This elegant and important study finds an association between a rare APP variant and a lower risk of AD, and it provides strong evidence to suggest that the protective effects of this variant may be attributable to reductions in BACE1-mediated APP cleavage. This study provides additional support for the amyloid hypothesis and the potential role of BACE1 inhibitors in the preclinical treatment of AD. It also illustrates the potential value of whole-genome sequencing studies, when used in conjunction with relevant basic scientific research, to advance the understanding of AD and the discovery of promising investigational treatments.

This study only adds to the interest that my Alzheimer's Prevention Initiative (API) colleagues, other researchers, and I have in the possibility of evaluating suitable BACE1 inhibitors (and related agents) in persons at increased risk of developing AD, and our interest in learning more about safety, tolerability, and certain other effects in clinically affected patients. We see particular value in the possibility of evaluating anti-amyloid...  Read more

This elegant and important study finds an association between a rare APP variant and a lower risk of AD, and it provides strong evidence to suggest that the protective effects of this variant may be attributable to reductions in BACE1-mediated APP cleavage. This study provides additional support for the amyloid hypothesis and the potential role of BACE1 inhibitors in the preclinical treatment of AD. It also illustrates the potential value of whole-genome sequencing studies, when used in conjunction with relevant basic scientific research, to advance the understanding of AD and the discovery of promising investigational treatments.

This study only adds to the interest that my Alzheimer's Prevention Initiative (API) colleagues, other researchers, and I have in the possibility of evaluating suitable BACE1 inhibitors (and related agents) in persons at increased risk of developing AD, and our interest in learning more about safety, tolerability, and certain other effects in clinically affected patients. We see particular value in the possibility of evaluating anti-amyloid production treatments like these in ApoE4 carriers and young adult PS1 mutation carriers, since these agents might have the best chance to exert a profound benefit if started before the accumulation of significant fibrillar amyloid.

View all comments by Eric M. Reiman

I agree with the comments underlying the importance of this paper, which supports the pathogenic role of APP processing by BACE in sporadic AD. As noted in many comments, these findings also suggest that inhibition of BACE processing of APP will be a beneficial therapeutic approach for both familial and sporadic AD. Perhaps, this treatment may also improve performance in elderly with no obvious cognitive deficiency. BACE1 inhibitors may, however, have toxic effects related to the important biological functions of BACE processing of other substrates. Therefore, as noted by Dr. Tanzi, "inhibitors might need to be selective for APP in order to be safe enough for such long-term use." Interestingly, a molecule with these features has been recently described—MoBA, Modulator of Β-processing of APP (Tamayev et al., 2012), and may represent a leading compound to develop drugs that interfere with BACE1 processing of APP without inhibiting the proteolytic activity of BACE1 on the other substrates.

However, contrary to what is said by many, I do not think that the finding validates or...  Read more

I agree with the comments underlying the importance of this paper, which supports the pathogenic role of APP processing by BACE in sporadic AD. As noted in many comments, these findings also suggest that inhibition of BACE processing of APP will be a beneficial therapeutic approach for both familial and sporadic AD. Perhaps, this treatment may also improve performance in elderly with no obvious cognitive deficiency. BACE1 inhibitors may, however, have toxic effects related to the important biological functions of BACE processing of other substrates. Therefore, as noted by Dr. Tanzi, "inhibitors might need to be selective for APP in order to be safe enough for such long-term use." Interestingly, a molecule with these features has been recently described—MoBA, Modulator of Β-processing of APP (Tamayev et al., 2012), and may represent a leading compound to develop drugs that interfere with BACE1 processing of APP without inhibiting the proteolytic activity of BACE1 on the other substrates.

However, contrary to what is said by many, I do not think that the finding validates or confirms the amyloid cascade hypothesis. Reduction of β-processing of APP will first result in a reduction of sAPPβ and β-CTFs. Therefore, this finding is also consistent with alternative hypotheses of AD pathogenesis which point to sAPPβ and/or β-CTFs, and not Aβ, as the main pathogenic APP-derived metabolites (Tamayev et al., 2012; Nikolaev et al., 2009; Tamayev and D'Adamio, 2012).

