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A slow decline scan, or upon autopsy. These include insoluble occurs long before symptoms of AD are pres-

in brain extracellular plaques made of beta-amyloid ent, and seems to be the first step in a long chain
peptide (Aβ); intracellular neurofibrillary tangles of events whose eventual end is overt AD. The
glucose usage (NFTs) resulting from the hyperphosphorylation decline can be detected in those at risk as young
can be seen of tau (a microtubule-associated protein); loss of as their twenties and thirties—decades before the
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as preclinical hippocampal neurons; a decrease in production manifestation of AD. More dramatic declines
of brain acetylcholine; and a marked decline in are seen in later years, with the largest declines
evidence that glucose usage in regions of the brain associated occurring in ApoE4 homozygotes. These de-
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something has with memory and learning. 5,11,20-22 All of these clines are associated with normal aging, but in
gone awry changes can be logically explained as the se- people at risk for AD, they begin at a younger
quelae resulting from long-term dysregulation age and decline more aggressively.
long before the of insulin signaling and glucose metabolism. It is noteworthy that the subjects tested in

appearance of Their damaging effects are compounded by other younger years are cognitively normal; they show
overt signs and features of a modern Western diet and lifestyle no clinical signs of AD, so there is little reason
apart from an evolutionarily discordant degree to suspect that metabolic and cognitive derange-
symptoms. of refined carbohydrate consumption—namely, ment are brewing. This slow decline in brain
a gross imbalance between n-6 and n-3 essential glucose usage can be seen as a kind of “canary
fatty acids, a lack of micronutrient and antioxi- in the coal mine”—preclinical evidence that
dant-rich vegetables and fruits, and a paucity of something has gone awry long before damage
physical activity. has progressed to the point of overt signs and
symptoms. With the brain’s disproportionate
PHYSICAL HALLMARKS OF AD: consumption of fuel (at just 2 percent of body
REDUCTION IN CEREBRAL weight, it uses around 20 percent of the body’s
USAGE OF GLUCOSE glucose and oxygen), any regional reduction in
One of the most striking observations in AD fuel metabolism will have dramatic effects.
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patients is a marked decline in the rate at which The extent of the reduction in CMRglu is
their brains use glucose (called the cerebral meta- tied to AD severity. A longitudinal study us-
bolic rate of glucose [CMRglu]). Specifically, ing PET scans to measure CMRglu in people
this reduced fuel usage is localized in regions ages fifty to eighty showed that people with
of the brain involved in memory processing and the lowest CMRglu at baseline experienced the
learning. 10,11,21,24 PET scans of people at high quickest development of overt AD. At baseline,
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risk for developing AD show that this decline hippocampal glucose metabolism in people who

WHAT IS APOLIPOPROTEIN E?

Lipoproteins are vesicles that transport non-water-soluble substances—such as fatty acids and cholesterol—through
the bloodstream. Apolipoproteins appear on the surface of lipoproteins, where they serve as ligands (recognition factors)
for receptors and as cofactors in enzymatic processes. The gene for ApoE occurs in three isoforms, and it is theorized that
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their distribution is related to human evolutionary migration patterns and the historic adoption of grain-based agriculture.
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Groups with the longest exposure to grain consumption have a lower E4 frequency, suggesting that high carbohydrate
intakes may have selected against E4.
5
The three ApoE isoforms differ by just one amino acid, but this substitution has dramatic biochemical implications.
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These single substitutions affect tendency to become glycated, as well as determine binding affinity to enzymes and
receptors, which is why the three isoforms are associated with different trends in serum LDL, VLDL, and triglyceride
measurements.
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Neurons have ApoE receptors, which suggests that ApoE plays a role in the delivery and clearance of fatty acids,
cholesterol, and phospholipids to and from the brain. Delivery and recycling of cholesterol in the brain is critical because
the brain contains 25 percent of the body’s total cholesterol—used as an antioxidant, electrical insulator and key struc-
tural component of plasma membranes. ApoE4 is associated with reduced LDL uptake and all the consequences that
would result from an inability to deliver cholesterol and fatty acids to target cells. Cholesterol is an essential contributor
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to structure and function in the brain, and any interruption in its supply would have extreme consequences for cognitive
function.
34 Wise Traditions SUMMER 2014 Wise Traditions

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