Alzheimer's disease research
In April 2014 there were 315 open clinical trials under way to understand and treat Alzheimer's disease. 42 of these studies were open, human phase three trials, the last step before United States Food and Drug Administration (FDA) approval and marketing.
There are different approaches. One approach is to reduce amyloid beta, for example with bapineuzumab, an antibody in phase III studies for patients in mild to moderate stage; semagacestat, a γ-secretase inhibitor, MPC-7869; and acc-001 or CAD106, vaccines against amyloid beta. Other approaches are neuroprotective agents, like AL-108 (phase II completed); or metal-protein interaction attenuation, as is the case of PBT2 (phase II completed). Yet another approach is to use general cognitive enhancers, as may be the case for memantine, a pharmaceutical approved in the United States and European Union to treat moderate-to-severe AD. Finally, there are basic investigations on the origin and mechanisms of Alzheimer's disease.
- 1 Treatments in clinical development
- 1.1 Immunotherapy to amyloid beta
- 1.2 Metabolic correction
- 1.3 Other pharmaceuticals
- 2 Disease-modifying drug candidates
- 3 Non-Imaging biomarkers
- 4 References
Treatments in clinical development
Several potential treatments for Alzheimer's disease are under investigation, including several compounds being studied in phase 3 clinical trials. The most important clinical research is focused on potentially treating the underlying disease pathology, for which reduction of amyloid beta is a common target of compounds under investigation.
Immunotherapy to amyloid beta
Immunotherapy or vaccination for Alzheimer's stimulates the immune system to attack beta-amyloid. One approach is active immunization, which would stimulate a permanent immune response. The vaccine AN-1792 showed promise in mouse and early human trials, but in a 2002 Phase II trial, 6% of subjects (18 of 300) developed serious brain inflammation resembling meningoencephalitis, and the trial was stopped. In long-term followups, 20% of subjects had developed high levels of antibodies to beta-amyloid. While placebo-patients and non-antibody responders worsened, these antibody-responders showed a degree of stability in cognitive levels as assessed by the neuropsychological test battery (although not by other measures), and had lower levels of the protein tau in their cerebrospinal fluid. These results may suggest reduced disease activity in the antibody-responder group. Autopsies found that immunization resulted in clearance of amyloid plaques, but did not prevent progressive neurodegeneration.
A Phase IIA study of ACC-001, a modified version of AN-1792, is now recruiting subjects.
Also derived from the AN-1792 immunotherapy program, there is an infused antibody approach termed a passive vaccine in that it does not invoke the immune system and would require regular infusions to maintain the artificial antibody levels. Micro-cerebral hemorrhages may be a threat to this process.
The most advanced such candidate is known as bapineuzumab or aab-001, and this antibody is designed as essentially identical to the natural antibody triggered by the earlier AN-1792 vaccine. The aab-001 antibody is in Phase 3 clinical trials for both Apolipoprotein E4 gene carriers, and Apolipoprotein E4 gene non-carriers.
Gamma secretase inhibition
Gamma secretase modulation
Tarenflurbil (MPC-7869, formerly R-flubiprofen) is a gamma secretase modulator sometimes called a selective amyloid beta 42 lowering agent. It is believed to reduce the production of the toxic amyloid beta in favor of shorter forms of the peptide. Negative results were announced regarding tarenflurbil in July 2008 and further development was canceled.
Metal-protein interaction attenuation
PBT2 is an 8-hydroxy quinoline that removes copper and zinc from cerebrospinal fluid, which are held to be necessary catalysts for amyloid beta aggregation. This drug has been in a Phase II trial for early Alzheimers and which has reported preliminarily promising, but not detailed, results.
Simvastatin, a statin, stimulates brain vascular endothelial cells to create a beta-amyloid ejector. The use of this statin may have a causal relationship to decreased development of the disease.
This approach is based on the prominent aspect of Alzheimer's disease, which is common for many other neurodegenerative diseases: energy deficit. It has first been noted for the case of insulin insufficiency in the brain of Alzheimer's patients. Because of that Alzheimer's disease has been called "Type 3 diabetes"  and the insulin modification therapies are in pharmaceutical's pipelines.
Several other pharmaceuticals are under investigation to treat Alzheimer's disease.
Allopregnanolone has been identified as a potential drug agent. Levels of neurosteroids such as allopregnanolone decline in the brain in old age and AD. Allopregnanolone has been shown to aid the neurogenesis that reverses cognitive deficits in a mouse model of AD.