References:
1. Tamayev R, Matsuda S, Arancio O, D'Adamio L (2012) β- but not gamma-secretase proteolysis of APP causes synaptic and memory deficits in a mouse model of dementia. EMBO Mol Med 4:171-179. Abstract

2. Nikolaev A, McLaughlin T, O'Leary DD, Tessier-Lavigne M (2009) APP binds DR6 to trigger axon pruning and neuron death via distinct caspases. Nature 457:981-9. Abstract

3. Tamayev R, D'Adamio L (2012) Inhibition of gamma-secretase worsens memory deficits in a genetically congruous mouse model of Danish dementia. Mol Neurodegener 7:19. Abstract

View all comments by Luciano D'Adamio

New APP Mutation Does Not Advance the Amyloid Hypothesis Debate
In response to the question, Does β amyloid accumulation drive Alzheimer’s disease?, the answer is “most likely no,” and the new data presented by Jonsson et al. does not change that answer.

That the amyloid hypothesis inadequately accounts for the current data has been known for some time. It lacks a theoretical foundation from which the physiological generation of Aβ can be understood, and therapeutic approaches based on its premises have all failed. Furthermore, there is no significant correlation between Aβ accumulation and cognitive deterioration in either humans or in mouse models, and Aβ-containing senile plaques have been found in the brains of approximately 30 percent of individuals with no signs of dementia (Crystal et al., 1988; Price et al., 2009).

This does not necessarily indicate that Aβ is not a key factor in AD. The weakness of the amyloid hypothesis is not that it links Aβ and AD, but rather that it places Aβ as the key pathogenic trigger of the disease and, accordingly, ought...  Read more

New APP Mutation Does Not Advance the Amyloid Hypothesis Debate
In response to the question, Does β amyloid accumulation drive Alzheimer’s disease?, the answer is “most likely no,” and the new data presented by Jonsson et al. does not change that answer.

That the amyloid hypothesis inadequately accounts for the current data has been known for some time. It lacks a theoretical foundation from which the physiological generation of Aβ can be understood, and therapeutic approaches based on its premises have all failed. Furthermore, there is no significant correlation between Aβ accumulation and cognitive deterioration in either humans or in mouse models, and Aβ-containing senile plaques have been found in the brains of approximately 30 percent of individuals with no signs of dementia (Crystal et al., 1988; Price et al., 2009).

This does not necessarily indicate that Aβ is not a key factor in AD. The weakness of the amyloid hypothesis is not that it links Aβ and AD, but rather that it places Aβ as the key pathogenic trigger of the disease and, accordingly, ought to be the main target for therapeutic purposes. To date, all the available evidence—including clinical drug trials—indicates that this is an increasingly unlikely scenario.

Rather, the hypothesis that best fits the current body of evidence in the AD field, including the work by Jonsson et al., is that Aβ is a key element of the brain’s adaptive response to stress. The idea of an adaptive response to stress in the brain, in the context of both aging and AD pathogenesis, has been put forward in various forms by scientists including George Perry, Mark Smith, Karl Herrup, and others (Stranahan et al., 2011; Stranahan and Mattson, 2012; Nunomura et al., 2001; Pappolla et al., 2002; Castellani et al., 2009; Herrup, 2010; Castello and Soriano, 2012). The idea is that failure of this adaptive response, or its chronic activation, is what leads to sporadic AD, instead of overproduction of Aβ itself. The nature of that stress in the brain is wide ranging, encompassing microglia activation, accumulation of reactive oxygen species, and cholesterol dysregulation, and the adaptive response it elicits involves regulation of APP through its cleavage products, including Aβ and sAPPα (Castello and Soriano, 2012; Stranahan and Mattson, 2012; Castellani et al., 2009).

