Neurology -- Correspondence for Tan et al., 68 (22) 1902-1908

Correspondence published:

Inflammatory markers and the risk of Alzheimer disease: The Framingham Study: Edward L. Tobinick (20 August 2007)

Inflammatory markers and the risk of Alzheimer disease: The Framingham Study: Daniel L. Menkes, Memphis, TN 38163 (20 August 2007)

Reply from the authors: Zaldy S. Tan, M.D., M.P.H. (20 August 2007)

Inflammatory markers and the risk of Alzheimer disease: The Framingham Study 20 August 2007

Edward L. Tobinick,
Assistant Clinical Professor of Medicine, UCLA
100 UCLA Medical Plaza, Suite 205, Los Angeles, California 90095
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Re: Inflammatory markers and the risk of Alzheimer disease: The Framingham Study

etmd{at}ucla.edu Edward L. Tobinick

I commend Tan et al whose excellent study provides substantial scientific support for the inflammatory hypothesis of AD and specifically suggests that patients whose peripheral blood mononuclear cells produce higher levels of the pro-inflammatory cytokine TNF-alpha may have an increased AD risk. [1]
The authors have avoided the necessity of taking serial CSF samples by using a surrogate marker of TNF-alpha, its production by peripheral blood mononuclear cells. This technique may have traversed the fact that large molecules such as TNF-alpha have difficulty in crossing the blood-brain barrier, although in the case of TNF-alpha there may be a modest degree of crossing due to the existence of active transport mechanisms. [2]
This study joins an increasing body of scientific evidence implicating excess TNF- alpha in the pathogenesis of AD, which now includes robust genetic evidence, new basic science data, and a pilot study examining the effect of a novel method of administration of the anti-TNF biologic, etanercept, in AD. [3-4]. A new study suggests that CNS synaptic function may be subject to regulation by the immune system, including TNF-alpha. [5]. It is possible that if excess TNF-alpha is present in the brain in AD (a fact which is not established, but only suggested by the present study), the excess TNF-alpha may contribute to the synaptic dysfunction that may be a component of AD pathology.
The authors also discuss that non- steroidal anti-inflammatory agents have not proven to prevent AD disease progression. This may be viewed as evidence against the inflammatory hypothesis of AD. Furthermore, it could then be argued that since NSAIDS are also unable to prevent the progression of rheumatoid arthritis, then RA is not an inflammatory disease. Since this is not the case, it is possible that NSAIDS are neither sufficiently potent nor sufficiently selective to successfully intervene in AD mechanisms.
In view of the increasing scientific evidence, further study of biologic anti-TNF agents in AD should be undertaken and perhaps these agents will be as beneficial in AD as they have in RA.
References
1 Tan, ZS, Beiser, AS, Vasan RS et al. Inflammatory markers and the risk of Alzheimer disease: The Framingham Study Neurology 2007; 68: 1902-1908.
2. Banks WA, Kastin AJ, Broadwell RD. Passage of cytokines across the blood-brain barrier. Neuroimmunomodulation 1995;2:241-248.
3. Ramos EM, Lin MT, Larson EB et al. Tumor necrosis factor alpha and interleukin 10 promoter region polymorphisms and risk of late-onset Alzheimer disease. Arch Neurol 2006; 63:1165-1169.
4. Tobinick E, Gross H, Weinberger A, Cohen H. TNF-alpha modulation for treatment of Alzheimer's disease: a 6-month pilot study. Medscape General Medicine 2006;8:25.
5. Goddard CA, Butts DA, Shatz CJ, Regulation of CNS synapses by neuronal MHC class I. Proc Natl Acad Sci U S A, 2007; 104: 6828-6833.
Disclosure: The author has disclosed that he has multiple issued and pending patents which detail methods of use of etanercept and other biologic TNF antagonists for the treatment of Alzheimer's Disease and other neurological disorders, including, but not limited to, U.S. patents 6015557, 6177077, 6419934, 6419944, 6537549, 6982089, and 7214658. The author has received royalties for these patents in excess of $10,000/year. In addition, the author owns stock in Amgen, the manufacturer of the biologic TNF-antagonist etanercept, and in Abbott Laboratories, the manufacturer of the biologic TNF-antagonist adalimumab.
The authors of the article were offered the opportunity to respond but declined.