Angiotensin receptor blockers
A retrospective analysis of five million patient records with the US Department of Veterans Affairs system found that different types of commonly used anti-hypertensive medications had very different AD outcomes. Those patients taking angiotensin receptor blockers (ARBs) were 35—40% less likely to develop AD than those using other anti-hypertensives.
Only one clinical trial is being done (at McMaster University) to investigate the efficacy of antibiotic therapy. The authors of the study indicated that it was effective in delaying the progress of the disease: "In conclusion, a 3-month course of doxycycline and rifampin reduced cognitive worsening at 6 months of follow-up in patients with mild to moderate AD." A re-examination of the same data using: "...AUC analysis of the pooled index showed significant treatment effect over the 12-month period".
Several studies using minocycline and doxycycline, in an animal model of Alzheimer's Disease, have indicated that minocycline and doxycycline exerts a protective effect in preventing neuron death and slowing the onset of the disease.
The endocannabinoid system may have a role in AD. For instance, THC, one of the active ingredients in marijuana, has been show to reduce amyloid beta plaque formation through inhibition of acetylcholinesterase (AChE).
Also in July 2008 results were announced of a study in which an antihistamine that was formerly available in Russia, Dimebon, was given to a group of AD patients. The group receiving Dimebon improved somewhat over the 6 months of the study (and this continued for the next six months), whereas those on placebo deteriorated. Unfortunately the consecutive phase-III trial failed to show significant positive effects in the primary and secondary endpoints. The sponsors acknowledged in March 2010 that initial results of the phase III trial showed that while the drug had been well tolerated, its outcomes did not significantly differ from the placebo control.
Insulin sensitizers and Intranasal insulin
Recent studies suggest an association between insulin resistance and AD (fat cell sensitivity to insulin can decline with aging): In clinical trials, a certain insulin sensitizer called "rosiglitazone" improved cognition in a subset of AD patients; in vitro, beneficial effects of Rosiglitazone on primary cortical rat neurons have been demonstrated. Initial research suggests intranasal insulin, increasing insulin levels in the brain with minimal insulin increase in the rest of the body, might also be utilized. Preclinical studies show that insulin clears soluble beta-amyloid from the brain within minutes after a systemic injection in diabetic transgenic mice modeling AD.
In July 2008, researchers announced positive results from methylthioninium chloride (MTC), (trade name: Rember) a drug that dissolved Tau polymers. Phase II results indicate that it is the first therapy that has success in modifying the course of disease in mild to moderate AD.
Originally considered an enigmatic protein, the sigma-1 receptor has been identified as a unique ligand-regulated molecular chaperone in the endoplasmic reticulum of cells. This discovery led to the review of many proposed roles of this receptor in many neurological diseases including Alzheimer's.
Disease-modifying drug candidates
|Target/Approach||Notes (Theoretical)||Candidate Name||Trial Phase||Trial Start Date||Expected End Date||Planned Enrollment||AD population targeted (severity)||AD population targeted (genetic)||Comments|
|Gamma Secretase Modulator/NSAID||Shifts amyloid beta production to shorter and less toxic species. Targets γ-secretase.||Flurizan (R-flurbiprofen, MPC-7869)||Phase III (completed)||Feb 2005||May 2008||1,600||Mild||n/a||Myriad Genetics concluded that the drug did not improve thinking ability or the ability of patients to carry out daily activities significantly more than those patients with placebo. Peter Meldrum, CEO of Myriad Genetics, announced on June 30, 2008 that the company will no longer be developing Flurizan|
|Gamma Secretase Inhibitor||Inhibits Gamma Secretase, which reduces amyloid beta levels||Semagacestat (LY450139)||Phase III (completed)||Sep 2008||Apr 2011||1,100||Mild-to-Moderate||n/a||On August 17, 2010, Eli Lilly announced that it "will halt development of semagacestat" as it "did not slow disease progression and was associated with worsening...cognition and the ability to perform activities of daily living." Also, it is "associated with an increased risk of skin cancer."|
