This paper is very important. That statins reduce 24S-cholesterol was to be expected from previous studies. Indeed, the major future application of this work may grow out of its demonstration that AD patients respond within only six weeks to dosages of 40 mg statin/day with a reduction of the plasma levels of a brain-derived cholesterol derivative.

Why is this so important? Well, this study has the potential of making future clinical trials a lot easier. The reduction in 24S-cholesterol indicates lowered brain cholesterol production. From a series of previous studies, it appeared very likely that reduced brain cholesterol levels correlate with reduced A? production. The technical problem is that brain cholesterol levels are extremely high, and likely to be significantly reduced only after extended exposure to statins either in time or dosage. Accordingly, A? levels are likely to drop slowly, as well.

This study now shows that instead of measuring A? levels, the quantification of 24S-cholesterol may be able to complement or even substitute for measuring A?, generating a...  Read more

This paper is very important. That statins reduce 24S-cholesterol was to be expected from previous studies. Indeed, the major future application of this work may grow out of its demonstration that AD patients respond within only six weeks to dosages of 40 mg statin/day with a reduction of the plasma levels of a brain-derived cholesterol derivative.

Why is this so important? Well, this study has the potential of making future clinical trials a lot easier. The reduction in 24S-cholesterol indicates lowered brain cholesterol production. From a series of previous studies, it appeared very likely that reduced brain cholesterol levels correlate with reduced A? production. The technical problem is that brain cholesterol levels are extremely high, and likely to be significantly reduced only after extended exposure to statins either in time or dosage. Accordingly, A? levels are likely to drop slowly, as well.

This study now shows that instead of measuring A? levels, the quantification of 24S-cholesterol may be able to complement or even substitute for measuring A?, generating a treatment marker readily available long before any alterations in A? levels are observable. Moreover, long-term, low-dose statin treatment may result in a long-term, low-level A? reduction that cannot be reliably quantified with currently available ELISA assays. Quantifications of 24S-cholesterol may be able to do just that.

Moreover, a major problem with useful A? measurements in clinical studies is the difficulty of obtaining CSF samples. Unlike A?, 24S-cholesterol is produced almost exclusively in the brain, and therefore allows one to examine brain metabolism from blood samples, obviating the need for spinal taps.

This is also the missing part of this work. If the authors had been able to correlate CSF and blood samples, these conclusions could have been made much stronger, and certainly more studies will be needed to tighten this issue.

View all comments by Tobias Hartmann

This study provides much food for thought and further investigation, though I think the interpretations of the results are a bit narrow. They are predicated on several debatable premises, for example, that the cholesterol pool in the brain is essentially stagnant, with no significant synthesis of cholesterol in the brain. There is evidence to suggest the opposite. Another assumption made is that the removal of cholesterol from the brain is mediated exclusively by LDL; however, there is also evidence suggesting that HDL plays a significant role in transporting cholesterol out of the brain.

It is also noteworthy that pravastatin was as effective as the other statins in reducing plasma 24S-OH-cholesterol, given that relatively little pravastatin crosses the blood-brain barrier. I think this finding can most easily be explained by a mechanism whereby statins decrease circulating cholesterol, thereby reducing the cholesterol available to pass from the circulation into the brain.

View all comments by Larry Sparks

Multiple studies suggest that statin treatment can lower Aβ production and might be beneficial in treating AD. Cell biology studies show that cells or animals treated with statins exhibit less Aβ production. Statins also lower Aβ levels in humans. Epidemiological studies point to a dramatically lower incidence and prevalence of AD among subjects taking statins. Prospective trials of statins, though, are mixed. One small study showed reduced progression of AD among subjects taking simvastatin, while a much larger study showed no reduction in the incidence of dementia among subjects at risk for cardiovascular disease who were taking pravastatin. One potentially important question surrounding the putative use of statins in AD is the question of whether blood-brain barrier permeability affects the ability of statins to alter cholesterol metabolism in the brain.

The current article by Vega and colleagues addresses this question by examining the levels of 24-hydroxycholesterol in subjects taking lovastatin, simvastatin, or pravastatin. Since oxysterol 24-hydroxycholesterol is a...  Read more

Multiple studies suggest that statin treatment can lower Aβ production and might be beneficial in treating AD. Cell biology studies show that cells or animals treated with statins exhibit less Aβ production. Statins also lower Aβ levels in humans. Epidemiological studies point to a dramatically lower incidence and prevalence of AD among subjects taking statins. Prospective trials of statins, though, are mixed. One small study showed reduced progression of AD among subjects taking simvastatin, while a much larger study showed no reduction in the incidence of dementia among subjects at risk for cardiovascular disease who were taking pravastatin. One potentially important question surrounding the putative use of statins in AD is the question of whether blood-brain barrier permeability affects the ability of statins to alter cholesterol metabolism in the brain.

The current article by Vega and colleagues addresses this question by examining the levels of 24-hydroxycholesterol in subjects taking lovastatin, simvastatin, or pravastatin. Since oxysterol 24-hydroxycholesterol is a brain-selective catabolite of cholesterol, levels of 24-hydroxycholesterol in the serum are thought to largely reflect cholesterol turnover in the brain. Lovastatin is relatively hydrophobic and is thought to penetrate the CNS, while pravastatin is hydrophilic and is thought to remain outside the brain. Simvastatin is intermediate. Despite these putative differences in brain permeability, the reductions in 24-hydroxycholesterol were the same among groups taking each of the statins. This result is quite surprising, but informative. The results are consistent with the epidemiological studies, which did not observe any differences in incidence or prevalence of AD among subjects taking these three statins. The curious result that a hydrophobic statin is as effective as a hydrophilic statin in lowering 24-hydroxycholesterol raises the possibility that export of 24-hydroxycholesterol from the brain is regulated by factors outside the brain. Alternatively, our understanding of the distribution of pravastatin might need to be updated. Regardless of the reason for the efficacy of all three statins in lowering serum 24-hydroxycholesterol, these results support the notion that the type of statin does not matter in terms of modulating brain cholesterol metabolism or affecting the pathophysiology of AD.

View all comments by Benjamin Wolozin