insulin resistance may be associated with neurogenerative diseases such as
Alzheimer’s disease, and the condition which precedes Alzheimer’s disease, known as amnestic mild cognitive impairment. In the
following review, we discuss the mechanisms through which insulin resistance may induce or potentiate pathological brain
ageing and thereby create a neurobiological environment that promotes neurodegeneration and associated cognitive decline.
This topic is timely, given that insulin resistance-associated conditions such as diabetes and obesity have reached epidemic
proportions. The prevalence of such chronic conditions, in combination with a rapidly ageing population, may result in a
corresponding increase in the prevalence of Alzheimer’s disease and other cognitive disorders. Fortunately, insulin resistance-
associated conditions are amenable to both pharmacologic and lifestyle interventions that may reduce the deleterious impact of
insulin resistance on the ageing brain.
Diabet. Med. 28, 1463–1475 (2011)
Keywords brain, insulin resistance
Abbreviations apo, apolipoprotein; GLUT, glucose transporter; GSK, glycogen synthase kinase; PPARc, peroxisome
proliferator-activated receptor gamma; TNF, tumour necrosis factor
they are selectively distributed, with high concentrations in the

Insulin and the brain
olfactory bulb, cerebral cortex, hippocampus, hypothalamus,
The peripheral effects of insulin, a hormone secreted by amygdala and septum [2,7–9].
pancreatic b-cells, have been well characterized. Recent
evidence demonstrates that insulin is also active in the central
nervous system. Although controversy exists as to whether Insulin and cognition
insulin is synthesized in the adult brain, it is readily transported Insulin receptors are densely localized in the hippocampus and
into the central nervous system across the blood–brain barrier by medial temporal cortex, areas which support memory. In rats,
a saturable, receptor-mediated process [1–3]. Raising peripheral acute intracerebroventricular insulin administration improves
insulin levels acutely elevates brain and cerebrospinal fluid memory on a passive-avoidance task [9]. In humans, acute
insulin levels, whereas prolonged peripheral hyperinsulinaemia intravenous insulin administration, while maintaining
down-regulates blood–brain barrier insulin receptors and euglycaemia, reliably enhances story recall [10–13]. Intranasal
reduces insulin transport into the brain [4,5]. Insulin receptors insulin administration using specialized nose-to-brain delivery
are located in the synapses of both astrocytes and neurons [6]. devices also enhances memory [14]. Conversely, learning may
Although insulin and insulin receptors are abundant in the brain, also influence insulin receptor expression and function. For
example, training rodents on a spatial memory task increased
Correspondence to: Suzanne Craft, VAPSHCS, GRECC-S182, 1660 S. insulin receptor expression in the hippocampal dentate gyrus and
Columbian Way, Seattle, WA 98108, USA. E-mail: scraft@u.washington.edu CA1 field [15]. Thus, the act of learning is accompanied by
ª 2011 The Authors.

