Editors' Blog

What is Aβ?

The search to find therapeutic targets in Alzheimer's disease (AD) has been dominated for over 25 years by research into the roles in the initiation and progression of dementia of the amyloid beta protein (Aβ) [1, 2], derived from the β-pathway of amyloid beta protein (AβPP) cleavage.

Last comment on 1 May 2018 by Sally Hunter

Alzheimer’s Disease Research: A Modern Version of the Parable of the Blind Men and an Elephant

An ancient Indian subcontinent parable tells a story in which a group of blind men each touch a different part of an elephant. They cannot agree on the nature of the elephant because none of them observed the elephant as a whole.

Dr. Oskar Fischer’s Mysterious Little Alzheimer’s Germ

Alois Alzheimer might have mentioned plaques and tangles in a single short paper on pre-senile dementia in 1907, but it was the co-discover of Alzheimer’s disease (AD), Oskar Fischer, who in that same year far more extensively reported neuritic plaque in 12 cases of senile dementia, a condition which he and many others refused to differentiate from Alzheimer’s “pre-senile” dementia.

Last comment on 31 July 2018 by Lawrence Broxmeyer, MD

 

 Is the Antibiotic Rifampicin Protective against Alzheimer’s disease?

 

Certain ideas in medical research do not go away easily, and rather keep reappearing. One of these is the topic of the possible use of rifampicin in Alzheimer’s.

By 1984, de Beer [1], studying the relationship between a major rise in serum amyloid and having tuberculosis, also saw a rapid descent in amyloid in patients treated with anti-tubercular drugs. As an offshoot of de Beer’s work, Tomiyama [2] dissolved ß-amy­loid plaque with rifampicin, a first-line drug in the treatment of TB, and one of the few agents, to this day, which is able to dissolve amyloid plaque. And so by 2004, Anthony L Fink et al., working out of the University of California, Santa Cruz concluded that rifampicin also inhibits α-Synuclein fibrillation and disaggregates fibrils. Government trials followed which used inadequate amounts of rifampicin for an inadequate time [3]. Yet such trials could not rule out a therapeutic role for its use in mild to moderate AD and the authors encouraged more research in this area.

In the meanwhile, a 2012 Journal of Alzheimer’s disease study pointed also to the enhanced brain Amyloid-β clearance by rifampicin and caffeine as a possible protective mechanism against Alzheimer’s disease [4]. The possible role of mycobacterial disease, a prominent genus of Actinobacteria, has been described for Alzheimer’s [5-7].

Takami Tomiyama revisited the preventative properties of rifampicin in Alzheimer’s, this time with Umeda and others in 2016, reporting that rifampicin inhibited amyloid-β oligomerization and tau hyperphosphorylation in mouse models and improved their memory in the Morris water maze [8]. The findings in mouse models indicated that rifampicin could serve as a promising available medicine for the prevention of AD. It therefore once again became of interest whether rifampicin had such preventive effects in humans. Thus by June of 2017, Iizuka et al. set out to determine this in a study using 40 patients with mycobacterial disease in which dementia had not yet set in and yet who showed AD-like hypometabolism patterns under stereotaxic statistical analysis [9]. As an important offshoot of this study, besides addressing whether rifampicin had preventative effects with Alzheimers, Iizuka’s raw data showed that in his two groups [Group A and Group B] of elderly patients with mycobacterial disease –approximately 46% of those in Group A showed Alzheimer’s type hypometabolism while in Group B approximately 55% showed AD-like hypometabolism. This averages out to slightly over half of the patients with mycobacterial disease showing AD-like hypometabolism on FDG-PET.

To examine whether rifampicin has such preventive effects in humans, Iizuka retrospectively reviewed FDG-PET scan findings of elderly patients with mycobacterial infection treated with rifampicin. For over 20 years, FDG-PET [also known as 18F-FDG-PET] has been used to measure cerebral metabolic rates of glucose (CMRglc), as a proxy for neuronal activity in AD. Many studies have shown that CMRglc reductions occur early in AD, both correlating with disease progression, and predicting histopathological diagnosis [10].