In the case of the A673T mutation, all other factors being comparable, the combination of lesser Aβ levels, changes in APP-driven cholesterol regulation, and/or higher levels of sAPPα would all result in a more efficient adaptive response, accounting for the delay in AD age of onset described by Jonsson et al. (Castello and Soriano, 2012). Note also that the A673T mutation, creating a stronger adaptive response, is also consistent with the superior performance in cognitive tests of patients with the mutation. Mutation carriers retain cognitive ability for a longer period of time even when they do develop AD, as is visually demonstrated by the supplementary figures in Jonsson et al.

Overall, the message is that we should not rush back into the race to find the best BACE inhibitors to fight AD, as many commentators and scientists have suggested here and in the media. The line of inquiry involving BACE biology in AD has been in progress for over a decade, with negative outcomes, recent examples of which appear in the sidebar next to this very article (ARF related news story; ARF news story).

We need to reassess the way we approach research in the AD field. Instead of continuing a never-ending search for the elusive final proof that the amyloid hypothesis is correct, we should begin first by restructuring AD diagnosis to focus on symptomatic changes rather than the neuropathological identification of amyloid plaques, as has been suggested (Dubois et al., 2010). The pathological process of AD suggests variations of the same stress response. Therefore, our research should focus on the primary issue—the sources of stress that create a need for the adaptive response involving APP and Aβ.

References:
Nunomura A, Perry G, Aliev G, Hirai K, Takeda A, Balraj EK, Jones PK, Ghanbari H, Wataya T, Shimohama S, Chiba S, Atwood CS, Petersen RB, Smith MA. Oxidative damage is the earliest event in Alzheimer disease. J Neuropathol Exp Neurol. 2001 Aug;60(8):759-67. Abstract

Dubois B, Feldman HH, Jacova C, Cummings JL, Dekosky ST, Barberger-Gateau P, Delacourte A, Frisoni G, Fox NC, Galasko D, Gauthier S, Hampel H, Jicha GA, Meguro K, O'brien J, Pasquier F, Robert P, Rossor M, Salloway S, Sarazin M, de Souza LC, Stern Y, Visser PJ, Scheltens P. Revising the definition of Alzheimer's disease: a new lexicon. Lancet Neurol. 2010 Nov;9(11):1118-27. Abstract

Herrup K. Reimagining Alzheimer's disease--an age-based hypothesis. J Neurosci. 2010 Dec 15;30(50):16755-62. Abstract

Price JL, McKeel DW, Buckles VD, Roe CM, Xiong C, Grundman M, Hansen LA, Petersen RC, Parisi JE, Dickson DW, Smith CD, Davis DG, Schmitt FA, Markesbery WR, Kaye J, Kurlan R, Hulette C, Kurland BF, Higdon R, Kukull W, Morris JC. Neuropathology of nondemented aging: presumptive evidence for preclinical Alzheimer disease. Neurobiol Aging. 2009 Jul;30(7):1026-36. Abstract

Stranahan AM, Cutler RG, Button C, Telljohann R, Mattson MP. Diet-induced elevations in serum cholesterol are associated with alterations in hippocampal lipid metabolism and increased oxidative stress. J Neurochem. 2011 Aug;118(4):611-5. Abstract

Stranahan AM, Mattson MP. Recruiting adaptive cellular stress responses for successful brain ageing. Nat Rev Neurosci. 2012 Mar;13(3):209-16. Abstract

Castellani RJ, Lee HG, Siedlak SL, Nunomura A, Hayashi T, Nakamura M, Zhu X, Perry G, Smith MA. Reexamining Alzheimer's disease: evidence for a protective role for amyloid-beta protein precursor and amyloid-beta. J Alzheimers Dis. 2009;18(2):447-52. Abstract

Pappolla MA, Smith MA, Bryant-Thomas T, Bazan N, Petanceska S, Perry G, Thal LJ, Sano M, Refolo LM. Cholesterol, oxidative stress, and Alzheimer's disease: expanding the horizons of pathogenesis. Free Radic Biol Med. 2002 Jul 15;33(2):173-81. Abstract

Crystal H, Dickson D, Fuld P, Masur D, Scott R, Mehler M, Masdeu J, Kawas C, Aronson M, Wolfson L. Clinico-pathologic studies in dementia: nondemented subjects with pathologically confirmed Alzheimer's disease. Neurology. 1988 Nov;38(11):1682-7. Abstract

View all comments by Michael Castello
View all comments by Salvador Soriano
View all comments by Matthew Zabel

This is a nice finding by Jonsson et al., and adds more evidence to the idea published in 2009 by an Italian group that changes to this amino acid position in APP can prevent or facilitate aggregation of human Aβ.

