Alzheimer’s Disease: Dawn of a New Era?
Open accessAbstract
Alzheimer's disease (AD) is an irreversible neurodegenerative disease characterized by a progressive decline in cognition and memory, leading to significant impairment in daily activities and ultimately death. It is the most common cause of dementia, the prevalence of which increases with age; however, age is not the only predisposing factor. The pathology of this cognitive impairing disease is still not completely understood, which has limited the development of valid therapeutic options. Recent years have witnessed a wide range of novel approaches to combat this disease, so that they greatly increased our understanding of the disease and of the unique drug development issues associated with this disease. In this paper, we provide a brief overview of the history, the clinical presentation and diagnosis, and we undertake a comprehensive review of the various approaches that have been brought to clinical trials in recent years, including immunotherapeutic approaches, tau-targeted strategies, neurotransmitter-based therapies, neurotropic and hematopoietic growth factors, and antioxidant therapies, trying to highlight the lessons learned from these approaches. This article is open to POST-PUBLICATION REVIEW. Registered readers (see "For Readers") may comment by clicking on ABSTRACT on the issue's contents page.
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Dementia risk rises with toxic exposure to heavy metals such as lead, mercury, and aluminum.
“Dementia risk has been shown to rise with toxic exposure to heavy metals as lead, mercury, and aluminum [45,46,47,48].”
From Recent Advances in Therapeutics for the Treatment of Alzheimer’s Disease (2024) · cites this paper as [46]
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ResultA PHASE 2 MULTIPLE ASCENDING DOSE TRIAL OF BAPINEUZUMAB IN MILD TO MODERATE ALZHEIMER DISEASE
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MethodPhase 3 solanezumab trials: Secondary outcomes in mild Alzheimer's disease patients
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“Plasma/cerebrospinal fluid biomarker findings also indicated target engagement by solanezumab and the incidence of ARIA with edema or hemorrhage was not significantly different from placebo (67, 68).”
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A novel GSK-3β inhibitor reduces Alzheimer's pathology and rescues neuronal loss in vivo
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“It acts as an irreversible GSK-3β inhibitor that has been shown to reverse amyloid in brain and prevent cell loss and reduce spatial memory deficits in preclinical studies (106, 107).”
BackgroundThe car☐yl third of tau is tightly bound to paired helical filaments
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The Relation Between Antioxidants and Memory Performance in the Old and Very Old
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“However, BACE1 targeted drugdevelopment has been hindered, because the enzyme has been found to have many substrates with important physiological roles and initial nonselective inhibition of the enzyme was found to have numerous toxic consequences (76).”
BackgroundTreatment of Alzheimer's Disease with the GSK-3 Inhibitor Tideglusib: A Pilot Study
del Ser, T., Steinwachs, K. C., Gertz, H. J., Andrés, M. V., Gómez-Carrillo, B., Medina, M., Vericat, J. A., Redondo, P., Fleet, D., & León, T. (2012) · Journal of Alzheimer's Disease · doi:10.3233/jad-2012-120805 · Cited by 329 · cited 1× · see citing works
“Phase IIa studies in 30 patients reported good tolerability except for a transient increase in serum transaminase levels (108).”
BackgroundPlasma nutrient status of patients with Alzheimer's disease: Systematic review and meta‐analysis
da Silva, S. L., Vellas, B. J., Elemans, S., Luchsinger, J. A., Kamphuis, P. J. G. H., Yaffe, K. S., Sijben, J., Groenendijk, M., & Stijnen, T. (2013) · Alzheimer s & Dementia · doi:10.1016/j.jalz.2013.05.1771 · Cited by 311 · cited 1× · see citing works
“Metaanalysis studies indicate a lower level of vitamin B12 in AD patients (215), and a recent study indicates that administration of vitamin B12, along with other vitamins, selenium, and phospholipids could preserve synaptic function (216).”
BackgroundMuscarinic receptor subtypes in neuronal and non‐neuronal cholinergic function
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BackgroundEfficacy of Souvenaid in Mild Alzheimer's Disease: Results from a Randomized, Controlled Trial
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“Metaanalysis studies indicate a lower level of vitamin B12 in AD patients (215), and a recent study indicates that administration of vitamin B12, along with other vitamins, selenium, and phospholipids could preserve synaptic function (216).”
