Key points are not available for this paper at this time.
24S-hydroxycholesterol is a side-chain oxidized oxysterol formed in the brain that is continuously crossing the blood-brain barrier to reach the circulation. There may be an opposite flux of 27-hydroxycholesterol, which is formed to a lower extent in the brain than in most other organs. Here we measured cholesterol, lathosterol, 24S- and 27-hydroxycholesterol, and plant sterols in four different brain areas of deceased Alzheimer's disease (AD) patients and controls. 24S-hydroxycholesterol was decreased and 27-hydroxycholesterol increased in all the brain samples from the AD patients. The difference was statistically significant in four of the eight comparisons. The ratio of 27-hydroxycholesterol to 24S-hydroxycholesterol was significantly increased in all brain areas of the AD patients and also in the brains of aged mice expressing the Swedish Alzheimer mutation APP751. Cholesterol 24S-hydroxylase and 27-hydroxylase protein was not significantly different between AD patients and controls. A high correlation was observed between the levels of 24S-hydroxycholesterol and lathosterol in the frontal cortex of the AD patients but not in the controls. Most probably the high levels of 27-hydroxycholesterol are due to increased influx of this steroid over the blood-brain barrier and the lower levels of 24S-hydroxycholesterol to decreased production.The high correlation between lathosterol and 24-hydroxycholesterol is consistent with a close coupling between synthesis and metabolism of cholesterol in the frontal cortex of the AD brain. 24S-hydroxycholesterol is a side-chain oxidized oxysterol formed in the brain that is continuously crossing the blood-brain barrier to reach the circulation. There may be an opposite flux of 27-hydroxycholesterol, which is formed to a lower extent in the brain than in most other organs. Here we measured cholesterol, lathosterol, 24S- and 27-hydroxycholesterol, and plant sterols in four different brain areas of deceased Alzheimer's disease (AD) patients and controls. 24S-hydroxycholesterol was decreased and 27-hydroxycholesterol increased in all the brain samples from the AD patients. The difference was statistically significant in four of the eight comparisons. The ratio of 27-hydroxycholesterol to 24S-hydroxycholesterol was significantly increased in all brain areas of the AD patients and also in the brains of aged mice expressing the Swedish Alzheimer mutation APP751. Cholesterol 24S-hydroxylase and 27-hydroxylase protein was not significantly different between AD patients and controls. A high correlation was observed between the levels of 24S-hydroxycholesterol and lathosterol in the frontal cortex of the AD patients but not in the controls. Most probably the high levels of 27-hydroxycholesterol are due to increased influx of this steroid over the blood-brain barrier and the lower levels of 24S-hydroxycholesterol to decreased production. The high correlation between lathosterol and 24-hydroxycholesterol is consistent with a close coupling between synthesis and metabolism of cholesterol in the frontal cortex of the AD brain. Transport and turnover of cholesterol in the brain seems to be of importance for development of Alzheimer's disease (AD) (1Puglielli L. Tanzi R.E. Kovacs D.M. Alzheimer's disease: the cholesterol connection.Nat. Neurosci. 2003; 6: 345-351Crossref PubMed Scopus (686) Google Scholar). Apolipoprotein E (apoE) is involved in transport of cholesterol in the brain, and there is a strong association between the apoE4 allele and AD (2Strittmatter W.J. Saunders A.M. Schmechel D. Pericak Vance M. Enghild J. Salvesen S. Roses A.D. Apolipoprotein E: high-avidity binding to β-amyloid and increased frequency of Type 4 allele in late-onset familial Alzheimer disease.Proc. Natl. Acad. Sci. USA. 1993; 90: 1977-1981Crossref PubMed Scopus (3634) Google Scholar). Cholesterol loading or depletion affects deposition of amyloid-β protein both in vitro (3Simons M. Keller P. De Strooper B. Beyreuther K. Dotti C.G. Simons K. Cholesterol depletion inhibits the generation of β-amyloid in hippocampal regions.Proc. Natl. Acad. Sci. USA. 1998; 95: 6460-6464Crossref PubMed Scopus (1067) Google Scholar, 4Howland D.S. Trusko S.P. Savage M.J. Reaume A.G. Lang D.M. Hirsch J.D. Maeda N. Siman R. Greenberg B.D. Scott R.W. Flood D.G. Modulation of secreted β-amyloid precursor protein and amyloid β-peptide by cholesterol.J. Biol. Chem. 1998; 273: 16576-16582Abstract Full Text Full Text PDF PubMed Scopus (237) Google Scholar) and in vivo (5Refolo L.M. Pappolla M.A. Malester B. LaFrancois J. Bryant-Thomas T. Wang R. Tint G.S. Sambamurti K. Duff K. Hypercholesterolemia accelerates the Alzheimer's amyloid pathology in a transgenic mouse model.Neurobiol. Dis. 2000; 7: 321-331Crossref PubMed Scopus (868) Google Scholar). Clinical studies with HMG-CoA reductase inhibitors suggest that reduction of cholesterol synthesis may have a preventive effect on development of AD (6Wolozin B. Kellman W. Ruosseau P. Decreased prevalence of Alzheimer disease associated with HMG CoA reductase inhibitors.Arch. Neurol. 2000; 57: 1439-1443Crossref PubMed Scopus (1325) Google Scholar, 7Jick H. Zornberg G.L. Jick S. Seshadri S. Drachman A. Statins and the risk of dementia.Lancet. 2000; 356: 1627-1631Abstract Full Text Full Text PDF PubMed Scopus (1563) Google Scholar, 8Buxbaum J.D. Cullen E.I. Friedhoff L.T. Pharmacological concentrations of the HMG CoA reductase inhibitor lovastatin decrease the formation of the Alzheimer beta-amyloid peptide in vitro and in patients.Front. Biosci. 2002; 7: 50-59Crossref PubMed Google Scholar). Under normal conditions, with an intact blood-brain barrier, there is little or no exchange of cholesterol over the blood-brain barrier (9Dietschy J.M. Turley S.D. Cholesterol metabolism in the brain.Curr. Opin. Lipidol. 2001; 12: 105-112Crossref PubMed Scopus (706) Google Scholar, 10Snipes G.J. Suter U. Cholesterol and myelin.in: Bittman R. Subcellular Biochemistry. Vol. 28. Plenum Press, New York1997: 173-204Google Scholar). We have defined a mechanism by which 6–7 mg of cholesterol is eliminated daily from the human brain in the form of a side-chain oxidized oxysterol, 24S-hydroxycholesterol (11Lütjohann D. Breuer O. Ahlborg G. Nennesmo I. Sidén Å. Diczfalusy U. Björkhem I. Cholesterol homeostasis in human brain: evidence for an age-dependent flux of 24S-hydroxycholesterol from the brain into the circulation.Proc. Natl. Acad. Sci. USA. 1996; 93: 9799-9804Crossref PubMed Scopus (556) Google Scholar, 12Björkhem I. Lütjohann D. Breuer O. Sakinis A. Wennmalm A. Importance of a novel oxidative mechanism for elimination of brain cholesterol. Turnover of cholesterol and 24(S)-hydroxycholesterol in rat brain as measured with 18O2 techniques in vivo and in vitro.J. Biol. Chem. 1997; 272: 30178-30184Abstract Full Text Full Text PDF PubMed Scopus (238) Google Scholar, 13Björkhem I. Lütjohann D. Diczfalusy U. Ståhle L. Ahlborg G. Wahren J. Cholesterol homeostasis in the human brain: turnover of 24S-hydroxycholesterol and evidence for a cerebral origin of most of this oxysterol in the circulation.J. Lipid Res. 1998; 39: 1594-1600Abstract Full Text Full Text PDF PubMed Google Scholar), which is able to pass the intact blood-brain barrier. The enzyme responsible for the conversion of cholesterol into 24S-hydroxycholesterol is the cytochrome P450 species cholesterol 24S-hydroxylase (CYP46), which has been reported to be almost exclusively expressed in the neuronal cells in the normal human brain (14Lund E.G. Guileyardo J.M. Russell D.W. cDNA cloning of cholesterol 24-hydroxylase, a mediator of cholesterol homeostasis in the brain.Proc. Natl. Acad. Sci. USA. 1999; 16: 7238-7243Crossref Scopus (513) Google Scholar). The neurodegeneration occurring in AD would be expected to eventually lead to loss of 24S-hydroxylase activity, with a resulting decrease in the flux of 24S-hydroxycholesterol from the brain into the circulation. In accordance with this, we found that patients with advanced AD had reduced plasma levels of 24S-hydroxycholesterol (15Bretillon L. Sidén Å. Wahlund L-O. Minthon L. Crisby M. Hillert J. Groth C-G. Diczfalusy U. Björkhem I. Plasma levels of 24S-hydroxycholesterol in patients with neurological diseases.Neurosci. Lett. 2000; 293: 87-90Crossref PubMed Scopus (128) Google Scholar). A population of AD patients with less-advanced disease