Diabetic Medicine ª 2011 Diabetes UK 1463
DIABETICMedicine Insulin resistance and brain ageing • B. Cholerton et al.
changes in insulin signalling molecules in the hippocampus. body systems, including the central nervous system, for some
Collectively, these studies suggest that insulin may contribute to time prior to the onset of frank diabetes. There is increasing
normal memory functioning. support that such early insulin abnormalities may be associated
There are several mechanisms through which insulin may with the initiation of the cascade of Alzheimer’s disease
affect memory. One mechanism may be through effects on pathology in some individuals, years or even decades before the
cerebral energy metabolism. Although insulin does not appear to first clinical dementia symptoms are manifest.
influence glucose transport into the brain, it may have more
selective effects on cerebral glucose metabolism. Bingham et al.
Insulin abnormalities and Alzheimer’s disease pathology
[16] demonstrated an increase in cerebral glucose metabolism
that was particularly pronounced in the cortex following Converging evidence supports that the presence of insulin
administration of a low dose of insulin. The basis for regional resistance raises the risk for developing Alzheimer’s disease
insulin effects on glucose metabolism may be attributable to the neuropathology. The manner in which insulin abnormalities may
distribution of glucose transporter isoforms (GLUTs) [17,18]. contribute to the symptoms and pathogenesis of Alzheimer’s
The insulin-sensitive GLUTs 4 and 8 are selectively distributed in disease have been examined in a variety of experimental models.
the brain and insulin increases brain GLUT 4 expression and Hoyer and colleagues were the first group to suggest that
translocation [19]. In rats, GLUT 4 is expressed in the desensitization of the neuronal insulin receptor plays a role in
cerebellum, sensorimotor cortex, hippocampus, pituitary and Alzheimer’s disease [31]. In support of his theory, he and
hypothalamus [20–23] and GLUT 8 has been observed in the colleagues have demonstrated a reduction in insulin receptors
hippocampus and hypothalamus [17]. Notably, substantial and tyrosine kinase activity markers in Alzheimer’s disease brain
co-localization exists for insulin-containing neurons, insulin [32]. This initial finding has been confirmed and extended in a
receptors and GLUTs 4 and 8 [18,20]. These overlapping larger sample of patients, which demonstrated reduced insulin
distributions are consistent with insulin-stimulated glucose message with increasing Alzheimer’s disease pathology and
uptake in selective brain regions, including medial temporal cholinergic deficit [33].
lobe structures that support learning and memory. Animal and in vitro studies have documented relationships
Other insulin-related mechanisms that are not directly related between insulin and mechanisms with clear pathogenic
to modulation of glucose uptake have also been implicated in implications for Alzheimer’s disease. In vitro, insulin
normal hippocampal functioning [24]. Long-term potentiation is modulates levels of the b-amyloid (A b) peptide, the
a process of synaptic circuit remodelling thought to play a critical aggregation of which is a fundamental neuropathological
role in memory formation. Insulin may influence components of hallmark of Alzheimer’s disease. For example, insulin
the long-term potentiation cascade, such as the cell membrane promotes release of intracellular A b in neuronal cultures,
expression of NMDA receptors [25], which affect the likelihood accelerating their trafficking from the Golgi and trans-Golgi
of long-term potentiation induction. Insulin also modulates network to the plasma membrane [34]. Thus, low brain insulin
central nervous system levels acetylcholine and norepinephrine, may reduce the release of Ab from intracellular to extracellular
neurotransmitters that are known to influence cognitive function compartments.
[26,27] Thus, insulin affects numerous mechanisms relating to Interestingly, Ab also regulates brain insulin signalling. Soluble
neuronal activity and cognitive function supported by such Ab binds to the insulin receptor and disrupts its signalling
activity. capacity and long-term potentiation induction in mouse
hippocampal slice preparations [35]. These effects could be
prevented by exposing tissue to insulin prior to Ab exposure.
Insulin resistance and impaired cognition
Synthetic soluble Ab oligomers, down-regulate plasma
In contrast to the beneficial effects of acute insulin elevations membrane insulin receptors in primary hippocampal cultured
described above, insulin dysfunction resulting from insulin neurons, leading to synaptic spine loss. This process was also
resistance and compensatory chronic elevations of circulating prevented by pretreatment with insulin [36]. A related
insulin may exert a negative influence on memory and other mechanism through which insulin and Ab may interact to
cognitive functions. For example, Type 2 diabetes has been modulate Alzheimer’s disease pathology is via synaptotoxic
associated with impaired learning in both animal and human effects. Loss of synapses is the earliest structural defect observed
studies [28]. Furthermore, impaired verbal memory has been in Alzheimer’s disease. Soluble oligomeric species of Ab are
observed in individuals with chronic hyperinsulinaemia in the synaptotoxic, and insulin prevents binding of Ab to synapses,
absence of hyperglycaemia [29]. Additionally, impaired glucose thereby preserving synaptic integrity [36]. Insulin also reduced
tolerance has been associated with reduced hippocampal volume oligomer formation, which may have additional protective
and memory impairment [30]. Taken together, these findings are effects; a functional consequence of these effects appears to be
consistent with the notion that acute and chronic protection against Ab-induced disruption of long-term
hyperinsulinaemia have opposing effects on the neural potentiation integrity, the process of synaptic remodelling
substrates of memory. Chronic high levels of insulin and believed to underlie memory formation [37]. Collectively, these
insulin resistance may exert a negative influence on several findings suggest that soluble Ab may induce neuronal insulin