In their introduction Iizuka et al mention that Alzheimer disease (AD) is the most common cause of neurodegenerative dementia and is becoming increasingly common as the global population ages [11]. And that therefore, development of preventive therapy for the disease has been urgently needed. As both amyloid-β and tau were believed to play central roles in AD pathogenesis, they have been targets of disease-modifying therapy. However clinical studies of amyloid-β-targeting therapies in AD have revealed that the treatments after disease onset have little effect on the cognition of patients [12–14].

One presumable reason why rifampicin was not performing up to expectations in previous Alzheimer’s studies might be that the treatment of AD should have been started prior to the onset of clinical symptoms [15]. Also, rifampicin is an antibiotic, which is easy for mycobacterium to gain resistance to. To prevent the manifestation of resistance to rifampicin in mycobacterium, it should be administered with other anti-mycobacterial antibiotics as a combination therapy.

Rifampicin had been routinely administered at Iizuka’s hospital to treat mycobacterial infections such as tuberculosis (TB) and mycobacterium avium complex (MAC) for many years. Therefore, there had been accumulated data on patients treated with rifampicin, and almost half of the patients were elderly. In addition, a considerable number of the elderly patients had undergone 18F-FDG-PET including brain scans for various reasons since 2005 and since then investigators had occasionally encountered AD-type findings. Accordingly, the investigators retrospectively reviewed FDG-PET findings of elderly patients with mycobacterial infection that were treated with rifampicin and were not demented at the start of treatment to examine the preventive effects of rifampicin on the progression of AD.

Their results showed that before treatment, AD-type hypometabolism was observed in 12 patients. The FDG uptake in the posterior cingulate cortex (PCC) was improved or stabilized in 6 patients after 12-month therapy (450 mg/day), whereas another 6 patients with 6-month therapy showed a decreased FDG uptake in the PCC. In patients who underwent FDG-PET only after treatment, the metabolic decline in the PCC was significantly milder in patients with ≥12 months of rifampicin treatment than in those with 6 months of treatment. Multiple regression analysis revealed that the dose of rifampicin and treatment duration significantly influenced FDG uptake in the PCC.

Their conclusion was that the preventive effect of rifampicin depended on the dose and the treatment duration, and that the desired effect required at least 450 mg daily for 1 year.

By March 2018, still another rifampicin/Alzheimer’s study appeared on Medline, this one a multi-center probe, concluding, once again, that rifampicin exerts significant brain protective functions in multiple experimental Alzheimer’s models [16]. In this capacity rifampicin was found to have a neuroprotective and pro-cognitive effect that was mediated by its anti-inflammatory, anti-tau, and anti-amyloid effects. Beyond suggesting that rifampicin shows strong brain protective effects in preclinical models of Alzheimer's disease, Yulug et al also provided substantial clinical evidence for the neuroprotective and pro-cognitive effects of rifampicin. Again, further future neuroimaging studies combined with clinical assessment scores were suggested.  

Just where such research dealing with anti-mycobacterial, anti-tubercular agents like rifampacin will go, no one can definitively predict. But its mere persistence suggests a continued interest on the part of more than a few. 

Keywords: Alzheimer disease, FDG-PET, Rifampicin, Amyloid-β, Oligomer, Preventive therapy

REFERENCES

1. De Beer FC, Nel AE. Serum Amyloid A-Protein and C - reactive protein Levels in Pulmonary Tuberculosis: Relationship to Amyloidosis,” Thorax 30, no. 3 (1984):196–200.

2. Tomiyama T, Asano S, Suwa Y, Morita T, Kataoka K, Mori H, Endo N. Rifampicin prevents the aggregation and neurotoxicity of amyloid beta protein in vitro. Biochem Biophys Res Commun. 1994 Oct 14;204 (1):76-83.

3. Loeb MB, Molloy, DW, Smieja M, Standish T, Goldsmith CH, Mahony J, Smith S, Borrie M, Decoteau E, Davidson W, Mcdougall A, Gnarpe J, O'donnell M, Chernesky M. (2004), A Randomized, Controlled Trial of Doxycycline and Rifampin for Patients with Alzheimer's Disease. Journal of the American Geriatrics Society, 52: 381–387.