was, however, reported to have slightly increased levels of 24S-hydroxycholesterol, possibly due to an ongoing active neuronal destruction with increased liberation of cholesterol and 24S-hydroxycholesterol (16Lütjohann D. Papassotiropoulos A. Björkhem I. Locatelli S. Bagli M. Rao M.L. von Bergmann K. Heun R. 24S-hydroxycholesterol (cerebrosterol) and Alzheimer's disease.J. Lipid Res. 2000; 41: 195-198Abstract Full Text Full Text PDF PubMed Google Scholar). Very recently, we studied the amount and distribution of CYP46 in autopsy brain material from AD and control patients (17Bogdanovic N. Bretillon L. Lund E. Diczfalusy U. Lannfelt L. B. Russell D. Björkhem I. the turnover of brain cholesterol in patients with Alzheimer's of the enzyme CYP46 in Lett. 2001; PubMed Scopus Google Scholar). cells from the frontal cortex of AD patients CYP46 than of the controls. a be in the cells in AD brain but not in the controls. that in the normal the flux of 24S-hydroxycholesterol from the brain into the is to be exclusively from the but possibly from both and cells in patients with In a D. A. E. D. M. von Bergmann K. Beyreuther K. G. of sterols in aged amyloid precursor protein transgenic mouse Lipid Res. 2002; Full Text Full Text PDF PubMed Scopus (128) Google Scholar), 24S-hydroxycholesterol was measured in the brains of transgenic mice the Swedish mutation which The levels of this oxysterol not significantly different between the transgenic mice and the controls. cholesterol 24S-hydroxylase has a distribution in mouse than in and is expressed to a extent also in the is to that are for the levels of plant sterols significantly increased in the brain of transgenic the of and D. A. E. D. M. von Bergmann K. Beyreuther K. G. of sterols in aged amyloid precursor protein transgenic mouse Lipid Res. 2002; Full Text Full Text PDF PubMed Scopus (128) Google Scholar). sterols are exclusively of the be that the transgenic mice had a in the blood-brain barrier. is that patients with advanced Alzheimer's disease may have K. A. P. I. C.G. L. brain barrier in patients with Alzheimer's disease is to Neurol. PubMed Scopus Google Scholar, G. Drachman D. M. R. D. Clinical of Alzheimer PubMed Google Scholar). is side-chain oxidized oxysterol, formed by 27-hydroxylase In to 24S-hydroxycholesterol, is formed in most and there is a flux of this oxysterol from to the E. O. J. A. Ahlborg G. Diczfalusy U. K. J. Björkhem I. Importance of a novel oxidative mechanism for elimination of cholesterol in Biol. 1996; 16: PubMed Scopus Google Scholar). There however, no flux of 27-hydroxycholesterol from the brain, and the levels of 27-hydroxycholesterol in this are lower than of 24S-hydroxycholesterol (11Lütjohann D. Breuer O. Ahlborg G. Nennesmo I. Sidén Å. Diczfalusy U. Björkhem I. Cholesterol homeostasis in human brain: evidence for an age-dependent flux of 24S-hydroxycholesterol from the brain into the circulation.Proc. Natl. Acad. Sci. USA. 1996; 93: 9799-9804Crossref PubMed Scopus (556) Google Scholar). In with 24S-hydroxycholesterol, 27-hydroxycholesterol is to pass the blood-brain barrier, and an between 27-hydroxycholesterol in the and in the brain is to Very recently, we that most of the 27-hydroxycholesterol in human is of origin M. T. P. S. Diczfalusy U. Björkhem I. oxidized in and of the blood-brain Lipid Res. 2003; Full Text Full Text PDF PubMed Scopus Google Scholar). In of the from in vivo studies in and the studies with the transgenic mouse we to be of to the levels of the 24S- and 27-hydroxycholesterol in autopsy from patients with Alzheimer's disease and from controls. In to the levels of cholesterol, lathosterol, and plant sterols also of we also 27-hydroxycholesterol in the brains of transgenic to cholesterol 24S-hydroxylase and 27-hydroxylase protein in the brain material in to between the protein and steroid There may be a close coupling between cholesterol synthesis and cholesterol elimination by the CYP46 mechanism in the brain I. Diczfalusy U. Lütjohann D. of cholesterol from by oxidative Opin. Lipidol. 