1464 Diabetic Medicine ª 2011 Diabetes UK
Review article DIABETICMedicine
resistance and synapse loss and that treatment with insulin, such insulin resistance can precipitate the neuropathological and
as is provided by intranasal insulin therapy, may prevent these behavioural features of Alzheimer’s disease and that raising brain
pathological processes. insulin levels may reduce neuropathological changes related to
A growing understanding of the importance of impaired Ab Alzheimer’s disease.
clearance as opposed to increased Ab production in late-onset A role for insulin has also been suggested for other Alzheimer’s
Alzheimer’s disease has created intense focus on mechanisms disease-related mechanisms. Insulin inhibits phosphorylation of
regulating Ab degradation. Insulin may modulate Ab tau, the protein that forms neurofibrillary tangles, a second
degradation by regulating expression of the insulin degrading neuropathological hallmark of Alzheimer’s disease. Insulin may
enzyme, a metalloprotease that catabolizes insulin [38]. The affect tau through its regulation of glycogen synthase kinase
insulin degrading enzyme is highly expressed in brain as well as in (GSK)3b, a downstream target in the insulin signalling pathway
liver, kidney and muscle [39] and may play a critical role in Ab [52]. Schubert and colleagues [53] abolished insulin signalling
clearance in brain [40–42]. The insulin degrading enzyme has in vivo with a conditional knockout mouse model in which the
also been implicated in the intracellular degradation of Ab [43]. insulin receptor gene was inactivated in the central nervous
Furthermore, decreased insulin degrading enzyme activity, levels system. Phosphorylation of GSK 3b and protein kinase B (Akt)
and mRNA have been observed in Alzheimer’s disease brain was reduced and phosphorylation of tau increased 3.5-fold.
tissue and insulin degrading enzyme knockout mice have reduced Recent work also implicates insulin receptor substrate 2, in that
degradation of Ab and insulin in brain [44–46]. Thus, low central mice in which this gene has been knocked out have increased
nervous system insulin may reduce insulin degrading enzyme tangles and hyperphosphorylated tau [54].
levels in brain and thereby impair Ab clearance.
Chronic peripheral hyperinsulinaemia may thus lower brain
Insulin resistance-related conditions and
insulin levels and interfere with peripheral Ab clearance. Chronic
dementia
peripheral hyperinsulinaemia has been associated with a pattern
in which brain insulin levels are initially higher, then decrease as The above research provides compelling evidence concerning
transport of insulin into the brain is down-regulated [47]. insulin’s role in the central nervous system and the connection
Consistent with this pattern, it has been shown that genetically between impaired insulin action and the pathology that underlies
obese Zucker rats have reduced insulin binding to brain Alzheimer’s disease. The association between dementia and
capillaries [4] and reduced hypothalamic insulin levels [48] in insulin resistance is further substantiated by investigations of
comparison with lean controls. Additionally, in a canine model conditions related to insulin dysfunction. Insulin resistance is a
of diet-induced insulin resistance, brain uptake of labelled insulin primary underlying cause of multiple chronic diseases and, as
was reduced and peripheral insulin clearance was inhibited[49]. such, a likely key risk factor for dementia. However, because
Adults with Alzheimer’s disease show lower cerebrospinal fluid insulin resistance is rarely identified in its earliest stages
insulin levels, higher plasma insulin levels and reduced and independent of these conditions, it is seldom incorporated
cerebrospinal fluid–plasma insulin ratios compared with healthy
control subjects. High plasma insulin levels may interfere with
degradation of Ab transported out of the brain, thereby
CENTRAL NERVOUS SYSTEM
obstructing a peripheral Ab-clearing ‘sink’. Concomitantly, low Aβ
LOW INSULIN
brain insulin levels reduce release of Ab from intracellular LOW IDE
compartments into extracellular compartments where clearance
-
is believed to occur. Thus, for some patients with Alzheimer’s
disease, high peripheral insulin levels and low brain insulin levels
-
would result in reduced clearance of Ab both in brain and in the Aβ
periphery (Fig. 1).
Support for the validity of this model is provided by a recent CNS MICROVASCULATURE AND BLOOD-BRAIN BARRIER
study that induced insulin resistance in the T2576 mouse model Aβ

of Alzheimer’s disease with a high-fat diet. Diet manipulation HIGH INSULIN &
INSULIN RESISTANCE
resulted in a metabolic profile of high peripheral insulin and low Muscle
brain insulin and insulin degrading enzyme levels compared with ADIPOCYTES
Tg2576 mice fed a normal diet [50]. Diet-induced insulin IDE

Aβ
Liver
FFA & TNFα
resistance caused twofold increases in Ab40 and 42, and earlier,
larger Ab deposits compared with non-insulin-resistant Tg2576
mice. Furthermore, insulin-resistant mice had impaired learning
PERIPHERY
on a water maze test. In another model of insulin resistance,
APP ⁄ PS1 mice were given sucrose-sweetened beverages and also FIGURE 1 Model of peripheral hyperinsulinaemia, insulin resistance and
demonstrated increased brain Ab deposition and reduced Morris Alzheimer’s disease pathological processes. CNS, central nervous system;
water maze learning [51]. Together these results suggest that IDE, insulin degrading enzyme.

as a primary variable of interest in population-based models. duration, treatment duration and dose, and concomitant
Here, we focus on the increased dementia risk associated vascular risk factors will certainly help to clarify these questions.
with insulin resistance-related syndromes, including diabetes,
hyperlipidaemia, hypertension and obesity.
Dyslipidaemia
Insulin is a key modulator of lipid metabolism, and insulin

