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Journal of Alzheimer’s Disease xx (20xx) x–xx
DOI 10.3233/JAD-141791
IOS Press
1
Long-Acting Intranasal Insulin Detemir
Improves Cognition for Adults with Mild
Cognitive Impairment or Early-Stage
Alzheimer’s Disease Dementia
1
2
3
4
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,∗
5
6
aGeriatric Research, Education, & Clinical Center, Veterans Affairs Puget Sound Health Care System, Seattle,
Washington, USA
7
8
bDepartment of Psychiatry & Behavioral Science, University of Washington School of Medicine, Seattle,
Washington, USA
9
10
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.
13
14
15
16
17
18
19
20
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22
23
24
25
26
Keywords: Alzheimer’s disease, clinical trials, randomized, insulin, intranasal drug administration, mild cognitive impairment27
INTRODUCTION28
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:
suzcraft@wakehealth.edu.
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
39
and protects against A-induced synaptotoxicty and
40
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
47
with progression of AD [7, 8]. Disruption in central48
insulin regulation (also referred to as brain insulin
49
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
54
[1, 9, 10]. Impaired transport of insulin across the
55
blood-brain barrier may also result in deficient lev-56
els of insulin in the central nervous system (CNS).
57
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
62
cognitive impairment (MCI) [11–13]. In a pilot trial,63
adults diagnosed with mild AD or MCI who received
64
a 20 IU daily dose of intranasal insulin improved in
65
delayed memory, and participants receiving either a 2066
or 40 IU dose improved on caregiver-rated functional
67
ability [13]. Both doses of insulin were associated
68
with preserved cognition for younger participants on69
the Alzheimer’s Disease Assessment Scale-Cognitive70
subscale, and preserved glucose uptake was noted
71
for participants taking intranasal insulin on FDG-PET72
scans in the parietotemporal, frontal, precuneus, and73
cuneus regions. The improvements in episodic mem-
74
ory were still present two months after cessation of
75
treatment [13].
76
Prior studies have also demonstrated that treatment
77
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
83
to increase the risk of developing sporadic AD, but
84
the mechanism of action is not fully elucidated [14].
85
Previous studies have demonstrated APOE-4-related
86
differences in response to various AD therapies, and in
87
particular to the therapeutic effects of insulin [16, 18].
88
In two pilot studies, treatment response was strongest
89
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
143
with AD or amnestic MCI compared with placebo,
144
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-
151
ses predicted that daily function and working memory152
would improve for adults with MCI or AD tak-
153
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-
158
ondary analyses.
159
MATERIALS AND METHODS
160
Participants161
The trial was registered at clinicaltrials.gov162
(NCT01547169) and conducted over a 2-year period.163
The study was approved by the Institutional Review
164
Boards of the University of Washington and the
165
Veterans Affairs Puget Sound Health Care System166
and was conducted in the Veterans Affairs Clini-
167
cal Research Unit. Written informed consent was
168
obtained from all participants. A total of 60 older
169
adults enrolled in our study (39 participants with
170
amnestic MCI and 21 participants with probable AD171
with Mini-Mental State Examination (MMSE) scores172
>15). Diagnoses and eligibility were determined by
173
consensus of expert physicians and neuropsycholo-174
gists following cognitive testing, evaluation of medical175
history, physical examination, and clinical laboratory
176
screening using modified Petersen criteria for the diag-
177
nosis of amnestic MCI [12, 31] and National Institute
178
for Neurological and Communicative Disorders and
179
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).
184
Participants whose delayed memory scores deviated at
185
least 1.5 SDs from this estimate were considered for
186
the diagnosis of amnestic MCI, which was then deter-
187
mined by expert consensus using all available data,
188
following published criteria [31].
189
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.
241
Immediate and delayed story recall [12] were deter-
242
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
248
on the verbal memory composite indicates a better249
performance on these verbal memory measures. The250
four secondary outcome measures include tests of
251
verbal working memory, visuospatial working mem-
252
ory, executive function, and caregiver-rated functional
253
ability. Verbal working memory was measured by
254
the Dot Counting N-back, in which participants were
255
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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A. Claxton et al. / Intranasal Insulin Detemir and Dementia 5
Age, diagnosis, MMSE score, gender, body mass index288
(BMI) and APOE-4 allele status were statistically
289
examined as covariates.