It seems that amino acids at position 2 of hAβ with larger side chains than alanine may prevent aggregation. Di Fede showed that a transition, A2V, in Aβ was protective in heterozygotes, whereas homozygotic individuals had a higher risk in the studied family tree.

They also presented aggregation profiles of pure and mixed Aβ species that nicely supported the aggregation idea. Thus, the question remains whether it is indeed a BACE-related mechanism or just an aggregation problem of these Aβ species due to stereology. In our hands, cerebral injection and chronic infusion of A2V Aβ1-6 peptides reduced plaque formation in mice. That could be exploited as a treatment option (unpublished data).

As we know, mouse Aβ is different in three amino acids at the N-terminal, and these differences completely prevent plaque formation and fibril generation in mice.

References:
Di Fede G, Catania M, Morbin M, Rossi G, Suardi S, Mazzoleni G, Merlin M, Giovagnoli AR, Prioni S, Erbetta A, Falcone C, Gobbi M, Colombo L, Bastone A, Beeg M, Manzoni C, Francescucci B, Spagnoli A, Cantù L, Del Favero E, Levy E, Salmona M, Tagliavini F. A recessive mutation in the APP gene with dominant-negative effect on amyloidogenesis. Science. 2009 Mar 13;323(5920):1473-7. Abstract

Giaccone G, Morbin M, Moda F, Botta M, Mazzoleni G, Uggetti A, Catania M, Moro ML, Redaelli V, Spagnoli A, Rossi RS, Salmona M, Di Fede G, Tagliavini F. Neuropathology of the recessive A673V APP mutation: Alzheimer disease with distinctive features. Acta Neuropathol. 2010 Dec;120(6):803-12. Abstract

View all comments by Jens Pahnke

This study provides elegant genetic evidence that reducing the BACE processing of APP protects against late-onset AD. The finding complements the long-standing observations that increased BACE processing (APPswe mutation or elevated BACE levels [1]) enhances the risk for AD.

What gets ignored in ensuing discussions, however, is the fact that BACE processing of APP generates not only Aβ peptides, but also β-CTFs and AICD peptides (studies from three groups show that BACE processing enhances AICD generation and signaling [2-4]). Since both β-CTF and AICD cause AD-like pathological features in vivo in mouse models (5,6), the present study is consistent with, but cannot be claimed to support, the amyloid hypothesis (the causal role of Aβ in AD).

Nonetheless, this study is important because it identifies a unique human population (A673T carriers) that can be used to further validate neuroimaging (PIB imaging) and CSF biomarkers. Indeed, it will be very informative to see whether biomarker changes in this population appear at the same time as in the non-carriers or are...  Read more

This study provides elegant genetic evidence that reducing the BACE processing of APP protects against late-onset AD. The finding complements the long-standing observations that increased BACE processing (APPswe mutation or elevated BACE levels [1]) enhances the risk for AD.

What gets ignored in ensuing discussions, however, is the fact that BACE processing of APP generates not only Aβ peptides, but also β-CTFs and AICD peptides (studies from three groups show that BACE processing enhances AICD generation and signaling [2-4]). Since both β-CTF and AICD cause AD-like pathological features in vivo in mouse models (5,6), the present study is consistent with, but cannot be claimed to support, the amyloid hypothesis (the causal role of Aβ in AD).

Nonetheless, this study is important because it identifies a unique human population (A673T carriers) that can be used to further validate neuroimaging (PIB imaging) and CSF biomarkers. Indeed, it will be very informative to see whether biomarker changes in this population appear at the same time as in the non-carriers or are significantly delayed.