Diabetes
resistance is associated with dyslipidaemia, a process that may
Diabetes is a strong predictor of cognitive decline in older adults represent yet another pathway by which insulin potentially
[55,56] and multiple population-based studies have reported an exacerbates pathological Ab processes in the brain. Although the
association between insulin resistance and cognitive impairment mechanisms underlying the association between lipids,
in elderly populations [57–64]. Type 2 diabetes confers a lipoproteins and Ab are not well understood, it is increasingly
significantly increased risk of dementia (both Alzheimer’s clear that these interactions play a vital role in Ab production and
disease and vascular dementia), a relationship that has been clearance. Animal models show greater VLDL secretion in
consistently reported in the literature [65–70]. For example, in advance of Ab deposits in the brain [79] and Alzheimer’s disease
the prospective, community-based Rotterdam study, Ott et al. is associated with increased postprandial chylomicron and LDL
[71] found that Type 2 diabetes significantly increased the risk levels [80]. Lipoproteins, including apolipoproteins E and J
for all-cause dementia and Alzheimer’s disease, with greater risk (apoE and apoJ), appear to play a significant role in mediating
apparent in people who were insulin-treated (and therefore likely central nervous system Ab transport and clearance. For example,
to be in the more severe stages of the disease) at baseline. Similar highly lipidated apoE increases Ab clearance and thus reduces
results were reported by Leibson et al. [72] and the Religious amyloid deposition in the brain, while poorly lipidated apoE
Orders Study reported a 65% increased risk for Alzheimer’s increases amyloid burden [81]. In the periphery, the Ab clearance
disease among those with Type 2 diabetes [73]. Findings from may also be mediated by apoE, apoJ and lipoprotein receptor-
the Mayo Clinic Alzheimer’s Disease Patient Registry show an related protein-2 [82]. Inhibition of peripheral Ab clearance may
increased prevalence of Type 2 diabetes (35 vs. 18% in non- in turn lead to increased accumulation of Ab in the brain.
demented control subjects) and impaired glucose tolerance (46 Given the above results, it is not surprising that a relationship
vs. 24%) for patients with Alzheimer’s disease [74]. Further, between hyperlipidaemia and Alzheimer’s disease has been
Alzheimer’s disease risk is raised independently from vascular postulated. However, the connection between cholesterol and
dementia or other dementias [67,75], a finding that is not dementia is complex. High plasma cholesterol at midlife is
surprising given the wealth of literature that connects insulin associated with higher Ab40 levels [83] and a 2- to 3-fold
dysfunction with Alzheimer’s disease-specific brain pathology. increased risk for later Alzheimer’s disease dementia [84].
Interestingly, dementia risk does not appear to be associated with Conversely, total cholesterol in late life does not appear to be
the age at which diabetes is diagnosed [76]. associated with Alzheimer’s disease risk [84] and may in fact be
Coupled with animal and in vitro studies that support the protective to some degree [85,86]. In addition, despite the
influence of insulin on Alzheimer’s disease pathophysiological relationship between hyperlipidaemia and vascular dysfunction,
processes, the above epidemiological evidence provides further high total cholesterol has not been linked with an increased risk
support for the association between diabetes and dementia. for vascular dementia in either mid or late life [84]. Further
Recent neuropathological studies, however, have produced investigation into the complex role of cholesterol, Ab and
interesting and somewhat conflicting results. For example, dementia is thus warranted.
dementia patients with treated diabetes had Ab plaque loads
that were similar to those of non-demented control subjects,
Hypertension
while dementia patients with untreated diabetes had plaque loads
consistent with dementia patients without diabetes [77]. Patients Through both direct effects and insulin resistance-related
with treated diabetes with dementia had higher levels of dyslipidaemia and inflammation, insulin dysfunction can
microvascular infarcts and anti-inflammatory markers to a substantially impact the vasculature. Insulin mediates capillary
degree not present in patients with untreated diabetes [78]. recruitment, vasodilation and regional blood flow [87,88].
Given the preliminary nature of these results and small sample Insulin resistance-associated declines in nitrous oxide and
sizes, these studies must be replicated prior to making any firm increases in endothelin-1 activity results in vasoconstriction
conclusions as to their meaning. If supported by larger studies, and reduced blood flow. In the brain, such vasoconstriction and
however, these findings could bring into question the relative reduced capillary recruitment may ultimately impede neural
impact of both Ab and microvascular disease in the development activity and thus negatively impact cognitive function.
of clinical dementia symptoms. It is possible that patients with Approximately one in three adults have hypertension [89] and
treated diabetes, who are likely to be at a more advanced stage of 50% of hypertensive patients are insulin resistant [90].
disease, are more susceptible to lower levels of amyloid burden Hypertension impairs neuron-dependent blood flow (known as
when they occur in the context of microvascular damage. Future functional hyperaemia) via a number of insulin resistance-related
neuropathological studies that carefully examine disease processes, including oxidative stress, dysregulation of vasoactive

