Etiologically-directed Approaches in AD(Alzheimer’s Disease)

Etiologically-directed Approaches in AD

Immune and Inflammatory Processes

Inflammatory processess may be seen in various neurodegen-erative disorders. Emerging evidence indicates overactivity of aspects of immune function in AD (Aisen and Davis, 1994). Im-mune/inflammatory reactions may be established by reactive mi-croglia surrounding senile plaques and astrocyte proliferation; and inflammatory cytokines are produced such as tumor necrosis factor alpha, interleukin-1 (IL-1), α-2-macroglobulin and α-1-an-tichymotrypsin. IL-1 and IL-6 promote the synthesis of β-amy-loid precursor protein.

Anti-infl ammatory medications

Epidemiological evidence supports the use of nonsteroidal anti-inflammatories as preventative of AD. However, clinical trials data is less encouraging. Thus, overall efficacy of anti-inflam-matories agents in AD has yet to be demonstrated.

Antioxidants

There are both theoretical reasons, and empirical findings, to suggest that free radical damage may be one of the mecha-nisms causing neuronal degeneration in a range of condi-tions including aging and Alzheimer’s disease. Many studies have found evidence of increased level of oxidative damage to neurons in Alzheimer’s disease, but neither Vitamin E nor ginkgo biloba can be recommended based on research results to date.

Calcium Channel Blockers

The process of neuronal death in aging and in AD may be medi-ated by an increase in intracellular free calcium, which activates various destructive enzymes (such as proteases, endonucleases and phospholipases) and disrupts intracellular processes. In prin-ciple, blocking the increase in intracellular free calcium may re-tard these mechanisms of neuronal death and thus slow progres-sion of disease.

Based on this hypothesis, two calcium channel block-ers that have been tested in AD patients are nimodipine and a Bristol-Myers Squibb investigational compound. In one trial, the low-dose nimodipine group (30 mg t.i.d.) showed less dete-rioration on several memory tests over a 10- to 12-week treat-ment period than the placebo or high-dose nimodipine (60 mg t.i.d.) group (Tollefson, 1990). A larger study showed significant cognitive effects for nimodipine compared with Hydergine^® and placebo (Kanowski et al., 1988). It is not clear, however, whether study subjects fulfilled criteria for possible AD. Ni-modipine is marketed to reduce the severity of neurological deficits resulting from vasospasm in patients who have had a recent subarachnoid hemorrhage. It is also used off-label as a cognitive enhancer. A continuing interest in calcium blockers is also spurred by results from a French hypertension trial that found that patients taking calcium blockers were less likely to develop dementia.

Combined Therapies

The combination of drugs with different mechanisms of action may be more effective than individual medications alone. The most relevant clinical questions are whether the available ChIs can or should be combined with other drugs. As a past example, choline precursors were combined with ChIs, but with no evident augmenting effect. Most practicing clinicians would take a dim view of combining two ChIs since their actions are additive. Phy-sicians should be skeptical also of combining available anti-in-flammatories or hormones with ChIs: first because of the lack of demonstrated efficacy of these drugs, and second because of the additive adverse events, especially gastrointestinal events. Some clinicians are combining memantine with of the ChIs. Clinical experience appears positive but there is no data from controlled trials.