|Antibody to amyloid beta||Mimics natural antibody triggered by AN-1792||Bapineuzumab (aab-001)||Phase III (completed)||Dec 2007||Apr 2012||1,121||Mild-to-Moderate||Apolipoprotein E4 Carriers only||On August 6, 2012, Pfizer and Johnson & Johnson said they are "ending development of an intravenous formulation" of bapineuzumab. Phase III trials "showed no treatment effect on either cognitive or functional outcomes. Biomarker analyses indicated that bapineuzumab engaged its target, but had no benefit."|
|Antibody to amyloid beta||Mimics natural antibody triggered by AN-1792||Bapineuzumab (aab-001)||Phase III (completed)||Dec 2007||Jun 2012||1,331||Mild-to-Moderate||Apolipoprotein E4 Non-Carriers only||On August 6, 2012, Pfizer and Johnson & Johnson said they are "ending development of an intravenous formulation" of bapineuzumab. Phase III trials "showed no treatment effect on either cognitive or functional outcomes. Biomarker analyses indicated that bapineuzumab engaged its target, but had no benefit."|
|Metal-Protein Interaction Attenuation||Primary targets are copper and zinc. Removes copper and zinc from cerebrospinal fluid.||PBT2 (8-hydroxy quinoline)||Phase II (completed)||Dec 2006||Dec 2007||80||Early Alzheimer's disease||n/a||"Did not meet its primary endpoint of a statistically significant reduction in the levels of beta-amyloid plaques in the brains prodromal/mild Alzheimer's disease patients." "No improvement was observed on the secondary endpoints of brain metabolic activity, cognition and function; however, there was a trend towards preserving hippocampal brain volume". "Specifically, there was less atrophy relative to the placebo group."|
|Fibrilization of amyloid beta||Breaks down neurotoxic fibrils, allowing amyloid peptides to clear the body rather than form amyloid plaques.||ELND005 (AZD-103, scyllo-Inositol)||Phase II (completed)||Dec 2007||May 2010||353||Mild-to-Moderate||n/a||Phase I produced encouraging results by August 2007. In December 2009, Elan and Transition jointly reported that the Phase II study has been modified so that only the 250 mg twice daily dose will be continued due to "greater rates of serious adverse events, including nine deaths," in the higher dose groups (1000 mg and 2000 mg dosed twice daily). It has received fast track designation from the U.S. FDA.|
|Neuroprotection||Neuroprotective Peptide, intra-nasal||AL-108||Phase II (completed)||Jan 2007||Jan 2008||120||Mild Cognitive Impairment||n/a||Deemed a Success; Phase III to start|
|Brain Cell Apoptosis Inhibitor||Operates through multiple mechanisms: Blocks the action of neurotoxic beta-amyloid proteins and inhibits L-type calcium channels, modulates the action of AMPA and NMDA glutamate receptors, may exert a neuroprotective effect by blocking a novel target that involves mitochondrial pores, and blocks a number of other receptors, including α-adrenergic, 5-HT2C, 5-HT5A, and 5-HT6||Dimebon (Latrepirdine)||Phase II (completed)||Sep 2006||Nov 2007 (actual)||183||Mild-to-Moderate||n/a||In March 2010, Pfizer announced that the Phase III CONNECTION trial failed to meet its primary and secondary endpoints. In January 2012, it was announced that the Phase III CONCERT study did not meet its co-primary endpoints. Both CONTACT and CONSTELLATION trials were terminated. Medivation and Pfizer discontinued development of dimebon and thus decided to end their co-development and marketing collaboration.|
|Natural Antibodies to amyloid beta||human plasma source limits supply||IVIg||Phase II (completed)||Feb 2006||June 2007||24||Mild-to-Moderate||n/a||Deemed a Success; Phase III to start|
|Vaccine to amyloid beta||Injects modified amyloid beta (active vaccine)||acc-001||Phase II||Nov 2007||Mar 2012||228||Mild-to-Moderate||n/a||Sequel to famous AN-1792 Vaccine Trial|
Recent studies have shown that people with AD had decreased glutamate (Glu) as well as decreased Glu/creatine (Cr), Glu/myo-inositol (mI), Glu/N-acetylaspartate (NAA), and NAA/Cr ratios compared to normal people. Both decreased NAA/Cr and decreased hippocampal glutamate may be an early indicator of AD.
Early research using a small cohort of Alzheimer's disease patients may have identified autoantibody markers for AD. The applicability of these markers is unknown.
A small human study in 2011 found that monitoring blood dehydroepiandrosterone (DHEA) variations in response to an oxidative stress could be a useful proxy test: the subjects with MCI did not have a DHEA variation, while the healthy controls did.
- "Clinical Trials. Found 1404 studies with search of: alzheimer". U.S National Institutes of Health. Retrieved 2014-04-24.