1999; PubMed Scopus Google Scholar). In of this, was of to a correlation be found between the levels of lathosterol for cholesterol and levels of 24S-hydroxycholesterol for cholesterol in the of patients. The human CYP46 a from D. W. Russell of of (14Lund E.G. Guileyardo J.M. Russell D.W. cDNA cloning of cholesterol 24-hydroxylase, a mediator of cholesterol homeostasis in the brain.Proc. Natl. Acad. Sci. USA. 1999; 16: 7238-7243Crossref Scopus (513) Google Scholar). the 27-hydroxylase protein in the of of or high autopsy from the frontal and was from ratio and AD patients ratio The control samples from had as a of The AD patients the for AD A. D. L.M. G. L. The to a for Alzheimer's disease of the of Alzheimer's 41: PubMed Google Scholar) and the for AD N. for Alzheimer's disease in brain R. M.L. for and Press, The Scholar). The AD patients as a of the samples for and all brain samples from all patients the in and ratio the of a of from of the AD patients and eight of the to form a and with a ratio of and a of for the and for the AD patients. The difference of in the was In to the brain samples from the four brain from AD patients and from and for of this material was also for of the The with transgenic mice expressing the Swedish mutation the control of the and control mice have been in D. A. E. D. M. von Bergmann K. Beyreuther K. G. of sterols in aged amyloid precursor protein transgenic mouse Lipid Res. 2002; Full Text Full Text PDF PubMed Scopus (128) Google Scholar). In of and transgenic mice the of and and and transgenic mice for as In the of of cholesterol, cholesterol and 24S-hydroxycholesterol have been The was the of 27-hydroxycholesterol by as to and the brain was from the of the The in accordance with the of the brains in for and in a The was and the with by The of this was to and for of cholesterol and Cholesterol and lathosterol by with the of cholesterol and lathosterol, as I. R. L. of cholesterol by PubMed Scopus Google Scholar, E. L. E. Björkhem I. of levels of lathosterol by J. PubMed Scopus Google Scholar). The plant sterols and in a 24-hydroxycholesterol as and and for and also by with the of an oxysterol in as S. Breuer O. Lund E.G. Diczfalusy U. of cholesterol in human plasma by PubMed Scopus Google Scholar). from the four brain of AD patients and control patients was and The samples and the samples The difference in and was to be the of the brain brain from brain of the and AD patients was in and to The and to and 4 of in and on The samples to and with in The with and with to CYP46 or by with and with for The protein was with an to the and to the for a was a significant or on the different found the of and AD patients. 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The of the frontal cortex of the AD and control samples was and The of the cortex was and for AD and control The of the was and for AD and control The of the was and for AD and control there was no significant difference between AD and control samples with to The levels of the by of the brain samples The in than be by cholesterol 24S-hydroxylase in and 27-hydroxylase in from the brain In accordance with studies (14Lund E.G. Guileyardo J.M. Russell D.W. cDNA cloning of cholesterol 24-hydroxylase, a mediator of cholesterol homeostasis in the brain.Proc. Natl. Acad. Sci. USA. 1999; 16: 7238-7243Crossref Scopus (513) Google Scholar, U. Russell D.W. in the enzyme 27-hydroxylase Biol. Chem. Full Text PDF PubMed Google Scholar), with the expected of was in the of with of and in the of In both no significant between AD and observed with to enzyme levels in the different areas of the brain. In the of the of CYP46 in the frontal cortex from the AD patients and from the the was and In the of the of the 27-hydroxylase protein in the the was and 4 also in the other brain The levels of 24S-hydroxycholesterol and 27-hydroxycholesterol also measured in the brain samples for significant found between levels and the levels of the enzyme protein not of sterols in the brain of and transgenic mice measured D. A. E. D. M. von Bergmann K. Beyreuther K. G. of sterols in aged amyloid precursor protein transgenic mouse Lipid Res. 2002; Full Text Full Text PDF PubMed Scopus (128) Google Scholar). The levels of 27-hydroxycholesterol not that The of the of 27-hydroxycholesterol in the brain of mice are in the of and the transgenic mice found to have