mediators (including nitrous oxide and endothelin-1), structural midlife. The reasons for this association are not entirely known;
alteration of the blood vessels and insufficient cerebral however, the neuropathological conditions associated with later
autoregulation [91]. Animal models evidence increased Ab dementia begin many years prior to the onset of the clinical
deposition with hypertension, which leads to vascular dementia syndrome. Risk for chronic disease increases
dysfunction and reduced functional hyperaemia [91]. In substantially at midlife and may set in motion the pathological
population-based studies, hypertension at midlife is a risk processes responsible for late-life dementia. Interestingly,
factor for Alzheimer’s disease and vascular dementia, lower diabetes even in late life increases dementia risk, a finding that
brain weight and Ab plaque load [92–95]. As with total underscores the likely presence of subclinical impaired glucose
cholesterol, however, studies examining the effects of late-life tolerance resulting from insulin resistance for years prior to the
hypertension on dementia are mixed and blood pressure may in onset of the disease.
fact decline in the years prior to and following clinical dementia
diagnosis [96].
Insulin resistance and Alzheimer’s disease:
preventative and therapeutic approaches
Obesity
Pharmacologic insulin sensitization
Obesity is a growing and dangerous epidemic in the USA and is
closely linked to insulin dysregulation; 80% of obese individuals Given the relationship between insulin resistance and memory
are insulin resistant [97]. Insulin typically inhibits adipocyte impairment, therapeutic strategies aimed at treating early Type 2
lipase action, which decreases the release of free fatty acids from diabetes may also benefit those patients with mild cognitive
adipose tissue. With obesity and insulin resistance, however, this impairment or Alzheimer’s disease. Peroxisome proliferator-
process is disturbed and leads to chronically elevated free fatty activated receptor gamma (PPAR-c) agonists improve insulin
acids [97]. Free fatty acids are linked to Alzheimer’s disease sensitivity, decreasing circulating insulin and increasing insulin-
pathology through a number of potential mechanisms, including mediated glucose uptake, with minimal risk of hypoglycaemia
inducing inflammation, promoting Ab deposition and inhibiting [108]. PPAR-c activity may also reduce both Ab accumulation
Ab clearance. Elevated free fatty acids inhibit the insulin and inflammation and thereby protect against neurotoxicity
degrading enzyme, which is both essential for normal insulin [109–111]. PPAR-c agonists inhibit Ab-stimulated secretion of
signalling and vital for Ab clearance [98]. Further, free fatty acids pro-inflammatory products and decreased oxidative stress in
promote the development of amyloid and tau filaments in vitro both in vitro and in vivo models [112,113]. PPAR-c agonists are
[99,100]. Free fatty acids also induce inflammation, particularly thus attractive candidates for the treatment of insulin resistance
through interactions with tumour necrosis factor alpha (TNF-a), and inflammation associated with early cognitive decline.
an inflammatory cytokine that has been implicated in Rosiglitazone, a compound that binds with high affinity to
Alzheimer’s disease pathogenesis, particularly Ab accumulation PPAR-c [114], has been used as an anti-diabetic insulin sensitizer.
in brain [101–103]. TNF-a is overexpressed in adipose tissue of Rosiglitazone normalizes the insulin response and ameliorates
obese animals and humans, whereas neutralization of TNF-a the associated impaired stress response in Alzheimer’s disease
increases insulin sensitivity and decreases plasma free fatty acid mouse models [115]. We conducted a parallel group, double-
levels [104]. blind, placebo-controlled trial to test the hypothesis that
Despite the associations between obesity and the mechanistic treatment with rosiglitazone would produce beneficial
processes leading to Alzheimer’s disease pathology, the cognitive effects for patients with amnestic mild cognitive
connection between obesity and dementia risk is not entirely impairment and early Alzheimer’s disease [116]. Participants
clear [65]. Although associated with other insulin resistance- received a daily dose of 4 mg of rosiglitazone (n = 20) or
related conditions, including diabetes, hypertension and poorly matched placebo (n = 10) for 6 months. Delayed memory was
controlled lipids, midlife obesity appears to confer a risk for later preserved and attention improved over the 6-month trial for the
dementia over and above these factors [105–107]. Evidence rosiglitazone-treated group, whereas the placebo-assigned group
concerning the effects of late-life adiposity on dementia risk is less showed the expected decline in performance. The degree of
clear, however [107], and individuals typically begin to lose memory preservation was related to treatment response as
weight with the onset of dementia. Despite conflicting literature indexed by fasting plasma insulin levels at 6 months. Plasma Ab
in this area, however, it is likely that targeting the obesity levels declined over the 6-month treatment period for the
epidemic across the lifespan would have substantial beneficial placebo-treated patients and remained stable in the
effects on overall health status and cognitive function. rosiglitazone-treated group. Despite these promising results, a
subsequent Phase III trial conducted by GlaxoSmithKline failed
to show a benefit of 2, 4 or 8 mg of rosiglitazone over a 6-month
Insulin resistance-related conditions: conclusions
period. These negative results, coupled with concerns about
For many of the insulin resistance-related conditions described possible negative cardiovascular effects of rosiglitazone, have
above, it is becoming increasingly apparent that dementia risk is dampened enthusiasm for its use as a therapeutic agent
particularly elevated when such disorders are present during for Alzheimer’s disease. However, the thiazolidinedione