- Dodel r, Neff F, Noelker C, Pul R, Du Y, Bacher M Oertel W.; Neff; Noelker; Pul; Du; Bacher; Oertel (2010). "Intravenous Immunoglobulins as a Treatment for Alzheimer's Disease: Rationale and Current Evidence". Drugs 70 (5): 513–528. doi:10.2165/11533070-000000000-00000. PMID 20329802.
- Gilman S et al. (2005). "Clinical effects of A-beta immunization (AN1792) in patients with AD in an interrupted trial". Neurology 64 (9): 1553–1562. doi:10.1212/01.WNL.0000159740.16984.3C. PMID 15883316.
- Hawkes CA, McLaurin J; McLaurin (2007). "Immunotherapy as treatment for Alzheimer's disease". Expert Reviews of Neurotherapy 7 (11): 1535–1548. doi:10.1586/1473722.214.171.1245. PMID 17997702.
- Solomon B (2007). "Clinical immunologic approaches for the treatment of Alzheimer's disease". Expert Opin Investig Drugs 16 (6): 819–828. doi:10.1517/135437126.96.36.1999. PMID 17501694.
- Woodhouse A, Dickson TC, Vickers JC; Dickson; Vickers (2007). "Vaccination strategies for Alzheimer's disease: A new hope?". Drugs Aging 24 (2): 107–119. doi:10.2165/00002512-200724020-00003. PMID 17313199.
- Holmes C, Boche D, Wilkinson D et al. (19 July 2008). "Long-term effects of Abeta42 immunisation in Alzheimer's disease: follow-up of a randomised, placebo-controlled phase I trial". Lancet 372 (9634): 180–2. doi:10.1016/S0140-6736(08)61075-2. PMID 18640458.
- "Study Evaluating ACC-001 in Mild to Moderate Alzheimers Disease Subjects". Clinical Trial. FDA/clinicaltrials.gov. 2008-03-11.
- Kitazawa M, Vasilevko V, Cribbs DH, LaFerla FM; Vasilevko; Cribbs; Laferla (13 May 2009). "Immunization with amyloid-β attenuates inclusion body myositis-like myopathology and motor impairment in a transgenic mouse model". The Journal of Neuroscience 29 (19): 6132–41. doi:10.1523/JNEUROSCI.1150-09.2009. PMC 3049190. PMID 19439591. Lay summary. "Inclusion body myositis...features include T-cell mediated inflammatory infiltrates and aberrant accumulations of proteins, including amyloid-β (Aβ), tau, ubiquitinated proteins, apolipoprotein E, and β-synuclein in skeletal muscle. ... active immunization markedly reduces intracellular Aβ deposits and attenuates the motor impairment compared with untreated mice...Aβ oligomers contribute to the myopathy process as they were significantly reduced in the affected skeletal muscle from immunized mice. In addition, the anti-Aβ antibodies produced in the immunized mice blocked the toxicity of the Aβ oligomers in vitro, providing a possible key mechanism for the functional recovery."
- "Bapineuzumab in Patients With Mild to Moderate Alzheimer's Disease/ Apo_e4 carriers". Clinical Trial. FDA/clinicaltrials.gov. 2008-02-29.
- "Bapineuzumab in Patients With Mild to Moderate Alzheimer's Disease/ Apo_e4 non-carriers". Clinical Trial. FDA/clinicaltrials.gov. 2008-02-29.
- "Effect of LY451039 on the Long Term Progression of Alzheimer's Disease". Clinical Trial. FDA/clinicaltrials.gov. 2008-01-11.
- Galasko DR, Graff-Radford N, May S, Hendrix S, Cottrell BA, Sagi SA, Mather G, Laughlin M, Zavitz KH, Swabb E, Golde TE, Murphy MP, Koo EH; Graff-Radford; May; Hendrix; Cottrell; Sagi; Mather; Laughlin; Zavitz; Swabb; Golde; Murphy; Koo (2007). "Safety, tolerability, pharmacokinetics, and Abeta levels after short-term administration of R-flurbiprofen in healthy elderly individuals". Alzheimer Disease and Associated Disorders 21 (4): 292–9. doi:10.1097/WAD.0b013e31815d1048. PMID 18090435.
- Eriksen JL, Sagi SA, Smith TE, Weggen S, Das P, McLendon DC, Ozols VV, Jessing KW, Zavitz KH, Koo EH, Golde TE; Sagi; Smith; Weggen; Das; McLendon; Ozols; Jessing; Zavitz; Koo; Golde (2003). "NSAIDs and enantiomers of flurbiprofen target gamma-secretase and lower Abeta 42 in vivo". J. Clin. Invest. 112 (3): 440–9. doi:10.1172/JCI18162. PMC 166298. PMID 12897211.
