I noticed some 15 percent of AD patients were dropped from entering the trial because the scan showed they did not have sufficient amyloid in the brain. Without dropping these people, the study would likely have had no chance of showing a positive result and might have also exposed more people to risks. This shows the power of PET amyloid imaging to select people who have pathology in order to maximize your chance of a drug effect. Prior to this, we were treating AD patients blindly without knowing how much amyloid they had in their brains, a bit like treating people with a statin without knowing their cholesterol level.

With regard to the bapineuzumab therapy, the magnitude of amyloid clearance seems consistent and real, but at around 20 percent is modest. That is far less than was expected from prior autopsy studies of immunized patients or animal studies which suggested the vaccines might have a much bigger...  Read more

I noticed some 15 percent of AD patients were dropped from entering the trial because the scan showed they did not have sufficient amyloid in the brain. Without dropping these people, the study would likely have had no chance of showing a positive result and might have also exposed more people to risks. This shows the power of PET amyloid imaging to select people who have pathology in order to maximize your chance of a drug effect. Prior to this, we were treating AD patients blindly without knowing how much amyloid they had in their brains, a bit like treating people with a statin without knowing their cholesterol level.

With regard to the bapineuzumab therapy, the magnitude of amyloid clearance seems consistent and real, but at around 20 percent is modest. That is far less than was expected from prior autopsy studies of immunized patients or animal studies which suggested the vaccines might have a much bigger effect. This is a new insight and we might need to lower our expectations. The potential promise with this technology is that we might be able to test how different doses of therapy affect amyloid clearance at an early stage, allowing companies to select the most optimal dose for definitive trials.

Going beyond amyloid, at the end of the day, one can clear all the amyloid in the brain and if the patient does not improve, it still is not a useful therapy. So what's missing is for the field to now show that clearing amyloid eventually leads to a meaningful cognitive and functional benefit for the individual.

Some minor methodologic issues: differences at baseline in cognition and amyloid burden (not unexpected in small studies) between treatment groups add a bit of uncertainty as to interpretation. The method for computing standardized uptake values relative to cerebellum (i.e., the amyloid ratios) varies slightly from one study to another, and one sees different ratios being called normal or abnormal. This makes it hard to compare findings across studies and across tracers. So I think we need head-to-head comparisons and also some standardization of the way one determines a positive from a negative scan.

At HAI and AAN in Toronto, and ICAD in Honolulu, we will see lots of new data on these tracers in terms of cognitive correlates in normals and MCI subjects. I also expect AVID's florbetapir (formerly known as AV-45) will be the first to present validation data from a multicenter autopsy study. Once the validation is complete, this will really jumpstart the use of PET amyloid imaging in secondary and primary prevention trials of both drugs and lifestyle interventions. It will also give us more insight into the role of amyloid in aging and dementia, and allow us to test mechanistic hypotheses.

View all comments by P. Murali Doraiswamy

These comments should be taken seriously, as they encapsulate key issues that must be addressed if the Aβ cascade hypothesis (or at least the future of immunization therapy) is to survive this trial. To the opponents of the Aβ cascade hypothesis, it might seem that we Aβ stalwarts run the risk of straining a hand-waving muscle right now,...  Read more

These comments should be taken seriously, as they encapsulate key issues that must be addressed if the Aβ cascade hypothesis (or at least the future of immunization therapy) is to survive this trial. To the opponents of the Aβ cascade hypothesis, it might seem that we Aβ stalwarts run the risk of straining a hand-waving muscle right now, but the evidence supporting a primary role of Aβ in disease pathogenesis remains considerable and compelling. Perhaps, as St. George-Hyslop and Morris say, a pluralistic approach will be necessary to address the complex degenerative process, but I believe that a monotherapy eventually will emerge from a deeper understanding of the disease process, particularly in the early stages of AD.

The future of the immunization approach to AD (or of any disease-modifying approach, for that matter) may well lie in prevention. But who will run the lengthy and expensive trials that are needed to determine whether it will work? And will the resolve to test preventive measures be weakened by the failure of therapeutic trials conducted long after the disease has begun to take its toll on the subjects?

View all comments by Lary Walker

Alzheimer's disease vaccine danger: take it straightforward, not double-edged.

Alexei R. Koudinov

BMJ online (23 March 2003) [ FullText ]

View all comments by Alexei R. Koudinov

However, a study by Friedhof and Buxbaum with healthy volunteers already indicated that altering APP processing may require higher levels of statins in humans (4).

This was confirmed and extended by a pilot study (prospective, double blind, placebo-controlled) designed to evaluate whether cerebral Aβ levels respond to statin treatment (5). Following 6 months of high-level simvastatin treatment (80 mg), a significant drop in CSF Aβ was found in the statin-treated AD group. Potentially more important, the decline in MMSE performance was significantly reduced as compared to the placebo-treated group....  Read more

However, a study by Friedhof and Buxbaum with healthy volunteers already indicated that altering APP processing may require higher levels of statins in humans (4).

This was confirmed and extended by a pilot study (prospective, double blind, placebo-controlled) designed to evaluate whether cerebral Aβ levels respond to statin treatment (5). Following 6 months of high-level simvastatin treatment (80 mg), a significant drop in CSF Aβ was found in the statin-treated AD group. Potentially more important, the decline in MMSE performance was significantly reduced as compared to the placebo-treated group. However, no difference in ADAS-cog was observed and the data indicated that patients in the moderate AD group profited less than those with mild AD from this experimental therapy. With the limited number of patients (20 statin-treated + 17 controls completed the trial), several questions where left open. Would moderate AD patients profit from longer treatment? Would other statins show similar effects? Most importantly, would other trials with a comparable design be able to repeat these findings?

Although the number of treated patients still remains low (26 statin-treated patients + 22 controls completed the trial), Larry Sparks et al. now present very informative answers to several of these questions:

• For a study of this size, the most careful way to approach the data might be to address the combined effect first. For this study, this provides a very clear answer. There is a profound trend in the statin-treated group to perform better than the placebo-treated patients.
• Although it is far too early to compare effectiveness of different statins, it becomes obvious that different statins, at least simvastatin and atorvastatin, apparently have a potential to reduce cognitive decline in AD patients.
• MMSE, ADAS-cog, and CGIC results indicate that treatment duration is important. Differences between the treated and placebo groups become apparent only after 6 months, but no differences were seen after 3 months. It is interesting in this respect that rodent data indicate that cholesterol turnover in the brain is very slow (approx. 4-6 months in rodents). Following the first 6 months, the decline appeared to follow the slope of the placebo-treated group. It will now be very important to break down the data into mild and moderate AD. However, the limited trial size may not permit the researchers to do so.
• In combination with the low/moderate dose trials, the two 80 mg AD trials indicate that the response is dose-dependent.

Taken together, one can only congratulate Larry Sparks et al. for this breakthrough. Nevertheless, one has to keep in mind that all of the above-mentioned studies are pilot trials designed to give direction, not to provide final answers. Of course, many open questions remain. The top three on my list are: Can we go below 80 mg when treatment is done for longer times? Would it help to treat AD patients earlier, as our pilot study indicated? Finally, if patients are treated as soon as the diagnosis becomes possible, would the remaining regenerative potential of the brain prevent further disease progression?