pioglitazone remains an attractive candidate and is currently within 10 min of administration compared with placebo, with
being investigated in a Phase III trial. peak levels noted within 30 min. Cerebrospinal fluid insulin
levels remained elevated for the 80-min study. Blood glucose and
insulin levels did not change, demonstrating that the effects in
Intranasal insulin
cerebrospinal fluid are not attributable to transport from the
Insulin and its signalling markers are reduced in the central nasal cavity to the systemic circulation. This is consistent with a
nervous system in Alzheimer’s disease. Multiple studies large literature that demonstrates insulin’s poor transport
demonstrate that supplementing insulin through intravenous from the nasal cavity into blood [122]. Although elevated
administration (while maintaining euglycaemia) acutely cerebrospinal fluid insulin levels do not conclusively demonstrate
increases central nervous system insulin and reliably improves that brain insulin levels are similarly elevated, animal studies
cognition [10,11,117]. However, chronic peripheral insulin have shown significant drug uptake to the hippocampus and
administration is not a viable therapeutic option because cortex. Francis et al. showed that intranasal insulin reversed the
of risks associated with hypoglycaemia. In addition, it is effects of diabetes in a murine model, reducing brain atrophy,
likely that such an approach would exacerbate peripheral increasing markers of synaptic function, increasing insulin
hyperinsulinaemia, with possible negative effects on Ab receptors and phosphorylation, reversing diabetes-related
clearance. Any long-term treatment strategy for normalizing reductions in choline acetyltranferase levels, reducing neuronal
central nervous system insulin levels in persons with Alzheimer’s NFjB activation and increased activation of Akt, cAMP
disease must avoid significantly increasing insulin in the response element binding protein and GSK3b. These
periphery. Such an approach is possible with an intranasal multifaceted effects were accompanied by a striking
administration technique. preservation of memory as measured by the Morris Waster
Maze and radial arm tasks [118].
Functional and cognitive studies of the acute and chronic
Intranasal pathways to the central nervous system
effects of intranasal administration also support insulin’s
The nasal cavity is unique in that olfactory sensory neurons are transport to the central nervous system. Sixty minutes of
directly exposed to the external environment in the upper nasal intranasal insulin treatment (20 IU every 15 min) induced
cavity, while their axons extend through the cribriform plate to changes in auditory-evoked brain potentials (AEPs) compared
the olfactory bulb. Following intranasal administration, low with placebo [123]. We have also demonstrated that intranasal
molecular weight drugs can be directly transported to the central insulin acutely improves verbal memory in memory-impaired
nervous system, bypassing the periphery. Several extraneuronal persons without affecting plasma insulin or glucose levels [124].
and intraneuronal pathways from the nasal cavity to the central Memory impaired and normal adults received saline and four
nervous system are possible. The extraneuronal pathways rely on doses of intranasally administed regular insulin (10, 20, 40 or
bulk flow transport through perineural channels to the brain or 60 IU insulin) on separate mornings. Per cent change in
cerebrospinal fluid. In recent studies, labelled intranasal insulin memory (story recall) relative to the placebo condition was
or a closely related peptide, insulin-like growth factor-I (IGF-I), enhanced for the three lower doses for the memory-impaired
were administered to rodents [118,119]. Within 30 min, an group.
IGF-I signal was detected along olfactory and trigeminal With respect to effects of chronic intranasal insulin
channels, with robust signal evident in hippocampus, amygdale administration, several studies reported that 2 months of daily
and cortex. An additional extracellular pathway was identified insulin administration (4 · 40 IU ⁄ day) significantly improves
with quick access to the cerebrospinal fluid after absorption into verbal memory and enhanced mood in young healthy adults
the submucosa along the olfactory nerve and cribriform plate [125,126]. In a recent pilot clinical trial we examined the effects
[119–121]. These extracellular pathways provide direct access to of short-term daily intranasal insulin administration in 25 adults
the central nervous system within minutes of intranasal with Alzheimer’s disease or mild cognitive impairment, who
administration. Additionally, an intraneuronal pathway were randomly assigned to receive insulin (20 IU twice daily;
delivers drugs to the central nervous system hours or days later. n = 13) or placebo (n = 12) for 21 days. Relative to their baseline
Anterograde axoplasmic transport within olfactory sensory performance, insulin-treated subjects had improved memory and
neurons has been demonstrated. attention at day 21 than did placebo-assigned subjects.
In a recently-concluded trial, we extended these preliminary
findings and examined the effects of two doses of intranasal
Intranasal insulin effects in the central nervous system
insulin (20 and 40 IU) compared with placebo administered for
Several studies have examined the effects of intranasal insulin in 4 months to 104 adults with Alzheimer’s disease or mild
human and animal models. Kern and colleagues [120] cognitive impairment [127]. Improved delayed memory was
administered 40 IU of insulin intranasally in young, healthy observed for the 20-IU group and performance preserved on
adults. Cerebrospinal fluid and blood were sampled every other measures of cognition and daily function for both insulin-
10–20 min for 80 min following administration. Insulin treated groups over the 4-month period. For a subset of
treatment resulted in increased cerebrospinal fluid insulin levels participants who received F-18 fluorodeoxyglucose (FDG)

