A well lived life can only be seen in retrospect of a lifetime of living and, in the view of the ancient Greeks, by one of moderation. Scientific support for this view is found in the health benefits of a balanced diet rich in fruits and vegetables ( Lin et al., 2002; Luchsinger et al., 2002) with the greatest health benefit, and increase in longevity, coming from dietary restriction. In this regimen, organisms consuming around 30 percent of calories below ad libum have an approximately 30 to 50 percent increase in lifespan. Decreased free radicals, increased cellular stress, and altered hormonal balance are all thought to play a role but have not been confirmed by mechanistic studies. A link between Alzheimer disease (AD) and caloric intake has been made by case...  Read more

A well lived life can only be seen in retrospect of a lifetime of living and, in the view of the ancient Greeks, by one of moderation. Scientific support for this view is found in the health benefits of a balanced diet rich in fruits and vegetables ( Lin et al., 2002; Luchsinger et al., 2002) with the greatest health benefit, and increase in longevity, coming from dietary restriction. In this regimen, organisms consuming around 30 percent of calories below ad libum have an approximately 30 to 50 percent increase in lifespan. Decreased free radicals, increased cellular stress, and altered hormonal balance are all thought to play a role but have not been confirmed by mechanistic studies. A link between Alzheimer disease (AD) and caloric intake has been made by case control studies showing that patients who go on to develop AD eat up to 500 more calories per day than controls in the decade prior to disease ( Smith et al., 1999.). Meta-analysis of world dietary habits shows that there is a strong correlation between the prevalence of AD and average caloric intake (( Grant et al., 1999.).

The complexity of the relationship between diet, aging and AD has been made all the more apparent by recent studies. In evaluating the contribution of caloric and fat intake in AD, Mayeux and colleagues (Luchsinger et al., 2002) found high caloric intake was associated with an increased risk of AD. The risk was most significant for those people having at least one copy of the apolipoprotein E4 allele. In consideration that high caloric diets are usually rich in fats, these data are consistent with work by Petot and Friedland in which a link between fat intake and risk of AD was shown and, again, this was dependent on apolipoprotein -E genotype with E4 showing the most pronounced result (Friedland et al., 2002).

Understanding the mechanism for increased risk from AD through high caloric intake may provide important insights into AD pathogenesis. The link between apolipoprotein-E genotype and fat intake suggests that lipid transport and metabolism may be critical to AD. Lessons might also be learned from studies of dietary restriction, which have been suggested to prolong lifespan through reduction of reactive oxygen formation, another mechanism involved in AD pathogenesis ( Perry et al., 1998). The recent finding of Lin and colleagues (2002), that the lifespan extending effect of dietary restriction relates to whether glycolysis or Krebs cycle metabolism dominates in yeast, is important because it suggests that it is not the total caloric intake but the outcome of dominance of one pathway or another that is critical to lifespan control. Therefore, caloric restriction may miss the point in that the consequences of differing metabolism strategies may have critical outcomes. Seen in light of the admonition for moderation by the ancient Greeks, it appears that the good life is not marked by extremes of diet but rather by a balance in metabolism.

References
Friedland RP, Petot GJ, Farrer LA (2002) Alzheimer’s disease and diet. Arab J Psychiatry, in press.

Grant WB (2002) Dietary links to Alzheimer's disease. J Alzheimer’s Disease 1, 197-201.

Lin S-J, Kaeberlein M, Andalis AA, Sturtz LA, Defossez P-A, Culotta VC, Fink GR, Guarente L (2002) Calorie restriction extends Saccharomyces cerevisiae lifespan by increasing respiration. Nature 418, 344-348. Abstract.

Luchsinger JA, Tang M-X, Shea S, Mayeux R (2002) Caloric intake and the risk of Alzheimer disease. Arch Neurol 59, 1258-1263. Abstract.

Perry G, Castellani RJ, Hirai K, Smith MA (1998) Reactive oxygen species mediate cellular damage in Alzheimer disease. J Alzheimer’s Disease 1, 45-55. Abstract.

