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Long Acting Intranasal Insulin Detemir Improves Cognition for Adults with Mild Cognitive Impairment or Early-Stage Alzheimer's Disease Dementia


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Previous trials have shown promising effects of intranasally administered insulin for adults with Alzheimer's disease dementia (AD) or amnestic mild cognitive impairment (MCI). These trials used regular insulin, which has a shorter half-life compared to long-lasting insulin analogues such as insulin detemir. The current trial examined whether intranasal insulin detemir improves cognition or daily functioning for adults with MCI or AD. Sixty adults diagnosed with MCI or mild to moderate AD received placebo (n = 20), 20 IU of insulin detemir (n = 21), or 40 IU of insulin detemir (n = 19) for 21 days, administered with a nasal drug delivery device. Results revealed a treatment effect for the memory composite for the 40 IU group compared with placebo (p < 0.05). This effect was moderated by APOE status (p < 0.05), reflecting improvement for APOE-ε4 carriers (p < 0.02), and worsening for non-carriers (p < 0.02). Higher insulin resistance at baseline predicted greater improvement with the 40 IU dose (r = 0.54, p < 0.02). Significant treatment effects were also apparent for verbal working memory (p < 0.03) and visuospatial working memory (p < 0.04), reflecting improvement for subjects who received the high dose of intranasal insulin detemir. No significant differences were found for daily functioning or executive functioning. In conclusion, daily treatment with 40 IU insulin detemir modulated cognition for adults with AD or MCI, with APOE-related differences in treatment response for the primary memory composite. Future research is needed to examine the mechanistic basis of APOE-related treatment differences, and to further assess the efficacy and safety of insulin detemir.
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Journal of Alzheimer’s Disease xx (20xx) x–xx
DOI 10.3233/JAD-141791
IOS Press
Long-Acting Intranasal Insulin Detemir
Improves Cognition for Adults with Mild
Cognitive Impairment or Early-Stage
Alzheimer’s Disease Dementia
Amy Claxtona,b, Laura D. Bakerc, Angela Hansona,b, Emily H. Trittschuha,b, Brenna Cholertonb,
Amy Morgana,b, Maureen Callaghana,b, Matthew Arbuckled, Colin Behla,band Suzanne Craftc,
aGeriatric Research, Education, & Clinical Center, Veterans Affairs Puget Sound Health Care System, Seattle,
Washington, USA
bDepartment of Psychiatry & Behavioral Science, University of Washington School of Medicine, Seattle,
Washington, USA
cDepartment of Internal Medicine, Wake Forest School of Medicine, Winston-Salem, North Carolina, USA11
dDepartment of Psychiatry, Oregon Health and Science University, Portland, Oregon, USA12
Accepted 29 September 2014
Abstract. Previous trials have shown promising effects of intranasally administered insulin for adults with Alzheimer’s disease
dementia (AD) or amnestic mild cognitive impairment (MCI). These trials used regular insulin, which has a shorter half-life
compared to long-lasting insulin analogues such as insulin detemir. The current trial examined whether intranasal insulin detemir
improves cognition or daily functioning for adults with MCI or AD. Sixty adults diagnosed with MCI or mild to moderate AD
received placebo (n= 20), 20 IU of insulin detemir (n= 21), or 40 IU of insulin detemir (n= 19) for 21 days, administered
with a nasal drug delivery device. Results revealed a treatment effect for the memory composite for the 40 IU group compared
with placebo (p< 0.05). This effect was moderated by APOE status (p< 0.05), reflecting improvement for APOE-4 carriers
(p< 0.02), and worsening for non-carriers (p< 0.02). Higher insulin resistance at baseline predicted greater improvement with
the 40 IU dose (r= 0.54, p< 0.02). Significant treatment effects were also apparent for verbal working memory (p< 0.03) and
visuospatial working memory (p< 0.04), reflecting improvement for subjects who received the high dose of intranasal insulin
detemir. No significant differences were found for daily functioning or executive functioning. In conclusion, daily treatment with
40 IU insulin detemir modulated cognition for adults with AD or MCI, with APOE-related differences in treatment response
for the primary memory composite. Future research is needed to examine the mechanistic basis of APOE-related treatment
differences, and to further assess the efficacy and safety of insulin detemir.
Keywords: Alzheimer’s disease, clinical trials, randomized, insulin, intranasal drug administration, mild cognitive impairment27
The importance of insulin in normal brain function29
is underscored by evidence that insulin dysregulation
Correspondence to: Suzanne Craft, PhD, Wake Forest School of
Medicine, Medical Center Boulevard, Winston-Salem, NC 27157-
1207, USA. Tel.: +1 336 713 8832; Fax: +1 336 713 8800; E-mail:
contributes to the pathophysiology of Alzheimer’s dis- 30
ease (AD) [1–3]. Research in animals and humans has 31
shown that AD pathology is associated with lower lev- 32
els of insulin in the cerebrospinal fluid [4]. Insulin has 33
a close relationship with amyloid-(A), the peptide 34
produced by cleavage of the amyloid-protein pre- 35
cursor. Apathologically aggregates to form plaques 36
in AD, and its oligomeric form is synaptotoxic even 37
ISSN 1387-2877/14/$27.50 © 2014 – IOS Press and the authors. All rights reserved
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2A. Claxton et al. / Intranasal Insulin Detemir and Dementia
prior to plaque deposition [5]. In vitro and in ani-38
mal models, insulin reduces Aoligomer formation
and protects against A-induced synaptotoxicty and
long-term potentiation disruption [2, 6]. Consequently,41
disruptions in brain insulin signaling have been sug-42
gested as one of the primary pathophysiological factors43
in the development of AD. Clinical studies have doc-44
umented substantial, progressive disturbances in brain45
glucose utilization and responsiveness to insulin and46
insulin-like growth factor stimulation that co-occur
with progression of AD [7, 8]. Disruption in central48
insulin regulation (also referred to as brain insulin
resistance) induces pathological features of AD, and50
can be caused by attenuated expression of insulin51
receptors and insulin-like growth factor, reduced brain52
insulin receptor sensitivity, or increased serine phos-53
phorylation of downstream insulin signaling molecules
[1, 9, 10]. Impaired transport of insulin across the
blood-brain barrier may also result in deficient lev-56
els of insulin in the central nervous system (CNS).
Thus, enhancing brain insulin may prevent AD-related58
pathological processes.59
Recent clinical trials have yielded promising effects60
of intranasally administered insulin for adults diag-61
nosed with mild AD dementia or amnestic mild
cognitive impairment (MCI) [11–13]. In a pilot trial,63
adults diagnosed with mild AD or MCI who received
a 20 IU daily dose of intranasal insulin improved in
delayed memory, and participants receiving either a 2066
or 40 IU dose improved on caregiver-rated functional
ability [13]. Both doses of insulin were associated
with preserved cognition for younger participants on69
the Alzheimer’s Disease Assessment Scale-Cognitive70
subscale, and preserved glucose uptake was noted
for participants taking intranasal insulin on FDG-PET72
scans in the parietotemporal, frontal, precuneus, and73
cuneus regions. The improvements in episodic mem-
ory were still present two months after cessation of
treatment [13].
Prior studies have also demonstrated that treatment
response to many AD therapies is moderated by car-78
riage of the apolipoprotein E-4 (APOE-4) allele79
[14]. In particular, research has indicated that both80
peripheral and central insulin metabolism, as well as81
insulin-altering therapies, are modulated by the APOE-82
4 allele [4, 15–17]. The APOE-4 allele is known
to increase the risk of developing sporadic AD, but
the mechanism of action is not fully elucidated [14].
Previous studies have demonstrated APOE-4-related
differences in response to various AD therapies, and in
particular to the therapeutic effects of insulin [16, 18].
In two pilot studies, treatment response was strongest
for APOE-4 negative older adults with mild mem- 90
ory problems or AD [11, 19], whereas in another 91
study, APOE-4 positive adults showed greater sensi- 92
tivity to insulin at lower doses [20]. Other studies have 93
also found interactions between APOE-4 carriage and 94
central insulin or glucose action [18, 21]. 95
The previous clinical trials for AD described above 96
have all used regular insulin, which has a relatively 97
short half-life and mimics post prandial release and 98
in general have observed the most reliable benefits 99
with doses of 20 or 40 IU daily. The long-acting 100
insulin analog insulin detemir, because of the acy- 101
lation of a 14-carbon fatty acid to lysine at locus 102
B29, displays increased self-association and reversible 103
albumin binding [22], which delays absorption of the 104
molecule and thereby reduces the risk of hypoglycemic 105
episodes [23]). Due to its increased lipophilicity, 106
detemir may reach higher concentrations in the cere- 107
brospinal fluid and brain than regular insulin [24]. 108
The issue of whether detemir crosses the blood-brain 109
barrier (BBB) is controversial. Although it has been 110
described to have greater capacity to cross the BBB 111
with potential for correspondingly increased cognitive 112
benefit [25], elegant work in rodents has suggested 113
that detemir does not penetrate the BBB [26], and 114
thus intranasal or intracerebroventricular administra- 115
tion may be needed to ensure delivery to the brain. 116
Although this issue remains unresolved in humans or in 117
diseases with impaired BBB permeability, detemir has 118
been shown to be as effective or more so than regular 119
insulin at reducing hyperglycemia and nocturnal hypo- 120
glycemic episodes [27]. In vivo studies have shown 121
that detemir demonstrates increased insulin-signaling 122
in the hypothalamus and cerebrocortical tissue com- 123
pared to regular insulin [28], suggesting that detemir 124
may have greater central action compared to regular 125
insulin. Another study comparing euglycemic infusion 126
of detemir with regular insulin reported that detemir 127
triggered a larger shift in EEG DC-potential recordings 128
in healthy men, supporting the hypothesis that detemir 129
affects brain functions to a greater extent than does 130
regular insulin [29]. The peripheral effects of detemir 131
also appear to vary according to baseline metabolic sta- 132
tus, with greater effects on weight and other metabolic 133
outcomes observed for adults who are more insulin 134
resistant or obese [25, 30]. 135
Intranasal administration of detemir has not pre- 136
viously been tested in adults with neurodegenerative 137
disease. Because it has a different structure than regu- 138
lar insulin, with more prolonged elevations and greater 139
CNS penetration, its safety and efficacy may differ 140
from regular insulin. In the current pilot study, we 141
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A. Claxton et al. / Intranasal Insulin Detemir and Dementia 3
examined the safety profile and efficacy of two doses142
of insulin detemir for treatment of adults diagnosed
with AD or amnestic MCI compared with placebo,
using a three week protocol that effectively revealed145
cognitive and safety profiles in early studies of reg-146
ular insulin [12], and that would provide necessary147
information to design future longer trials. We hypoth-148
esized that, compared with placebo, intranasal detemir149
would be associated with improved performance on150
an episodic memory composite. Secondary hypothe-
ses predicted that daily function and working memory152
would improve for adults with MCI or AD tak-
ing intranasal insulin detemir versus placebo. Given154
previous findings of APOE-related differences and155
metabolism-related differences in treatment response,156
APOE-4 carrier and peripheral metabolic status were157
examined as possible mediating factors in a priori sec-
ondary analyses.
