Page 36 - Summer2014

High plaque present and its density are directly influ- of time, and the functional “hyperglycemia”

cholesterol enced by ApoE genotype, with E4 homozygotes in the brain will provide an elevated level of
having the densest and most extensive plaques. glucose—the perfect storm for glycation of Aβ
levels later in Sections from the brains of homozygous ApoE4 and its aggregation into insoluble plaques. As
life are AD patients are so riddled with Aβ plaques that if that were not challenge enough for a brain
associated they can often be distinguished from those of E3 that is already struggling to metabolize fuel ef-
ficiently, AGEs themselves have been shown to
carriers without a microscope.
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with reduced ApoE particles themselves have been be neurotoxic, likely by inducing apoptosis (cell
risk of identified in amyloid plaques. However, strong death) and lipid peroxidation—a process that is
dementia. evidence that they bind directly to the plaques especially damaging to cells whose membranes
is lacking. What has been established is the fact are particularly rich in PUFAs.
10,33
that ApoE particles bind to advanced glycation Similar to the reduction in the CMRglu,
end products (AGEs), and yet another factor AGE accumulation is a normal product of aging,
contributing to the insolubility of the plaques is but AGE formation occurs more quickly and to a
their degree of glycation. The plaques become greater degree in AD patients. AD brains show
glycated (bonded to sugar) and form cross-link- more AGEs than those of healthy, age-matched
ages with each other, resulting in toxic AGEs. It controls. ApoE4 particles have been shown
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is the glycated plaques and AGEs that the ApoE to have three times greater AGE-binding af-
particles actually bind to. Glycation is a factor finity than ApoE3, and apolipoprotein particles
of glucose concentration exposure and time, themselves are subject to glycation. Increased
with more AGEs forming upon longer exposure glycated ApoE particles have been detected in
to higher concentrations of glucose. It follows the cerebrospinal fluid (CSF) of AD patients. 34,35
33
that in a body that is hyperinsulinemic, and a The physiological insult of glycated ApoE is that
brain that is insulin-resistant, the peripheral ApoE helps transport LDL particles (and their
hyperinsulinism will inhibit the clearance of critical cholesterol and fatty acid passengers)
soluble Aβ by IDE, thereby causing it to remain across the blood brain barrier. LDL containing
in the extracellular space for an extended amount normal ApoE will be recognized by its receptor

WHAT TO AVOID TO HELP PREVENT ALZHEIMER'S DISEASE

• STATIN DRUGS: Cholesterol is a vital part of the myelin sheath insulating neurons and assisting in propagation of
nerve impulses; metabolites in the cholesterol biosynthesis pathway inhibited by statins are required to produce CoQ 10
as well as functional GLUT4s. Cholesterol is also an integral part of plasma membranes, lending structural stability.
Any pharmaceutically-induced disruption in endogenous synthesis of cholesterol—especially when combined with
long-standing, population-wide recommendations to limit dietary intake—would starve the struggling brain of this
absolutely critical nutrient. In fact, high cholesterol levels later in life are associated with reduced risk of dementia,
and the CSF of AD patients has been shown to be lower in cholesterol than that of healthy controls. 62,63 HMG CoA
reductase—the target of statin therapy—is abundant in brain cells. They require a constant supply of cholesterol, and
when its production is inhibited, the result is a loss of myelin as well as malformation of membranes—including those
of the mitochondria. Compromised mitochondrial function deprives the brain of ATP. It is no surprise that decades
8
of recommendations to reduce consumption of cholesterol and perhaps overzealous prescription of statin drugs have
paralleled the rise in AD incidence.
6
• PROCESSED FOODS: These present a quadruple nutritional assault upon a brain suffering the ravages of the modern
diet: they are usually high in refined carbohydrate; high in rancid, easily oxidized vegetable oils; low in antioxidants;
and low in vitamins and minerals.

• EXOGENOUS INSULIN: Although insulin has been shown to improve memory and cognition acutely, chronically
high insulin levels are known to impair brain function. 42,64 Exogenous insulin would serve to inhibit IDE more strongly,
thereby preventing the clearance of Aβ, causing it to linger in the brain interstitial fluid even longer, where it is sub-
ject to glycation and oxidation. As noted, the greatest risk for AD is reserved for ApoE4 carriers who are treated with
exogenous insulin.
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