4. Qosa H, Abuznait AH, Hill RA, Kaddoumi A. Enhanced Brain Amyloid-β Clearance by Rifampicin and Caffeine as a Possible Protective Mechanism Against Alzheimer’s Disease. Journal of Alzheimer’s disease : JAD. 2012;31(1):151-165.

5. Broxmeyer L. Are the Infectious Roots of Alzheimer’s Buried Deep in the Past? J of MPE Mol Pathol Epidem 2017, Feb Vol 3 No S2:2: 1-19. http://molecular-pathological-epidemiology.imedpub.com/are-the-infectious-roots-of-alzheimersburied-deep-in-the-past.pdf 

6. Broxmeyer L. Dr. Oskar Fischer’s Curious Little Alzheimer’s Germ. Current Opinions in Neurological Science Vol 1 Issue 3 2017, Oct pp 160-178. https://scientiaricerca.com/srcons/SRCONS-01-00026.php

7. Broxmeyer L. Alzheimer's Disease –How Its Bacterial Cause Was Found and Then Discarded. CreateSpace Independent Publishing Platform (August 3, 2016). 190 pages. ISBN-10: 1491287357; ISBN-13: 978-1491287354.

8. Umeda T, Ono K, Sakai A, Yamashita M, Mizuguchi M, Klein WL, Yamada M, Mori H, Tomiyama T: Rifampicin is a candidate preventive medicine against amyloid-β and tau oligomers. Brain 2016; 139: 1568–1586.

9. Iizuka T, Morimoto K, Sasaki Y, et al. Preventive Effect of Rifampicin on Alzheimer Disease Needs at Least 450 mg Daily for 1 Year: An FDG-PET Follow-Up Study. Dementia and Geriatric Cognitive Disorders EXTRA. 2017;7(2):204-214.  https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5498941/

10. Mosconi L, Berti V, Glodzik L, Pupi A, De Santi S, de Leon MJ. Pre-Clinical Detection of Alzheimer’s Disease Using FDG-PET, with or without Amyloid Imaging. Journal of Alzheimer’s disease : JAD. 2010;20(3):843-854.

 11. Alzheimer’s Association: 2016 Alzheimer’s disease facts and figures. Alzheimers Dement 2016; 12: 459–509.

12. Iizuka T, Kameyama M: Cholinergic enhancement increases regional cerebral blood flow to the posterior cingulate cortex in mild Alzheimer’s disease. Geriatr Gerontol Int 2016, Epub ahead of print.

13. Iizuka T, Kameyama M: Cingulate island sign on FDG-PET is associated with medial temporal lobe atrophy in dementia with Lewy bodies. Ann Nucl Med 2016; 30: 421–429.

14. Molloy DW, Standish TI, Zhou Q, Guyatt G; DARAD Study Group: A multicenter, blinded, randomized, factorial controlled trial of doxycycline and rifampin for treatment of Alzheimer’s disease: the DARAD trial. Int J Geriatr Psychiatry 2013; 28: 463–470.

15. Sperling RA, Jack CR Jr, Aisen PS: Testing the right target and right drug at the right stage. Sci Transl Med 2011;3: 111cm33

16. Yulug B, Hanoglu L, Ozansoy M, Isık D, Kilic U, Kilic E, Schabitz WR. Therapeutic role of rifampicin in Alzheimer's disease. Psychiatry Clin Neurosci. 2018 Mar;72(3):152-159.

 

 

 

 

 

 

 

 

 

 

 

 

 

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Last comment on 14 April 2017 by Francis Hane, PhD

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Last comment on 15 April 2017 by Markku Kurkinen, PhD

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When do we diagnose severe Alzheimer's disease?

Among patients diagnosed with Alzheimer's disease (AD), the percentage in the severe stage ranges from 28% [1] to 33% [2] to a maximum of 50% [3]. In institutionalized patients, prevalence is higher, with an estimated 75% of patients with severe AD [4].