Fortunately, all of these questions can be addressed relative safely. Several studies are ongoing which, unlike the previous studies, are powered to answer these questions. It is the results of such studies that may allow us to eventually come to final conclusions regarding the use of statins in prevention and therapy of AD.

References:
1. Hoglund K, Wiklund O, Vanderstichele H, Eikenberg O, Vanmechelen E, Blennow K. Plasma levels of beta-amyloid(1-40), beta-amyloid(1-42), and total beta-amyloid remain unaffected in adult patients with hypercholesterolemia after treatment with statins. Arch Neurol. 2004 Mar;61(3):333-7. Abstract

2. Sjogren M, Gustafsson K, Syversen S, Olsson A, Edman A, Davidsson P, Wallin A, Blennow K. Treatment with simvastatin in patients with Alzheimer's disease lowers both alpha- and beta-cleaved amyloid precursor protein. Dement Geriatr Cogn Disord. 2003;16(1):25-30. Abstract

3. Ishii K, Tokuda T, Matsushima T, Miya F, Shoji S, Ikeda S, Tamaoka A. Pravastatin at 10 mg/day does not decrease plasma levels of either amyloid-beta (Abeta) 40 or Abeta 42 in humans. Neurosci Lett. 2003 Oct 30;350(3):161-4. Abstract

4. Buxbaum JD, Cullen EI, Friedhoff LT. 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 Apr 1;7:a50-9. Abstract

5. 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

View all comments by Tobias Hartmann

The positive results observed by Sparks and Simons contrast sharply with the negative results reported by the PROSPER study and the Heart Study Group (Shepherd et al., 2002; Group...  Read more

The positive results observed by Sparks and Simons contrast sharply with the negative results reported by the PROSPER study and the Heart Study Group (Shepherd et al., 2002; Group 2002). For simplicity, I will refer to the studies by Sparks et al. and Simons et al. as "Alzheimer studies," and I will refer to the studies for PROSPER and Heart Study Group as "cardiovascular," although I am aware that the cardiovascular studies had a significant neurologic component. The cardiovascular studies were originally designed to examine the effects of statins on the incidence of cardiovascular disease, and the investigators added on a cognitive component to examine whether statins might also influence the incidence of Alzheimer disease. The seemingly contradictory results among the cardiovascular studies and the Alzheimer studies raise important questions that beg resolution. While we do not currently know the reason for the contradictory results, these studies differ in important respects, which could provide important clues for future and current studies testing the efficacy of statins in AD.

The subject populations differed greatly between the cardiovascular studies (PROSPER and the Heart Study Group) and the Alzheimer studies (Sparks et al. and Simons et al.). The cardiovascular studies were truly massive studies, one with ~9,000 subjects initially (2,891 treated with pravastatin) and the other with ~20,000 subjects initially (~10,000 treated with simvastatin). In comparison, the two Alzheimer studies were small. The study by Sparks examined 56 subjects (25 treated subjects completing the study), while the study by Simons examined 37 subjects (17 treated) (Sparks et al., 2005; Simons et al., 2002). However, the actual number of Alzheimer cases studied in each group was surprisingly similar. Only 31 subjects (0.3 percent) of the subjects in the Heart PROSPER Study were characterized as having Alzheimer disease, and the PROSPER study did not specifically list people with the diagnosis of Alzheimer disease (Shepherd et al., 2002; Group 2002).

The differing numbers of patients among the two types of studies reflect an important conceptual difference between the cardiovascular and Alzheimer studies. The study by Sparks et al. sought to measure progression of AD. Because of the focus on progression of symptoms, Sparks and colleagues designed their study to carefully quantify cognitive function among the study participants. The Simons study also quantified progression of cognitive loss in Alzheimer subjects, although the level of detail was far less than that documented by Sparks and colleagues. By contrast, the cardiovascular studies did not strongly address the issue of Alzheimer disease. The PROSPER study looked at cognitive decline among the entire cohort of subjects, which is a general measure that does not specifically address the pathophysiology of Alzheimer disease. It is possible that any effect relevant to Alzheimer disease was lost among the signal of other factors contributing to cognitive decline. The Heart Study Group examined the incidence of Alzheimer disease rather than progression of the disease. Because of this objective, the cardiovascular studies simply assessed whether there was dementia, which is a binary "yes/no" measure. I believe that if the results of Sparks et al. are borne out by future studies, the distinction between looking at progression of cognitive loss in Alzheimer cases, rather than incidence of Alzheimer disease or cognitive loss in the general population, will be key factors.

A second important difference might lie in dosing; I have heard other investigators mention this as a significant consideration. I do not know how important this issue is, but it is well worth considering. The cardiovascular studies utilized doses of statins that were at the moderate end of the recommended doses (up to 40 mg QD of simvastatin or pravastatin). In contrast, Sparks and colleagues used dosing that is on the moderate to high end (40/80 mg) of recommended dosing. This difference could have important consequences. Studies by Sparks et al., Friedhoff et al., Simons et al., and Hogland et al. have all examined the effects of statins on Aβ levels (Sparks et al., 2005; Friedhoff et al., 2001; Hoglund et al., 2004; Simons et al., 2002). Sparks used a relatively high dose of atorvastatin (40/80 mg QD) and has reported at meetings a dose-dependent reduction in Aβ. Friedhoff used a high dose of slow release lovastatin, and observed a reduction in Aβ levels associated with statin use (Friedhoff et al., 2001). In contrast, Hoglund et al. used doses of statins on the lower end of the recommended range (20 mg atorvastatin QD or 40 mg simvastatin QD) and failed to observe a reduction of Aβ levels with statin use (Simons et al., 2002). The confusing aspect of this issue is that Simons and colleagues also used 40 mg QD of simvastatin and observed a reduction in Aβ. Although not entirely consistent, these results raise the possibility that higher levels of statins might exert effects relevant to AD not observed with lower doses of statins. If true, use of lower doses of statins might also contribute to the negative outcome of the cardiovascular studies with respect to prevention of Alzheimer disease. However, this argument is quite tenuous.

It is possible that the small sample sizes of the Sparks and Simons studies contributed to false positive results. However, it is also possible that the results from both the cardiovascular studies and the Alzheimer studies are real. How could this be? Perhaps statins reduce the progression of AD, but do not prevent the incidence of AD and also do not prevent other forms of dementia. Our current knowledge of the pathophysiology of AD does not provide a clear mechanism for distinguishing between processes that might occur earlier in the disease process, and be associated with incidence of AD, from those that occur later in the disease and be associated with progression of existing disease. However, these studies might be identifying just such a distinction.

