DƯỢC LÍ Goodman & Gilman's The Pharmacological Basis of Therapeutics 12th, 2010

620 year to AD (Petersen et al., 2005), although not all MCI
patients will develop AD. The decline in both cognitive
and functional capacity follows a course of gradual but
relentless progression in AD, spreading to involve other
cognitive domains including visuospatial and executive
function. The later stages of the disease are characterized
by increasing dependence and progression toward the
akinetic-mute state that typifies end-stage neurologic disease.
Death, most often from a complication of immobility
such as pneumonia or pulmonary embolism,
usually ensues within 6-12 years of onset.
At present, the diagnosis of AD is based on the
clinical assessment of the patient. Structural neuroimaging
and appropriate laboratory tests are used to
exclude other disorders that may mimic AD. In the near
future, laboratory measures to specifically identify AD,
including analysis of biomarkers such as CSF or serum
factors, genetic testing, and molecular or functional
neuroimaging, are likely to be incorporated into AD
diagnostic criteria to enhance the sensitivity of diagnosis,
especially at early stages of the disease (Dubois
et al., 2007). A direct antemortem confirmatory test currently
does not exist.
SECTION II
NEUROPHARMACOLOGY
Genetics. Mutations in three genes have been identified as causes of
autosomal dominant, early-onset AD: APP, which encodes amyloid-β
precursor protein, and PSEN1 and PSEN2, encoding presenilin 1 and 2.
All three genes are involved in the production of amyloid-β
peptides (Aβ). Aβ is generated by sequential proteolytic cleavage of
APP by two enzymes, β-secretase and γ-secretase; the presenilins
form the catalytic core of γ-secretase. The genetic evidence, combined
with the fact that Aβ accumulates in the brain in the form of
soluble oligomers and amyloid plaques, and is toxic when applied to
neurons, forms the basis for the amyloid hypothesis of AD pathogenesis
(Tanzi and Bertram, 2005).
Autosomal-dominant cases of AD are quite rare, but there is
also a significant genetic component to the more common, sporadic,
late-onset cases of AD. Many genes have been identified as having
alleles that increase AD risk (Bertram et al., 2007). By far the most
important of these is APOE, which encodes the lipid carrier protein
apolipoprotein E (apoE) (Raber et al., 2004). Individuals inheriting
the ε4 allele of APOE have a more than 3-fold higher risk of developing
AD. While they make up less than one-fourth of the population,
they account for more than half of all AD cases. Several clinical trials
have shown a different response rate between apoE4-carriers and
noncarriers, suggesting an important potential pharmacogenetic influence
of apoE genotype on the choice of therapy. However, at this
point genetic testing for apoE status is not a routine part of the clinical
evaluation for AD.
Pathophysiology. The pathological hallmarks of AD are amyloid
plaques, which are extracellular accumulations of Aβ, and intracellular
neurofibrillary tangles composed of the microtubule-associated
protein tau (Figure 22–6). While the development of amyloid
plaques is an early and invariant feature of AD, tangle burden accrues
over time in a manner that correlates more closely with the development
of cognitive impairment. The current consensus is that Aβ
accumulation is an upstream event that triggers tau pathology, resulting
in impaired neuronal function and cell loss. In autosomal dominant
AD, Aβ accumulates due to mutations that cause its
overproduction. The cause of high cerebral Aβ levels in late-onset
sporadic AD is unclear but is likely caused by impaired clearance
rather than overproduction.
Mitochondrion
Aβ
Neuron
Neurofibrillary
tangles
Truncated
Apo E4
Nucleus
Apo E4
Tau
Impaired
synapse
Oligomers
Microglial
cell
Signaling
molecules
Neurite
Amyloid
plaque
Figure 22–6. Molecular and cellular processes presumed to participate in AD pathogenesis. (From Roberson ED, Mucke L. 100 years
and counting: Prospects for defeating Alzheimer’s disease. Science, 2006, 314:781–784. Reprinted with permission from AAAS.)