C h a p t e r 3 7
Disorders of Brain Function
949
Pathology
Alzheimer disease most often presents with a subtle onset
of memory loss followed by slowly progressive demen-
tia that has a course of several years. Evidence from
familial forms of AD indicates that the accumulation of
a peptide (amyloid beta or A
β
) in the brain initiates a
chain of events that result in the morphologic changes of
AD and dementia. This peptide is derived from a larger
membrane-spanning protein known as
amyloid precur-
sor protein
(APP), which can be processed in either of
two ways. It can be cleaved by the enzymes,
α
-secretase
and
γ
-secretase, in a proteolytic pathway that prevents
the formation of A
β
, or it can be cleaved by
β
-secretase
and
γ
-secretase in a pathway that generates A
β
.
1
Diagnostic imaging of the brain reveals diffuse atro-
phy of the cerebral cortex with enlargement of the ven-
tricles (Fig. 37-18). The major microscopic features
of Alzheimer disease include
neuritic (senile) plaques
,
patches or flat areas composed of clusters of degenerat-
ing nerve terminals arranged around a central amyloid
core. In the cytoplasm of abnormal neurons are
neuro-
fibrillary tangles,
which consist of fibrous proteins that
are wound around each other in a helical fashion. These
tangles are resistant to chemical or enzymatic break-
down, and they persist in brain tissue long after the
neuron in which they arose has died and disappeared.
Smaller cerebral vessels also exhibit amyloid angiopa-
thy, in which there is deposition of A
β
in vessel walls.
Some plaques and tangles can be found in the brains
of older persons who do not show cognitive impairment.
The number and distribution of the plaques and tangles
appear to contribute to the intellectual deterioration
that occurs with Alzheimer disease. In persons with the
disease, the plaques and tangles are found throughout
the neocortex and in the hippocampus and amygdala,
with relative sparing of the primary sensory cortex.
1
Hippocampal function in particular may be compro-
mised by the pathologic changes. The hippocampus is
crucial to information processing, acquisition of new
memories, and retrieval of old memories.
Neurochemically, AD has been associated with a
decrease in the level of choline acetyltransferase activity
in the cortex and hippocampus. This enzyme is required
for the synthesis of acetylcholine, a neurotransmitter
that is associated with memory. The reduction in choline
acetyltransferase is quantitatively related to the numbers
of neuritic plaques and severity of dementia.
It is likely that AD is caused by several factors that
interact differently in different persons. Progress in the
genetics of inherited early-onset AD shows that muta-
tions in at least three genes—the
APP
gene on chromo-
some 21; presenilin-1 (
PS1
), a gene on chromosome 14;
and presenilin-2 (
PS2
), a gene on chromosome 1—can
cause AD in certain families.
1,4
The
APP
gene is associ-
ated with an autosomal dominant form of early-onset
AD and can be tested clinically. Virtually all persons
with Down syndrome (trisomy 21) exhibit the patho-
logic features of AD as they age. Presenilin-1 and pre-
senilin-2, both intracellular proteins, are components of
γ
-secretase and possibly part of a multiprotein complex
containing the proteolytic site for breakdown of A
β
.
A fourth gene, the apolipoprotein E (ApoE) gene, has
been found to increase the risk of AD and lowers the age
of onset of the disease.
4,68
The gene, which is found on
chromosome 19, has three common alleles—E2, E3, or
E4. Each person inherits one copy of the gene from each
parent. An increased risk of late-onset and sporadic AD
is associated with inheritance of the E4 gene, particu-
larly if it is inherited from both parents. Conversely, the
E2 gene may confer some protection. The age of onset in
late-onset AD also correlates with the gene, with E4/E4
FIGURE 37-18.
Functional imaging of the brain with positron emission tomography (PET). Perfusion
and metabolism in a normal brain
(A)
and hypoperfusion and hypometabolism due to brain atrophy
in a brain with Alzheimer disease
(B)
(From Alzheimer’s Disease: Unraveling the Mystery Images.
National Institutes of Health, National Institute of Aging.)
A
B