Last comment on 2 December 2016 by Maheen Adamson, PhD

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Last comment on 30 September 2016 by Thomas B. Shea, PhD

The case for a viral role in Alzheimer's disease

Most of us harbour in our body several types of herpes virus—perhaps as many as five—and we provide them with a safe and secluded haven for life, as there are no methods for eliminating or expelling them.

Last comment on 19 August 2016 by Brian Balin, PhD

Molecular Neuroresilience Biomarkers and the Prediction of Brain Health Across Lifespan

The ability to maintain normal psychological and physical functioning and avoid serious mental illness when exposed to stress and trauma, a phenomenon known as resilience, is a topic that has been investigated over the past several years with increasing attention [1,2].

Last comment on 5 August 2016 by Heather Snyder, Ph.D.

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Due to the aging of the population and to unhealthy lifestyle habits, age-related metabolic and neurodegenerative diseases are a growing and alarming problem around the globe.

Last comment on 23 May 2017 by Lawrence Broxmeyer, MD

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On this Fathers’ Day, June 19, 2016, I would like to share a revelation that I had in college, at the University of California, Berkeley, in the anti-war days of the late 1960s.

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Last comment on 29 April 2016 by Philip Scheltens, Prof.dr

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Alzheimer’s disease (AD) transgenic mice have been used as a standard model for AD drug discovery and basic mechanistic studies. These mouse models overexpress amyloid β precursor protein (APP) or APP/presenilin (PS) with single or multiple familial AD (FAD) mutations, which lead to excess accumulation of amyloid β (Aβ), a well-known driver for AD pathogenesis.

Last comment on 8 April 2016 by Christopher Navara

Early and Late Onset Alzheimer’s Disease: Two Different Entities?

The first case of Alzheimer’s disease (AD), a 51-year-old woman, was described in 1906. For several years, AD was assumed to be a rare form of presenile dementia.

Last comment on 19 February 2016 by Gianluigi Zanusso, Medical

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The microtubule-associated protein tau is mainly expressed within neurons where it performs its physiological function of microtubule stability. However, extracellular tau is found in models of tau overexpression in which neuronal degeneration and cell death is prominent.

Last comment on 8 January 2016 by Alejandra Alonso, PhD

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The field of Alzheimer research has reached an impasse after more than 100,000 clinical and scientific papers published in the last 40 years, because there is yet no hope, no effective treatment, and no knowledge of what causes this dementia.

Last comment on 24 November 2015 by Gustavo Román, MD, DrHC

Is There Alzheimer’s Disease?

Of course there is, but, as the expression goes, “It’s complicated”. Our contention is that Alzheimer’s is more of a disease of minds than a disease of brains.

Last comment on 5 February 2016 by J. Wesson Ashford, MD, PhD

Diagnosing Subjective Cognitive Impairment: A Non-Dementia Related Context

For most people, older adulthood is associated with some decline in memory and in some aspects of cognitive function. These are age-related changes [1] that are widely expected, understood, and accepted by the general public.

Last comment on 16 October 2015 by Amy Jenkins, MSc MSc PhD

Protecting Progress

Over the past few years there has been tremendous progress in diagnosis and therapeutic trials on Alzheimer’s disease (AD) and related dementias. Overall, the cost/benefit relationship is shifting with success.

Last comment on 21 October 2016 by Allyson Rosen, PhD, ABPP-CN

Depression in Alzheimer's Disease

Depression in Alzheimer’s disease (AD) has a substantial impact on disability, disease progression, and caregiver burden. Furthermore, depressive symptoms in normal aging, as well as in mild cognitive impairment (MCI), are associated with cognitive and functional decline.

Introducing the JAD Editors' Blog

Two hundred issues and nearly twenty years have positioned JAD at the center of printed and electronic peer-reviewed publications in Alzheimer's disease, as a venue that reflects the breadth of research in the field worldwide.

Last comment on 28 March 2017 by Lawrence Broxmeyer, MD