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progressed from normal to AD was 26 percent age of amyloid precursor protein (APP), but The occasional
below that of people who did not develop AD, and its accumulation and aggregation into plaques
27 foibles and
the annual rate of decline averaged 4.4 percent. represents the quintessential feature of AD.
Assuming the rates of decline were somewhat Aβ is found in orders of magnitude greater in forgetfulness
constant, extrapolating backward indicates that AD brains than in healthy brains. This fact is we associate
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the decline may have started several years before noteworthy because lower concentrations of Aβ
baseline testing, and possibly decades before tend to stay soluble; higher concentrations form with normal
any overt signs of AD were present. At baseline, plaques more readily. 29 aging could
despite the already decreased CMRglu in some If these plaques are either causing or exac- in fact be the
subjects, all subjects were cognitively normal. erbating AD, it is crucial to identify why they’re
This suggests that reduced glucose utilization being secreted out of the cell and why they are earliest signs
in the brain might be one of the earliest events not degraded normally. It has been shown that that the brain

in AD. The occasional foibles and forgetfulness insulin is behind both of these phenomena: in- is losing its
we associate with normal aging could, in fact, sulin stimulates the secretion of the two forms
be the earliest signs that the brain is losing its of Aβ associated with AD, and it also inhibits its ability to fuel
ability to fuel itself effectively. degradation and clearance. 30 itself
Rather than increased production of Aβ effectively.
NEUROFIBRILLARY TANGLES inside the cell, research indicates that reduced
A second physical hallmark of AD is intra- extracellular clearance is what causes Aβ to
cellular neurofibrillary tangles (NFTs) made of accumulate. Aβ is cleared primarily by insulin
hyperphosphorylated tau protein. Tau is a protein degrading enzyme (IDE). The affinity of IDE for
that binds to microtubules and promotes stabi- insulin is so high, however, that the presence of
lization of the cell’s internal structure. Hyper- even small amounts of insulin completely inhib-
phosphorylated tau does not bind to microtubules its the degradation of Aβ. Insulin acts as a kind
30
and instead tangles in upon itself, leaving this of competitive inhibitor, such that when insulin
debris inside the cell, and also resulting in an is present, IDE will be “busy” clearing it, leaving
improperly constructed cytoskeleton, leading to Aβ to accumulate. Hyperinsulinemia equates to a
compromised cell function. 12,26 A critical result of functional (if not clinical) “IDE deficiency.” This
malformed microtubules is loss of structure and strikes an even bigger blow to aging populations
function in neuronal axons and dendrites—the because IDE production declines with age, so
projections responsible for cellular communica- there is an increasing amount of substrate com-
tion—sending and receiving electrical impulses bined with lower enzyme activity.
31
and metabolic materials. Just as insulin can be seen as a competitive
26
What, then, causes the phosphorylation of inhibitor of IDE for degradation of Aβ, Aβ can be
tau? This is regulated by the enzyme glycogen viewed as a competitive inhibitor of insulin for
synthase kinase 3β (GSK-3β). Insulin inhibits this its receptor. This has been proven in human cells
enzyme, so if the brain is insulin resistant, the in vitro—Aβ reduces the binding of insulin to its
process is not inhibited. An interesting feature receptor in a dose-dependent manner. Insulin
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ties hyperphosphorylated tau back to ApoE4. Of levels are already reduced in the brain of AD
the three isoforms of ApoE, E4 is unique in its patients, and now there is something interfering
inability to bind tau. The E3 isoform has been with the proper binding of what little insulin is
proven to bind to tau (with the same suspected present.
for E2), thus preventing or minimizing its phos- Due to reduced clearance via IDE, Aβ ac-
phorylation. cumulates, and the more it accumulates, the more
prone it is to form insoluble plaques. Two other
BETA-AMYLOID PEPTIDE factors contributing to plaque formation are in-
The most prominent physical characteristic timately related to the genetic and metabolic risk
of an AD brain is the accumulation of insoluble factors for AD—ApoE genotype and hyperinsu-
extracellular plaques consisting of beta-amyloid linism (with attendant hyperglycemia). Autopsy
peptide (Aβ). Aβ results from the normal cleav- of human AD brains shows that the amount of
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