References:
1. Zhao J, Fu Y, Yasvoina M, Shao P, Hitt B, O'Connor T, Logan S, Maus E, Citron M, Berry R, Binder L, Vassar R. Beta-site amyloid precursor protein cleaving enzyme 1 levels become elevated in neurons around amyloid plaques: implications for Alzheimer's disease pathogenesis. J Neurosci. 2007 Apr 4;27(14):3639-49. Abstract

2. Goodger ZV, Rajendran L, Trutzel A, Kohli BM, Nitsch RM, Konietzko U. Nuclear signaling by the APP intracellular domain occurs predominantly through the amyloidogenic processing pathway. J Cell Sci. 2009 Oct 15;122(Pt 20):3703-14. Abstract

3. Belyaev ND, Kellett KA, Beckett C, Makova NZ, Revett TJ, Nalivaeva NN, Hooper NM, Turner AJ. The transcriptionally active amyloid precursor protein (APP) intracellular domain is preferentially produced from the 695 isoform of APP in a {beta}-secretase-dependent pathway. J Biol Chem. 2010 Dec 31;285(53):41443-54. Abstract

4. Tian Y, Crump CJ, Li YM. Dual role of alpha-secretase cleavage in the regulation of gamma-secretase activity for amyloid production. J Biol Chem. 2010 Oct 15;285(42):32549-56. Abstract

5. Berger-Sweeney J, McPhie DL, Arters JA, Greenan J, Oster-Granite ML, Neve RL. Impairments in learning and memory accompanied by neurodegeneration in mice transgenic for the carboxyl-terminus of the amyloid precursor protein. Brain Res Mol Brain Res. 1999 Mar 20;66(1-2):150-62. Abstract

6. Ghosal K, Vogt DL, Liang M, Shen Y, Lamb BT, Pimplikar SW. Alzheimer's disease-like pathological features in transgenic mice expressing the APP intracellular domain. Proc Natl Acad Sci U S A. 2009 Oct 27;106(43):18367-72. Abstract

View all comments by Sanjay W. Pimplikar

What could possibly go wrong with the use of BACE inhibitors for the prevention or treatment of AD?

The latest flurry of results from pharmaceutical companies showing that BACE inhibitors reduce the levels of amyloid-β in the brain has led to a renewed wave of optimism that this approach may lead to an effective treatment for AD, possibly even a cure. This optimism has been amplified by the recent report of a mutation in the APP gene, A673T, that reduces BACE activity and protects against AD (Jonsson et al., 2012).

We have recently suggested that there is a plausible explanation for the effect of the APP A673T mutation on AD rates that goes beyond the conventional wisdom of “less Aβ protects, more Aβ harms” involving a fine-tuning effect on Aβ levels by the A673T mutation that improves the adaptive response of APP to AD-causing brain stress (Castello and Soriano, 2012). In other words, there is likely a range of Aβ that optimizes the adaptive response of APP to brain stress, and the A673T mutation helps to maintain Aβ levels within that range.

It is very unlikely...  Read more

What could possibly go wrong with the use of BACE inhibitors for the prevention or treatment of AD?

The latest flurry of results from pharmaceutical companies showing that BACE inhibitors reduce the levels of amyloid-β in the brain has led to a renewed wave of optimism that this approach may lead to an effective treatment for AD, possibly even a cure. This optimism has been amplified by the recent report of a mutation in the APP gene, A673T, that reduces BACE activity and protects against AD (Jonsson et al., 2012).

We have recently suggested that there is a plausible explanation for the effect of the APP A673T mutation on AD rates that goes beyond the conventional wisdom of “less Aβ protects, more Aβ harms” involving a fine-tuning effect on Aβ levels by the A673T mutation that improves the adaptive response of APP to AD-causing brain stress (Castello and Soriano, 2012). In other words, there is likely a range of Aβ that optimizes the adaptive response of APP to brain stress, and the A673T mutation helps to maintain Aβ levels within that range.

It is very unlikely that any laboratory-led BACE manipulation may result in a better therapeutic outcome than what this mutation provides. Indeed, a reduction in Aβ levels through BACE inhibition that is too dramatic would compromise Aβ physiological function and have a catastrophic impact on neuronal function, even if there were no fears of potential BACE side effects, which is also an unlikely scenario (see, e.g., note of caution by Weihong Song above).