The trial was registered at clinicaltrials.gov162
(NCT01547169) and conducted over a 2-year period.163
The study was approved by the Institutional Review
Boards of the University of Washington and the
Veterans Affairs Puget Sound Health Care System166
and was conducted in the Veterans Affairs Clini-
cal Research Unit. Written informed consent was
obtained from all participants. A total of 60 older
adults enrolled in our study (39 participants with
amnestic MCI and 21 participants with probable AD171
with Mini-Mental State Examination (MMSE) scores172
>15). Diagnoses and eligibility were determined by
consensus of expert physicians and neuropsycholo-174
gists following cognitive testing, evaluation of medical175
history, physical examination, and clinical laboratory
screening using modified Petersen criteria for the diag-
nosis of amnestic MCI [12, 31] and National Institute
for Neurological and Communicative Disorders and
Stroke–Alzheimer’s Disease and Related Disorders180
Association criteria for AD [32]. For participants with181
amnestic MCI, cognitive scores were compared with182
an age- and education-adjusted estimate of the par-183
ticipant’s premorbid ability (Shipley Vocabulary test).
Participants whose delayed memory scores deviated at
least 1.5 SDs from this estimate were considered for
the diagnosis of amnestic MCI, which was then deter-
mined by expert consensus using all available data,
following published criteria [31].
Participants were free from psychiatric disorders, 190
alcoholism, severe head trauma, hypoxia, neurologic 191
disorders other than amnestic MCI or AD, renal or 192
hepatic disease, diabetes mellitus, chronic obstruc- 193
tive pulmonary disease, and unstable cardiac disease. 194
Participants and all study personnel involved in data 195
collection were blinded to treatment assignment. Treat- 196
ment groups did not differ significantly in terms of age, 197
education, body mass index, general cognitive status 198
as assessed by the modified MMMSE, gender, diagno- 199
sis, whether they received anticholinesterase inhibitors 200
or memantine, or whether they carried the APOE- 201
4 allele. Enrollment data are presented in Fig. 1, 202
and baseline demographic information is presented in 203
Table 1. 204
Procedures 205
Participants were randomly assigned to receive a 206
daily dosage of 20 IU of insulin detemir (10 IU detemir 207
b.i.d.), 40 IU of insulin detemir (20 IU detemir b.i.d.), 208
or placebo (saline b.i.d.) for 21 days. Saline or insulin 209
detemir (Levemir®; Novo Nordisk, Princeton, New 210
Jersey) was administered after breakfast and dinner 211
with a ViaNase nasal drug delivery device (Kurve 212
Technology, Bothell, Washington) designed to deliver 213
drugs to the olfactory cleft region to maximize trans- 214
port to the CNS. This device released a metered dose 215
of saline or detemir into a chamber covering the par- 216
ticipant’s nose over a 2-min period, which was inhaled 217
by breathing regularly. The choice of the 20 and 40 IU 218
doses was based on our prior work in which similar 219
doses of regular insulin enhanced cognition [11–13]. 220
Dosing of insulin analogues has been calibrated to reg- 221
ular insulin by the pharmaceutical industry such that 222
IU measurements of regular insulin and insulin detemir 223
are equivalent. As this pilot study represents the first 224
attempt to administer detemir to older adults with neu- 225
rodegenerative disease, we used 20 and 40 IU doses 226
and a three-week treatment duration that in previous 227
studies of regular insulin provided initial indications 228
of safety and efficacy to support additional longer-term 229
investigation. 230
Parallel versions of the cognitive and functional pro- 231
tocol were administered at baseline and after 21 days 232
of treatment. Testing occurred in the morning after 233
a standard meal. Participants were instructed to skip 234
their morning dose on the day of testing and thus had 235
received their last dose more than 12 h prior to cog- 236
nitive testing. The primary outcome measure was a 237
verbal memory composite score calculated from the 238
sum of z-scores from the following four measures: 239
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4A. Claxton et al. / Intranasal Insulin Detemir and Dementia
Fig. 1. Patient enrollment flowchart for the trial, which examines the effects of intranasal insulin detemir administration on cognition and
function in adults with amnestic mild cognitive impairment or Alzheimer’s disease.
immediate story recall, delayed story recall, imme-240
diate word list recall, and delayed word list recall.
Immediate and delayed story recall [12] were deter-
mined after a story containing 44 informational bits243
was read a single time to participants, who were244
then asked to recall the story immediately and again245
after a 20-min delay. Immediate and delayed word246
list recall scores were derived from a 12-word Selec-247
tive Reminding Word List task [33]. A higher score
on the verbal memory composite indicates a better249
performance on these verbal memory measures. The250
four secondary outcome measures include tests of
verbal working memory, visuospatial working mem-
ory, executive function, and caregiver-rated functional
ability. Verbal working memory was measured by
the Dot Counting N-back, in which participants were
asked to count out loud the number of targets on256
consecutive computer displays. After n-number of dis-257
plays, subjects recalled the number of targets presented258
on previous displays. Visuospatial working memory259
was assessed using the Benton Visual Retention Test260
(BVRT), Forms F and G, which is an object recognition261
memory paradigm [34]. For this task, subjects viewed262
a 2-D design and then identified this design included263
in an array containing three additional, highly simi- 264
lar distractors. Executive functioning was determined 265
with a computer-administered version of Stroop Color- 266
Word Interference task, a test of selective attention 267
and response inhibition. In this task, color names were 268
presented on a computer screen in concordant or dis- 269
cordant font colors (e.g., the word “red” was presented 270
in either red or green font). For each of four alternating 271
trial blocks, participants either read the word or named 272
the font color as quickly as possible, and response 273
latency (voice onset) and content were recorded. The 274
reaction time variable was determined by taking the 275
average of the response latency from each correct trial. 276
Each trial was preceded by a displayed reminder of 277
task instruction to minimize memory load. Finally, 278
caregiver-rated functional ability was measured by the 279
Dementia Severity Rating Scale (DSRS) [35], in which 280
the study partner rated the change in the participant’s 281
cognitive, social, and functional status over a specified 282
period of time, with higher scores indicating greater 283
impairment. 284
Cognitive scores for each of the two detemir dose 285
groups were compared to the placebo group using 286
repeated measures analysis of covariance (ANCOVA). 287
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Age, diagnosis, MMSE score, gender, body mass index288
(BMI) and APOE-4 allele status were statistically
examined as covariates.
Metabolic Measures291
Participants underwent oral glucose tolerance test-292
ing (OGTT) 1–2 days prior to cognitive baseline testing
and study drug initiation and 1–2 days after cognitive294
testing on day 21 but prior to study drug discontinua-295
tion. Blood was collected from fasting participants and
they then consumed a drink containing 75 g glucose.