References:
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

Heart Protection Study Group. MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20,536 high-risk individuals: a randomised placebo-controlled trial. Lancet. 2002 Jul 6;360(9326):7-22. Abstract

Hoglund K, Wiklund O, Vanderstichele H, Eikenberg O, Vanmechelen E and Blennow K. Plasma Levels of Beta-Amyloid(1-40), Beta-Amyloid(1-42), and Total Beta-Amyloid Remain Unaffected in Adult Patients With Hypercholesterolemia After Treatment With Statins. Arch Neurol. 2004 Mar;61(3):333-7. 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; PROSPER study group. PROspective Study of Pravastatin in the Elderly at Risk. 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, 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

Sparks DL, Sabbagh MN, Connor DJ, Lopez J, Launer LJ, Browne P, Wasser D, Johnson-Traver S, Lochhead J, Ziolwolski C. Atorvastatin for the Treatment of Mild to Moderate Alzheimer Disease: Preliminary Results. Arch Neurol. 2005 May;62(5):753-7. Abstract

View all comments by Benjamin Wolozin

This puts the dosing of the Alzheimer sudies, which found a beneficial cognitive response in a distinct group, using at least twice the statin amount than other studies which did not observe a beneficial effect. Ben Wolozin very importantly raises the point of lower doses in respect to "beneficial side effects" and to prevention.

View all comments by Tobias Hartmann

The preliminary findings described in the current paper are certainly promising in terms of identifying a possible clinical therapy, but the mechanism of action remains to be defined. The pleiotrophic effects of statins, including inflammatory and vascular effects, could conceivably impact AD pathogenesis. The authors themselves acknowledge the possibility of a non-cholesterol-lowering mechanism for the observed effect on cognition. In terms of the possible Aβ connection, it would be interesting to know if CSF and/or plasma levels of Aβ in their cohort were altered with statin use, comparing levels at study entry with levels at the time of study completion. This would provide some insight into effects on Aβ metabolism as a possible mechanism of action.

Despite the abundant literature suggesting a connection between cholesterol metabolism and AD-related processes, I am still not convinced that the effects of hypercholesterolemia or statin use on cognitive or biological (e.g., plaque load, Aβ levels) outcomes involve cholesterol per se. We recently reported a lack of effect of endogenous plasma cholesterol levels on brain Aβ levels and pathology in the PDAPP mouse model of AD (Fagan et al., 2004). We wanted to test the role of plasma cholesterol levels on Aβ pathology in this model without resorting to the use of non-physiologic high-fat diets (known to cause pathology in multiple systems) or pharmacologic manipulations with drugs with possible pleiotrophic effects (e.g., statins). To do this, we took a genetic approach and bred PDAPP mice with mice lacking ApoA1. ApoA1-null mice have severely reduced plasma cholesterol levels (by ~75 percent) due to the virtual absence of HDL, the primary lipoprotein in mice. Despite a marked reduction in plasma (and brain, ~40 percent) cholesterol levels in PDAPP/ApoA1-/- mice, Aβ-related parameters were not changed. Furthermore, while plasma ApoE levels actually increased in PDAPP/ApoA1-/- mice compared to littermate controls, brain ApoE levels remained unchanged. We hypothesized that it is perhaps the level of brain ApoE, and not the level of brain or plasma cholesterol per se that influences Aβ metabolism, and by extension, perhaps dementia risk. In view of the published literature, it is conceivable that effects of high-fat diets and statin treatment previously attributed to cholesterol may actually be due to altered levels of brain ApoE. High-fat diets not only increase the level of cholesterol, but also ApoE, in the brain (Sparks et al., 1995; Howland et al., 1998; Wu et al., 2003), and statins decrease them both (Naidu et al., 2002; Petanceska et al., 2003). Thus, it has not been possible to distinguish putative effects of cholesterol from those of ApoE in the many studies published to date. Does this mechanistic nuance have any bearing on whether statins will have therapeutic value in AD? No, probably not. Consideration of this alternative hypothesis does, however, open up the possibility of additional targets (e.g., ApoE) that warrant exploration, and cautions against an automatic presumption of a cholesterol mechanism in the hypercholesterolemia/statin/AD connection.

References:
Fagan A, Christopher E, Taylor J, Parsadanian M, Spinner M, Watson M, Fryer J, Wahrle S, Bales K, Paul S, Holtzman D. ApoAI deficiency results in marked reductions in plasma cholesterol but no alterations in amyloid-beta pathology in a mouse model of Alzheimer's disease-like cerebral amyloidosis. Am J Pathol. 2004 Oct;165(4):1413-22. Abstract

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. Epub 2001 Apr 10. Abstract

Frears E, Stephens D, Walters C, Davies H, Austen B. The role of cholesterol in the biosynthesis of beta-amyloid. Neuroreport. 1999 Jun 3;10(8):1699-705. Abstract

Heart Protection Study Collaborative Group. MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20,536 high-risk individuals: a randomised placebo-controlled trial. Lancet. 2002 Jul 6;360(9326):7-22. Abstract

Howland D, Trusko S, Savage M, Reaume A, Lang D, Hirsch J, Maeda N, Siman R, Greenberg B, Scott R, Flood D. Modulation of secreted beta-amyloid precursor protein and amyloid beta-peptide in brain by cholesterol. J Biol Chem. 1998 Jun 26;273(26):16576-82. Abstractc

Jarvik J, Wijsman E, Kukull W, Schellenberg G, Yu C, Larson E. Interactions of apolipoprotein E genotype, total cholesterol level, age, and sex in prediction of Alzheimer's disease: a case-control study. Neurology. 1995 Jun;45(6):1092-6. Abstract

Jick H, Zornberg G, Jick S, Seshadri S, Drachman D. Statins and the risk of dementia. Lancet. 2000 Nov 11;356(9242):1627-31. Erratum in: Lancet 2001 Feb 17;357(9255):562. Abstract

Kalmijn S, Launer L, Ott A, Witteman J, Hofman A, Breteler M. Dietary fat intake and the risk of incident dementia in the Rotterdam Study. Ann Neurol. 1997 Nov;42(5):776-82. Abstract

Kuo Y, Emmerling M, Bisgaier C, Essenburg A, Lampert H, Drumm D, Roher A. Elevated low-density lipoprotein in Alzheimer's disease correlates with brain Abeta 1-42 levels. Biochem Biophys Res Commun. 1998 Nov 27;252(3):711-5. Abstract

Naidu A, Xu Q, Catalano R, Cordell B. Secretion of apolipoprotein E by brain glia requires protein prenylation and is suppressed by statins. Brain Res. 2002 Dec 20;958(1):100-11. Abstract

Notkola I, 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

Petanceska S, Papolla M, Refolo L. (2003) Modulation of Alzheimer's amyloidosis by statins: Mechanisms of action. Curr Med Chem-Immun, Endoc & Metab Agents 3:233-243.