- Christensen DD (2007). "Alzheimer's disease: progress in the development of anti-amyloid disease-modifying therapies". CNS Spectrum 12 (2): 113–116, 119–123. PMID 17277711.
- Strozyk D, Launer LJ, Adlard PA et al. (2007). "Zinc and copper modulate Alzheimer Abeta levels in human cerebrospinal fluid". Neurobiol Aging 30 (7): 1069–77. doi:10.1016/j.neurobiolaging.2007.10.012. PMC 2709821. PMID 18068270.
- Whitfield JF (2007). "The road to LOAD: late-onset Alzheimer's disease and a possible way to block it". Expert Opinion on Therapeutic Targets 11 (10): 1257–1260. doi:10.1517/14728188.8.131.527. PMID 17907956.
- Li G, Larson EB, Sonnen JA, Shofer JB, Petrie EC, Schantz A, Peskind ER, Raskind MA, Breitner JC, Montine TJ; Larson; Sonnen; Shofer; Petrie; Schantz; Peskind; Raskind; Breitner; Montine (2007). "Statin therapy is associated with reduced neuropathologic changes of Alzheimer disease". Neurology 69 (9): 878–85. doi:10.1212/01.wnl.0000277657.95487.1c. PMID 17724290.
- de la Monte, S. M., Tong, M., Lester-Coll, N., Plater, Jr, M., & Wands, J. R. (2006). Therapeutic rescue of neurodegeneration in experimental type 3 diabetes: relevance to Alzheimer's disease. Journal of Alzheimer's Disease, 10(1), 89-109.
- Marx, C, Trost, W, Shampine, L, Stevens, R, Hulette, C, Steffens, D, Ervin, J, Butterfield, M et al. (December 2006). "The Neurosteroid Allopregnanolone Is Reduced in Prefrontal Cortex in Alzheimer's Disease". Biological Psychiatry 60 (12): 1287–94. doi:10.1016/j.biopsych.2006.06.017. PMID 16997284.
- Wang, JM, Singh, C, Liu, L, Irwin, RW, Chen, S, Chung, EJ, Thompson, RF, Brinton, RD. (2010). "Allopregnanolone reverses neuron and cognitive deficits in a mouse model of Alzheimer's disease". Proceedings of the National Academy of Sciences of the United States of America 107 (14): 6498–6503. doi:10.1073/pnas.1001422107. PMC 2851948. PMID 20231471.
- "Angiotensin receptor blockers are lower incidence, progression of Alzheimer's disease"
- http://clinicaltrials.gov/ct2/results?term=antibiotic&recr=&rslt=&type=&cond=%22Alzheimer+Disease%22&intr=&outc=&lead=&spons=&id=&state1=&cntry1=&state2=&cntry2=&state3=&cntry3=&locn=&gndr=&rcv_s=&rcv_e=&lup_s=&lup_e= clinicaltrials.gov
- Loeb MB, Molloy DW, Smieja M et al. (March 2004). "A randomized, controlled trial of doxycycline and rifampin for patients with Alzheimer's disease". J Am Geriatr Soc 52 (3): 381–387. doi:10.1111/j.1532-5415.2004.52109.x. PMID 14962152.
- Carusone SC, Goldsmith CH, Smieja M, Loeb M; Goldsmith; Smieja; Loeb (April 2006). "Summary measures were a useful alternative for analyzing therapeutic clinical trial data". J Clin Epidemiol 59 (4): 387–392. doi:10.1016/j.jclinepi.2005.05.009. PMID 16549261.
- Choi Y, Kim HS, Shin KY et al. (November 2007). "Minocycline attenuates neuronal cell death and improves cognitive impairment in Alzheimer's disease models". Neuropsychopharmacology 32 (11): 2393–2404. doi:10.1038/sj.npp.1301377. PMID 17406652.
- Hunter CL, Quintero EM, Gilstrap L, Bhat NR, Granholm AC; Quintero; Gilstrap; Bhat; Granholm (June 2004). "Minocycline protects basal forebrain cholinergic neurons from mu p75-saporin immunotoxic lesioning". Eur. J. Neurosci. 19 (12): 3305–16. doi:10.1111/j.0953-816X.2004.03439.x. PMID 15217386.
