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and proceed through, while glycated ApoE is not Entry of insulin into the brain is a saturable Acute
recognized, thus depriving brain cells of these mechanism; there comes a point when increased
essential building blocks. 6 peripheral insulin levels no longer elevate levels administration
There is even more to the interaction of in the central nervous system (CNS). Entry of of insulin
ApoE genotype and Aβ. ApoE genotype influ- glucose into the brain can be seen as saturable improves
ences insulin degrading enzyme production, as well. GLUT1 transporters at the BBB are
with E4 homozygotes expressing 50 percent less saturated by normal physiological concentra- performance
hippocampal IDE than non-E4 carriers. It is tions of glucose. Therefore, increasing glucose on tests of
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not known whether the ApoE4 genotype causes uptake by the brain would require an upregula- memory and
reduced IDE. They could both arguably be the tion of insulin receptors or GLUT4s. But when
result of an overall hunter-gatherer genotype the receptors have been compromised, it could cognition but
not designed for the carbohydrate-rich Western equate to a functional hypoglycemia in the chronically

diet. Pre-agriculturalists presumably would brain, which would account for the decreasing elevated
have derived more of their calories from fat and rate of brain glucose metabolism that is one of
protein and would therefore have had a lower the defining features of AD. On the other hand, insulin levels
requirement for both insulin and IDE. 36,37 if a physiologically normal amount of glucose is have the
Several authors have asserted that Aβ is tox- entering the brain interstitial fluid but there’s a opposite
ic. Aβ is believed to penetrate neuronal plasma lack of insulin, this could result in the increased
membranes, where it leads to lipid peroxidation. glycation observed in AD brains. The presence effect.
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It has also been implicated in deactivating a of glucose with an inability to metabolize it
subunit of the pyruvate dehydrogenase complex, would account for both the reduced CMRglu and
thereby inhibiting conversion of pyruvate to increased AGE formation.
acetyl CoA and the eventual production of cel- A noteworthy feature of AD is the intriguing
lular energy as ATP. Another way Aβ affects combination of hyperinsulinism (too much) in
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glucose metabolism in the brain is that fragments the periphery and hypoinsulinism (not enough)
of Aβ disrupt insulin signaling by binding to in the CNS. Patients with advanced AD show
neuronal synapses, which alters their shape and higher plasma but lower CSF insulin concentra-
function. 15,38 Insulin receptors are abundant at tions than healthy controls. Clearly, then, the
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synapses, so if the integrity of the synapse itself lower concentration of insulin in the brain is not
has been compromised, the receptors won’t func- a result of reduced circulating levels in the blood.
tion effectively. Somehow—partly through the effects of Aβ, but
It’s easy to see why one school of thought more likely due to long-term overconsumption
subscribes to the belief that Aβ plaques cause of refined carbohydrates—the brain becomes
AD. However, an alternative theory is emerging insulin-resistant.
wherein Aβ is argued to be protective. This more Insulin plays a definite role in cognitive
holistic view of AD pathology will be addressed function. However, as is true of most biological
after a discussion of the critical role of insulin in mechanisms, context must be taken into account:
AD causation and progression. acute administration of insulin improves perfor-
mance on tests of memory and cognition, but
INSULIN’S ROLE IN AD PATHOLOGY chronically elevated insulin levels have the op-
It had long been believed that glucose uptake posite effect. 4,42,43 This is akin to the pathology of
in the brain was entirely independent of insulin, T2D, in which normal, acute doses of insulin help
as the common brain glucose transporters— regulate glucose uptake, but chronically elevated
GLUT1 and GLUT3—are non-insulin-sensitive. levels lead to insulin resistance, hyperglycemia,
However, it is now recognized that there are and the attendant inflammation and vascular
insulin receptors and insulin-sensitive glucose damage. Chronically elevated insulin levels in
transporters (GLUT4) at the blood brain barrier the periphery, it seems, depress insulin sensitiv-
(BBB) and in certain brain cells. They are par- ity at the BBB and therefore glucose utilization
ticularly abundant in regions involved in memory in the brain. In the absence of an alternative
and learning. 39,40 fuel source, brain cells starve. Metabolic fuel is
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