See comment by Benjamin Wolozin
See reply by Monique Breteler
Comment by Benjamin Wolozin:
Thinking about brain and serum cholesterol metabolism in Alzheimer’s disease.—Posted 24 December 2002.
The recent study by Engelhart and colleagues investigates the relationship of serum cholesterol and serum polyunsaturated fatty acids (PUFA) to the incidence of Alzheimer’s disease in the cohort of patients present in the Rotterdam study. Engelhart et al. do not observe any clear relationship between the intake of cholesterol, total PUFA, n-3 PUFA or n-6 PUFA and the incidence of Alzheimer’s disease.
The literature on the relationship between cholesterol and Alzheimer’s disease is quite confusing, and at times contradictory. Studies in cell culture, transgenic mice, and rabbits indicate that production of Aβ is sensitive to cellular cholesterol. Reducing cholesterol, by treating with β-methylcyclodextran, statins, or BM15.766 (a cholesterol-lowering drug that acts distal to HMG CoA reductase) reduces the production of Aβ and accumulation of neuritic plaques (Fassbender et al., 2001; Refolo et al., 2001; Simons et al., 1998). Human subjects treated with simvastatin or lovastatin also have less Aβ (Friedhoff et al., 2001; Simons et al., 2002). Several retrospective studies and one prospective study indicate that there is a lower prevalence of Alzheimer’s disease or delayed progression of Alzheimer’s disease among subjects taking statins (Jick et al., 2000; Rockwood et al., 2002; Simons et al., 2002; Wolozin et al., 2000; Yaffe et al., 2002). Together, these studies suggest some link between cholesterol and Alzheimer’s disease.
However, studies that examine the relationship between serum cholesterol and Alzheimer’s disease have produced mixed results. Engelhart’s study is the most recent of several studies demonstrating the lack of any linkage between serum cholesterol and AD (Prince et al., 2000; AbstractYoshitake et al., 1995
). Some recent studies did observe a possible effect of serum cholesterol and AD (Kivipelto et al., 2002; Kivipelto et al., 2001; Notkola et al., 1998).
Analysis of the biology of cholesterol suggests a potential reason explaining why measurements of serum cholesterol might not show a strong association with AD. Alzheimer’s disease is thought to be caused, at least in part, by the accumulation of aggregated Aβ in the brain. If true, this suggests that the most important site for regulating Aβ production is also in the brain. This logic is important because cholesterol in the brain is synthesized de novo. Little, if any, cholesterol comes from the blood. The independence of brain and serum cholesterol is reflected by the different half-lives of cholesterol in the two organs. The half-life of cholesterol in the rodent brain is six months (although there is likely to be a large difference between turnover of cholesterol in myelin and in neurons), and probably longer in humans (AbstractAndersson et al., 1990; Bogdanovic et al., 2001; Dietschy and Turley, 2001). The half-life of cholesterol in serum is hours. The independence of serum and brain cholesterol could readily account for the lack of any clear association between serum cholesterol and Alzheimer’s disease.
If cholesterol in the brain is the critical issue, how might it affect Aβ? There are several possible scenarios. One possibility is that reducing neuronal cholesterol reduces the production of Aβ because the γ- or β-secretase complex requires a high-cholesterol environment to be active. Studies of the enzymes that produce Aβ indicate that these proteins reside in cholesterol-rich regions of the membrane, termed lipid rafts (Wahrle et al., 2002). A second possibility is that statins or cholesterol-lowering diets (in mice) lower apolipoprotein E levels. This could occur because statins prevent isoprenylation of ras, rac and rho, which is required for activation of rho and stimulation of apolipoprotein E production (Martin et al., 2001; Takemoto and Liao, 2001). Isoprenylation is also important in inflammation, and statin-mediated inhibition of the inflammatory response might also be beneficial in AD (Takemoto and Liao, 2001).
Whether cholesterol is truly important in AD, and whether statins are actually beneficial as an anti-Alzheimer’s therapy remains to be determined. Alzheimer’s research is littered with theories and medications that look promising in the lab or in epidemiological studies, but have proved to be disappointing in the clinic. Although a small preliminary study suggested that statins might prevent the progression of dementia in patients in early stages of Alzheimer’s disease, a much larger study has failed to show a beneficial effect of statins on dementia (Shepherd et al., 2002). On the other hand, molecular genetic studies increasingly suggest a linkage between cholesterol and AD because AD has been associated with two genes related to cholesterol metabolism—apolipoprotein E and cholesterol 24 hydroxylase (Cyp46), and there might also be a link between AD and α2-macroglobulin, which is also important for cholesterol metabolism (Blacker et al., 1998; Corder et al., 1993; Kolsch et al., 2002). The putative linkage between cholesterol 24 hydroxylase and AD is particularly notable because this enzyme does not exist outside the brain, which emphasizes the potential importance of cerebral cholesterol metabolism in AD (Lund et al., 1999). Strong genetic validation of the putative link between brain cholesterol metabolism and the pathophysiology of AD would provide important support for the concept of modulating brain cholesterol metabolism to treat AD, whether or not statins prove to be the best tool for this approach.
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