Refolo L, Pappolla M, Malester B, LaFrancois J, Bryant-Thomas T, Wang R, Tint G, Sambamurti K, Duff K. Hypercholesterolemia accelerates the Alzheimer's amyloid pathology in a transgenic mouse model. Neurobiol Dis. 2000 Aug;7(4):321-31. Erratum in: Neurobiol Dis 2000 Dec;7(6 Pt B):690. Abstract

Refolo L, Pappolla M, LaFrancois J, Malester B, Schmidt S, Thomas-Bryant T, Tint G, Wang R, Mercken M, Petanceska S, Duff K. 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

Romas S, Tang M, Berglund L, Mayeux R. ApoE genotype, plasma lipids, lipoproteins, and AD in community elderly. Neurology. 1999 Aug 11;53(3):517-21. Abstract

Shepherd J, Blauw G, Murphy M, Bollen E, Buckley B, Cobbe S, Ford I, Gaw A, Hyland M, Jukema J, Kamper A, Macfarlane P, Meinders A, Norrie J, Packard C, Perry I, Stott D, Sweeney B, Twomey C, Westendorp R. Pravastatin in elderly individuals at risk of vascular disease (PROSPER): a randomized controlled trial. Lancet. 2002 Nov 23;360(9346):1623-30. Abstract

Simons M, Keller P, De Strooper B, Beyreuther K, Dotti C. 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

Sparks D, Liu H, Gross D, Scheff S. Increased density of cortical apolipoprotein E immunoreactive neurons in rabbit brain after dietary administration of cholesterol. Neurosci Lett. 1995 Mar 3;187(2):142-4. Abstract

Sparks D, Sabbagh M, Connor D, Lopez J, Launer L, Browne P, Wasser D, Johnson-Traver S, Lochhead J, Ziolwolski C. Atorvastatin for the treatment of mild to moderate Alzheimer disease: preliminary results. Arch Neurol. 2005 May;62(5):753-7. Abstract

Wolozin B, Kellman W, Ruosseau P, Celesia G, 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

Wu C, Liao P, Lin C, Kuo C, Chen S, Chen H, Kuo Y. Brain region-dependent increases in beta-amyloid and apolipoprotein E levels in hypercholesterolemic rabbits. J Neural Transm. 2003 Jun;110(6):641-9. Abstract

View all comments by Anne Fagan

It is widely believed that the potential beneficial effects of statin treatment as an AD therapeutic are related to the cholesterol-lowering properties of statins....  Read more

It is widely believed that the potential beneficial effects of statin treatment as an AD therapeutic are related to the cholesterol-lowering properties of statins. However, whether benefit is mediated through changes in serum or brain cholesterol, or whether the effects are direct (e.g., lower brain cholesterol causing reduced Aβ generation) or indirect (e.g., lower serum cholesterol causing improved cerebrovascular function, thus reducing AD progression) remains unknown. As Drs. Gandy and Petanceska point out in their commentary, lipophilic statins such as simvastatin penetrate the blood-brain barrier (BBB), whereas hydrophilic statins such as atorvastatin do not. Interestingly, Simons et al. reported a 26-week randomized, placebo-controlled, double-blind trial using simvastatin that showed a significant benefit in the MMSE scores of the simvastatin treated group as compared to placebo (Simons et al., 2002). As anticipated, statin treatment in both Sparks and Simons trials significantly lowered plasma cholesterol levels, and in the Simons study, cerebral cholesterol metabolism was also affected following treatment. It is interesting to note that both trials showed statin-related cognitive benefits, although one used a BBB-penetrant statin while the other did not. This would seem to support the notion that the beneficial effect was associated with lower serum, rather than brain, cholesterol levels. As discussed by Drs. Wolozin and Hartmann, use of high-dose simvastatin was also associated with reduced Aβ levels (Simons et al., 2002). However, whether or not atorvastatin treatment affected either cerebral cholesterol or Aβ levels (or both) was not determined in the Sparks study, and the mechanisms underlying the potential benefits of statins on measures of cognition remain a mystery.

Given the relatively short time frame of both the Sparks and Simons trials, it should be considered that any putative beneficial effects that the statins exert may be entirely independent of changes in amyloid load and could instead be a secondary effect due to an improvement in cardiovascular or cerebrovascular function. Indeed, recent data has indicated that atorvastatin treatment promotes both angiogenesis and neuronal plasticity (Chen et al., 2005). Obviously, further trials involving the use of statins of different lipophilicity, over a range of doses for more prolonged periods, are required to obtain definitive results.

In light of the relatively short trial time, and given the fact that stroke benefit from statins is not apparent until ~3 years of treatment (Byington et al., 2001; Pedersen et al., 1998), increasing the trial time beyond 1 year may reveal more robust positive effects on AD progression. However, a note of caution: Although a ~5-year administration of high-dose atorvastatin (similar to the dosage used by Sparks) to patients with stable coronary heart disease provided significant clinical benefit beyond that afforded by 10 mg per day atorvastatin, this benefit occurred with a greater incidence of elevated aminotransferase levels (LaRosa, et al., 2005). While Sparks and colleagues screened for adverse changes in liver function and monitored for muscle derangements and rhabdomyolysis following administration of 80 mg per day atorvastatin, it remains unclear as to why, out of the 63 patients considered evaluable after completing the 3-month visit, only 46 individuals completed the 12-month study.

In summary, while not all the large-scale epidemiologic studies have found a link between statin use and AD prevention, the small-scale, randomized clinical trial of Sparks et al. appears to support the notion that statin treatment may reduce AD progression. However, given the small sample sizes of both the Sparks and the Simons studies, the data from well-designed, large-scale multicenter clinical trials clarifying the safety and efficacy of long-term, high-dose statin treatment on AD progression is avidly awaited.

References:
Jick H, Zornberg GL, Jick SS, Seshadri S, Drachman DA. Statins and the risk of dementia. Lancet. 2000 Nov 11;356(9242):1627-31. Erratum in: Lancet 2001 Feb 17;357(9255):562. 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

Heart Protection Study Group. MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20,536 high-risk individuals: a randomised placebo-controlled trial. Lancet. 2002 Jul 6;360(9326):7-22. 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; PROSPER study group. PROspective Study of Pravastatin in the Elderly at Risk. Pravastatin in elderly individuals at risk of vascular disease (PROSPER): a randomised controlled trial. Lancet. 2002 Nov 23;360(9346):1623-30. Abstract

Zandi PP, Sparks DL, Khachaturian AS, Tschanz J, Norton M, Steinberg M, Welsh-Bohmer KA, Breitner JC; Cache County Study investigators. Do statins reduce risk of incident dementia and Alzheimer disease? The Cache County Study. Arch Gen Psychiatry. 2005 Feb;62(2):217-24. Abstract

Sparks DL, Sabbagh MN, Connor DJ, Lopez J, Launer LJ, Browne P, Wasser D, Johnson-Traver S, Lochhead J, Ziolwolski C. Atorvastatin for the treatment of mild to moderate Alzheimer disease: preliminary results. Arch Neurol. 2005 May;62(5):753-7. 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

Chen J, Zhang C, Jiang H, Li Y, Zhang L, Robin A, Katakowski M, Lu M, Chopp M. Atorvastatin induction of VEGF and BDNF promotes brain plasticity after stroke in mice. J Cereb Blood Flow Metab. 2005 Feb;25(2):281-90. Abstract