positron emission tomography, cerebral glucose metabolism decline and increased Alzheimer’s disease and vascular dementia
declined for the placebo group and remained stable or improved risk [138].
for both insulin-treated groups. These two studies provide the Despite the overall promising epidemiological support, not all
first evidence of cognitive improvement following daily longitudinal studies have found an association between fat intake
intranasal insulin administration for patients with early profile and cognitive decline or dementia risk [139]. In addition,
Alzheimer’s disease and support brain insulin signalling as a large clinical trials that incorporated specific fatty acids have
promising target in the search for new therapeutic avenues in generally failed to produce substantial positive results [140]. It
Alzheimer’s disease. has thus been postulated that a ‘whole diet’ approach, which
mimics overall nutritive consumption patterns, may be a more
useful and valid method of study. For example, the
Lifestyle modification: strategies for
‘Mediterranean diet’, which emphasizes consumption of
prevention
complex carbohydrates, unsaturated fats and fruits and
Although mediated by genetic influences, insulin resistance vegetables, and is low in saturated fats and simple
occurs largely as a result of lifestyle factors, including carbohydrates, has received a great deal of attention for its
hypercaloric diets high in simple carbohydrates and saturated association with reduced risk for both Alzheimer’s disease and
fats, and physical inactivity. Implementation of intervention mild cognitive impairment [141–143]. In a recent controlled
programmes that address these challenges could significantly intervention trial aimed at examining the effects of diet on
reduce the social and economic burden associated with late-onset cognitive function and cerebrospinal fluid biomarkers in older
dementia. Here, we examine two promising non- adults with and without cognitive impairment, subjects were
pharmacological strategies aimed at reducing pathological assigned to a 4-week isocaloric diet that consisted of either high
processes associated with ageing and dementia: diet saturated fat ⁄ high simple carbohydrates (a pattern associated
modification and physical exercise. with Type 2 diabetes and insulin resistance) or low saturated
fat ⁄ low simple carbohydrates [144]. The diets produced
pronounced changes in cerebrospinal fluid biomarker profiles,
Diet modification
modulating levels of Ab and the oxidative injury marker
A typical ‘Western’ diet consists of high levels of saturated F2-isoprostane, and the low saturated fat ⁄ low glycaemic index
fats and simple carbohydrates, a pattern of consumption that diet was associated with improved memory. Taken together,
substantially raises the risk of insulin resistance, Type 2 diabetes, these animal, population-based and human intervention studies
obesity, cardiovascular disease and hypercholesterolaemia [128– suggest that dietary factors may influence the expression of
130], as well as the likelihood for cognitive impairment and Alzheimer’s disease.
Alzheimer’s disease [131–135]. Conversely, improving the
dietary profile to include reduced saturated fat and increased
Physical exercise
mono- and polyunsaturated fats may produce protective effects
on cognitive functioning and Alzheimer’s disease risk [131–134]. A sedentary lifestyle is likely a key factor in the increase in insulin
Animal models that examine the effects of diet intervention on resistance-related conditions noted in recent years. Aerobic
Alzheimer’s disease neuropathology have demonstrated that exercise, known to be an effective treatment for diabetes and
diets high in either saturated fat or sucrose modify processing of related conditions, also has potent salutary effects in the brain
the amyloid precursor protein from which the Ab peptide is [145,146]. Increased physical activity is consistently linked
produced, increase Ab-related cerebrovascular disturbance and with improved learning and memory both in humans and
reduce brain insulin signalling and expression of the insulin in animal models [147]. The favourable effects of exercise
degrading enzyme [136,137]. This section highlights the are likely exerted through multiple pathways known to
emerging support from recent human studies that suggest be influenced by insulin resistance, including improved
dietary intervention may play a key role in the prevention and cardiovascular and cerebrovascular function [148,149], anti-
treatment of cognitive decline in ageing. inflammatory processes [150,151] and enhanced insulin-
dependent energy metabolism [152]. Thus, aerobic exercise has
Dietary patterns, cognition and dementia risk the potential to modify multiple processes compromised in
Evidence from population-based studies generally supports that pathological brain ageing. In the following sections, we review
improved dietary profile leads to a reduced risk of age-related the evidence supporting a protective role of physical exercise
cognitive decline and dementia. These studies often focus on intervention on dementia risk throughout the lifespan.
specific dietary elements and the role of fatty acids has received
particularly close attention. For example, greater fish
Lifetime exercise and dementia risk
consumption and overall polyunsaturated fat intake has been
associated with both improvements in cognition and reduced Observational studies suggest that moderate physical activity
Alzheimer’s disease risk; conversely, high saturated and trans- throughout the lifespan is associated with improved cognitive
unsaturated fats are associated with worse cognition, greater function and reduced dementia risk in older age. For example,