Blood was collected at 15, 30, 60, 90, and 120 min298
after beverage consumption. Samples were immedi-
ately placed on ice and spun at 2,200 rpm in a cold300
centrifuge for 15 min, after which plasma, serum, lym-
phocytes, and red blood cells were aliquoted into302
separate storage tubes and flash frozen at –70C. Blood
glucose was measured via Accu-chek®glucose meters.304
Insulin resistance was calculated using the homeostatic305
model assessment of insulin resistance (HOMA-IR),
a well-validated measure of insulin resistance calcu-307
lated using fasting glucose and fasting insulin values308
obtained prior to administration of the OGTT bev-309
erage [36]. Another index of insulin resistance was
derived from insulin and glucose levels during the311
OGTT: Insulin Area under the Curve (Insulin AUC)
adjusted for glucose AUC was calculated using the
trapezoidal rule in order to provide a secondary mea-
sure of insulin resistance that takes insulin response to315
a glucose challenge into account.316
Safety and Compliance
Study partners supervised participants in the admin-318
istration of intranasal treatment. Blood glucose levels
were measured daily for the first week and then320
weekly thereafter; no episodes of hypoglycemia were321
observed. Compliance was monitored by quantifying
unused medication and via self-report. Safety data
were reviewed semiannually by a data safety monitor-
ing board. Adverse event reporting followed standard
guidelines. Fasting plasma glucose values obtained
from each study visit are reported in Supplementary327
Table 1.328
Statistical Analyses
Data were analyzed with SPSS version 18. For330
the intent-to-treat sample, primary and secondary
cognitive and functional outcome scores were log-
transformed to normalize distributions. To test the
primary hypothesis that 21 days of treatment with 334
detemir would improve cognition and daily func- 335
tion, the a priori analytic plan called for each of 336
the insulin-treated groups to be compared with the 337
placebo group. Outcomes scores were subjected to 338
mixed-model repeated-measures analysis of covari- 339
ance, including treatment group (placebo and 20 IU of 340
detemir; placebo and 40 IU of detemir) as the between- 341
subjects factor, and time (baseline and day 21) as the 342
repeated factor, using the general linear models proce- 343
dure, type III sums of squares. Age, diagnosis (MCI 344
or AD), gender, APOE-4 carriage status (yes or no), 345
BMI, baseline modified MMSE score, and years of 346
education were also included as covariates. Nonsignif- 347
icant covariates were dropped from the final model. 348
The three treatment groups did not differ at baseline 350
on any outcome measure. There were also no group 351
differences with respect to age, education, BMI, fast- 352
ing insulin, fasting glucose, gender, APOE-4 carriage 353
status, or MMSE score. For ease of interpretation, the 354
change in adjusted means from Time 1 (pre-treatment) 355
to Time 2 (post-treatment) is graphed to illustrate 356
significant results (Figs. 2–5). Non-log transformed 357
baseline and post-treatment group means for all mea- 358
sures are included in Supplementary Table 2 and are 359
presented by diagnosis in Supplementary Table 3. 360
Primary Outcome 361
No significant overall effects for the verbal memory 362
composite were observed for the 20 or 40 IU dose com- 363
parisons. However, a significant treatment by time by 364
APOE-4 carriage interaction was observed for the 40 365
IU dose comparison (p= 0.03); interestingly, planned 366
post hoc analyses revealed that APOE-4 positive car- 367
riers taking 40 IU intranasal detemir showed significant 368
improvement in verbal memory (p= 0.02), whereas 369
APOE-4 negative participants taking 40 IU intranasal 370
detemir showed a significant decline in verbal mem- 371
ory (p= 0.02) (see Fig. 2). No effects were observed 372
for other covariates. 373
Secondary Cognitive Outcomes 374
Overall analyses revealed significant improvement 375
for the 40 IU group on both working memory tasks. For 376
verbal working memory (Dot Counting N-back), a sig- 377
nificant overall treatment group ×time interaction was 378
observed indicating improved verbal working memory 379
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6A. Claxton et al. / Intranasal Insulin Detemir and Dementia
Fig. 2. Change in composite memory score from baseline to day 21, by treatment group and APOE-4 carriage.
Fig. 3. Change in verbal working memory as measured by the Dot
Counting N-Back Task from baseline to day 21, by treatment group.
in the 40 IU group versus the placebo group (p= 0.03;380
see Fig. 3). For visuospatial working memory (BVRT),381
a significant overall treatment group ×time interaction382
was also observed (p= 0.04; see Fig. 4), indicating that383
subjects taking 40 IU of intranasal detemir showed
improved visuospatial working memory versus those385
in the placebo group. No significant interactions were386
observed with APOE status or other covariates, and387
no significant differences were noted for subjects who388
received the 20 IU dose versus placebo. For tests389
of executive function (Stroop) and daily functioning390
(DSRS), there were no significant treatment ×group391
effects for either dose comparison.392
Metabolic Outcomes393
As expected, higher baseline BMI was associated394
with higher baseline insulin resistance (p< 0.01).395
Fig. 4. Change in visuospatial working memory as measured by the
BVRT from baseline to day 21, by treatment group.
In addition, APOE-4 carriage was associated with 396
higher baseline Insulin AUC (t=2.05; p< 0.05). 397
There were no significant differences between APOE- 398
4 carriers and non-carriers in the cholesterol 399
profile (see Supplementary Table 4). For insulin 400
resistance (HOMA-IR), the overall treatment ×time 401
effect was not significant. However, there was a 402
treatment effect on insulin resistance with respect 403
to APOE-4 carriage status for the 40 IU dose 404
of detemir (treatment×time×APOE-4 interaction: 405
p< 0.01 compared to the placebo group). For those 406
with APOE-4 negative status, the higher dose of 407
intranasal insulin detemir was associated with an 408
increase in insulin resistance across 21 days. For 409
those with APOE-4 positive status, taking intranasal 410
detemir was associated with reduced insulin resistance 411
across the 21 days (see Fig. 5). There were no signifi- 412
cant treatment effects for Insulin AUC. 413
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A. Claxton et al. / Intranasal Insulin Detemir and Dementia 7
Fig. 5. Change in HOMA-IR from baseline to day 21, by treatment group and APOE-4 carriage.
Safety and Compliance
No treatment-related severe adverse events occurred
during the study, and most adverse events were minor,
such as dizziness or mild rhinitis. There were no
episodes of hypoglycemia. The adverse events are418
listed in Table 3. The total number of adverse events419
was lower for the 20 IU detemir group compared with420
the placebo group (p< 0.05). Mean compliance (num-
ber of completed doses) was 98% and ranged from 89%422
to 100%. Compliance did not differ across treatment423
Treatment with 40 IU intranasal detemir was asso-426
ciated with improved verbal memory for adults with427
MCI and AD who were APOE-4 allele carriers, and428
improved visuospatial and verbal working memory
for all participants. APOE-4 allele carriers taking430
the higher dose of intranasal detemir also experi-431
enced improvement in peripheral insulin resistance
across three weeks of treatment. Conversely, APOE-
4 negative individuals treated with the higher dose
of detemir experienced increased peripheral insulin435
resistance across three weeks of treatment. No effect436
was shown for executive functioning or caregiver-rated437
daily functioning with 40 IU detemir, or for any of the438
cognitive outcomes after treatment with 20 IU detemir.439
The current study marks the first time a long-acting440
insulin analogue has been administered intranasally
to individuals with AD or amnestic MCI. This pilot
study provides initial evidence that detemir can be
safely administered to individuals with AD or MCI, 444
and may enhance cognition for some groups. Of note, 445
there were some key differences in the response to 446
intranasal detemir compared with previous clinical 447
trials that utilized regular insulin that support the pos- 448
sibility that insulin analogues may differ with respect 449
to optimal therapeutic doses. Whereas a lower dose 450
(20 IU daily) of regular insulin was effective for ver- 451
bal memory in a previous study of individuals with 452
AD or MCI, the 40 IU dose of intranasal detemir was 453
most consistently associated with positive outcomes in 454
the current study. It is possible that the different phar- 455
macodynamic profiles of insulin formulations explain 456
this finding. While detemir has a longer half-life that 457
results in greater cumulative exposure, regular insulin 458
mimics postprandial release and reaches a higher peak, 459
and thus may activate mechanisms underlying episodic 460
memory enhancement at lower doses. Interestingly, 461
rapid acting insulin aspart, which achieves the highest 462
peak concentration after administration, reportedly has 463
greater memory-enhancing effects than regular insulin 464
[37]. Detemir also has a lower affinity for insulin 465
receptors than does regular insulin, which may induce 466
different dose requirements [38]. 467
Our results provide additional evidence that APOE 468
genotype may influence response to intranasal insulin 469
treatment in adults with MCI and AD. Interestingly, 470
unlike previous studies with regular insulin, APOE-4471
positive carriers showed greater improvement in ver- 472
bal episodic memory with 40 IU intranasal detemir. 473
Although the mechanisms underlying this effect can- 474
not be determined from the present study, detemir’s 475
greater lipophilicity and albumin-binding properties 476
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8A. Claxton et al. / Intranasal Insulin Detemir and Dementia
that are the basis of its protracted exposure profile may477
have played a role. Differences in amount or char-
acteristics of albumin have been shown to modulate
detemir’s efficacy [39]. Albumin binding capacity and480
the albuminome are reportedly affected in various dis-481
ease states such as cardiovascular and renal disease.482
Higher levels of post-translational glycation and nitra-483
tion have reported in plasma and brain albumin in484
ADs patients that affect its ability to bind A[40, 41].485
APOE4 carriers with AD have increased vulnerability
to nitration [42], and thus may have a greater ten-487
dency for post-translational modifications of albumin,
ultimately contributing to APOE-related differences in489
response to detemir [43]. These interesting possibilities490
require confirmation and further elucidation.491
We also noted APOE-related differences in the492
effects of detemir on an index of insulin resistance,
such that APOE4 participants in the 40 IU group had
improved insulin resistance whereas participants with-495
out the APOE4 allele had worsened insulin resistance,
changes which paralleled detemir effects on verbal497
episodic memory. Although peripherally-administered498
detemir has been shown to improve glucose regula-499
tion in adults with diabetes, some investigators have500
suggested that prolonged insulin exposure may pro-
mote insulin resistance in vulnerable individuals. For502
example, detemir has been shown to worsen insulin
resistance in adults with particular metabolic profiles
that may associate with APOE genotype, such as non-505
alcoholic steatosis (“fatty liver”) [44–46]. Although
there were no differences between APOE4 carriers and
non-carriers with respect to BMI or fasting glucose508
values, more in depth metabolic characteristics such509
as liver fat were not assessed.