Byington RP, Davis BR, Plehn JF, White HD, Baker J, Cobbe SM, Shepherd J. Reduction of stroke events with pravastatin: the Prospective Pravastatin Pooling (PPP) Project. Circulation. 2001 Jan 23;103(3):387-92. Abstract

Pedersen TR, Kjekshus J, Pyorala K, Olsson AG, Cook TJ, Musliner TA, Tobert JA, Haghfelt T. Effect of simvastatin on ischemic signs and symptoms in the Scandinavian simvastatin survival study (4S). Am J Cardiol. 1998 Feb 1;81(3):333-5. Abstract

LaRosa JC, Grundy SM, Waters DD, Shear C, Barter P, Fruchart JC, Gotto AM, Greten H, Kastelein JJ, Shepherd J, Wenger NK; Treating to New Targets (TNT) Investigators. Intensive lipid lowering with atorvastatin in patients with stable coronary disease. N Engl J Med. 2005 Apr 7;352(14):1425-35. Epub 2005 Mar 8. Abstract

View all comments by Sarah L. Cole
View all comments by Robert Vassar

As noted by Dr. Hartman, the Simons study was a 26-week study of simvastatin where stable performance on the Mini Mental State Exam (MMSE) in the treatment group was significantly different from the placebo group. This was...  Read more

As noted by Dr. Hartman, the Simons study was a 26-week study of simvastatin where stable performance on the Mini Mental State Exam (MMSE) in the treatment group was significantly different from the placebo group. This was because the placebo group showed a somewhat accelerated 4-point deterioration between baseline and the 6-month evaluation. At the 6-month time-point in the ADCLT, we observed stable performance on the MMSE in the atorvastatin-treated population that was not significantly different from the placebo group—as the placebo group only deteriorated two points. The differences between the studies on the MMSE are more due to the rate of deterioration in untreated participants with AD.

Dr. Wolozin indicates that we reported a significant difference on the Alzheimer’s Disease Cooperative Study Activities of Daily Living (ADCS-ADL) index, when in fact this was the one of six clinical instruments where there was no positive signal produced by atorvastatin. This investigator suggests that the Simons trial and the ADCLT were of similar size when actually the ADCLT included twice as many subjects with mild to moderate AD. We include data from 63 participants—32 on atorvastatin and 31 placebo with 25 treated subjects completing the 1-year investigation, whereas the Simons study included 37 subjects, with 13 of 17 simvastatin-treated subjects completing the 6-month study. Dr. Wolozin also suggests that we have reported a dose-related decrease in circulating Aβ levels with atorvastatin treatment, when in fact we have found slight gradual increases in both Aβ40 and 42 that were not significant. These data will be published in the near future (2).

We agree with Drs. Gandy and Petanceska that atorvastatin may partially reinstate clearance of Aβ from the brain. The observed gradual increase in circulating Aβ levels among subjects treated with atorvastatin may be associated with the gradual reductions of ceruloplasmin—the copper chaperone in the blood. We have shown that increased copper/ceruloplasmin levels promote central accumulation of Aβ in the cholesterol-fed rabbit model of AD, while reduced circulating copper/ceruloplasmin allows clearance to the blood and minimal accumulation in brain (3-5).

In reply to Dr. Fagan, as part of the preplanned design of the ADCLT, we explored many more circulating markers than initially published to assess multiple mechanistic avenues. As noted above, we have determined the effect of atorvastatin treatment on Aβ levels. We have also established that atorvastatin produces reduced circulating ApoE levels during the time-course of treatment (2). I would also note that in addition to cholesterol-fed animals, nondemented individuals with autopsy-confirmed critical coronary artery disease (>75 percent stenosis) exhibit increased accumulation of Aβ and ApoE in the brain (6-8), thus making it difficult to separate the interrelationships among cholesterol, ApoE and Aβ.

In answer to Dr. Cole's and Dr. Vassar's queries, as part of the investigation of possible mechanisms of atorvastatin action in association with observed clinical benefit, we will soon report the effect of treatment on circulating free radical load (superoxide dismutase and glutathione peroxidase activities) and HDL/LDL/VLDL levels (9). In addition, we will be reporting the effect of active treatment on volumetric alterations measured by MRI, assessment of clinical parameters during the 1-year “open-label" extension of the ADCLT (Geneva/Springfield Conference, 2006), and treatment-related changes in circulating levels of ApoA1, ApoB, copper, 24OH- and 27OH-cholesterol, CRP, and CD40. Furthermore, in two weeks we will be reporting at the Alzheimer’s Association meeting in Washington, DC, the influence of initial cognitive impairment, initial cholesterol levels, and ApoE genotype on the clinical benefit produced by atorvastatin.

References:
1. Sparks DL, Sabbagh MN, Connor DJ, Lopez J, Launer LJ, Browne P, Wasser D, Johnson-Traver S, Lochhead J, Ziolwolski C. Atorvastatin for the treatment of mild to moderate Alzheimer disease: preliminary results. Arch Neurol. 2005 May;62(5):753-7. Abstract

2. Sparks DL, Petanceska S, Sabbagh M, et al. Cholesterol, copper and Ab in controls, MCI, AD and the AD Cholesterol-Lowering Treatment trial (ADCLT). Curr Alz Res 2005; in press.

3. Sparks DL, Lochhead J, Horstman D, Wagoner T, Martin T. Water quality has a pronounced effect on cholesterol-induced accumulation of Alzheimer amyloid beta (Abeta) in rabbit brain. J Alzheimers Dis. 2002 Dec;4(6):523-9. Abstract

4. Sparks DL, Schreurs BG. Trace amounts of copper in water induce beta-amyloid plaques and learning deficits in a rabbit model of Alzheimer's disease. Proc Natl Acad Sci U S A. 2003 Sep 16;100(19):11065-9. Epub 2003 Aug 14. Erratum in: Proc Natl Acad Sci U S A. 2003 Sep 30;100(20):11816. Abstract

5. Sparks DL, Cholesterol, copper, and accumulation of thioflavine S-reactive Alzheimer's-like amyloid beta in rabbit brain. J Mol Neurosci. 2004;24(1):97-104. Abstract

6. Sparks DL, Hunsaker JC 3rd, Scheff SW, Kryscio RJ, Henson JL, Markesbery WR. Cortical senile plaques in coronary artery disease, aging and Alzheimer's disease. Neurobiol Aging. 1990 Nov-Dec;11(6):601-7. Abstract

7. Sparks DL, Scheff SW, Liu H, Landers T, Danner F, Coyne CM, Hunsaker JC 3rd. Increased density of senile plaques (SP), but not neurofibrillary tangles (NFT), in non-demented individuals with the apolipoprotein E4 allele: comparison to confirmed Alzheimer's disease patients. J Neurol Sci. 1996 Jun;138(1-2):97-104. Abstract

8. Sparks DL. Coronary artery disease, hypertension, ApoE, and cholesterol: a link to Alzheimer's disease? Ann N Y Acad Sci. 1997 Sep 26;826:128-46. Abstract

9. Sparks DL, Sabbagh MN, Connor DJ, et al. Atorvastatin therapy lowers circulating cholesterol but not free radical activity in advance of identifiable clinical benefit in the treatment of mild-to-moderate AD. Curr AD Res 2005; in press.