Overall, everything we know very strongly suggests that inhibiting BACE activity in the brain to treat AD may not be the most sensible way forward.

References:
Jonsson et al. A mutation in APP protects against Alzheimer’s disease and age-related cognitive decline. Nature. 2000;488 ;96–99. Abstract

Castello MA, Soriano S. Rational heterodoxy: Cholesterol reformation of the amyloid doctrine. Ageing Res Rev. 2012 Jul 6. Abstract

View all comments by Michael Castello
View all comments by Salvador Soriano
View all comments by Matthew Zabel

BACE1 inhibition is an important potential theurapeutic arm of the β amyloid clearance phenomenon in Alzheimer's which needs to be realized clinically.

However, another BACE1 inhibitor, minocycline, which is also neuroprotective and is already an approved therapeutic agent, is now undergoing trials in cognitively normal individuals and patients with mild cognitive impairment (MCI) or Alzheimer's disease (AD) at Huntington Medical Research Institute. Patients and controls will undergo clinical screening, neuropsychological tests, blood and urine analyses, quantitative magnetic resonance imaging (MRI), and 1H and 13C magnetic resonance spectroscopy (MRS). Each individual will receive minocycline oral administration for four weeks initially, after which MRI, MRS, and neuropsych results will be recorded. If no adverse side effects occur, subjects will continue minocycline administration for an additional five months.

A study by Ferretti demonstrated recently that minocycline corrects early, pre-plaque neuroinflammation and inhibits BACE1 in a transgenic model of Alzheimer's...  Read more

BACE1 inhibition is an important potential theurapeutic arm of the β amyloid clearance phenomenon in Alzheimer's which needs to be realized clinically.

However, another BACE1 inhibitor, minocycline, which is also neuroprotective and is already an approved therapeutic agent, is now undergoing trials in cognitively normal individuals and patients with mild cognitive impairment (MCI) or Alzheimer's disease (AD) at Huntington Medical Research Institute. Patients and controls will undergo clinical screening, neuropsychological tests, blood and urine analyses, quantitative magnetic resonance imaging (MRI), and 1H and 13C magnetic resonance spectroscopy (MRS). Each individual will receive minocycline oral administration for four weeks initially, after which MRI, MRS, and neuropsych results will be recorded. If no adverse side effects occur, subjects will continue minocycline administration for an additional five months.

A study by Ferretti demonstrated recently that minocycline corrects early, pre-plaque neuroinflammation and inhibits BACE1 in a transgenic model of Alzheimer's disease-like amyloid pathology (Ferretti et al., 2012).

There are a small group of Alzforum members who are interested in the emerging role of pathogens in Alzheimer's disease, and feel that β amyloid clearance problems may be the result of pathogenic inflammation (spirochetal) with and without viruses.

Chronic spirochetal infection can cause slowly progressive dementia, cortical atrophy, and amyloid deposition in the atrophic form of general paresis. There is a significant association between Alzheimer's disease (AD) and various types of spirochetes (including the periodontal pathogen Treponemas and Borrelia burgdorferi), and other pathogens such as Chlamydophyla pneumoniae and herpes simplex virus type 1 (Miklossy, 2011). Miklossy’s lab at the University Medical School (CHUV), Lausanne, Switzerland, exposed mammalian glia and neuronal cells in vitro to Borrelia burgdorferi spirochetes and bacterial lipopolysaccharides. Morphological changes analogous to amyloid deposits were observed at two to eight weeks' exposure. Increased levels of β amyloid precursor protein and hyperphosphorylated tau were detected by Western blot (Miklossy et al., 2004).

Seven out of 10 brains from the Harvard McLean Brain Bank were positive for Borrelia DNA. Alan MacDonald demonstrated this, and feels “Borrelia burgdorferi infection is the root cause of at least 70 percent of Alzheimer's disease, based on the detection of positive in-situ DNA hybridization results in the cytoplasmic granulovacuolar bodies of hippocampal neurons (with no positive signals detected in the nucleus) for flagellin B DNA sequences of Borrelia burgdorferi" (MacDonald, 2007).