It is also interesting that beneficial effects of 40511
IU detemir on working memory were independent512
of APOE status. Working memory is preferentially
mediated by the prefrontal and limbic systems [47],
whereas verbal memory is associated with medial tem-
poral/hippocampal circuits [48]. This pattern of results
is consistent with previous clinical trials that show517
that different cognitive functions may have different518
dose response profiles [19], and underscore the impor-519
tance of examining cognitive functions individually in520
addition to examining performance on global cognitive521
An important goal of the present pilot study was
to determine whether insulin detemir held sufficient
promise as an AD treatment to support further inves-
tigation. Taken together, the benefits of detemir on
memory and metabolic status provide a strong rationale
for further examination of its therapeutic potential in
APOE-4 carriers. In APOE-4 non-carriers, a mixed 529
picture was obtained, with improved working memory 530
but worsened episodic memory and metabolic status. 531
Additional study is needed to confirm this APOE- 532
related pattern, potentially in a future Phase II study 533
of moderate duration. If confirmed, this pattern would 534
represent an important pharmacogenomic advance for 535
AD therapeutics. 536
In conclusion, AD is a devastating illness, for which 537
even small therapeutic gains have the potential to 538
improve quality of life and significantly reduce the 539
overall burden for patients, families, and society. Pre- 540
vious work has suggested that intranasal insulin may 541
be a safe and effective treatment for the cognitive 542
decline associated with AD. The current pilot study 543
provides preliminary evidence that 40 IU intranasal 544
detemir may provide effective treatment for individuals 545
diagnosed with MCI and AD dementia, and in partic- 546
ular for memory-impaired adults who are APOE-4547
carriers, a subgroup of patients notoriously resistant 548
to therapeutic intervention [49]. Future longer-term 549
studies are warranted to confirm this pattern and fur- 550
ther examine the safety and efficacy for this promising 551
treatment. 552
Suzanne Craft and Amy Claxton had full access to 554
all of the data in the study and take responsibility for the 555
integrity of the data and the accuracy of the data analy- 556
sis. This research was supported by National Institute 557
of Aging grants P50 AG05136 (to Dr. Craft) and T32 558
AG000258 (to Dr. Claxton), and the Department of 559
Veterans Affairs. 560
Authors’ disclosures available online (http://www.j- 561
[]). 562
The supplementary material is available in the 564
electronic version of this article: 565
10.3233/JAD-141791. 566
[1] Rivera EJ, Goldin A, Fulmer N, Tavares R, Wands JR, de 568
la Monte SM (2005) Insulin and insulin-like growth fac- 569
tor expression and function deteriorate with progression of 570
Alzheimer’s disease: Link to brain reductions in acetyl- 571
choline. J Alzheimers Dis 8, 247-268. 572
[2] Gasparini L, Gouras GK, Wang R, Gross RS, Beal MF, 573
Greengard P, Xu H (2001) Stimulation of beta-amyloid pre- 574
cursor protein trafficking by insulin reduces intraneuronal 575
Uncorrected Author Proof
A. Claxton et al. / Intranasal Insulin Detemir and Dementia 9
beta-amyloid and requires mitogen-activated protein kinase
signaling. J Neurosci 21, 2561-2570.577
[3] Craft S, Watson GS (2004) Insulin and neurodegenerative578
disease: Shared and specific mechanisms. Lancet Neurol 3,
[4] Craft S, Peskind E, Schwartz MW, Schellenberg GD, Raskind581
M, Porte D, Jr. (1998) Cerebrospinal fluid and plasma insulin582
levels in Alzheimer’s disease: Relationship to severity of583
dementia and apolipoprotein E genotype. Neurology 50,584
[5] Tomiyama T (2010) [Involvement of beta-amyloid in586
the etiology of Alzheimer’s disease]. Brain Nerve 62,
[6] Lee CC, Kuo YM, Huang CC, Hsu KS (2009) Insulin rescues
amyloid beta-induced impairment of hippocampal long-term590
potentiation. Neurobiol Aging 30, 377-387.591
[7] de la Monte SM, Wands JR (2008) Alzheimer’s disease is592
type 3 diabetes-evidence reviewed. J Diabetes Sci Technol 2,593
[8] de la Monte SM (2012) Brain insulin resistance and deficiency
as therapeutic targets in Alzheimer’s disease. Curr Alzheimer
Res 9, 35-66.597
[9] Talbot K, Wang HY, Kazi H, Han LY, Bakshi KP, Stucky
A, Fuino RL, Kawaguchi KR, Samoyedny AJ, Wilson RS,
Arvanitakis Z, Schneider JA, Wolf BA, Bennett DA, Tro-
janowski JQ, Arnold SE (2012) Demonstrated brain insulin601
resistance in Alzheimer’s disease patients is associated with602
IGF-1 resistance, IRS-1 dysregulation, and cognitive decline.603
J Clin Invest 122, 1316-1338.604
[10] Bomfim TR, Forny-Germano L, Sathler LB, Brito-Moreira605
J, Houzel JC, Decker H, Silverman MA, Kazi H, Melo
HM, McClean PL, Holscher C, Arnold SE, Talbot K, Klein607
WL, Munoz DP, Ferreira ST, De Felice FG (2012) An anti-608
diabetes agent protects the mouse brain from defective insulin609
signaling caused by Alzheimer’s disease- associated Abeta610
oligomers. J Clin Invest 122, 1339-1353.611
[11] Reger MA, Watson GS, Green PS, Baker LD, Cholerton B,612
Fishel MA, Plymate SR, Cherrier MM, Schellenberg GD,613
Frey WH, 2nd, Craft S (2008) Intranasal insulin administra-
tion dose-dependently modulates verbal memory and plasma
amyloid-beta in memory-impaired older adults. J Alzheimers616
Dis 13, 323-331.617
[12] Reger MA, Watson GS, Green PS, Wilkinson CW, Baker LD,618
Cholerton B, Fishel MA, Plymate SR, Breitner JC, DeGroodt
W, Mehta P, Craft S (2008) Intranasal insulin improves cogni-
tion and modulates beta-amyloid in early AD. Neurology 70,
[13] Craft S, Baker LD, Montine TJ, Minoshima S, Watson GS,623
Claxton A, Arbuckle M, Callaghan M, Tsai E, Plymate SR,624
Green PS, Leverenz J, Cross D, Gerton B (2012) Intranasal625
insulin therapy for Alzheimer disease and amnestic mild cog-
nitive impairment: A pilot clinical trial. Arch Neurol. 69,627
[14] Farrer LA, Cupples LA, Haines JL, Hyman B, Kukull WA,629
Mayeux R, Myers RH, Pericak-Vance MA, Risch N, van630
Duijn CM (1997) Effects of age, sex, and ethnicity on the asso-631
ciation between apolipoprotein E genotype and Alzheimer632
disease. A meta-analysis. APOE and Alzheimer Disease Meta633
Analysis Consortium. JAMA 278, 1349-1356.634
[15] Craft S, Asthana S, Schellenberg G, Cherrier M, Baker635
LD, Newcomer J, Plymate S, Latendresse S, Petrova636
A, Raskind M, Peskind E, Lofgreen C, Grimwood K
(1999) Insulin metabolism in Alzheimer’s disease dif-638
fers according to apolipoprotein E genotype and gender.
Neuroendocrinology 70, 146-152.640
[16] Craft S, Asthana S, Schellenberg G, Baker L, Cherrier M, 641
Boyt AA, Martins RN, Raskind M, Peskind E, Plymate S 642
(2000) Insulin effects on glucose metabolism, memory, and 643
plasma amyloid precursor protein in Alzheimer’s disease dif- 644
fer according to apolipoprotein-E genotype. Ann N Y Acad 645
Sci. 903, 222-228. 646
[17] Aisen PS, Berg JD, Craft S, Peskind ER, Sano M, Teri L, 647
Mulnard RA, Thomas RG, Thal LJ (2003) Steroid-induced 648
elevation of glucose in Alzheimer’s disease: Relationship to 649
gender, apolipoprotein E genotype and cognition. Psychoneu- 650
roendocrinology 28, 113-120. 651
[18] Craft S, Peskind E, Schwartz MW, Schellenberg GD, Raskind 652
M, Porte D, Jr. (1998) Cerebrospinal fluid and plasma insulin 653
levels in Alzheimer’s disease: Relationship to severity of 654
dementia and apolipoprotein E genotype. Neurology 50, 164- 655
168. 656
[19] Claxton A, Baker LD, Wilkinson CW, Trittschuh EH, Chap- 657
man D, Watson GS, Cholerton B, Plymate SR, Arbuckle 658
M, Craft S (2013) Sex and ApoE genotype differences in 659
treatment response to two doses of intranasal insulin in 660
adults with mild cognitive impairment or Alzheimer’s disease. 661
J Alzheimers Dis 35, 789-797. 662
[20] Craft S, Asthana S, Cook DG, Baker LD, Cherrier M, 663
Purganan K, Wait C, Petrova A, Latendresse S, Watson 664
GS, Newcomer JW, Schellenberg GD, Krohn AJ (2003) 665
Insulin dose-response effects on memory and plasma amy- 666
loid precursor protein in Alzheimer’s disease: Interactions 667
with apolipoprotein E genotype. Psychoneuroendocrinology 668
28, 809-822. 669
[21] Reiman EM, Chen K, Alexander GE, Caselli RJ, Bandy D, 670
Osborne D, Saunders AM, Hardy J (2004) Functional brain 671
abnormalities in young adults at genetic risk for late-onset 672
Alzheimer’s dementia. Proc Natl Acad SciUSA101, 284- 673
289. 674
[22] Kurtzhals P (2004) Engineering predictability and protrac- 675
tion in a basal insulin analogue: The pharmacology of insulin 676
detemir. Int J Obes Relat Metab Disord 28, S23-28. 677
[23] De Leeuw I, Vague P, Selam JL, Skeie S, Lang H, Draeger E, 678