View all comments by Larry Sparks

An important effect of immunization that has not been reported on in the current study is cerebral amyloid angiopathy (CAA) and microhemorrhage. It has been shown that passive immunotherapy increases CAA in transgenic mice (Wilcock et al., 2004) and causes increased incidence of microhemorrhage (Pfeifer et al., 2001, Wilcock et al., 2004, Racke et al., 2005). We also reported that these adverse events occurred with active vaccination (Wilcock et al., 2007). Indeed, the authors of the current report use CAA and Aβ accumulation around capillaries as histopathological factors used to determine the degree of amyloid clearance. It also seems the microhemorrhage occurrence will be difficult to overcome. The recent report from Schroeter et al. showed that even low doses of antibody, which were associated with essentially no amyloid removal, resulted in an apparent subtle increase in microhemorrhage (Schroeter et al., 2008; control mice had no animals with microhemorrhage rated 2 or 3 while the lowest dose of 3D6 had three mice rated 2 or 3). Accumulation of CAA and associated microhemorrhage likely contributes significantly to the clinical progression of disease. Additionally, as the authors suggest, a change in inflammatory state could certainly contribute to further cognitive decline. Recent data show that the inflammatory profile of Alzheimer’s and transgenic mouse brain is highly complex (Colton et al., 2006). It is likely that Fcγ receptor activation affects the inflammatory state.

These data highlight the significant differences between human and mouse studies. Since neurodegeneration is not abundant in the majority of mouse models, it has not been possible, to date, to study this. It is likely that while amyloid may initiate the cascade, neurodegeneration may be self-perpetuating and neuroprotection may also be critical for successful anti-amyloid therapeutics. It has been suggested that passive immunization will overcome some of the limitations of active vaccination, and we certainly eagerly anticipate the data from Elan’s passive immunization trial of bapineuzumab.

References:
Colton CA, Mott RT, Sharpe H, Xu Q, Van Nostrand WE, Vitek MP. Expression profiles for macrophage alternative activation genes in AD and in mouse models of AD. J Neuroinflammation. 2006 Sep 27;3:27. Abstract

Hock C, Konietzko U, Streffer JR, Tracy J, Signorell A, Müller-Tillmanns B, Lemke U, Henke K, Moritz E, Garcia E, Wollmer MA, Umbricht D, de Quervain DJ, Hofmann M, Maddalena A, Papassotiropoulos A, Nitsch RM. Antibodies against beta-amyloid slow cognitive decline in Alzheimer's disease. Neuron 2003 May 22;38(4):547-554. Abstract

Pfeifer M, Boncristiano S, Bondolfi L, Stalder A, Deller T, Staufenbiel M, Mathews PM, Jucker M. Cerebral hemorrhage after passive anti-Abeta immunotherapy. Science 2002 Nov 15;298 (5597):299. Abstract

Racke MM, Boone LI, Hepburn DL, Parsadainian M, Bryan MT, Ness DK, Piroozi KS, Jordan WH, Brown DD, Hoffman WP, Holtzman DM, Bales KR, Gitter BD, May PC, Paul SM, DeMattos RB. Exacerbation of cerebral amyloid angiopathy-associated microhemorrhage in amyloid precursor protein transgenic mice by immunotherapy is dependent on antibody recognition of deposited forms of amyloid beta. J Neurosci 2005 Jan 19;25(3):629-636. Abstract

Schroeter S, Khan K, Barbour R, Doan M, Chen M, Guido T, Gill D, Basi G, Schenk D, Seubert P, Games D. Immunotherapy reduces vascular amyloid-β in PDAPP mice. J Neurosci 2008 Jul 2; 28(27): 6787-6793. Abstract

Wilcock DM, Rojiani A, Rosenthal A, Subbarao S, Freeman MJ, Gordon MN, Morgan D. Passive immunotherapy against Abeta in aged APP-transgenic mice reverses cognitive deficits and depletes parenchymal amyloid deposits in spite of increased vascular amyloid and microhemorrhage. J Neuroinflammation 2004 Dec 8;1(1):24. Abstract

Wilcock DM, Jantzen PT, Li Q, Morgan D, Gordon MN. Amyloid-beta vaccination, but not nitro-nonsteroidal anti-inflammatory drug treatment, increases vascular amyloid and microhemorrhage while both reduce parenchymal amyloid. Neuroscience. 2007 Feb 9;144(3):950-60. Abstract

View all comments by Donna Wilcock

We suggest a number of possible explanations for our findings:

1. The...  Read more

We suggest a number of possible explanations for our findings:

1. The presence of Aβ plaques is required to initiate, but not to maintain the progressive neurodegeneration in AD.

2. Amyloid plaques are an epiphenomenon, and extracellular soluble/oligomeric or intraneuronal forms of Aβ are responsible for the neurodegeneration in AD.

3. Immunization activates microglia, which may be beneficial (by removing plaques) but at the same time neurotoxic.

4. The plaques could have been removed shortly before the patients died, after their cognitive function had declined—this seems rather unlikely.

A major driver of the immunization strategies currently in clinical trials has been to avoid a T lymphocyte reaction in the belief that this is what underlay the side effect noted in the second study of AN1792. Passive immunization, in particular, should theoretically not be able to provoke a T cell response and has the additional benefit that the bioavailability of the antibodies can be controlled. However, it is not clear by what mechanism lymphocytes in the leptomeninges, identified in patients with the side effect, can cause changes in the cerebral white matter (a consistent feature on brain imaging of the affected patients). An alternative explanation for the side effect is that it was due to disaggregation and solubilization of plaque Aβ which then tracks to the cerebral vasculature, increasing the severity of cerebral amyloid angiopathy (CAA). We know from previous studies that severe cerebral amyloid angiopathy is associated with abnormalities in the white matter. Interestingly, the new information from the current Elan trial of passive immunization (bapineuzumab) seems to be showing evidence of white matter abnormalities which are occurring more frequently in patients with ApoE4—known to be associated with more severe CAA.

On the basis of our findings, we would predict that other immunization protocols (e.g., passive immunization and active immunization with truncated versions of the Aβ peptide) will also be effective in clearance of plaques. A number of current studies have before and after immunization in vivo plaque imaging, for example, with PIB, built into their design. We would predict that these will demonstrate plaque clearance following immunization. However, on the basis of our findings, we would speculate that plaque removal will not correlate well with any changes in cognitive function.

It is possible that some of the new immunization protocols will have a different balance of effects on the different forms of Aβ (e.g., plaque, soluble, oligomeric, intraneuronal) and may therefore have different effects on cognitive function. One of the approaches being trialled involves passive immunization with an Fc-truncated antibody, and this may have the potentially beneficial effect of not provoking microglial activation.