BackgroundSafety and biomarker effects of solanezumab in patients with Alzheimer's disease
Farlow, M. R., Arnold, S. E., van Dyck, C. H., Aisen, P. S. S., Snider, B. J., Porsteinsson, A. P., Friedrich, S. W., Dean, R. A., Gonzales, C., Sethuraman, G., et al. (2012) · Alzheimer s & Dementia · doi:10.1016/j.jalz.2011.09.224 · Cited by 280 · cited 1× · see citing works
“This later phase II trial showed no benefits in secondary clinical outcome measures and CSF and MRI biomarkers at the end of the 12week treatment period (66); however, it showed dose-dependent increases in unbound CSF Aβ1-42 suggesting that solanezumab may shift Aβ equilibria and mobilize Aβ1-42 from amyloid plaques.”
BackgroundLaske, C., Stransky, E., Leyhe, T., Eschweiler, G. W., Maetzler, W., Wittorf, A., Soekadar, S., Richartz, E., Koehler, N., Bartels, M., et al. (2007) · Journal of Psychiatric Research · doi:10.1016/j.jpsychires.2006.01.014 · Cited by 272 · cited 1× · see citing works
“Multiple studies have revealed a drop in BDNF levels in AD patients (156-159), while other reports indicate an increase in BNDF expression compared to control (160), which could be a compensatory repair mechanism during early stages of AD.”
ResultWischik, C. M., Staff, R. T., Wischik, D. J., Bentham, P., Murray, A. D., Storey, J. M. D., Kook, K. A., & Harrington, C. R. (2015) · Journal of Alzheimer's Disease · doi:10.3233/jad-142874 · Cited by 269 · see citing works
Cognitive impairment and vitamin B12: a review
Moore, E. M., Mander, A. G., Ames, D. J., Carne, R. P., Sanders, K. M., & Watters, D. A. (2012) · International Psychogeriatrics · doi:10.1017/s1041610211002511 · Cited by 265 · cited 1× · see citing works
“Vitamin B12: Low levels of vitamin B12 are shown to be associated with neurodegenerative disease and cognitive impairment (214).”
BackgroundStem cell factor stimulates neurogenesis in vitro and in vivo
Jin, K., Mao, X. O., Sun, Y., Xie, L., & Greenberg, D. A. (2002) · Journal of Clinical Investigation · doi:10.1172/jci15251 · Cited by 263 · cited 1× · see citing works
“Stem Cell Factor Stem cell factor (SCF) is a hematopoietin expressed in CNS that enhances neurogenesis (191).”
BackgroundTau-aggregation inhibitor therapy for Alzheimer's disease
Wischik, C. M., Harrington, C. R., & Storey, J. M. D. (2013) · Biochemical Pharmacology · doi:10.1016/j.bcp.2013.12.008 · Cited by 263 · see citing works
Beneficial action of resveratrol: How and why?
Díaz-Gerevini, G. T., Repossi, G., Daín, A., Tarrés, M. C., Das, U. N., & Eynard, A. R. (2015) · Nutrition · doi:10.1016/j.nut.2015.08.017 · Cited by 262 · cited 7× · see citing works
“Loss of BDNF function has been reported in neurodegenerative and psychiatric diseases (153, 154).”
BackgroundInfluentialTheunis, C., Crespo-Biel, N., Gafner, V., Pihlgren, M., López-Deber, M. P., Reis, P., Hickman, D. T., Adolfsson, O., Chuard, N., Ndao, D. M., et al. (2013) · PLoS ONE · doi:10.1371/journal.pone.0072301 · Cited by 259 · cited 1× · see citing works
“In pre-clinical studies it rapidly generated high titers of polyclonal IgG antibodies specifically directed against phosphorylated tau, rather than non-phosphorylated tau, reducing soluble tau as well as insoluble, aggregated tau in brain extracts (105).”
BackgroundThe multifaceted nature of amyloid precursor protein and its proteolytic fragments: friends and foes
Nhan, H. S., Chiang, K., & Koo, E. H. (2014) · Acta Neuropathologica · doi:10.1007/s00401-014-1347-2 · Cited by 256 · cited 1× · see citing works
“APP seems to be involved in neuronal plasticity and synapse formation (20).”
