COMMENTARY
Insulin and cognitive function of ␤ amyloid from neurons (potentially a favourable
Alzheimer’s dementia is currently one of the major
public-health problems in developed countries and, with
recent demographic changes, the population burden is
expected to increase. Current therapies, such as acetyl-
cholinesterase inhibitors, may slow cognitive decline in
some patients, but the absolute changes are modest.
There is, therefore, a clear need for novel therapies that
improve cognitive performance and perhaps even alter
the disease process in Alzheimer’s dementia. Stennis
Watson and colleagues1 recently examined the effects of
intravenous insulin on cognitive performance and
concentrations of ␤-amyloid protein in cerebrospinal
fluid. Does this study offer new hope in the treatment of
Alzheimer’s dementia?
Insulin receptors are found in high concentrations
within the limbic system and a growing body of data has
raised the prospect that insulin might affect cognitive
performance and may even contribute to the dev-
elopment of Alzheimer’s dementia. In vitro, insulin can
alter the rate of firing of hippocampal neurons and
enhance uptake of neuronal glucose. When injected into
the cerebral ventricles of rats, insulin improves memory
function.2 By contrast, in epidemiological studies of non-
diabetic human beings, hyperinsulinaemia has been
associated with poorer cognitive performance and an
increased risk of Alzheimer’s dementia.3–6 Although this
association might have been confounded by other
factors, such as increased concentrations of gluco-
corticoids, the apparent conflict between the laboratory
and epidemiological data could be explained by invoking
the concept of insulin resistance. Thus, the laboratory
data suggest that insulin is good for cognition, whereas
the human data imply that hyperinsulinaemia is bad for
cognition. However, hyperinsulinaemia is a mani-
festation of insulin resistance and if that also occurred
within the brain, hippocampal neurons might, in effect,
be functionally insulin-deficient. Indeed, in Alzheimer’s
dementia, the brain can be deficient in insulin. In a small
case-control study, people with moderate to severe
Alzheimer’s dementia had higher levels of plasma
insulin, but lower concentrations of insulin in the cere-
brospinal fluid than cognitively intact controls.7 In a
subsequent study, normoglycaemic hyperinsulinaemia
actually improved mean memory performance in adults
with Alzheimer’s dementia.8
The report by Watson and colleagues1 comes from the
same group that did the above studies in adults with
Alzheimer’s dementia. 16 adults without cognitive im-
pairment attended on two separate days for study. On
one occasion, the participants received a peripheral
infusion of insulin (and 20% dextrose, to maintain
normoglycaemia), and on the other, saline. A battery of
cognitive tests was administered after 90 min during
each session and, after 120 min, samples of
cerebrospinal fluid were taken. Insulin infusion was
associated with improved memory performance and
increased concentrations, in the cerebrospinal fluid, of
insulin and a long form of ␤-amyloid protein, A␤42.
There was some evidence that the rise in A␤42 was
greater in patients aged 70 years and older, and that
improved memory performance was attenuated in those
who had the largest rise in A␤42 in the cerebrospinal
fluid.
␤-amyloid protein aggregates in the plaques that are
the neuropathological hallmark of Alzheimer’s dementia.
Theoretically, insulin might increase ␤-amyloid levels
within the cerebrospinal fluid by increasing the secretion
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For personal use. Only reproduce with permission from The Lancet.
scenario for neuronal health) and/or by reducing its
breakdown (potentially an unfavourable scenario). In
vitro, insulin stimulates the release of ␤-amyloid protein
from cultures of neurons and may also compete for
binding sites on insulin-degrading enzyme, one of the
key enzymes involved in the breakdown of ␤-amyloid
protein.9 Watson and colleagues did not address which
mechanism might be involved, and so we cannot assess
whether or not the increased concentrations of A␤42 in
the cerebrospinal fluid represent a beneficial outcome in
terms of cognition and risk of Alzheimer’s dementia.10
The study can be criticised on several other counts.
The sample size was small, the cognitive testing was
limited, and only one form of A␤42 was measured in the
cerebrospinal fluid. Moreover, it was not possible to
separate out the effects of the concurrent dextrose and
insulin infusions on the outcome variables, and the
researchers could not readily explain the apparent
paradox that insulin raised A␤42 concentrations in the
cerebrospinal fluid and improved memory, yet those
patients with the greatest rise in A␤42 concentrations in
the cerebrospinal fluid had the least improvement in
memory.
However, despite these limitations the results of the
study are intriguing. It could be possible to manipulate
insulin and ␤-amyloid protein concentrations in the
cerebrospinal fluid. We already have agents—metformin
and thiazolidinediones—that can reduce insulin
resistance and hyperinsulinaemia. Trials investigating
the effect of improving insulin sensitivity on cognitive
performance are underway. So, although Watson and
colleagues’ report may have important drawbacks, the
issues raised undoubtedly merit further consideration
because of the potential they offer for new avenues of
clinical and therapeutic research.
I have received honoraria from Takeda and GlaxoSmithKline for
speaking and have received consultancy fees from GlaxoSmithKline.
Mark W J Strachan
Metabolic Unit, Western General Hospital, Edinburgh EH4 2XU, UK
(e-mail: mark.strachan@luht.scot.nhs.uk)
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