Elte JW (2005) Insulin detemir used in basal-bolus therapy in 679
people with type 1 diabetes is associated with a lower risk of 680
nocturnal hypoglycaemia and less weight gain over 12 months 681
in comparison to NPH insulin. Diabetes Obes Metab 7, 73-82. 682
[24] Shen DD, Artru AA, Adkison KK (2004) Principles and appli- 683
cability of CSF sampling for the assessment of CNS drug 684
delivery and pharmacodynamics. Adv Drug Deliv Rev 56,685
1825-1857. 686
[25] Tschritter O, Hennige AM, Preissl H, Porubska K, Schafer 687
SA, Lutzenberger W, Machicao F, Birbaumer N, Fritsche A, 688
Haring HU (2007) Cerebrocortical beta activity in overweight 689
humans responds to insulin detemir. PLoS One 2, e1196. 690
[26] Banks WA, Morley JE, Lynch JL, Lynch KM, Mooradian AD 691
(2010) Insulin detemir is not transported across the blood- 692
brain barrier. Peptides 31, 2284-2288. 693
[27] Monami M, Marchionni N, Mannucci E (2009) Long-acting 694
insulin analogues vs. NPH human insulin in type 1 diabetes. 695
A meta-analysis. Diabetes Obes Metab 11, 372-378. 696
[28] Hennige AM, Sartorius T, Tschritter O, Preissl H, Fritsche A, 697
Ruth P, Haring HU (2006) Tissue selectivity of insulin detemir 698
action in vivo.Diabetologia 49, 1274-1282. 699
[29] Hallschmid M, Jauch-Chara K, Korn O, Molle M, Rasch 700
B, Born J, Schultes B, Kern W (2010) Euglycemic infusion 701
of insulin detemir compared with human insulin appears to 702
increase direct current brain potential response and reduces 703
food intake while inducing similar systemic effects. Diabetes 704
59, 1101-1107. 705
Uncorrected Author Proof
10 A. Claxton et al. / Intranasal Insulin Detemir and Dementia
[30] Hermansen K, Davies M, Derezinski T, Martinez Ravn G,
Clauson P, Home P (2006) A 26-week, randomized, paral-707
lel, treat-to-target trial comparing insulin detemir with NPH708
insulin as add-on therapy to oral glucose-lowering drugs in
insulin-naive people with type 2 diabetes. Diabetes Care 29,
[31] Roberts RO, Geda YE, Knopman DS, Cha RH, Pankratz712
VS, Boeve BF, Ivnik RJ, Tangalos EG, Petersen RC, Rocca713
WA (2008) The Mayo Clinic Study of Aging: Design and714
sampling, participation, baseline measures and sample char-715
acteristics. Neuroepidemiology 30, 58-69.716
[32] McKhann G, Drachman D, Folstein M, Katzman R, Price
D, Stadlan EM (1984) Clinical diagnosis of Alzheimer’s dis-
ease: Report of the NINCDS-ADRDA Work Group under the
auspices of Department of Health and Human Services Task720
Force on Alzheimer’s Disease. Neurology 34, 939-944.721
[33] Coen RF, Kinsella A, Lambe R, Kenny M, Darragh A (2004)722
Creating equivalent word lists for the Buschke Selective723
Reminding Test. Hum Psychopharmacol Clin Exp 5, 47-51.724
[34] Brickman AM, Stern Y, Small SA (2011) Hippocampal subre-
gions differentially associate with standardized memory tests.
Hippocampus 21, 923-928.727
[35] Clark CM, Ewbank DC (1996) Performance of the demen-
tia severity rating scale: A caregiver questionnaire for rating
severity in Alzheimer disease. Alzheimer Dis Assoc Disord
10, 31-39.731
[36] Matthews DR, Hosker JP, Rudenski AS, Naylor BA, Treacher732
DF,Turner RC (1985) Homeostasis model assessment: Insulin733
resistance and beta-cell function from fasting plasma glucose734
and insulin concentrations in man. Diabetologia 28, 412-419.735
[37] Benedict C, Hallschmid M, Schmitz K, Schultes B, Ratter F,
Fehm HL, Born J, Kern W (2007) Intranasal insulin improves737
memory in humans: Superiority of insulin aspart. Neuropsy-738
chopharmacology 32, 239-243.739
[38] Sciacca L, Cassarino MF, Genua M, Pandini G, Le Moli740
R, Squatrito S, Vigneri R (2010) Insulin analogues differ-741
ently activate insulin receptor isoforms and post-receptor742
signalling. Diabetologia 53, 1743-1753.743
[39] Wada T, Azegami M, Sugiyama M, Tsuneki H, Sasaoka T
(2008) Characteristics of signalling properties mediated by
long-acting insulin analogue glargine and detemir in target746
cells of insulin. Diabetes Res Clin Pract 81, 269-277.
[40] Prajapati KD, Sharma SS, Roy N (2012) Hepatocyte nuclear 747
factor-1alpha mediated upregulation of albumin expression in 748
focal ischemic rat brain. Neurol Res. 34, 25-31. 749
[41] Ramos-Fernandez E, Tajes M, Palomer E, Ill-Raga G, Bosch- 750
Morato M, Guivernau B, Roman-Degano I, Eraso-Pichot 751
A, Alcolea D, Fortea J, Nunez L, Paez A, Alameda F, 752
Fernandez-Busquets X, Lleo A, Elosua R, Boada M, Valverde 753
MA, Munoz FJ (2014) Posttranslational nitro-glycative 754
modifications of albumin in Alzheimer’s disease: Implica- 755
tions in cytotoxicity and amyloid-beta peptide aggregation. 756
J Alzheimers Dis 40, 643-657 757
[42] Colton CA, Needham LK, Brown C, Cook D, Rasheed K, 758
Burke JR, Strittmatter WJ, Schmechel DE, Vitek MP (2004) 759
APOE genotype-specific differences in human and mouse 760
macrophage nitric oxide production. J Neuroimmunol 147,761
62-67. 762
[43] Gundry RL, Fu Q, Jelinek CA, Van Eyk JE, Cotter RJ (2007) 763
Investigation of an albumin-enrichedfraction of human serum 764
and its albuminome. Proteomics Clin Appl. 1, 73-88. 765
[44] Cao W, Ning J, Yang X, Liu Z (2011) Excess exposure to 766
insulin is the primary cause of insulin resistance and its asso- 767
ciated atherosclerosis. Curr Mol Pharmacol 4, 154-166. 768
[45] Cao W, Liu HY, Hong T, Liu Z (2010) Excess exposure to 769
insulin may be the primary cause of insulin resistance. Am J 770
Physiol Endocrinol Metab 298, E372. 771
[46] Mensenkamp AR, Havekes LM, Romijn JA, Kuipers F (2001) 772
Hepatic steatosis and very low density lipoprotein secretion: 773
The involvement of apolipoprotein E. J Hepatol 35, 816-822. 774
[47] Langner R, Sternkopf MA, Kellermann TS, Grefkes C, Kurth 775
F, Schneider F, Zilles K, Eickhoff SB (2014) Translating 776
working memory into action: Behavioral and neural evidence 777
for using motor representations in encoding visuo-spatial 778
sequences. Hum Brain Mapp 35, 3465-3484. 779
[48] Helkala EL, Laulumaa V, Soininen H, Riekkinen PJ (1988) 780
Recall and recognition memory in patients with Alzheimer’s 781
and Parkinson’s diseases. Ann Neurol 24, 214-217. 782
[49] Panza F, Frisardi V, Imbimbo BP, D’Onofrio G, Pietrarossa 783
G, Seripa D, Pilotto A, Solfrizzi V (2010) Bapineuzumab: 784
Anti-beta-amyloid monoclonal antibodies for the treatment 785
of Alzheimer’s disease. Immunotherapy 2, 767-782. 786
... Similar to imaging studies assessing the response to an external stimulus, such as insulin administration, an alternative approach assessing cognitive response can be used as a proxy for BIR. Insulin administration either via a hyperinsulinemic clamp [48] or via INL delivery [228][229][230][231][232] may enhance memory in selected populations [233]. Therefore, impaired cognitive responses to insulin administration in this setting may be a result of BIR, more specifically impaired insulin transport across the BBB resulting in insulin deficiency in the brain. ...
... In addition, there is also an observation of antiproliferative and tumor suppressor pathways. This counterintuitive observation can be explained by the fact that over the long-term treatment, the hippocampus became less responsive to insulin, potentially as part of negative feedback, which is often not exhibited in the clinical setting [232,235,302]. An alternative animal model of BIR is the SAMP8 mouse that is prone to accelerated aging [303]. ...
Full-text available
Type 2 diabetes mellitus (T2DM) is common and increasing in prevalence worldwide, with devastating public health consequences. While peripheral insulin resistance is a key feature of most forms of T2DM and has been investigated for over a century, research on brain insulin resistance (BIR) has more recently been developed, including in the context of T2DM and non-diabetes states. Recent data support the presence of BIR in the aging brain, even in non-diabetes states, and found that BIR may be a feature in Alzheimer's disease (AD) and contributes to cognitive impairment. Further, therapies used to treat T2DM are now being investigated in the context of AD treatment and prevention, including insulin. In this review, we offer a definition of BIR, and present evidence for BIR in AD; we discuss the expression, function, and activation of the insulin receptor (INSR) in the brain; how BIR could develop; tools to study BIR; how BIR correlates with current AD hallmarks; and regional/cellular involvement of BIR. We close with a discussion on resilience to both BIR and AD, how current tools can be improved to better understand BIR, and future avenues for research. Overall, this review and position paper highlights BIR as a plausible therapeutic target for the prevention of cognitive decline and dementia due to AD.