BackgroundJama, J. W., Launer, L. J., Witteman, J. C. M., den Breeijen, J. H., Breteler, M. M. B., Grobbee, D. E., & Hofman, A. (1996) · American Journal of Epidemiology · doi:10.1093/oxfordjournals.aje.a008922 · Cited by 252 · cited 1× · see citing works
“However, there have been reports on the positive effect of β-carotene on cognitive function (208), and a correlation between higher βcarotene plasma levels and memory in elderly individuals (65-94 years old) (209).”
BackgroundJones, C. K., Brady, A. E., Davis, A. A., Xiang, Z., Bubser, M., Tantawy, M. N., Kane, A. S., Bridges, T. M., Kennedy, J. P., Bradley, S. R., et al. (2008) · Journal of Neuroscience · doi:10.1523/jneurosci.1850-08.2008 · Cited by 248 · cited 1× · see citing works
“TBPB promotes the processing of APP towards the non- amyloidogenic pathway, decreases Aβ production in vitro, and has been shown to improve cognition in animal models (122).”
BackgroundKontseková, E., Žilka, N., Kováčech, B., Novák, P., & Novák, M. (2014) · Alzheimer s Research & Therapy · doi:10.1186/alzrt278 · Cited by 248 · cited 1× · see citing works
“An extra N-terminal cysteine residue is added to obtain attachment of the peptide to the keyhole limpet hemocyanin and coupled to using aluminum hydroxide carrier (103).”
MethodDecreased level of nerve growth factor (NGF) and its messenger RNA in the aged rat brain
Lärkfors, L., Ebendal, T., Whittemore, S. R., Persson, H., Hoffer, B. J., & Olson, L. (1987) · Molecular Brain Research · doi:10.1016/0169-328x(87)90044-1 · Cited by 245 · cited 1× · see citing works
“A drop in NGF levels with aging has been reported in many animal models (175-177), which could be an indication of the beneficial effects of NGF in AD patients.”
BackgroundGoozee, K. G., Shah, T. M., Sohrabi, H. R., Rainey‐Smith, S. R., Brown, B. M., Verdile, G., & Martins, R. N. (2015) · British Journal Of Nutrition · doi:10.1017/s0007114515004687 · Cited by 245 · cited 1× · see citing works
“Curcumin has been extensively studied for anticancer, antioxidant, and anti-inflammatory properties (163).”
BackgroundExalto, L. G., Biessels, G. J., Karter, A. J., Huang, E. S., Katon, W. J., Minkoff, J. R., & Whitmer, R. A. (2013) · The Lancet Diabetes & Endocrinology · doi:10.1016/s2213-8587(13)70048-2 · Cited by 244 · see citing works
Zetterberg, H. (2012) · Archives of Neurology · doi:10.1001/archneurol.2012.90 · Cited by 234 · cited 17× · see citing works
“Phase II/III trials of gantenerumab were initiated in July 2010 and enrolled 799 patients (SCarlet RoAD NCT01224106) and was the first large trial to utilize new diagnostic criteria by the International Working Group to enroll a homogenous population of early symptomatic patients whose memory deficit was likely due to…”
MethodInfluentialEsposito, D., Patel, P. P., Stephens, R. M., Pérez, P., Chao, M. V., Kaplan, D. R., & Hempstead, B. L. (2001) · Journal of Biological Chemistry · doi:10.1074/jbc.m011674200 · Cited by 234 · cited 1× · see citing works
“213 Nerve Growth Factor Another member of neurotrophic factors is nerve growth factor (NGF), which is a glycoprotein synthesized from the inactive form, pro-NGF (172), and exerts its trophic effect via TrkA and P57 receptors (173).”
BackgroundStackman, R. W., Eckenstein, F., Frei, B., Kulhanek, D., Nowlin, J., & Quinn, J. F. (2003) · Experimental Neurology · doi:10.1016/s0014-4886(03)00399-6 · Cited by 230 · cited 1× · see citing works
“Gingko biloba, a natural plant containing flavonoids and terpenoids, has both antioxidant and anti-inflammatory properties, as well as free radical scavenging ability, can reduce amyloid precursor protein and inhibit Aβ aggregation (223).”