- Jankowsky JL, Slunt HH, Gonzales V et al. (December 2005). "Persistent amyloidosis following suppression of Abeta production in a transgenic model of Alzheimer disease". PLoS Med. 2 (12): e355. doi:10.1371/journal.pmed.0020355. PMC 1283364. PMID 16279840.
- Khlistunova I, Biernat J, Wang Y et al. (January 2006). "Inducible expression of Tau repeat domain in cell models of tauopathy: aggregation is toxic to cells but can be reversed by inhibitor drugs". J. Biol. Chem. 281 (2): 1205–1214. doi:10.1074/jbc.M507753200. PMID 16246844.
- Wozniak M, Mee A, Itzhaki R; Mee; Itzhaki (2008). "Herpes simplex virus type 1 DNA is located within Alzheimer's disease amyloid plaques". J Pathol 217 (1): 131–138. doi:10.1002/path.2449. PMID 18973185.
- Benito C, Núñez E, Pazos MR, Tolón RM, Romero J; Núñez; Pazos; Tolón; Romero (August 2007). "The endocannabinoid system and Alzheimer's disease". Mol Neurobiol 36 (1): 75–81. doi:10.1007/s12035-007-8006-8. PMID 17952652.
- Campbell VA, Gowran A; Gowran (November 2007). "Alzheimer's disease; taking the edge off with cannabinoids?". Br J Pharmacol 152 (5): 655–62. doi:10.1038/sj.bjp.0707446. PMC 2190031. PMID 17828287.
- Eubanks LM, Rogers CJ, Beuscher AE 4th, Koob GF, Olson AJ, Dickerson TJ, Janda KD; Rogers; Beuscher Ae; Koob; Olson; Dickerson; Janda (Nov–Dec 2006). "A molecular link between the active component of marijuana and Alzheimer's disease pathology". Mol Pharm 3 (6): 773–777. doi:10.1021/mp060066m. PMC 2562334. PMID 17140265.
- Doody RS, Gavrilova SI, Sano M, Thomas RG, Aisen PS, Bachurin SO, Seely L, Hung D; dimebon investigators (2008). "Effect of dimebon on cognition, activities of daily living, behaviour, and global function in patients with mild-to-moderate Alzheimer's disease: a randomised, double-blind, placebo-controlled study". The Lancet 372 (9634): 207–15. doi:10.1016/S0140-6736(08)61074-0. PMID 18640457.
- Dimebon Disappoints in Phase 3 Trial
- "Pfizer And Medivation Announce Results From Two Phase 3 Studies In Dimebon (latrepirdine*) Alzheimer's Disease Clinical Development Program" (Press release). Business Wire. 3 March 2010.
- Tobinick E (2007). "Perispinal etanercept for treatment of Alzheimer's disease". Curr Alzheimer Res 4 (5): 550–2. doi:10.2174/156720507783018217. PMID 18220520.
- "Amgen Statement on Alzheimer's Case Study". Amgen. Retrieved 18 September 2014.
- Steven Novella (May 8, 2013). "Enbrel for Stroke and Alzheimer’s". Science Based Medicine. Retrieved 18 September 2014.
- Watson GS, Cholerton BA, Reger MA, Baker LD, Plymate SR, Asthana S, Fishel MA, Kulstad JJ, Green PS, Cook, Kahn et al. (2005). "Preserved cognition in patients with early Alzheimer disease and amnestic mild cognitive impairment during treatment with rosiglitazone: a preliminary study". Am J Geriatr Psychiatry 13 (11): 950–958. doi:10.1176/appi.ajgp.13.11.950. PMID 16286438.
- Risner ME, Saunders AM, Altman JFB, Ormandy GC, Craft S, Foley IM, Zvartau-Hind ME, Hosford DA, Roses AD; Saunders; Altman; Ormandy; Craft; Foley; Zvartau-Hind; Hosford; Roses; Rosiglitazone in Alzheimer's Disease Study Group (2006). "Efficacy of rosiglitazone in a genetically defined population with mild-to-moderate Alzheimer's disease". Pharmacogenomics J 6 (4): 246–254. doi:10.1038/sj.tpj.6500369. PMID 16446752.
- Brodbeck J, Balestra M, Saunders A, Roses A, Mahley R, Huang Y; Balestra; Saunders; Roses; Mahley; Huang (2008). "Rosiglitazone increases dendritic spine density and rescues spine loss caused by apolipoprotein E4 in primary cortical neurons". Proceedings of the National Academy of Sciences of the United States of America 105 (4): 1343–1346. doi:10.1073/pnas.0709906104. PMC 2234140. PMID 18212130.