Inflammatory markers and the risk of Alzheimer disease: The Framingham Study 20 August 2007

Daniel L. Menkes,
University of Tennessee Health Sciences Center at Memphis
855 Monroe Avenue, Link Building, Room 415,
Memphis, TN 38163
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Re: Inflammatory markers and the risk of Alzheimer disease: The Framingham Study

dmenkes{at}utmem.edu Daniel L. Menkes, et al.

Tan et al should be commended for another significant contribution of the Framingham Study to the epidemiology of prevalent diseases. [1] This study provides statistical evidence that supports the role of inflammation in the pathophysiology of Alzheimer's disease (AD). They conclude by stating that these findings ought to be "hypothesis generating." In this vein, I would hypothesize that frequent blood donation would reduce the risk for AD by removing peptides, proteinaceous waste products and cytokines.
No organism can recycle all materials used in normal metabolic function. While many protein waste products can be deaminated and broken into moieties that can be excreted, some products will be degraded into amyloid that will remain in the bloodstream. Over time, these peptide and protein waste products may lead to accumulation in various organs including the brain. One result may be the development of cerebral amyloid angiopathy, a disorder with many features in common with AD. [2] A similar pathophysiology may be involved in the generation of AD.
A report published over 40 years ago observed that a single unit donation had no effect on serum protein levels whereas serum protein depletion did occur after five days of plasmapheresis. [3] However, this study did not address the effect of blood donation on cytokines which are a group of proteins and peptides. Furthermore, it has been proposed that cytokines derived from donor blood may be responsible for a significant number of non-antibody-mediated transfusion reactions. [4]
One advantage of blood donation is that these insoluble protein products and inflammatory may be removed in the process. Therefore, patients who donate blood frequently may reduce the total amount of amyloid precursor protein (APP) and the Interleukin 1 that has a role in regulating APP's synthesis. [5]
If the authors have this information perhaps they can assess the risk of developing AD with the amount of blood donated. I would predict that the risk of developing AD is inversely proportional to the amount of blood donated over a person�s lifetime.
References
1. Tan, ZA, Beiser, AS, Vasan, RS et al. Inflammatory markers and the risk of Alzheimer disease: The Framingham Study. NEUROLOGY 2007:68;1902-1908
2. Vinters HV. Cerebral Amyloid Angiopathy: A Critical Review. Stroke 1987; 18:311-324.
3. Kliman A, Carbone PP, Gaydos LA, Freireich EJ. Effect of intensive plasmapheresis on normal blood donors. Blood 1964; 23:647-656.
4. Weisbach V, Wanke C, Zingsem J, Zimmermann R, Eckstein R. Cytokine generation in whole blood, leukocyte-depleted and temporarily warmed red blood cell concentrates. Vox Sanguinis 1999; 76:100-106.
5. Goldgaber D, Harris HW, Hla T, Maciag T, Donnelly RJ, Jacobsen JS et al. Interleukin 1 regulates synthesis of amyloid �-protein precursor mRNA in human endothelial cells. PNAS 1989; 7606-7610.
Disclosure: The authors report no conflicts of interest.

Reply from the authors 20 August 2007

Zaldy S. Tan, M.D., M.P.H.,
Hebrew Senior Life Department of Medicine
1200 Centre Street, Boston, MA 02131
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Re: Reply from the authors

ztan{at}hms.harvard.edu Zaldy S. Tan, M.D., M.P.H.

We thank the Dr. Menkes et al for their interest in our report and for their interesting hypothesis. We do not have systematic data on the blood donation habits of Framingham Study participants and hence we can neither support not refute the author�s hypothesis. However, while our study found a relationship between peripheral blood mononuclear cell (PBMC) production of cytokines and the risk of AD, we found no such relationship between serum cytokines concentrations and incident AD.
Disclosure: The author reports no conflicts of interest.