... In recent years, more and more literature has focused on the impact of anti-diabetes drugs on DACD, which is becoming a new trend in the study of DACD treatment strategies. Earlier studies have demonstrated that insulin (Claxton et al., 2014), insulin sensitizer metformin (Koenig et al., 2017), dipeptidyl peptidase 4 (DPP4) inhibitors vildagliptin (Pipatpiboon et al., 2013), and peroxisome proliferator-activated receptor-γ (PPARγ) agonists rosiglitazone (Pathan et al., 2008) can improve cognitive dysfunction. Studies in rodent models show that insulin could improve cognitive performance by activating insulin receptor signaling in the hippocampus (Biessels and Reagan, 2015). ...
... Interestingly, compared to direct injection of insulin, intranasal insulin could directly supply insulin to brain target and penetrate the bloodbrain barrier, thereby result in enhancing cognitive performance in mice (Chen et al., 2021). In adults with mild cognitive impairment, daily treatment with long-acting intranasal insulin could also mitigate cognition dysfunction (Claxton et al., 2014). Similarly, metformin, an insulin response enhancer, can improve cognitive dysfunction (Lin et al., 2018;Samaras et al., 2020) by modulating Akt/ glycogen synthase kinase 3 (GSK3) or cAMP response element binding (CREB) / brainderived neurotrophic factor (BDNF) signaling pathway (Keshavarzi et al., 2019), and inhibiting cyclin-dependent kinase 5 (CDK5) hyperactivation and CDK5-dependent tau hyperactivation (Wang et al., 2020). ...
Full-text available
Background Diabetes-associated cognitive dysfunction (DACD) is a common and serious complication in diabetes and has a high impact on the lives of both individuals and society. Although a number of research has focused on DACD in the past two decades, there is no a study to systematically display the knowledge structure and development of the field. Thus, the present study aimed to show the landscape and identify the emerging trends of DACD research for assisting researchers or clinicians in grasping the knowledge domain faster and easier and focusing on the emerging trends in the field. Methods We searched the Web of Science database for all DACD-related studies between 2000 and 2022. Bibliometric analysis was conducted using the VOSviewer, CiteSpace, Histcite, and R bibliometric package, revealing the most prominent research, countries, institutions, authors, journals, co-cited references, and keywords. Results A total of 4,378 records were selected for analysis. We found that the volume of literature on DACD has increased over the years. In terms of the number of publications, the USA ranked first. The most productive institutions were the University of Washington and the University of Pittsburgh. Furthermore, Biessels GJ was the most productive author. Journal of Alzheimers Disease , Diabetes Care , and Frontiers in Aging Neuroscience had the most publications in this field. The keywords“dementia,” “alzheimers-disease,” “cognitive impairment” and “diabetes” are the main keywords. The burst keywords in recent years mainly included “signaling pathway” and “cognitive deficit.” Conclusion This study systematically illustrated advances in DACD over the last 23 years. Current findings suggest that exploring potential mechanisms of DACD and the effect of anti-diabetes drugs on DACD are the hotspots in this field. Future research will also focus on the development of targeted drugs that act on the DACD signaling pathway.
... These hypotheses have been explored by studies evaluating cognitive performance by intranasal insulin administration, showing a positive effect on memory [21], verbal memory [22], delayed memory, and cognition [23] in adults with amnestic mild cognitive impairment or AD. Intranasal insulin administration has also been demonstrated to improve functional connectivity among brain regions regulating memory and complex cognitive behaviors [24]. ...
Full-text available
Glucagon-like peptide 1 (GLP-1) is a hormone of the incretin family, secreted in response to nutrient ingestion, and plays a role in metabolic homeostasis. GLP-1 receptor agonist has a peripheral and a central action, including stimulation of glucose-dependent insulin secretion and insulin biosynthesis, inhibition of glucagon secretion and gastric emptying, and inhibition of food intake. Through their mechanism, their use in the treatment of type 2 diabetes has been extended to the management of obesity, and numerous trials are being conducted to assess their cardiovascular effect. Type 2 diabetes appears to share common pathophysiological mechanisms with the development of cognitive disorders, such as Alzheimer's and Parkinson's disease, related to insulin resistance. In this review, we aim to examine the pathological features between type 2 diabetes and dementia, GLP-1 central effects, and analyze the relevant literature about the effect of GLP-1 analogs on cognitive function of patients with type 2 diabetes but also without. Results tends to show an improvement in some brain markers (e.g. hippocampal connections, cerebral glucose metabolism, hippocampal activation on functional magnetic resonance imaging), but without being able to demonstrate a strong correlation to cognitive scores. Some epidemiological studies suggest that GLP-1 receptor agonists may offer a protective effect, by delaying progression to dementia when diabetic patients are treated with GLP-1 receptor agonists. Ongoing trials are in progress and may provide disease-modifying care for Alzheimer's disease and Parkinson's disease patients in the future.
... According to mounting research, insulin resistance may impair cognitive functioning by resulting in mitochondrial malfunction, changes in synaptic plasticity, development of Aβ plaques, hyperphosphorylation of Tau, among other things (Jayaraman and Pike, 2014;Biessels and Despa, 2018). Furthermore, clinical research has shown that insulin therapy improves cognitive performance in both T2DM and AD, indicating that poor insulin signaling may be a major contributor to diabetic cognitive impairment (Novak et al., 2014;Claxton et al., 2015;Chapman et al., 2018). It is well known that hyperglycemia can trigger and promote inflammatory processes. ...
Full-text available
Background: One of the typical symptoms of diabetes mellitus patients was memory impairment, which was followed by gradual cognitive deterioration and for which there is no efficient treatment. The anti-diabetic incretin hormones glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) were demonstrated to have highly neuroprotective benefits in animal models of AD. We wanted to find out how the GLP-1/GIP dual agonist tirzepatide affected diabetes’s impairment of spatial learning memory. Methods: High fat diet and streptozotocin injection-induced diabetic rats were injected intraperitoneally with Tirzepatide (1.35 mg/kg) once a week. The protective effects were assessed using the Morris water maze test, immunofluorescence, and Western blot analysis. Golgi staining was adopted for quantified dendritic spines. Results: Tirzepatide significantly improved impaired glucose tolerance, fasting blood glucose level, and insulin level in diabetic rats. Then, tirzepatide dramatically alleviated spatial learning and memory impairment, inhibited Aβ accumulation, prevented structural damage, boosted the synthesis of synaptic proteins and increased dendritic spines formation in diabetic hippocampus. Furthermore, some aberrant changes in signal molecules concerning inflammation signaling pathways were normalized after tirzepatide treatment in diabetic rats. Finally, PI3K/Akt/GSK3β signaling pathway was restored by tirzepatide. Conclusion: Tirzepatide obviously exerts a protective effect against spatial learning and memory impairment, potentially through regulating abnormal insulin resistance and inflammatory responses.
... Intranasal insulin (4 × 40 IU/d for 8-weeks) improved memory, attention, and mood in healthy subjects without perceivable side effects [38,39]. Pilot studies with MCI or early AD patients indicate that intranasal insulin improved cognition and Aβ 40/42 ratio in plasma; the improvement was only observed in APOE-e4 carriers [40,41]. The insulin treatment also correlated with preserved brain volume (MRI) and a reduction of the tau-P181/Aβ42 ratio in subjects with MCI or mild-to-moderate AD [42]. ...
Full-text available
The progressive deterioration of function and structure of brain cells in neurodegenerative diseases is accompanied by mitochondrial dysfunction, affecting cellular metabolism, intracellular signaling, cell differentiation, morphogenesis, and the activation of programmed cell death. However, most of the efforts to develop therapies for Alzheimer’s and Parkinson’s disease have focused on restoring or maintaining the neurotransmitters in affected neurons, removing abnormal protein aggregates through immunotherapies, or simply treating symptomatology. However, none of these approaches to treating neurodegeneration can stop or reverse the disease other than by helping to maintain mental function and manage behavioral symptoms. Here, we discuss alternative molecular targets for neurodegeneration treatments that focus on mitochondrial functions, including regulation of calcium ion (Ca2+) transport, protein modification, regulation of glucose metabolism, antioxidants, metal chelators, vitamin supplementation, and mitochondrial transference to compromised neurons. After pre-clinical evaluation and studies in animal models, some of these therapeutic compounds have advanced to clinical trials and are expected to have positive outcomes in subjects with neurodegeneration. These mitochondria-targeted therapeutic agents are an alternative to established or conventional molecular targets that have shown limited effectiveness in treating neurodegenerative diseases.
... According to RoB2, we found four studies with an overall low risk of bias [9][10][11][12], and eight had some concerns. The reasons for some concerns are that four studies had some concerns in the randomization process [13][14][15][16] and four had some concerns in the selection of the reported results [17][18][19][20] Figure 2. ...
Full-text available
Background and aim: We performed this meta-analysis to evaluate the safety and efficacy of intranasal insulin in Alzheimer's disease (AD) patients. Methods: A literature search was conducted for PubMed, Scopus, and Web of Science from inception till August 2022. Documents were screened for qualified articles, and all concerned outcomes were pooled as risk ratios (RR) or mean difference (MD) in the meta-analysis models using Review Manager (RevMan version 5.4). Results: Our results from 12 studies favored intranasal insulin over placebo in terms of Alzheimer Disease’s Assessment Scale–cognitive subscale (ADAS-cog) 20IU, (MD = -0.13, 95% CI [-0.22, -0.05], P = 0.003). The overall effect did not favor either of the two groups for ADAS-cog 40IU, memory composite 20IU and 40IU, and adverse events. (MD = -0.08, 95% CI [-0.16, 0.01], P = 0.08), (MD = 0.65, 95% CI [-0.08, 1.39], P = 0.08), (MD = 0.25, 95% CI [-0.09, 0.6], P = 0.15), (MD = 1.28, 95% CI [0.75, 2.21], P = 0.36), respectively. Conclusion: Ultimately, this meta-analysis showed that intranasal insulin in small doses (20IU) significantly affects patients with AD. Further studies are recommended on reliable insulin delivery devices to increase insulin in the central nervous system. Relevance for patients: Intranasal insulin has shown promising results in treating patients with AD. The lower doses (20 IU) can play a positive role in improving the disease. As research continues, it is likely that this treatment will become more widely accepted and utilized in clinical practice.
