2.2.1 ALZHEIMER’S DISEASE
The detected risk factors for AD include Down
Syndrome (Wisniewsky et al., 1985), female sex (Gao et al., 1998), low
education level (Launer et al., 1999), family history of dementia (Mohs et
al., 1987), depression and depressive symptoms (Devanad wt al., 1996),
small head size (Reynolds et al., 1999), myocardial ischemia and history
of myocardial infarction (Sparks et al., 1990), and hypothyroidism (Breteler
et al., 1991). The reported protective factors against dementia, AD, or
cognitive impairment include greater educational attainment, APOE-e2
allele, use of antioxidants, use of estrogen supplements in women, use of
anti-inflammatory drugs, cigarette smoking and being married (Kukull and
Ganguly, 2000).
The genetic risk factors associated with AD and other
dementias can be categorized into deterministic genes and susceptibility
genes. Deterministic genes are autosomal dominant, are causally associated
with certain dementias that appear to be single gene disorders, and
include the gene for amyloid precursor protein on chromosome 21, the
presenilin-1 gene on chromosome 14, and presenilin-2 gene on chromosome 1.
Susceptibility genes appear to increase the risk for dementia, but are
neither necessary nor sufficient to cause it. The best-established
susceptibility gene is the apolipoprotein E gene located on chromosome 19
(Kukull and Ganguly, 2000).
Pathophysiology
Neurofibrillary tangles and neuritic amyloid plaques
represent the core neuropathologic features of AD (Clark and Karlawish,
2003). Amyloid plaques are primarily composed of extracellular deposits of
the 39 to 42–amino acid proteolytic derivatives of the transmembrane
amyloid precursor protein in addition to the flotsam and jetsam of
degenerative neurons; reactive glial cells; and other various
proteinaceous components. On the basis of the structure of amyloid
plaques, they are classified as diffuse or neuritic. Neurofibrillary
tangles are relatively insoluble intracellular aggregates composed of
paired helical filaments of the abnormally hyperphosphorylated
microtubule-associated protein, tau. Phosphates are attached and removed
from tau in a dynamic process that regulates the ability of the protein to
facilitate the assembly and stabilization of microtubules. In AD the tau
protein accumulates an excess number of phosphates and becomes
dysfunctional, dissociating from the microtubule and resulting in the
destabilization and disrupted assembly of this important cytoskeletal
component of the intracellular transport system
(Clark et al., 1997; Lee et al., 1991).
These lesions are regionally specific, occurring
predominantly in the hippocampus, entorhinal cortex, and association areas
of the neocortex
(Arnold et al., 1991). The development of these lesions leads to
neuronal death; impaired cognition; and, ultimately, brain failure and
death. Neuronal death is the result of a complex cascade of intracellular
events that is most likely triggered by various intracellular or
extracellular factors
(Cotman and Anderson, 2000). The process is termed "apoptotic" (i.e.,
programmed cell death) to distinguish it from cell death due to ischemia
or necrosis.
Pharmacologic Management
Four medications - tacrine (Davis et al., 1992),
donepezil (Rogers et al., 1998), rivastigmine (Rösler et al., 1999) and
galantamine (Tariot et al., 2000) - have been found efficacious and
relatively safe for symptomatic management of patients with AD. All are
cholinesterase inhibitors that produce essentially the same degree of
modest improvement in approximately 30% to 40% of patients with mild to
moderate (MMSE score between 10 and 26) AD (Clark
and Karlawish, 2003). Tacrine produces liver toxicity and must be
administered four times daily. Donepezil has a very low incidence of
nausea and diarrhea at the 10-mg dose (the higher of the two doses
available) and is administered once daily. Both 5-mg and 10-mg doses of
donepezil were effective in improving cognitive and global functioning
after six months of treatment, and when data were pooled across the
studies, the higher dose appeared to be more effective (Wilcock et al.,
2001). Most neurologists recommend starting rivastigmine at a dose of 1.5
mg twice daily and then gradually increasing the dose every 4 weeks by 1.5
mg, to a maximum of 6 mg twice daily, if tolerated and if cognitive and
global functioning continue to improve. The need for twice daily doses of
rivastigmine will usually require more supervision for patients living
alone (Gauthier, 2002). The major effect of cholinesterase inhibitors,
which remains to be confirmed in prospective longitudinal clinical trials,
lies in their potential to slow the rate of progression of AD. An
additional benefit of cholinesterase inhibitors is their ability to reduce
some of the neuropsychiatric symptoms associated with AD, especially
apathy and visual hallucinations (Cummings, 2000).
It is impossible to compare the efficacy of these
cholinesterase inhibitors because they have not been adequately studied in
head-to-head trials. There is some preliminary evidence that, if a patient
does not respond to one cholinesterase inhibitor, switching to another may
be beneficial (Robillard et al., 2001). Switches can also be done to cope
with side effects (Robillard et al., 2002). No wash out periods are
recommended before switching unless there are unresolved side effects from
the first drug, in which case a wash-out period of 1 week or until
symptoms resolve is recommended. Combination of cholinesterase inhibitors
is not recommended (Morris et al., 2001).
Vitamin
E, an antioxidant, has been found effective in delaying
institutionalization and death and in delaying the cognitive decline (Sano
et al., 1997), and the American Academy of Neurology now recommends 1000
IU of vitamin E twice daily as a standard care for the treatment of
patients with AD (Doody et al., 2001).
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