BackgroundA phase1 study of stereotactic gene delivery of AAV2-NGF for Alzheimer’s disease
Rafii, M. S., Baumann, T. L., Bakay, R. A. E., Ostrove, J. M., Siffert, J., Fleisher, A. S., Herzog, C. D., Barba, D., Pay, M., Salmon, D. P., et al. (2014) · Alzheimer's & Dementia · doi:10.1016/j.jalz.2013.09.004 · Cited by 223 · cited 1× · see citing works
“Also, a more recent Phase I clinical study with ex vivo gene delivery to AD patients demonstrated enhanced cerebral metabolism and cognitive function without significant adverse effects (180).”
BackgroundLloret, A., Badía, M.-C., Mora, N. J., Pallardó, F. V., Alonso, M.-D., & Viña, J. (2009) · Journal of Alzheimer s Disease · doi:10.3233/jad-2009-1033 · Cited by 222 · cited 1× · see citing works
“In another clinical study published more than a decade later, however, patients who received 800 IU vitamin E per day and did show a reduction in oxidative stress, no significant difference compared to placebo group was observed in terms of MiniMental State Examination (MMSE) score after six months (199).”
ResultMechanisms of n-3 fatty acid-mediated development and maintenance of learning memory performance
Su, H. (2010) · The Journal of Nutritional Biochemistry · doi:10.1016/j.jnutbio.2009.11.003 · Cited by 222 · cited 1× · see citing works
“DHA is selectively accumulated in synaptic membranes and oligodendrocytes (219).”
BackgroundClaxton, A., Baker, L. D., Wilkinson, C. W., Trittschuh, E. H., Chapman, D., Watson, G. S., Cholerton, B., Plymate, S. R., Arbuckle, M., & Craft, S. (2013) · Journal of Alzheimer’s Disease · doi:10.3233/jad-122308 · Cited by 215 · cited 1× · see citing works
“Differential effects of insulin by ApoE genotype has also been proposed (112).”
BackgroundThe Clinical Introduction of Genetic Testing for Alzheimer Disease An Ethical Perspective
Post, S. G. (1997) · JAMA · doi:10.1001/jama.277.10.832 · Cited by 204 · cited 1× · see citing works
“Other genes were subsequently found to be linked to AD (8) identifying possible genetic etiologies for some forms of AD.”
BackgroundAlterations of Serum Levels of BDNF-Related miRNAs in Patients with Depression
Li, Y., Xu, M., Zong-hua, G., Wang, Y., Yue, Z., Zhang, Y.-X., Li, X., Zhang, C. M., Xie, S., & Wang, P. (2013) · PLoS ONE · doi:10.1371/journal.pone.0063648 · Cited by 204 · cited 1× · see citing works
“Antidepressants have also reported to increase BDNF levels in AD patients (165).”
BackgroundBymaster, F. P., McKinzie, D. L., Felder, C. C., & Wess, J. (2003) · Neurochemical Research · doi:10.1023/a:1022844517200 · Cited by 203 · see citing works
Antioxidant strategies for Alzheimer's disease
Grundman, M., & Delaney, P. (2002) · Proceedings of The Nutrition Society · doi:10.1079/pns2002146 · Cited by 193 · cited 1× · see citing works
“Several studies have indicated a decrease in plasma levels of vitamin A and α-carotene (but not β-carotene) in AD patients compared to control individuals (207).”
BackgroundSiemers, E., Friedrich, S. W., Dean, R. A., Gonzales, C., Farlow, M. R., Paul, S. M., & Demattos, R. B. (2010) · Clinical Neuropharmacology · doi:10.1097/wnf.0b013e3181cb577a · Cited by 192 · cited 1× · see citing works
“Later phase II single dose studies (NCT00329082, NCT00749216) completed in 2008 and 2009 (64, 65) and an additional phase II, randomized, doubleblind, placebo-controlled trial evaluating patients exposed to repeated doses completed in 2012 (NCT01148498), confirmed the antibody's safety and tolerability.”
BackgroundCorcoran, J. P. T., So, P. L., & Maden, M. (2004) · European Journal of Neuroscience · doi:10.1111/j.1460-9568.2004.03563.x · Cited by 190 · cited 1× · see citing works
“Also, vitamin A deprivation could cause β-amyloid accumulation (211) and memory deficit (212) in adult rodents.”