... Both studies found that insulin treatment was associated with improvements in cognitive function in patients with MCI or early-stage AD. Additionally, the second clinical trial found that insulin treatment was also associated with reductions in Aβ and tau abnormality in cerebrospinal fluid, supporting that insulin may have a disease-modifying effect on AD pathologies [133,134]. On the other hand, a more recent trial, which was meant to extend the previous findings in a longer and larger multisite randomized double-blinded clinical trial, could not observe any significant cognitive improvement from the participants diagnosed with amnestic MCI or AD after being treated with intranasal insulin for more than 12 months (NCT01767909). Nonetheless, this trial showed no adverse side effects after the treatment, assuring that intranasal insulin can be considered a safe therapy [135]. ...
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Insulin resistance as a hallmark of type 2 DM (T2DM) plays a role in dementia by promoting pathological lesions or enhancing the vulnerability of the brain. Numerous studies related to insulin/insulin-like growth factor 1 (IGF-1) signaling are linked with various types of dementia. Brain insulin resistance in dementia is linked to disturbances in Aβ production and clearance, Tau hyperphosphorylation, microglial activation causing increased neuroinflammation, and the breakdown of tight junctions in the blood–brain barrier (BBB). These mechanisms have been studied primarily in Alzheimer’s disease (AD), but research on other forms of dementia like vascular dementia (VaD), Lewy body dementia (LBD), and frontotemporal dementia (FTD) has also explored overlapping mechanisms. Researchers are currently trying to repurpose anti-diabetic drugs to treat dementia, which are dominated by insulin sensitizers and insulin substrates. Although it seems promising and feasible, none of the trials have succeeded in ameliorating cognitive decline in late-onset dementia. We highlight the possibility of repositioning anti-diabetic drugs as a strategy for dementia therapy by reflecting on current and previous clinical trials. We also describe the molecular perspectives of various types of dementia through the insulin/IGF-1 signaling pathway.
In numerous brain structures, insulin signaling modulates the homeostatic processes, sensitivity to reward pathways, executive function, memory, and cognition. Through human studies and animal models, mounting evidence implicates central insulin signaling in the metabolic, physiological, and psychological consequences of early life adversity. In this review, we describe the consequences of early life adversity in the brain where insulin signaling is a key factor and how insulin may moderate the effects of adversity on psychiatric and cardio-metabolic health outcomes. Further understanding of how early life adversity and insulin signaling impact specific brain regions and mental and physical health outcomes will assist in prevention, diagnosis, and potential intervention following early life adversity.
Introduction: Triglyceride-glucose (TyG) index is a reliable surrogate marker of insulin resistance (IR), whereas IR has been implicated in Alzheimer's disease (AD) pathophysiology. However, the relationship between the TyG index and AD remains unclear. Herein, this study aimed to evaluate the association of the TyG index with the risk of AD. Methods: This prospective study included 2,170 participants free of AD from the Framingham Heart Study Offspring cohort Exam 7 (1998-2001), whose follow-up data were collected until 2018. The TyG index was calculated as ln[fasting triglyceride (mg/dL) × fasting glucose (mg/dL)/2]. The association of the TyG index with AD was evaluated by the competing risk regression model. Statistical analyses were performed in 2023. Results: During a median follow-up of 13.8 years, 163 (7.5%) participants developed AD. When compared to the reference (TyG index ≤8.28), a significantly elevated risk of AD in the group with TyG index of 8.68-9.09 (adjusted HR 1.69, 95% CI 1.02-2.81). When the TyG index was considered as a continuous variable, each unit increment in the TyG index was not significantly associated with the risk of AD (adjusted HR 1.32, 95% CI 0.98-1.77). Conclusions: This study showed that moderately elevated TyG index was independently associated with a higher incidence of AD. The TyG index might be used to define a high-risk population of AD.
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Vanadium is a well-known essential trace element, which usually exists in oxidation states in form of vanadate cation intracellularly. The pharmacological study of vanadium begins at the discovery of its unexpected inhibitory effect on ATPase. Thereafter, the protective effects on cells and the abilities in glucose metabolism regulation were observed from vanadium compound, leading to the application of vanadium compounds in clinical trials for curing diabetes. Alzheimer’s dis-ease (AD) is the most common dementia disease in elderly people. However, there is still no efficient agents for treating AD safely to date. This is mainly because of the complexity of the pathology, which are characterized by the senile plaques composed by amyloid-beta (Aβ) protein in the parenchyma of brain and the neurofibrillary tangles (NFTs) derived from hyperphosphorylated tau protein in neurocyte, along with mitochondrial damage, and eventually the central nervous system (CNS) atrophy. AD was also illustrated as type-3 diabetes, because of the observations of insulin deficiency and the high level of glucose in cerebrospinal fluid (CSF), as well as the im-paired insulin signaling in brain. In this review, we summarized the advance of applicating vanadium compound on AD treatment in experimental research and pointed out the limitation of the current study on using vanadium compounds in AD treatment. We hope it will help the future study in this field.
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Glycation and nitrotyrosination are pathological posttranslational modifications that make proteins prone to losing their physiological properties. Since both modifications are increased in Alzheimer's disease (AD) due to amyloid-β peptide (Aβ) accumulation, we have studied their effect on albumin, the most abundant protein in cerebrospinal fluid and blood. Brain and plasmatic levels of glycated and nitrated albumin were significantly higher in AD patients than in controls. In vitro turbidometry and electron microscopy analyses demonstrated that glycation and nitrotyrosination promote changes in albumin structure and biochemical properties. Glycated albumin was more resistant to proteolysis and less uptake by hepatoma cells occurred. Glycated albumin also reduced the osmolarity expected for a solution containing native albumin. Both glycation and nitrotyrosination turned albumin cytotoxic in a cell type-dependent manner for cerebral and vascular cells. Finally, of particular relevance to AD, these modified albumins were significantly less effective in avoiding Aβ aggregation than native albumin. In summary, nitrotyrosination and especially glycation alter albumin structural and biochemical properties, and these modifications might contribute for the progression of AD.
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While a potential causal factor in Alzheimer's disease (AD), brain insulin resistance has not been demonstrated directly in that disorder. We provide such a demonstration here by showing that the hippocampal formation (HF) and, to a lesser degree, the cerebellar cortex in AD cases without diabetes exhibit markedly reduced responses to insulin signaling in the IR→IRS-1→PI3K signaling pathway with greatly reduced responses to IGF-1 in the IGF-1R→IRS-2→PI3K signaling pathway. Reduced insulin responses were maximal at the level of IRS-1 and were consistently associated with basal elevations in IRS-1 phosphorylated at serine 616 (IRS-1 pS⁶¹⁶) and IRS-1 pS⁶³⁶/⁶³⁹. In the HF, these candidate biomarkers of brain insulin resistance increased commonly and progressively from normal cases to mild cognitively impaired cases to AD cases regardless of diabetes or APOE ε4 status. Levels of IRS-1 pS⁶¹⁶ and IRS-1 pS⁶³⁶/⁶³⁹ and their activated kinases correlated positively with those of oligomeric Aβ plaques and were negatively associated with episodic and working memory, even after adjusting for Aβ plaques, neurofibrillary tangles, and APOE ε4. Brain insulin resistance thus appears to be an early and common feature of AD, a phenomenon accompanied by IGF-1 resistance and closely associated with IRS-1 dysfunction potentially triggered by Aβ oligomers and yet promoting cognitive decline independent of classic AD pathology.
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Defective brain insulin signaling has been suggested to contribute to the cognitive deficits in patients with Alzheimer's disease (AD). Although a connection between AD and diabetes has been suggested, a major unknown is the mechanism(s) by which insulin resistance in the brain arises in individuals with AD. Here, we show that serine phosphorylation of IRS-1 (IRS-1pSer) is common to both diseases. Brain tissue from humans with AD had elevated levels of IRS-1pSer and activated JNK, analogous to what occurs in peripheral tissue in patients with diabetes. We found that amyloid-β peptide (Aβ) oligomers, synaptotoxins that accumulate in the brains of AD patients, activated the JNK/TNF-α pathway, induced IRS-1 phosphorylation at multiple serine residues, and inhibited physiological IRS-1pTyr in mature cultured hippocampal neurons. Impaired IRS-1 signaling was also present in the hippocampi of Tg mice with a brain condition that models AD. Importantly, intracerebroventricular injection of Aβ oligomers triggered hippocampal IRS-1pSer and JNK activation in cynomolgus monkeys. The oligomer-induced neuronal pathologies observed in vitro, including impaired axonal transport, were prevented by exposure to exendin-4 (exenatide), an anti-diabetes agent. In Tg mice, exendin-4 decreased levels of hippocampal IRS-1pSer and activated JNK and improved behavioral measures of cognition. By establishing molecular links between the dysregulated insulin signaling in AD and diabetes, our results open avenues for the investigation of new therapeutics in AD.