self-reported lifelong moderate exercise was associated with controlled 6-month trial of aerobic exercise vs. a stretching
improved working memory, processing speed and global control condition for sedentary adults with mild cognitive
intelligence in post-menopausal women [153]. Regular exercise impairment [178], Baker et al. [165] found that the aerobic
during midlife, when many pathological disease processes likely exercise condition improved cardiorespiratory fitness, increased
begin, has been linked to reduced dementia risk and improved insulin sensitivity, reduced plasma Ab levels and augmented
cognitive profile in older adults [154,155]. Long-term exercise performance on multiple executive function tasks. In a 6-month,
has been shown to impact Alzheimer’s disease pathology as well. randomized, controlled trial [179], subjects who exercised at a
In a recent study, older adults who exercised at least 30 min per moderate intensity level demonstrated significant improvements
day, 5 days per week for at least 10 years demonstrated lower on the Alzheimer Disease Assessment Scale (Alzheimer’s
brain Ab deposition [using Pittsburgh compound B, PiB, on diseaseAS-Cog). Despite these positive findings, however,
positron emission tomography (PET) scan] [156]. Animal another recent study that employed a multi-modal exercise
models suggest that the benefits of aerobic exercise may begin programme for older adults with mild cognitive impairment who
early during the course of development by boosting neural lived in a structured living environment failed to show
reserves at a young age [157,158]. Human studies that rely on improvements in cognitive function despite an enhanced
retrospective self-report have connected level of physical activity cardiovascular profile [180]. The reason behind this
during adolescence and young adulthood to higher global discrepancy is not clear, but may suggest that, as cognitive
cognitive functioning in women and improved processing impairment progresses and a greater level of structure is required,
speed in men during older age [153,159]. Taken together, these individuals may benefit to a lesser degree from exercise
results suggest that a consistent lifelong exercise routine is likely intervention. These findings may thus have important
an important component in the primary prevention of cognitive implications for the potential of exercise to mediate cognition
decline and dementia. as neuropathological Alzheimer’s disease processes progress.
Despite a favourable relationship between cardiorespiratory
fitness and parietal and medial temporal lobe volume in patients
The impact of exercise during older age
with Alzheimer’s disease [181], the small number of exercise
Exercise and normal ageing: risk reduction intervention trials completed to date do not provide support for
Physical activity during older age is associated with improved improvements in cognitive abilities once clinical Alzheimer’s
cognitive functioning in areas commonly affected by the disease dementia is diagnosed [182]. A confounding factor,
normal ageing process, including processing speed, executive however, is the degree to which a moderate level of intensity may
function and memory [145,160–165]. Numerous large-scale be achieved in these studies.
epidemiological studies provide evidence that links physical
activity in older adults with reductions in the cognitive decline
experienced by non-exercisers [166–169]. Although large-scale Summary
exercise intervention trials have yet to be completed, smaller Himsworth’s astute observations 75 years ago regarding the
trials demonstrate that aerobic exercise has particularly clinical manifestations accompanying differences in insulin
significant effects for cognitive processes related to executive sensitivity remain remarkably relevant today, and have
functions, including selective and divided attention. These results expanded to encompass factors related to brain ageing and
are seen in both healthy and pre-diabetic older adults [145,170]. neurodegenerative disease. This expansion has led to the
Further, imaging studies demonstrate that exercise interventions identification of novel mechanisms that may contribute to the
result in reductions in age-related volume loss [171,172] and pathogenesis of conditions such as Alzheimer’s disease and,
more efficient brain activity in executive networks [173]. Indeed, subsequently, to a new array of therapeutic targets. The
12 months of exercise training increased hippocampal volume concurrent increase in the ageing population and in the
significantly, reversing age-related decline by approximately prevalence of insulin resistance raises the specter of a rapid
2 years [174]. Interestingly, some have suggested that older escalation in the incidence of dementia. Fortunately, insulin
adults may derive even more benefit from exercise than younger resistance and related factors that predispose the central nervous
adults with regard to improved cerebral vascular tone [175] and system toward Alzheimer’s disease pathology are responsive to
reduced cognitive decline [176]. lifestyle modification, offering a clear avenue to prevention.
Unlike many pharmacologic treatments, lifestyle intervention
Exercise and cognitive impairment: disease intervention strategies have pleiotropic effects and, as such, may be more
Recently, physical exercise has received attention as a potentially efficacious for treating multifactorial diseases such as
effective non-pharmacological strategy to prevent or slow decline Alzheimer’s disease. Alzheimer’s disease pathology begins
in older adults already experiencing mild cognitive changes many years prior to clinical symptomatology; thus, strategies
[177]. Although there are a limited number of intervention trials that focus on a ‘lifespan approach’ may achieve greater success
that specifically target mild cognitive impairment, initial results than tertiary pharmacologic interventions to reduce the terrible
from studies that include moderate- to high-intensity exercise burden of dementia to families and society. Although it is
interventions present promising results. In a small, randomized, not likely that Himsworth envisioned this goal directly, if

accomplished it will become one of the most important facets of expression, tyrosine phosphorylation, and signaling molecules in
his legacy. the hippocampus of water maze trained rats. J Biol Chem 1999;
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DIABETICMedicine

B. Cholerton, L. D. Baker and S. Craft

Accepted 28 September 2011

they are selectively distributed, with high concentrations in the

ª 2011 The Authors.

ª 2011 The Authors.

study that induced insulin resistance in the T2576 mouse model Aβ

Tg2576 mice fed a normal diet [50]. Diet-induced insulin IDE

ª 2011 The Authors.

Insulin is a key modulator of lipid metabolism, and insulin

ª 2011 The Authors.

ª 2011 The Authors.

ª 2011 The Authors.

ª 2011 The Authors.

ª 2011 The Authors.

ª 2011 The Authors.

ª 2011 The Authors.

ª 2011 The Authors.

ª 2011 The Authors.

ª 2011 The Authors.

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