Second edition

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338 Neurodegenerative and movement disorders
In addition, there appears to be a correlation between
the depth of the memory loss in Alzheimer’s disease and
the extent of damage in the cholinergic nucleus basalis of
Meynert (Neary et al. 1986; Rasool et al. 1986; Whitehouse
et al. 1982). There is also a correlation between depression
and cell loss in the superior central nucleus (Zweig et al.
1988) and probably the locus ceruleus (Zubenko and
Moosy 1988; Zweig et al. 1988), although not all have replicated
this finding (Hoogendijk et al. 1999).
Much progress has been made in the search for the etiology
of Alzheimer’s disease, especially with regard to genetic
factors. In a small minority of cases, probably less than 1 percent,
especially those of early onset before the age of 50 years,
Alzheimer’s disease is clearly inherited in an autosomal
dominant fashion. Mutations have been identified in three
genes (Janssen et al. 2003): the APP (amyloid precursor protein)
gene on chromosome 21 (Brouwers et al. 2006;
Chartier-Harlin et al. 1991), the presenilin-1 gene on chromosome
14 (Bird et al. 1996; Wasco et al. 1995), and the
presenilin-2 gene on chromosome 1 (Levy-Lahad et al. 1995).
The role of genetic factors in the remaining vast majority of
cases of apparently sporadic Alzheimer’s disease is not clear.
Some (Bergem et al. 1997; Breitner et al. 1995; Gatz et al.
1997), but not all (Cook et al. 1981), studies support a higher
concordance among monozygotic than dizygotic twins.
Likewise, whereas some studies indicate a higher prevalence
of Alzheimer’s disease among the first-degree relatives of
probands than among the equivalent relatives of controls,
others do not. One of the reasons for these discordant results
might be that, although Alzheimer’s disease may be inherited,
there is such great intrafamily variability in the age of its
expression that most cases among relatives are missed in
cross-sectional studies. Life-table studies support this
notion; indeed, studies using the life-table approach have
found that the projected risk among first-degree relatives is
approximately 50 percent (Mohs et al. 1987), just what
would be expected if sporadic Alzheimer’s disease was, in
fact, an autosomal dominant disorder.
Another gene associated with Alzheimer’s disease is that
for apolipoprotein E on chromosome 19. Apolipoprotein
E occurs in several forms, depending on which alleles are
present – epsilon-2, epsilon-3, or epsilon-4 – and there is a
correlation between which alleles are present and the risk
of Alzheimer’s disease. Thus, the risk for patients with one
or two of the epsilon-4 alleles is substantially higher
(Corder et al. 1993; Saunders et al. 1993) than that for
patients who lack this allele. Importantly, the presence of
the epsilon-4 allele is merely a ‘risk factor’: patients without
this allele can and do get the disease and, conversely,
those with it may never develop Alzheimer’s.
In contrast to these positive results in genetic studies,
efforts to identify environmental causes have generally been
unsuccessful, with possibly one exception: it does appear
that a history of significant head trauma may increase the
risk of Alzheimer’s disease (Schofield et al. 1997).
The actual mechanism or mechanisms responsible for
the formation of neurofibrillary tangles and neuritic
plaques remain unclear. One current hypothesis (the ‘amyloid
cascade hypothesis’) focuses on the neurotoxicity of
one form of beta-amyloid, the 42-amino acid form. APP is
a transmembrane protein that is normally cleaved by several
secretases, namely alpha, beta, and gamma secretase.
Depending on which secretases are involved, different
fragments are produced; when cleavage is via beta and then
gamma secretase it appears that two forms of beta-amyloid
are produced, a 40-amino acid form and a 42-amino acid
form. The 42-amino acid form of beta-amyloid is relatively
insoluble and undergoes fibrillization to form what are
known as ‘diffuse’ plaques. These diffuse plaques prompt
an inflammatory response and are neurotoxic; according
to the theory, this neurotoxicity leads both to the breakdown
of axons, thus creating neurites that surround the
‘diffuse’ plaques, thereby creating classic neuritic plaques,
and to the formation of neurofibrillary proteins in surviving
neurons. This amyloid cascade hypothesis gains support
from several quarters. First, it is well known that
patients with Down’s syndrome, should they survive past
the age of 40 years, almost always develop Alzheimer’s disease
(Evenhuius 1990; Jervis 1948; Lai and Williams 1989;
Olson and Shaw 1969). Down’s syndrome occurs secondary
to an extra chromosome 21, with a consequent extra
gene for APP; this leads in turn to an overproduction of
APP, which would ‘start’ the amyloid cascade going from
the top. Second, as noted earlier, there are rare inherited
cases of Alzheimer’s disease that are caused by mutations
in the gene for APP, which, again, could start the cascade
going. Third, it appears that presenilin interacts with
gamma secretase and, as noted earlier, there are also rare
inherited forms of Alzheimer’s disease that occur secondary
to mutations in the genes for presenilin-1 or -2; conceivably,
if these mutations lead to an increased activity of
gamma secretase, this would lead to an overproduction of
beta-amyloid, specifically of the neurotoxic 42-amino acid
form. Finally, it also appears that the epsilon-4 form of
apolipoprotein E increases the rate of beta-amyloid production.
Although taken together these considerations
lend considerable weight to the ‘amyloid cascade’ hypothesis,
it should be borne in mind that the hypothesis
remains simply that, an hypothesis, and as yet has not
been proven.
Differential diagnosis
As noted above, the typical presentation of Alzheimer’s
disease is characterized by the gradual onset of amnesia,
with a subsequent accrual of other cognitive deficits; a personality
change may occur, but usually only after cognitive
deficits have become prominent, and, at least in the mild
stage of the disease, there are few distinctive features. The
differential diagnosis for such a dementia of gradual onset,
lacking in distinctive features, as detailed in Section 5.1 and
Table 5.1, is fairly wide, but certain considerations enable
one to narrow it down.