significantly brain levels of 27-hydroxycholesterol than the control mice of and and The ratio of 27-hydroxycholesterol to 24S-hydroxycholesterol a to that of the levels of The ratio of was in the brain of transgenic mice with in the the of A difference was found the of A significant correlation was found between levels of 27-hydroxycholesterol and as as between 27-hydroxycholesterol and Cholesterol is by neuronal cells and and brain cholesterol is found in G.J. Suter U. Cholesterol and myelin.in: Bittman R. Subcellular Biochemistry. Vol. 28. Plenum Press, New York1997: 173-204Google Scholar, U. in cholesterol and Alzheimer 1999; PubMed Scopus Google Scholar). The seems to be the most active in the synthesis of the cholesterol that in The of cholesterol in the brain of patients with AD has been reported in most studies to be G.J. Suter U. Cholesterol and myelin.in: Bittman R. Subcellular Biochemistry. Vol. 28. Plenum Press, New York1997: 173-204Google Scholar). In the slightly increased levels of cholesterol found in most areas of the brain of AD patients in the but not in the The was observed with The ratio of lathosterol to cholesterol is to cholesterol ratio not between the however, that the of cholesterol synthesis had been the in the AD and in the control The levels of 24S-hydroxycholesterol lower in all areas of AD brains with controls. decrease is to the lower of neuronal cells in is that the of CYP46 in cells in AD brains observed in a (17Bogdanovic N. Bretillon L. Lund E. Diczfalusy U. Lannfelt L. B. Russell D. Björkhem I. the turnover of brain cholesterol in patients with Alzheimer's of the enzyme CYP46 in Lett. 2001; PubMed Scopus Google Scholar) is not able to for the loss of the neuronal The are consistent with that patients with advanced AD have significantly reduced plasma levels of 24S-hydroxycholesterol as with (15Bretillon L. Sidén Å. Wahlund L-O. Minthon L. Crisby M. Hillert J. Groth C-G. Diczfalusy U. Björkhem I. Plasma levels of 24S-hydroxycholesterol in patients with neurological diseases.Neurosci. Lett. 2000; 293: 87-90Crossref PubMed Scopus (128) Google Scholar). The that we not a significant reduction of CYP46 enzyme protein in may be due to the which is not to There was a however, lower levels in the frontal cortex of the AD A significant of the was the high in 27-hydroxycholesterol levels in all areas of the brain In of that most of the 27-hydroxycholesterol in human in the M. T. P. S. Diczfalusy U. Björkhem I. oxidized in and of the blood-brain Lipid Res. 2003; Full Text Full Text PDF PubMed Scopus Google Scholar), seems that a of the 27-hydroxycholesterol in the brain is from 27-hydroxylase is in the brain, but In the we not evidence of a difference in the levels of the enzyme in the brain of AD patients and controls. A blood-brain barrier would be expected to an increased flux of 27-hydroxycholesterol from the into the brain. blood-brain barrier in been reported in of AD patients K. A. P. I. C.G. L. brain barrier in patients with Alzheimer's disease is to Neurol. PubMed Scopus Google Scholar, G. Drachman D. M. R. D. Clinical of Alzheimer PubMed Google Scholar). We have that a blood-brain in other neurological to increased flux of 27-hydroxycholesterol from the into the M. T. P. S. Diczfalusy U. Björkhem I. oxidized in and of the blood-brain Lipid Res. 2003; Full Text Full Text PDF PubMed Scopus Google Scholar). with in patients with increased levels of 27-hydroxycholesterol found also in the mice the of and is of that there may be in the blood-brain barrier of mice expressing both and G.L. Malester B. Duff K. of the blood-brain barrier in the normal mouse and transgenic mouse of Alzheimer's Dis. 2001; PubMed Scopus Google Scholar). there is an increased flux of 27-hydroxycholesterol from the into the brain as a of a blood-brain barrier, there may also be an increased flux of other levels of plant sterols found in most areas of the AD brain and in the a statistically significant of the plant sterols and has been reported D. A. E. D. M. von Bergmann K. Beyreuther K. G. of sterols in aged amyloid precursor protein transgenic mouse Lipid Res. 2002; Full Text Full Text PDF PubMed Scopus (128) Google Scholar). In the transgenic