Using immunization as prevention rather than treatment would likely avoid these complications which seem to be due to the presence of substantial quantities of Aβ already being present in the brain. On the basis of the animal studies, immunization at a young age can prevent the formation of plaques in later life. Of course, we don’t yet know if this can be done safely in humans—we don’t know the physiological function of Aβ and if immunization might interfere with this function. A study to determine if Aβ immunization at a young age could prevent the development of AD later in life would be the ultimate test of the Aβ hypothesis.

View all comments by Delphine Boche
View all comments by Clive Holmes
View all comments by James Nicoll

The Next Phase: Prevention. Where Do I Sign Up?
The Aβ vaccination strategy failed because it was not used early enough in the course of the disease.

Come again?

We know this apparently because Aβ oligomers, which are artifacts of ultracentrifugation, when injected into the ventricles of mice, cause mice to navigate water mazes poorly, and press levers inappropriately. We know this because when hippocampal slices are bathed in a suspension of the artifact, they demonstrate electrophysiological abnormalities. And we know this because transgenic mice, which are engineered to overproduce Aβ, and then administered antibodies against it, improve in their ability to navigate water mazes and press the appropriate levers.

We apparently also must set aside the ad hoc revisions and contortions of the amyloid cascade hypothesis over the years (1-3), and the plethora of problems with experimental AD models, from lack of cognitive dysfunction, to lack of...  Read more

The Next Phase: Prevention. Where Do I Sign Up?
The Aβ vaccination strategy failed because it was not used early enough in the course of the disease.

Come again?

We know this apparently because Aβ oligomers, which are artifacts of ultracentrifugation, when injected into the ventricles of mice, cause mice to navigate water mazes poorly, and press levers inappropriately. We know this because when hippocampal slices are bathed in a suspension of the artifact, they demonstrate electrophysiological abnormalities. And we know this because transgenic mice, which are engineered to overproduce Aβ, and then administered antibodies against it, improve in their ability to navigate water mazes and press the appropriate levers.

We apparently also must set aside the ad hoc revisions and contortions of the amyloid cascade hypothesis over the years (1-3), and the plethora of problems with experimental AD models, from lack of cognitive dysfunction, to lack of neuronal loss, to necessity of multiple mutations, to hyperphysiologic production of a target protein. We set this aside because we apparently now know that synaptic damage, a process never directly assessed, and which probably has the same specificity as gliosis, is the pathological substrate for this laboratory artifact in AD (1).

So a strategy, founded in the analysis of a pathological lesion (once said to be toxic and now discarded as a distraction, except of course for the two subjects who found to be “cleared” of plaques at autopsy), based on an ad hoc modification of a hypothesis that a laboratory artifact specifically causes nonspecific damage that has never been analyzed directly, verified in a transgenic mouse construct that generally does not lose neurons, and which was tested and failed in human disease subjects, must now be used on normal people. Where do I sign up?

References:
1. Castellani RJ, Lee HG, Zhu X, Perry G, Smith MA. Alzheimer disease pathology as a host response. J Neuropathol Exp Neurol. 2008;67:523-531. Abstract

2. Castellani RJ, Lee HG, Zhu X, Nunomura A, Perry G, Smith MA. Neuropathology of Alzheimer disease: pathognomonic but not pathogenic. Acta Neuropathol. 2006;111:503-509. Abstract

3. Smith MA, Casadesus G, Joseph JA, Perry G. Amyloid-beta and tau serve antioxidant functions in the aging and Alzheimer brain. Free Radic Biol Med. 2002;33:1194-1199. Abstract

View all comments by Rudy Castellani
View all comments by Hyoung-gon Lee
View all comments by George Perry
View all comments by Mark A. Smith
View all comments by Xiongwei Zhu

I have often used the analogy that anti-Aβ therapy for AD is analogous to treating patients whose coronary arteries are 99 percent clogged with a statin and hoping for a clinical effect. These new data raise the possibility that anti-Aβ immunotherapy is more like trying to treat somebody with massive myocardial contraction deficits following multiple MIs with a statin and a bypass. So much damage has been done that targeting the trigger, by itself, is simply too little too late. Indeed, we would not approach the treatment of a patient...  Read more

I have often used the analogy that anti-Aβ therapy for AD is analogous to treating patients whose coronary arteries are 99 percent clogged with a statin and hoping for a clinical effect. These new data raise the possibility that anti-Aβ immunotherapy is more like trying to treat somebody with massive myocardial contraction deficits following multiple MIs with a statin and a bypass. So much damage has been done that targeting the trigger, by itself, is simply too little too late. Indeed, we would not approach the treatment of a patient in severe cardiac dysfunction that has resulted from multiple MIs as a result of long-standing atherosclerotic disease with a statin alone. It simply is not going to work, though it might have some benefit in combination with other therapeutic agents.

Though a small and vociferous group of colleagues are publicly using such data to refute the role of Aβ aggregation in AD and thus indirectly attempting to invalidate it, Aβ or Aβ aggregates, as a target, I think a more parsimonious approach and one discussed to an extent by the authors is to really think carefully about these data and how we as a field might modify our approach to AD therapy and research based on such studies. Although there are numerous potential implications of these data, I will limit myself to a few issues that I see as most important. Obviously, the following comments may be tempered somewhat by any future demonstration of efficacy in Phase 3 studies of anti-Aβ therapies, but I think they will likely hold even in that event.

From a basic research point of view, this ups the ante on two critical issues.

In order to enable better preclinical studies, we still need better animal models of AD that fully recapitulate all the features of the human disease—especially neuronal loss. Given that this appears very difficult to do in APP mice, we probably need to consider looking at other species. Indeed, this report suggests the AN1792 trial appears to have “worked” in humans as it did in mice. Of course, APP mice are good models of Aβ deposition but not real models of AD. If we had a complete animal model of AD, we might be better able to evaluate therapeutic paradigms for impact on neurodegeneration. Tau mice might be better predictors for effects on neuronal loss, but obviously aren’t much use for testing anti-Aβ therapies. Hopefully they will be predictive of clinical outcomes when novel anti-tau therapies are moved into the clinic.

We need a real understanding of why neurons die in AD, and we need to identify additional therapeutic targets that will protect or restore neuronal function. Indeed, though my own research is Aβ-centric, I believe it is of paramount importance to identify targets beyond Aβ and, for that matter, tau. I think that it is more important to explicitly state that we need additional targets than to try and invalidate current ones.

From a clinical perspective, I think this reinforces our need to figure out how to prophylactically treat AD. We need to directly confront and overcome the challenges that distinguish therapeutic trials from prevention trials. We also need to figure out whether a trial of MCI of the AD type to AD conversion is really a prevention trial or just a very early therapeutic trial. Current predictive AD biomarker initiatives will certainly help to frame and define some aspects of the problem in more detail, but we also need to find common ground on how to actually execute a prophylactic trial that is economically feasible, ethical, and appropriately powered. Such trials will almost certainly require the joint efforts of academic, government, and commercial sectors, and of course, “safe agents.” Indeed, the true test of the Aβ “aggregate/amyloid” hypothesis of AD is a trial to prevent Aβ deposition in humans, not a therapeutic treatment of patients with clinical symptoms.

