Alzheimer’s disease is a common form of dementia
affecting 3% of those 65–74 years old, 18.7% of those
75–84, and 47.2% of those over 85 years of age [63].
Approximately 20–30% of Alzheimer’s disease results in
defects in 6 different genes. Defects in chromosome 1
and 14, encoding presenilin 1 and 2; in chromosome 21,
encoding amyloid precursor protein, lead to early onset
Alzheimer’s disease. Defects in chromosome 21, encoding
a2 microglobulin; or in chromosome 19, encoding
apolipoprotein E is associated with late onset Alzheimer’s
disease. All of the genetic defects result in
excessive accumulation of amyloid protein. The remaining
70–80% of Alzheimer’s disease have the same
pathological findings of amyloid plaques, phosphorylated
microtubular proteins and loss of hippocampal
neurons associated with memory loss and increasing
dementia, but from causes which include ischemia [64]
mild trauma [65] elevated plasma homocystine [66]
insulin resistance [67] and impaired brain energy
metabolism [68]. The clinical phenotype of Alzheimer’s
disease is clearly a complex multifactoral disease.
A major finding in Alzheimer’s disease is the decrease
in brain acetyl choline [69]. This finding has led to the
widespread use of acetyl cholinesterase inhibitor in the
treatment of the disease, but with only very limited if
any improvement [70]. However this pharmacological
approach fails to address the underlying pathophysiology
of the disease. The common feature of Alzheimer’s
disease is the elevated levels of proteolytic fragments of
b amyloid both extra and intracellularly [71]. It is
reported that the 1–42 fragment of b amyloid, Ab142,
stimulates a mitochondrial isoform of glycogen synthase
kinase 3b [72] which phosphorylates and inactivates the
pyruvate dehydrogenase multienzyme complex [73] and
results in the decrease in acetyl choline synthesis [74]
characteristic of the Alzheimer’s disease phenotype.
Since under normal conditions brain is entirely dependent
on glucose as an energy source, inhibition of PDH
would be expected to decrease mitochondrial acetyl
CoA formation and hence citrate formation, a necessary
precursor of acetyl choline. Blockade of PDH is
characteristic of insulin lack in heart and ketone bodies
are the physiological mechanism which overcomes this
inhibition. If this were to occur in neurons, administration
of ketone bodies should by-pass this block. We
tested this hypothesis in primary rat hippocampal
neuronal cultures exposed to 5 mM Ab142 and found
that the addition of 4mM Na d-b-hydroxybutyrate
protected against Ab142 toxicity [62]. Induction of mild
ketosis would therefore seem a reasonable potential
therapy in Alzheimer’s disease.