Smith MA, Petot GJ, Perry G (1999) Diet and oxidative stress: a novel synthesis of epidemiological data on Alzheimer’s disease. J Alzheimer’s Disease 1, 203-206. Abstract.

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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)...  Read more

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.

References:
Andersson M, Elmberger PG, Edlund C, Kristensson K, and Dallner G. Rates of cholesterol, ubiquinone, dolichol and dolichyl-P biosynthesis in rat brain slices. FEBS Lett. 1990;269:15-18. Abstract

Blacker D, Wilcox M, Laird N, Rodes L, Horvath S, Go R, Perry R, Watson BJ, Bassett S, McInnis M, et al. Alpha-2 macroglobulin is genetically associated with Alzheimer disease. Nat Gen.1998;19:357-360. Abstract

Bogdanovic N, Bretillon L, Lund EG, Diczfalusy U, Lannfelt L, Winblad B, Russell DW, and Bjorkhem I. On the turnover of brain cholesterol in patients with Alzheimer's disease. Abnormal induction of the cholesterol-catabolic enzyme CYP46 in glial cells. Neurosci Lett. 2001;314:45-48. Abstract

Corder EH, Saunders AM, Strittmatter WJ, Schmechel DE, Gaskell PC, Small GW, Roses AD, Haines JL, Pericak-Vance MA. Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer's disease in late onset families. Science. 1993 Aug 13;261(5123):921-3. Abstract

Dietschy JM, Turley SD. Cholesterol metabolism in the brain. Curr Opin Lipidol. 2001 Apr;12(2):105-12. Abstract

Engelhart MJ, Geerlings MI, Ruitenberg A, van Swieten JC, Hofman A, Witteman JC, and Breteler MM. Diet and the risk of dementia: Does fat matter? Neurology. 2002;59:19-15-21.

Fassbender K, Simons M, Bergmann C, Stroick M, Lutjohann D, Keller P, Runz H, Kuhl S, Bertsch T, von Bergmann K, Hennerici M, Beyreuther K, Hartmann T. Simvastatin strongly reduces levels of Alzheimer's disease beta -amyloid peptides Abeta 42 and Abeta 40 in vitro and in vivo. Proc Natl Acad Sci U S A. 2001 May 8;98(10):5856-61. Abstract

Friedhoff LT, Cullen EI, Geoghagen NS, Buxbaum JD. Treatment with controlled-release lovastatin decreases serum concentrations of human beta-amyloid (A beta) peptide. Int J Neuropsychopharmacol. 2001 Jun;4(2):127-30. Abstract

Jick H, Zornberg GL, Jick SS, Seshadri S, Drachman DA. Statins and the risk of dementia. Lancet. 2000 Nov 11;356(9242):1627-31. Abstract

Kivipelto M, Helkala EL, Laakso MP, Hanninen T, Hallikainen M, Alhainen K, Iivonen S, Mannermaa A, Tuomilehto J, Nissinen A, Soininen H. Apolipoprotein E epsilon4 allele, elevated midlife total cholesterol level, and high midlife systolic blood pressure are independent risk factors for late-life Alzheimer disease. Ann Intern Med. 2002 Aug 6;137(3):149-55. Abstract

Kivipelto M, Helkala EL, Hanninen T, Laakso MP, Hallikainen M, Alhainen K, Soininen H, Tuomilehto J, Nissinen A. Midlife vascular risk factors and late-life mild cognitive impairment: A population-based study. Neurology. 2001 Jun 26;56(12):1683-9. Abstract

Kolsch H, Lutjohann D, Ludwig M, Schulte A, Ptok U, Jessen F, von Bergmann K, Rao ML, Maier W, Heun R. Polymorphism in the cholesterol 24S-hydroxylase gene is associated with Alzheimer's disease. Mol Psychiatry. 2002;7(8):899-902. Abstract

Lund EG, Guileyardo JM, Russell DW. cDNA cloning of cholesterol 24-hydroxylase, a mediator of cholesterol homeostasis in the brain. Proc Natl Acad Sci U S A. 1999 Jun 22;96(13):7238-43. Abstract