290
Metabolic Measures291
Participants underwent oral glucose tolerance test-292
ing (OGTT) 1–2 days prior to cognitive baseline testing
293
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
296
they then consumed a drink containing 75 g glucose.
297
Blood was collected at 15, 30, 60, 90, and 120 min298
after beverage consumption. Samples were immedi-
299
ately placed on ice and spun at 2,200 rpm in a cold300
centrifuge for 15 min, after which plasma, serum, lym-
301
phocytes, and red blood cells were aliquoted into302
separate storage tubes and flash frozen at –70◦C. Blood
303
glucose was measured via Accu-chek®glucose meters.304
Insulin resistance was calculated using the homeostatic305
model assessment of insulin resistance (HOMA-IR),
306
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
310
derived from insulin and glucose levels during the311
OGTT: Insulin Area under the Curve (Insulin AUC)
312
adjusted for glucose AUC was calculated using the
313
trapezoidal rule in order to provide a secondary mea-
314
sure of insulin resistance that takes insulin response to315
a glucose challenge into account.316
Safety and Compliance
317
Study partners supervised participants in the admin-318
istration of intranasal treatment. Blood glucose levels
319
were measured daily for the first week and then320
weekly thereafter; no episodes of hypoglycemia were321
observed. Compliance was monitored by quantifying
322
unused medication and via self-report. Safety data
323
were reviewed semiannually by a data safety monitor-
324
ing board. Adverse event reporting followed standard
325
guidelines. Fasting plasma glucose values obtained
326
from each study visit are reported in Supplementary327
Table 1.328
Statistical Analyses
329
Data were analyzed with SPSS version 18. For330
the intent-to-treat sample, primary and secondary
331
cognitive and functional outcome scores were log-
332
transformed to normalize distributions. To test the
333
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
RESULTS 349
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
384
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
414
No treatment-related severe adverse events occurred
415
during the study, and most adverse events were minor,
416
such as dizziness or mild rhinitis. There were no
417
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-
421
ber of completed doses) was 98% and ranged from 89%422
to 100%. Compliance did not differ across treatment423
groups.
424
DISCUSSION
425
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
429
for all participants. APOE-4 allele carriers taking430
the higher dose of intranasal detemir also experi-431
enced improvement in peripheral insulin resistance
432
across three weeks of treatment. Conversely, APOE-
433
4 negative individuals treated with the higher dose
434
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
441
to individuals with AD or amnestic MCI. This pilot
442
study provides initial evidence that detemir can be
443
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-
478
acteristics of albumin have been shown to modulate
479
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
486
to nitration [42], and thus may have a greater ten-487
dency for post-translational modifications of albumin,
488
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,
493
such that APOE4 participants in the 40 IU group had
494
improved insulin resistance whereas participants with-495
out the APOE4 allele had worsened insulin resistance,
496
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-
501
mote insulin resistance in vulnerable individuals. For502
example, detemir has been shown to worsen insulin
503
resistance in adults with particular metabolic profiles
504
that may associate with APOE genotype, such as non-505
alcoholic steatosis (“fatty liver”) [44–46]. Although
506
there were no differences between APOE4 carriers and
507
non-carriers with respect to BMI or fasting glucose508
values, more in depth metabolic characteristics such509
as liver fat were not assessed.
510
It is also interesting that beneficial effects of 40511
IU detemir on working memory were independent512
of APOE status. Working memory is preferentially
513
mediated by the prefrontal and limbic systems [47],
514
whereas verbal memory is associated with medial tem-
515
poral/hippocampal circuits [48]. This pattern of results
516
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
indicators.
522
An important goal of the present pilot study was
523
to determine whether insulin detemir held sufficient
524
promise as an AD treatment to support further inves-
525
tigation. Taken together, the benefits of detemir on
526
memory and metabolic status provide a strong rationale
527
for further examination of its therapeutic potential in
528
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
ACKNOWLEDGMENTS 553
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
[alz.com/disclosures/view.php?id=2576]). 562
SUPPLEMENTARY MATERIAL 563
The supplementary material is available in the 564
electronic version of this article: http://dx.doi.org/ 565
10.3233/JAD-141791. 566
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