there was a correlation between the levels of the plant sterols and 27-hydroxycholesterol, the that the increased flux of 27-hydroxycholesterol is to a in the blood-brain barrier. The for the flux of 24S-hydroxycholesterol from the brain into the is to be the difference between the The ratio of 24S-hydroxycholesterol to cholesterol is in the brain than in the and a difference is between the brain and most other (11Lütjohann D. Breuer O. Ahlborg G. Nennesmo I. Sidén Å. Diczfalusy U. Björkhem I. Cholesterol homeostasis in human brain: evidence for an age-dependent flux of 24S-hydroxycholesterol from the brain into the circulation.Proc. Natl. Acad. Sci. USA. 1996; 93: 9799-9804Crossref PubMed Scopus (556) Google Scholar). In the ratio of 27-hydroxycholesterol to cholesterol is of a in the and the brain this ratio is in almost all other and in the In the the ratio is than in the and the brain A. O. D. J. B. Lütjohann D. Diczfalusy U. Björkhem I. of cholesterol as in human by evidence that most of this steroid in the is of Lipid Res. 1999; Full Text Full Text PDF PubMed Google Scholar). In of this, flux of 27-hydroxycholesterol into the brain seems to A for a is a transport over the blood-brain barrier. is that both 24S- and 27-hydroxycholesterol are able to pass a than cholesterol S. K. Diczfalusy U. Björkhem I. the of in vitro and in vivo of the in human importance of the of the Lipid Res. 2003; Scholar). The of transport of 27-hydroxycholesterol however, significantly than that of may be the for that the ratio of 27-hydroxycholesterol to cholesterol was almost in all the brain areas studied in the concentrations of 24S-hydroxycholesterol found in the different brain areas 24S-hydroxycholesterol and 27-hydroxycholesterol are for the which is high levels in the brain. The binding however, with 24S-hydroxycholesterol than with 27-hydroxycholesterol, and the is almost J.M. of the by a Biol. Chem. 1997; 272: Full Text Full Text PDF PubMed Scopus Google Scholar). is that the of cholesterol 24S-hydroxylase and are M.A. M.J. of cholesterol homeostasis by the in the 2002; 16: PubMed Scopus Google Scholar). In of the of as of cholesterol and M.A. M.J. of cholesterol homeostasis by the in the 2002; 16: PubMed Scopus Google Scholar), the be that a in the ratio of to 24S-hydroxycholesterol may the of the with for homeostasis in the brain. was reported that a of the with of loss of and L. G. K. S. in the from homeostasis to neuronal Natl. Acad. Sci. USA. 2002; PubMed Scopus Google Scholar). the most the levels of cholesterol in the brain be the of synthesis and the of metabolism by the Very recently, was reported that a of the CYP46 a reduction of cholesterol synthesis in mouse brain E.G. T. Turley S.D. J.M. Russell D.W. of the cholesterol in mice a mechanism of cholesterol Biol. Chem. 2003; Full Text Full Text PDF PubMed Scopus Google Scholar). Under conditions, a would be expected between a for cholesterol synthesis and a for cholesterol metabolism A high correlation was found between levels of in the frontal and cortex of the brains from the AD patients. A correlation has also been observed in transgenic mice D. A. E. D. M. von Bergmann K. Beyreuther K. G. of sterols in aged amyloid precursor protein transgenic mouse Lipid Res. 2002; Full Text Full Text PDF PubMed Scopus (128) Google Scholar). A high correlation between 24S-hydroxycholesterol and 27-hydroxycholesterol was also found in areas of the brains from the AD patients. is consistent with a between increased metabolism of cholesterol in the brain and a decreased blood-brain barrier in the most significant in the frontal cortex is consistent with a that this of the brain seems to be to in cholesterol homeostasis than most other areas of the brain, in mice M.A. The of 2002; Scholar). There was a difference between the in the AD brains and the control possibly as a of the ongoing in the we have that the ratio of of cerebral and of is in all brain areas of patients with Alzheimer's as as in brains of transgenic mice the Swedish Alzheimer The and studies cholesterol turnover in this was by from the Swedish for the Swedish the Swedish the for the Alzheimer the and the of
Heverin et al. (Thu,) studied this question.