Martin G, Duez H, Blanquart C, Berezowski V, Poulain P, Fruchart JC, Najib-Fruchart J, Glineur C, Staels B. Statin-induced inhibition of the Rho-signaling pathway activates PPARalpha and induces HDL apoA-I. J Clin Invest. 2001 Jun;107(11):1423-32. Abstract

Notkola IL, Sulkava R, Pekkanen J, Erkinjuntti T, Ehnholm C, Kivinen P, Tuomilehto J, Nissinen A. Serum total cholesterol, apolipoprotein E epsilon 4 allele, and Alzheimer's disease. Neuroepidemiology. 1998;17(1):14-20. Abstract

Prince M, Lovestone S, Cervilla J, Joels S, Powell J, Russ C, Mann A. The association between APOE and dementia does not seem to be mediated by vascular factors. Neurology. 2000 Jan 25;54(2):397-402. Abstract

Refolo LM, Pappolla MA, LaFrancois J, Malester B, Schmidt SD, Thomas-Bryant T, Tint GS, Wang R, Mercken M, Petanceska SS, Duff KE. A cholesterol-lowering drug reduces beta-amyloid pathology in a transgenic mouse model of Alzheimer's disease. Neurobiol Dis. 2001 Oct;8(5):890-9. Abstract

Rockwood K, Kirkland S, Hogan DB, MacKnight C, Merry H, Verreault R, Wolfson C, McDowell I. Use of lipid-lowering agents, indication bias, and the risk of dementia in community-dwelling elderly people. Arch Neurol. 2002 Feb;59(2):223-7. Abstract

Shepherd J, Blauw GJ, Murphy MB, Bollen EL, Buckley BM, Cobbe SM, Ford I, Gaw A, Hyland M, Jukema JW, Kamper AM, Macfarlane PW, Meinders AE, Norrie J, Packard CJ, Perry IJ, Stott DJ, Sweeney BJ, Twomey C, Westendorp RG. Pravastatin in elderly individuals at risk of vascular disease (PROSPER): a randomised controlled trial. Lancet. 2002 Nov 23;360(9346):1623-30. Abstract

Simons M, Keller P, De Strooper B, Beyreuther K, Dotti CG, Simons K. Cholesterol depletion inhibits the generation of beta-amyloid in hippocampal neurons. Proc Natl Acad Sci U S A. 1998 May 26;95(11):6460-4. Abstract

Simons M, Schwarzler F, Lutjohann D, von Bergmann K, Beyreuther K, Dichgans J, Wormstall H, Hartmann T, Schulz JB. Treatment with simvastatin in normocholesterolemic patients with Alzheimer's disease: A 26-week randomized, placebo-controlled, double-blind trial. Ann Neurol. 2002 Sep;52(3):346-50. Abstract

Takemoto M, Liao JK. Pleiotropic effects of 3-hydroxy-3-methylglutaryl coenzyme a reductase inhibitors. Arterioscler Thromb Vasc Biol. 2001 Nov;21(11):1712-9. Review. Abstract

Wahrle S, Das P, Nyborg AC, McLendon C, Shoji M, Kawarabayashi T, Younkin LH, Younkin SG, Golde TE. Cholesterol-dependent gamma-secretase activity in buoyant cholesterol-rich membrane microdomains. Neurobiol Dis. 2002 Feb;9(1):11-23. Abstract

Wolozin B, Kellman W, Ruosseau P, Celesia GG, Siegel G. Decreased prevalence of Alzheimer disease associated with 3-hydroxy-3-methyglutaryl coenzyme A reductase inhibitors. Arch Neurol. 2000 Oct;57(10):1439-43. Abstract

Yaffe K, Barrett-Connor E, Lin F, Grady D. Serum lipoprotein levels, statin use, and cognitive function in older women. Arch Neurol. 2002 Mar;59(3):378-84. Abstract

Yoshitake T, Kiyohara Y, Kato I, Ohmura T, Iwamoto H, Nakayama K, Ohmori S, Nomiyama K, Kawano H, Ueda K, et al. Incidence and risk factors of vascular dementia and Alzheimer's disease in a defined elderly Japanese population: the Hisayama Study. Neurology. 1995 Jun;45(6):1161-8. Abstract

View all comments by Benjamin Wolozin

2. Wolozin B. Cholesterol and Alzheimer's disease. Biochem Soc Trans. 30(4), 525-9 (2002). Abstract. Also see: Wolozin B. A fluid connection: cholesterol and Abeta. Proc Natl Acad Sci U S A. 98(10), 5371-3 (2001). Abstract.