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Alzheimer's disease [AD] is the most common cause of dementia in North America. Despite 30+ years of intense investigation, the field lacks consensus regarding the etiology and pathogenesis of sporadic AD, and therefore we still do not know the best strategies for treating and preventing this debilitating and costly disease. However, growing evidence supports the concept that AD is fundamentally a metabolic disease with substantial and progressive derangements in brain glucose utilization and responsiveness to insulin and insulin-like growth factor [IGF] stimulation. Moreover, AD is now recognized to be heterogeneous in nature, and not solely the end-product of aberrantly processed, misfolded, and aggregated oligomeric amyloid-beta peptides and hyperphosphorylated tau. Other factors, including impairments in energy metabolism, increased oxidative stress, inflammation, insulin and IGF resistance, and insulin/IGF deficiency in the brain should be incorporated into all equations used to develop diagnostic and therapeutic approaches to AD. Herein, the contributions of impaired insulin and IGF signaling to AD-associated neuronal loss, synaptic disconnection, tau hyperphosphorylation, amyloid-beta accumulation, and impaired energy metabolism are reviewed. In addition, we discuss current therapeutic strategies and suggest additional approaches based on the hypothesis that AD is principally a metabolic disease similar to diabetes mellitus. Ultimately, our ability to effectively detect, monitor, treat, and prevent AD will require more efficient, accurate and integrative diagnostic tools that utilize clinical, neuroimaging, biochemical, and molecular biomarker data. Finally, it is imperative that future therapeutic strategies for AD abandon the concept of uni-modal therapy in favor of multi-modal treatments that target distinct impairments at different levels within the brain insulin/IGF signaling cascades.
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Exogenous human albumin has been shown to be neuroprotective in experimental ischemic stroke and it is currently investigated in clinical trials. However, the role of endogenous expression of albumin and its transcriptional regulation in the ischemic brain is not known. We have previously reported the upregulation of de novo synthesis of albumin in the ischemic rat brain (at 0 and 22 hours of reperfusion after 2 hours of ischemia). In this study, we analyzed the role of transcription factors in albumin expression in ischemic rat brain. The putative transcription factor binding sites for the albumin promoter was analyzed using transcription factor search computational tool and validated in rat middle cerebral artery occlusion model of transient cerebral ischemia. Computational analysis predicted approximately 20 transcription factor binding sites including hepatocyte nuclear factor-1alpha (HNF-1alpha). We found for the first time mRNA and protein expression of HNF-1alpha in the control and ischemic rat brain. There was no significant difference in mRNA and protein expression of HNF-1alpha between control and ischemic (0, 2 and 22 hours of reperfusion) group but there was increased interaction of HNF-1alpha with p300 (known interacting partner for HNF-1alpha, a histone acetyl-transferase) in 0- and 22-hour reperfusion groups. Also albumin promoter binding activity of HNF-1alpha in ischemic animals of 0- and 22-hour reperfusion groups significantly increased compared to respective control group animals. Although, HNF-1alpha is mainly expressed in the rat liver and involved in hepatic expression of albumin, our study conclusively shows for the first time de novo synthesis of HNF-1alpha in rat brain. Moreover, an increased interaction of HNF-1alpha with p300 and albumin promoter seems to be responsible for overexpression of albumin in ischemic conditions.
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To examine the effects of intranasal insulin administration on cognition, function, cerebral glucose metabolism, and cerebrospinal fluid biomarkers in adults with amnestic mild cognitive impairment or Alzheimer disease (AD). Randomized, double-blind, placebo-controlled trial. Clinical research unit of a Veterans Affairs medical center. The intent-to-treat sample consisted of 104 adults with amnestic mild cognitive impairment (n = 64) or mild to moderate AD (n = 40). Intervention Participants received placebo (n = 30), 20 IU of insulin (n = 36), or 40 IU of insulin (n = 38) for 4 months, administered with a nasal drug delivery device (Kurve Technology, Bothell, Washington). Primary measures consisted of delayed story recall score and the Dementia Severity Rating Scale score, and secondary measures included the Alzheimer Disease's Assessment Scale-cognitive subscale (ADAS-cog) score and the Alzheimer's Disease Cooperative Study-activities of daily living (ADCS-ADL) scale. A subset of participants underwent lumbar puncture (n = 23) and positron emission tomography with fludeoxyglucose F 18 (n = 40) before and after treatment. Outcome measures were analyzed using repeated-measures analysis of covariance. Treatment with 20 IU of insulin improved delayed memory (P < .05), and both doses of insulin (20 and 40 IU) preserved caregiver-rated functional ability (P < .01). Both insulin doses also preserved general cognition as assessed by the ADAS-cog score for younger participants and functional abilities as assessed by the ADCS-ADL scale for adults with AD (P < .05). Cerebrospinal fluid biomarkers did not change for insulin-treated participants as a group, but, in exploratory analyses, changes in memory and function were associated with changes in the Aβ42 level and in the tau protein-to-Aβ42 ratio in cerebrospinal fluid. Placebo-assigned participants showed decreased fludeoxyglucose F 18 uptake in the parietotemporal, frontal, precuneus, and cuneus regions and insulin-minimized progression. No treatment-related severe adverse events occurred. These results support longer trials of intranasal insulin therapy for patients with amnestic mild cognitive impairment and patients with AD. Trial Registration Identifier: NCT00438568.
The neurobiological organization of action-oriented working memory is not well understood. To elucidate the neural correlates of translating visuo-spatial stimulus sequences into delayed (memory-guided) sequential actions, we measured brain activity using functional magnetic resonance imaging while participants encoded sequences of four to seven dots appearing on fingers of a left or right schematic hand. After variable delays, sequences were to be reproduced with the corresponding fingers. Recall became less accurate with longer sequences and was initiated faster after long delays. Across both hands, encoding and recall activated bilateral prefrontal, premotor, superior and inferior parietal regions as well as the basal ganglia, whereas hand-specific activity was found (albeit to a lesser degree during encoding) in contralateral premotor, sensorimotor, and superior parietal cortex. Activation differences after long versus short delays were restricted to motor-related regions, indicating that rehearsal during long delays might have facilitated the conversion of the memorandum into concrete motor programs at recall. Furthermore, basal ganglia activity during encoding selectively predicted correct recall. Taken together, the results suggest that to-be-reproduced visuo-spatial sequences are encoded as prospective action representations (motor intentions), possibly in addition to retrospective sensory codes. Overall, our study supports and extends multi-component models of working memory, highlighting the notion that sensory input can be coded in multiple ways depending on what the memorandum is to be used for. Hum Brain Mapp, 2013. © 2013 Wiley Periodicals, Inc.
A previous clinical trial demonstrated that four months of treatment with intranasal insulin improves cognition and function for patients with Alzheimer's disease (AD) or mild cognitive impairment (MCI), but prior studies suggest that response to insulin treatment may differ by sex and ApoE ε4 carriage. Thus, responder analyses using repeated measures analysis of covariance were completed on the trial's 104 participants with MCI or AD who received either placebo or 20 or 40 IU of insulin for 4 months, administered by a nasal delivery device. Results indicate that men and women with memory impairment responded differently to intranasal insulin treatment. On delayed story memory, men and women showed cognitive improvement when taking 20 IU of intranasal insulin, but only men showed cognitive improvement for the 40 IU dose. The sex difference was most apparent for ApoE ε4 negative individuals. For the 40 IU dose, ApoE ε4 negative men improved while ApoE ε4 negative women worsened. Their ApoE ε4 positive counterparts remained cognitively stable. This sex effect was not detected in functional measures. However, functional abilities were relatively preserved for women on either dose of intranasal insulin compared with men. Unlike previous studies with young adults, neither men nor women taking intranasal insulin exhibited a significant change in weight over 4 months of treatment.
Higher fasting plasma insulin levels and reduced CSF-to-plasma insulin-ratios, suggestive of insulin resistance, have been observed in patients with Alzheimer's disease (AD) who do not possess an apolipoprotein E (ApoE)-ɛ4 allele. Insulin has also been implicated in processing of β-amyloid and amyloid precursor protein (APP). We examined the effects of intravenous insulin administration while maintaining euglycemia on insulin-mediated glucose disposal, memory, and plasma APP in patients with AD and normal adults of varying ApoE genotypes. AD subjects without an ɛ4 allele had significantly lower insulin-mediated glucose disposal rates than did AD patients with an ɛ4 allele (p < 0.03) or than did normal adults without an ɛ4 allele (p < 0.02). AD subjects without an ɛ4 allele also showed significant memory facilitation with insulin administration (p < 0.04), whereas the AD-ɛ4 group did not. Insulin reduced APP levels for AD patients without an ApoE ɛ4 allele, but raised APP for AD patients with an ApoE ɛH4 allele These results document ApoE-related differences in insulin metabolism in AD that may relate to disease pathogenesis.
The main goal of this review is to provide more specific and effective targets for prevention and treatment of insulin resistance and associated atherosclerosis. Modern technologies and medicine have vastly improved human health and prolonged the average life span of humans primarily by eliminating various premature deaths and infectious diseases. The modern technologies have also provided us abundant food and convenient transportation tools such as cars. As a result, more people are becoming overfed and sedentary. People are generally ingesting more calories than their bodies' need, leading to the so-called "positive energy imbalance", which is inseparable from the development of insulin resistance and its associated atherosclerosis. A direct consequence of insulin resistance is hyperinsulinemia. The current general view is that insulin is not functional properly in the presence of insulin resistance. Thus, the role of insulin itself in the development of insulin resistance and associated atherosclerosis has not been recognized. We have recently observed that the basal level of insulin signaling is increased in the presence of insulin resistance and hyperinsulinemia. In this review, we will explain how the increased basal insulin signaling contributes to the development of insulin resistance and associated atherosclerosis. We will first explain how insulin causes insulin resistance through two arbitrary stages (before and after the presence of obvious insulin resistance), and, then, explain how the excess exposure to insulin and the relative insulin insufficiency contributes to the atherosclerotic diseases. We propose that blockade of the excess insulin signaling is a viable approach to prevent and/or reverse insulin resistance and its associated atherosclerosis.