A randomized controlled trial of doxycycline and rifampin for patients with Alzheimer’s disease demonstrated that cognitive decline was statistically improved in the treatment arm over placebo (Loeb et al., 2004).

Minocycline protected basal forebrain cholinergic neurons from murine-p75-saporin immunotoxic lesioning in animal models (Hunter et al., 2004). Minocycline attenuates neuronal cell death and improves cognitive impairment in Alzheimer’s disease models (Choi et al., 2007). Minocycline does not affect amyloid-β phagocytosis by human microglia cells. Minocycline attenuates the release of TNF-α by human microglia upon exposure to Aβ, SAP, and C1q (Familian et al., 2007).

Moderate magnetic field therapy (0.5 Tesla) in 15 Alzheimer’s patients was demonstrated by this author in 2006 on the hypothesis that the outer protein of the Borrelia burgdorferi bacteria is strongly electron-negatively charged and will be repelled by the negative pole of a 0.5 Tesla electromagnet below and a positive pole above the patient's head. Cognition improved. However, this improvement was gradually lost from several weeks to six months in these patients in an open-label, IRB-approved pilot study. All patients had moderate to severe Alzheimer's disease (Nichols et al., 2006).

The mechanism may also be related to crosstalk between SMF and IL-6, as well as the upregulation or downregulation of over 2,600 genes (Wang et al., 2009).

References:
Ferretti MT, Allard S, Partridge V, Ducatenzeiler A, Cuello AC. Minocycline corrects early, pre-plaque neuroinflammation and inhibits BACE-1 in a transgenic model of Alzheimer's disease-like amyloid pathology. J Neuroinflammation. 2012;9:62. Abstract

Miklossy J. Emerging roles of pathogens in Alzheimer disease. Expert Rev Mol Med. 2011;13:e30. Abstract

Miklossy J, Khalili K, Gern L, Ericson RL, Darekar P, Bolle L, Hurlimann J, Paster BJ. Borrelia burgdorferi persists in the brain in chronic lyme neuroborreliosis and may be associated with Alzheimer disease. J Alzheimers Dis. 2004 Dec;6(6):639-49; discussion 673-81. Abstract

MacDonald AB. Alzheimer's neuroborreliosis with trans-synaptic spread of infection and neurofibrillary tangles derived from intraneuronal spirochetes. Med Hypotheses. 2007;68(4):822-5. Abstract

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. A randomized, controlled trial of doxycycline and rifampin for patients with Alzheimer's disease. J Am Geriatr Soc. 2004 Mar;52(3):381-7. Abstract

Hunter CL, Quintero EM, Gilstrap L, Bhat NR, Granholm AC. Minocycline protects basal forebrain cholinergic neurons from mu p75-saporin immunotoxic lesioning. Eur J Neurosci. 2004 Jun;19(12):3305-16. Abstract

Choi Y, Kim HS, Shin KY, Kim EM, Kim M, Kim HS, Park CH, Jeong YH, Yoo J, Lee JP, Chang KA, Kim S, Suh YH. Minocycline attenuates neuronal cell death and improves cognitive impairment in Alzheimer's disease models. Neuropsychopharmacology. 2007 Nov;32(11):2393-404. Abstract

Familian A, Eikelenboom P, Veerhuis R. Minocycline does not affect amyloid beta phagocytosis by human microglial cells. Neurosci Lett. 2007 Apr 6;416(1):87-91. Abstract

Nichols et al. Medical Hypothesis; elctromagnetic field therapy using Magnetic Molecular Energising (MME) and Antibiotic Therapy: A Pilot Study. 31/01/2006. E pub; European Biology and Bioelectromagnetics.

Wang Z, Sarje A, Che PL, Yarema KJ. Moderate strength (0.23-0.28 T) static magnetic fields (SMF) modulate signaling and differentiation in human embryonic cells. BMC Genomics. 2009;10:356. Abstract

View all comments by Trent Nichols