Etiology

for example, reports that 40 percent of the autopsied brains of participants in the Nun Study who died between the ages of 85 and 89 showed marked Alzheimer's pathology whereas only 22 percent of brains from persons who reached at least 100 years before death showed such pathology.

Genetic predisposition plays a predominant role in cases of early-onset AD and interacts with environmental and life-history factors to produce late-onset cases. A number of dominantly inherited genetic mutations can cause early-onset AD, but such cases account for less than 1 percent of the total AD population. Mutations in the pre-senilin 1 gene on chromosome 14, which codes for one of the secreteases that cleave the amyloid precursor protein (APP), account for 50 percent or more of the dominantly inherited, early-onset AD cases (Schellenberg et al., 1992). Most individuals with tri-somy 21 (Down syndrome) develop cortical amyloid plaques consistent with AD by age 40 as a result of carrying an extra copy of the APP gene, which is found on chromosome 21. Patients without Down syndrome who have APP gene mutations can likewise develop AD and account for about 1 to 3 percent of the dominantly inherited, early-onset AD cases (Saint George-Hyslop et al., 1987). Mutations in the presenilin 2 gene on chromosome 1, which code another secretase that cleaves APP, cause about 5 to 10 percent of the dominantly inherited, early-onset AD cases (Levy-Lihad et al., 1995). The apolipoprotein E (APOE) gene on chromosome 19 codes for apolipoprotein E (apoE), which plays a role in cholesterol transport and possibly in neuronal repair and neuroplasticity. There are three alleles of this gene: The E3 allele is by far the most common in all populations, and this is followed by the E4 and E2 alleles. It has been shown that the various APOE genotypes alter the risk of late-onset AD: The E2 allele seems to decrease risk, and the E4 allele seems to increase risk in a dose-dependent fashion. E4 gene dose is likewise inversely related to age of disease onset, with almost all E 4/4 homozygotes developing AD by age 80 (Corder et al., 1993; Mayeux et al., 1993; Pericak-Vance et al., 1991).

In recent years a cognitive reserve hypothesis has been developed that holds that individuals with greater premorbid intelligence, language abilities, and educational achievement can more effectively compensate for losses caused by AD than individuals with lesser abilities (Mesulam, 2000; Snowdon et al., 1996). Functional imaging studies have supported the reserve hypothesis by showing that, at a given level of dementia severity, patients with higher premorbid intelligence quotients (IQs) and levels of education have more severe deficits on imaging than patients with lesser abilities (Alexander et al., 1997; Stern et al., 1992). Studies examining brain size (which correlates positively with both IQ and education) have similarly found that increased premorbid brain mass may have a protective effect against the clinical manifestation of AD (Schofield, 1999).

Studies examining the relationship between head trauma and the subsequent development of AD have yielded conflicting results. Traumatic brain injuries could increase the risk of AD by decreasing brain reserve or by playing a facilitative role in the pathogenesis of AD. Brain trauma can cause an increase in the deposition of beta-amyloid, the main constituent of AD plaques, in the brain. An interaction between head trauma and APOE genotype has also been noted (Jordan, 1997; Mayeux et al.,

1995) wherein the APOE E4 gene dose correlates positively with the manifestation of AD after brain trauma.

Sapolsky and colleagues (McEwen and Sapolsky, 1995; Sapolsky, 1996) have demonstrated that stress and subsequent hyperactivity of the hypothala-mic/pituitary/adrenal axis may lead to cell death in the hippocampus. While this process seems to occur in individuals with posttraumatic stress disorder (PTSD), traumatic stress victims have not been shown to be at increased risk for AD.

Recent large-scale studies conducted in Finland (Kivipelto et al., 2002) and the United States (Knopman et al., 2001a) suggest that many of the risk factors for cardiovascular disease and vascular dementia, including diabetes mellitus, high cholesterol, and hypertension, also increase the risk of developing AD. Indeed, the increase in risk for these factors, which are treatable, appears to be greater than the increase in risk provided by the APOE E4 allele (Kivipelto et al., 2002). These findings provide hope that medications commonly used in primary care may have a preventive effect with respect to AD. Initial results with statins appear promising and argue that control over risk factors for cardiovascular (CV) disease is one way to substantially reduce the risk for AD (Samuels and Davis, 2003).

Mesulam (2000) has integrated data regarding the etiology of AD into a "neuro-plasticity failure" hypothesis that posits that the genetic, environmental, general health, and life-history risk factors compromise neuronal repair mechanisms that would otherwise inhibit or prevent the neuropathological cascade leading to AD. Accordingly, effective treatment and prevention of AD will involve reducing neuroplasticity burden and/or enhancing plasticity mechanisms.

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