- "Alzheimer's 'is brain diabetes'". BBC News. 2009-02-03.[unreliable medical source?]
- Freiherr, J; Hallschmid, M; Frey, WH 2nd; Brünner, YF; Chapman, CD; Hölscher, C; Craft, S; De Felice, FG; Benedict, C (Jul 2013). "Intranasal insulin as a treatment for Alzheimer's disease: a review of basic research and clinical evidence". CNS Drugs 27 (7): 505–14. doi:10.1007/s40263-013-0076-8. PMC 3709085. PMID 23719722.
- Vandal, M; White, PJ; Tremblay, C, et al. et al. (2014). "Insulin Reverses the High-Fat Diet-Induced Increase in Brain Aβ and Improves Memory in an Animal Model of Alzheimer Disease". Diabetes. doi:10.2337/db14-0375. PMID 25008180.
- Afrezza, a New Inhaled Insulin, Is Approved by the F.D.A
- Wischik CM, Bentham P, Wischik DJ, Seng KM; Bentham; Wischik; Seng (July 2008). "Tau aggregation inhibitor (TAI) therapy with Rember arrests disease progression in mild and moderate Alzheimer's disease over 50 weeks". Alzheimer's & Dementia 4 (4S): T167. doi:10.1016/j.jalz.2008.05.438.
- Bulic, B; Pickhardt, M; Schmidt, B; Mandelkow, EM; Waldmann, H; Mandelkow, E (2009). "Development of tau aggregation inhibitors for Alzheimer's disease". Angewandte Chemie (International ed. in English) 48 (10): 1740–52. doi:10.1002/anie.200802621. PMID 19189357.
- "Sigma Receptors". Anavex Life Sciences Corporation. Retrieved June 27, 2012.
- Maurice, T., & Su, T.-P.; Su (2009). "The pharmacology of sigma-1 receptors". Pharmacology & Therapeutics 124 (2): 195. doi:10.1016/j.pharmthera.2009.07.001.
- "Researchers Closer to Alzheimer's Prevention, Treatment". Bioscience Technology. 2013-05-22. Retrieved 2013-05-26.
- Barron, A. M.; Garcia-Segura, L. M.; Caruso, D.; Jayaraman, A.; Lee, J. -W.; Melcangi, R. C.; Pike, C. J. (2013). "Ligand for Translocator Protein Reverses Pathology in a Mouse Model of Alzheimer's Disease". The Journal of Neuroscience 33 (20): 8891–8897. doi:10.1523/JNEUROSCI.1350-13.2013. PMID 23678130.
- "Efficacy Study of MPC-7869 to Treat Patients With Alzheimer's". Clinical Trial. FDA/clinicaltrials.gov. 2005-03-15.
- "Myriad Genetics Reports Results of U.S. Phase 3 Trial of Flurizan™ in Alzheimer's Disease". Myriad Genetics. 2008-06-30.
- "Effects of LY450139, on the Progression of Alzheimer's Disease as Compared With Placebo (IDENTITY-2)". Clinical Trial. FDA/clinicaltrials.gov. 2008-09-26.
- "Lilly Halts Development of Semagacestat for Alzheimer's Disease Based on Preliminary Results of Phase III Clinical Trials". investor.lilly.com. 2010-08-17.
- "Bapineuzumab in Patients With Mild to Moderate Alzheimer's Disease (ApoE4 Carrier)". Clinical Trial. FDA/clinicaltrials.gov.
- "J&J, Pfizer to drop intravenous Alzheimer's drug". businessweek.com. 2012-08-06.
- "Bapineuzumab". alzforum.org.
- "Bapineuzumab in Patients With Mild to Moderate Alzheimer's Disease (ApoE4 Non-Carrier)". Clinical Trial. FDA/clinicaltrials.gov.
- "Study Evaluating the Safety, Tolerability and Efficacy of PBT2 in Patients With Early Alzheimer's Disease". Clinical Trial. FDA/clinicaltrials.gov.
- "Prana Biotechnology announces preliminary results of Phase 2 IMAGINE trial of PBT2 in Alzheimer's disease". prnewswire.com.
- "ELND005 in Patients With Mild to Moderate Alzheimer's Disease". Clinical Trial. FDA/clinicaltrials.gov. 2011-09-27.
- "RPT-UPDATE 2-Elan, Transition drop top drug doses after deaths". reuters.com.