3. Koudinov AR, Koudinova NV. Alzheimer‚s anti-amyloid vaccination and statins: two approaches, one dogma. The time for change. British Medical Journal (2002). Abstract

4. Koudinov AR, Koudinova NV. Brain Cholesterol Pathology is the Cause of Alzheimer's Disease. ARF hypotheses. Posted 19 August 2002.

5. Alzheimer's research forum. Cholesterol and Alzheimer's-Charging Fast but Still at a Distance From Solid Answers. ARF live discussion held 19 November 2002.

6. Gaist D et al. Statins and risk of polyneuropathy: a case-control study. Neurology. 58(9), 1333-7 (2002). Abstract

7. Gaist D, et al. Are users of lipid-lowering drugs at increased risk of peripheral neuropathy? Eur J Clin Pharmacol 56(12), 931-3 (2001). Abstract

8. Koudinov AR, Berezov TT, Koudinova NV. Cholesterol and Alzheimer's disease: is there a link? Neurology. 58(7), 1135 (2002). Abstract

View all comments by Alexei R. Koudinov

Benjamin Wolozin lists several factors that are related to cholesterol and possibly to risk of Alzheimer’s disease (statin use, serum cholesterol levels, dietary fat intake, brain cholesterol metabolism). Obviously, this does not imply that if they are indeed related to risk of Alzheimer's disease this is all through the same mechanism, nor that this is always through a direct effect of cholesterol.

The studies that did observe a relation between plasma cholesterol levels and risk of AD evaluated mid-life cholesterol levels in relation to late-life dementia risk (Kivipelto et al., 2002; Kivipelto et al., 2001; Notkola et al., 1998). It is well conceivable that this relation is mediated by a...  Read more

Benjamin Wolozin lists several factors that are related to cholesterol and possibly to risk of Alzheimer’s disease (statin use, serum cholesterol levels, dietary fat intake, brain cholesterol metabolism). Obviously, this does not imply that if they are indeed related to risk of Alzheimer's disease this is all through the same mechanism, nor that this is always through a direct effect of cholesterol.

The studies that did observe a relation between plasma cholesterol levels and risk of AD evaluated mid-life cholesterol levels in relation to late-life dementia risk (Kivipelto et al., 2002; Kivipelto et al., 2001; Notkola et al., 1998). It is well conceivable that this relation is mediated by a detrimental effect of high cholesterol levels on the vasculature (Breteler, 2000). Interestingly, studies evaluating late-life cholesterol levels do not find a relation with increased risk of Alzheimer’s disease (Slooter, 2000). This suggests that the claimed effect of statin use on risk of Alzheimer’s disease, if real, is not through lowering of peripheral cholesterol levels. This fits with our current finding that late-life dietary fat intake is not related to risk of Alzheimer’s disease within six years. Several other mechanisms can be conceived through which statins might affect Alzheimer risk, and these should be evaluated. We emphasize, though, that convincing evidence for an effect of statins on risk of Alzheimer’s disease is still lacking. The observational studies thus far were all potentially biased and their findings, though hypothesis-raising, cannot be considered evidence. The fact that they showed largely similar results may just as well reflect that they are biased in an identical way as it could mean that there is indeed a beneficial effect of statins on disease risk.

The notion that cholesterol and cerebral cholesterol metabolism are critical in the development of Alzheimer's disease remains an extremely interesting hypothesis in need of further investigation. Basic scientists, epidemiologists and clinical researchers may provide complementary evidence to further our understanding of this possible mechanism.

View all comments by Monique M.B. Breteler