On a final, more technical note, following the initial report (Nicoll et al., 2003) of plaque clearance in one patient, I was less than convinced that there was clearance. The new data do make me more convinced. However, I would like to see some rigorous biochemical analysis of Aβ levels in the brains of these subjects. Even in mouse models, “plaque loads” seem to overestimate reductions in Aβ as compared to biochemical measures. I am also struck by what appears to be patchy clearance. I find it hard to rationalize how patchy clearance can occur with an antibody-mediated mechanism and wonder whether cellular immune responses play some role in the actual clearance.

References:
Golde TE. Alzheimer disease therapy: can the amyloid cascade be halted? J Clin Invest. 2003 Jan;111(1):11-8. Abstract

Golde TE. Disease modifying therapy for AD? J Neurochem. 2006 Nov;99(3):689-707. Abstract

Nicoll JA, Wilkinson D, Holmes C, Steart P, Markham H, Weller RO. Neuropathology of human Alzheimer disease after immunization with amyloid-beta peptide: a case report. Nat Med. 2003 Apr;9(4):448-52. Abstract

View all comments by Todd E. Golde

There are a few issues that I’d like to comment on. I find it noteworthy that seven out of eight cases had MMSE scores of zero when last screened. The authors point out that these were “end stage” AD cases—and judging from the MMSE scores, that’s an understatement. I agree with Todd Golde...  Read more

There are a few issues that I’d like to comment on. I find it noteworthy that seven out of eight cases had MMSE scores of zero when last screened. The authors point out that these were “end stage” AD cases—and judging from the MMSE scores, that’s an understatement. I agree with Todd Golde that AD immunotherapy in this small, severely affected cohort is not a robust test of the amyloid cascade hypothesis in humans. But, I don’t believe that this detracts at all from the provocative nature of the findings, and from the message to keep an open mind and to critically consider the etiological contribution of Aβ to AD. More than likely, what these data are telling us is that there is a cutoff beyond which severe neuronal damage/loss has already occurred, and removing Aβ from the equation will have little if any effect clinically. This has prompted a number of researchers to conclude that prevention by immunotherapy is a more viable strategy. That may be true, but when should vaccination be initiated—five, 10, 20, or more years before symptoms manifest? Also, what biomarkers should be used to determine those at risk: APOE genotype, CSF Aβ, CSF tau, plasma Aβ? At this stage, a preventative Aβ vaccine seems much more viable for the <5 percent of individuals genetically predisposed to familial AD, but again—when would treatment need to be initiated and how often would it need to be given to be efficacious and safe?

It is unfortunate that an adjuvant-alone (placebo) treatment group could not be evaluated side-by-side with the AN1792-treated cases, and that historical non-vaccinated AD cases had to be used as controls. It is possible that the inflammatory side effects of the Th1-biasing vaccine adjuvant (QS-21) negatively impacted cognitive function and/or survival independently of the synthetic Aβ42 peptide. Along those lines, the authors comment that “only one patient had clinical features of meningoencephalitis….” Did the authors evaluate CD4+ T cells in these vaccinated cases, and if so, were they present in greater quantity than in the historical non-vaccinated AD cases?

In summary, this paper represents a timely, thought-provoking examination of the clinical and pathological correlates of Aβ vaccination. As we move forward in this exciting time of AD therapeutics, it will be important to view the results of such clinical trials with open eyes and without bias toward whichever AD pathogenic hypothesis we hold close to our hearts.

References:
Holmes C, Boche D, Wilkinson D, Yadegarfar G, Hopkins V, Bayer A, Jones RW, Bullock R, Love S, Neal JW, Zotova E, Nicoll JA. Long-term effects of Abeta42 immunisation in Alzheimer’s disease: follow-up of a randomized, placebo-controlled phase I trial. Lancet 2008 July 19;372:216-223. Abstract

Nicoll JA, Wilkinson D, Holmes C, Steart P, Markham H, Weller RO. Neuropathology of human Alzheimer disease after immunization with amyloid-beta peptide: a case report. Nat Med. 2003 Apr;9(4):448-52. Abstract

View all comments by Terrence Town

Data derived from our ongoing clinical molecular pathologic investigations of MCI using the cholinotrophic basal forebrain system as a model for neuronal selective vulnerability has shown that these neurons display a...  Read more

Data derived from our ongoing clinical molecular pathologic investigations of MCI using the cholinotrophic basal forebrain system as a model for neuronal selective vulnerability has shown that these neurons display a myriad of biochemical and molecular alterations, which appear to be unrelated to amyloid deposition (Counts and Mufson, 2004). For example, cholinergic neurons are simultaneously undergoing re-expression of cell cycle markers, alterations in neurotrophic support and the ratio of tau epitopes but not changes in APP or presenilin expression. The molecular signature of these neurons is commensurate with a hypothesis related to multiple cellular and connectivity-based dysregulation, which probably begins several decades before the onset of clinical symptoms. What initiates neuronal dysfunction remains unknown, and merits serious research in relevant animal models as well as in well-characterized postmortem human brain tissues. In this regard, it would be of interest to examine the molecular pathology of the cholinergic basal forebrain (CBF) neurons in the same vaccine treated brains examined by Holmes et al. to determine whether amyloid removal from cortical and hippocampal parenchymal projection sites of the CBF neurons rejuvenates these cell bodies.

To anyone who has ever examined the brain of a patient with AD, it is evident that the disease is not simply an amyloidosis. AD is a multi-neuronal system disconnection syndrome of unknown etiology, with pronounced selective cell loss, synaptic dysfunction, atrophy, vascular pathology, tau pathology, in addition to intracellular Aβ disturbances and extracellular amyloid deposition, among other problems that may yet be discovered. It is not our intention to advocate any singular hypothesis of AD, rather to suggest that other treatment approaches and modalities should be pursued with a solid federal and private funding base in addition to amyloid-based clinical trials. An effective treatment will ultimately be a poly-pharmaceutical approach that targets both mechanisms underlying neurodegeneration as well as symptoms of cognitive decline until the etiology of AD is revealed.

References:
Forman, M.S. Mufson, E.J., Leurgans, S., Pratico, D., Joyce, S., Leight, S., Lee, V.M.-Y. and J.Q. Trojanowski: Cortical Biochemistry in MCI and Alzheimer Disease, Neurology, 68: 757-763, 2007. Abstract

Mufson, E. J., Chen, E-Y., Cochran, E. J., Beckett, L. A., Bennett, D. A. and Kordower, J. H.: Entorhinal cortex beta amyloid load in individuals with mild cognitive impairment. Exp. Neurol., 158, 469-490, 1999. Abstract

Counts, S.E. and Mufson, E. J.: The role of nerve growth factor receptors in cholinergic basal forebrain degeneration in prodromal Alzheimer’s disease, J. Neuropath. Exper. Neurol., 64, 263-272, 2005. Abstract

View all comments by Stephen D. Ginsberg
View all comments by Elliott Mufson