- "FDA Grant Fast Track Designation to ELND005 for the Treatment of Neuropsychiatric Symptoms in Alzheimer's Disease". prnewswire.com.
- "Safety, Tolerability and Efficacy Study to Evaluate Subjects With Mild Cognitive Impairment". Clinical Trial. FDA/clinicaltrials.gov. 2008-03-11.
- Lermontova, N. N., Redkozubov, A. E., Shevtsova, E. F., Serkova, T. P., Kireeva, E. G., Bachurin, S. O.; Redkozubov; Shevtsova; Serkova; Kireeva; Bachurin (Nov 2001). "Dimebon and Tacrine Inhibit Neurotoxic Action of b-Amyloid in Culture and Block L-type Ca2+ Channels". Bulletin of Experimental Biology and Medicine 132 (5): 1079–1083. doi:10.1023/A:1017972709652. PMID 11865327.
- Grigor'ev V. V., Dranyi O. A., Bachurin S. O.; Dranyi; Bachurin (Nov 2003). "Comparative Study of Action Mechanisms of Dimebon and Memantine on AMPA- and NMDA-Subtypes Glutamate Receptors in Rat Cerebral Neurons". Bulletin of Experimental Biology and Medicine 136 (5): 474–477. doi:10.1023/B:BEBM.0000017097.75818.14. PMID 14968164.
- BACHURIN, S. O., SHEVTSOVA, E. P., KIREEVA, E. G., OXENKRUG, G. F. and SABLIN, S. O. (May 2003). "Mitochondria as a Target for Neurotoxins and Neuroprotective Agents". Annals of the New York Academy of Sciences 993: 334–344. doi:10.1111/j.1749-6632.2003.tb07541.x. PMID 12853325.
- Wu J., Li Q., Bezprozvanny I.; Li; Bezprozvanny (Oct 2008). "Evaluation of Dimebon in cellular model of Huntington's disease". Molecular Neurodegeneration 3: 15. doi:10.1186/1750-1326-3-15. PMC 2577671. PMID 18939977.
- "Double-Blind, Placebo-Controlled Study of Oral Dimebon in Subjects With Mild to Moderate Alzheimer's Disease". Clinical Trial. FDA/clinicaltrials.gov. 2007-12-27.
- "Pfizer And Medivation Announce Results From Two Phase 3 Studies In Dimebon (latrepirdine*) Alzheimer's Disease Clinical Development Program". medivation.com. 2010-03-03.
- "Medivation and Pfizer Announce Results from Phase 3 Concert Trial of Dimebon in Alzheimer's Disease". medivation.com. 2012-01-17.
- "Pfizer, Medivation Nix Development of Alzheimer Disease Therapy". genengnews.com. 2012-01-17.
- "Phase II Study of Intravenous Immunoglobulin (IVIg) for Alzheimer's Disease". Clinical Trial. FDA/clinicaltrials.gov. 2007-08-03.
- Rupsingh R, Borrie M, Smith M, Wells JL, Bartha R. Reduced Hippocampal Glutamate in Alzheimer Disease. Neurobiol Aging. 2009;32(5):802–810. doi:10.1016/j.neurobiolaging.2009.05.002. PMID 19501936.(primary source)
- Reddy MM, Wilson R, Wilson J, Connell S, Gocke A, Hynan L, German D, Kodadek T. Identification of Candidate IgG Antibody Biomarkers for Alzheimer's Disease Through Screening of Synthetic Combinatorial Libraries. Cell. 2011;144(1):132–42. doi:10.1016/j.cell.2010.11.054. PMID 21215375. (primary source)
- Rammouz G, Lecanu L, Aisen P, Papadopoulos V. A Lead Study on Oxidative Stress-mediated Dehydroepiandrosterone Formation in Serum: The Biochemical Basis for a Diagnosis of Alzheimer's Disease. J Alzheimers Dis. 2011-01-01;24(1):5–16. doi:10.3233/JAD-2011-101941. PMID 21335661. (primary source)
- Leidinger, P.; Backes, C.; Deutscher, S.; Schmitt, K.; Muller, S. C.; Frese, K.; Haas, J.; Ruprecht, K.; Paul, F.; Stahler, C.; Lang, C. J.; Meder, B.; Bartfai, T.; Meese, E.; Keller, A. (2013). "A blood based 12-miRNA signature of Alzheimer disease patients". Genome Biology 14 (7): R78. doi:10.1186/gb-2013-14-7-r78. PMID 23895045.