BackgroundVitamin C transport and its role in the central nervous system
May, J. M. (2012) · Subcellular Biochemistry · doi:10.1007/978-94-007-2199-9_6 · Cited by 186 · cited 5× · see citing works
“Stem cell factor (SCF) is a hematopoietin expressed in CNS that enhances neurogenesis (191).”
BackgroundInfluentialEtchamendy, N., Enderlin, V., Marighetto, A., Pallet, V., Higueret, P., & Jaffard, R. (2003) · Behavioural Brain Research · doi:10.1016/s0166-4328(03)00099-8 · Cited by 185 · cited 1× · see citing works
“Also, vitamin A deprivation could cause β-amyloid accumulation (211) and memory deficit (212) in adult rodents.”
BackgroundAmyloid cascade in Alzheimer's disease: Recent advances in medicinal chemistry
Mohamed, T., Shakeri, A., & Rao, P. P. N. (2016) · European Journal of Medicinal Chemistry · doi:10.1016/j.ejmech.2016.02.049 · Cited by 181 · see citing works
Formation and function of apolipoprotein E-containing lipoproteins in the nervous system
Vance, J. E., & Hayashi, H. (2010) · Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids · doi:10.1016/j.bbalip.2010.02.007 · Cited by 178 · cited 1× · see citing works
“specifically reduced with age, leading to reduced availability of ApoE in brain, which in turn results in accumulation of toxic cholesterol and Aβ oligomers, increasing the risk of AD (24), while Apo E2 and”
BackgroundSerum BDNF, TNF-α and IL-1β levels in dementia patients
Yasutake, C., Kuroda, K., Yanagawa, T., Okamura, T., & Yoneda, H. (2006) · European Archives of Psychiatry and Clinical Neuroscience · doi:10.1007/s00406-006-0652-8 · Cited by 177 · cited 1× · see citing works
“Multiple studies have revealed a drop in BDNF levels in AD patients (156-159), while other reports indicate an increase in BNDF expression compared to control (160), which could be a compensatory repair mechanism during early stages of AD.”
ResultMuhs, A., Hickman, D. T., Pihlgren, M., Chuard, N., Giriens, V., Meerschman, C., der Auwera, I. V., LEUVEN, F. V., Sugawara, M., Weingertner, M.-C., et al. (2007) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0703137104 · Cited by 176 · cited 1× · see citing works
“The vaccine consists of an array of Aβ1-15 sequences that are sandwiched between palmitoylated lysines at either end and are anchored onto the surface of the liposomes so that the peptides adopt an aggregated β-sheet structure, forming a conformational epitope (51).”
BackgroundEffects of Vitamin E on Cognitive Performance during Ageing and in Alzheimer’s Disease
Fata, G. L., Weber, P., & Mohajeri, M. H. (2014) · Nutrients · doi:10.3390/nu6125453 · Cited by 174 · cited 1× · see citing works
“The potential effect of vitamin E on cognitive function of AD patients was recently reviewed by La Fata et al (201).”
Gender, cognitive decline, and risk of AD in older persons
Barnes, L. L., Wilson, R. S., Schneider, J. A., Bienias, J. L., Evans, D. A., & Bennett, D. A. (2003) · Neurology · doi:10.1212/01.wnl.0000065892.67099.2a · Cited by 173 · cited 1× · see citing works
“The greater prevalence of AD in women could be attributed to the higher life expectancy in women, since the incidence of AD in earlier ages is comparable between sexes (16).”
BackgroundBarten, D. M., Fanara, P., Andorfer, C. A., Hoque, N., Wong, P. A., Husted, K. H., Cadelina, G. W., DeCarr, L. B., Yang, L., Liu, V., et al. (2012) · Journal of Neuroscience · doi:10.1523/jneurosci.0188-12.2012 · Cited by 173 · cited 1× · see citing works
“In tau transgenic animals, BMS-241027 restored microtubule dynamics to baseline levels with beneficial effects seen on performance in the Morris water maze deficits, tau pathology, and neurodegeneration (100).”
BackgroundThomas, J., Thomas, C. J., Radcliffe, J., & Itsiopoulos, C. (2015) · BioMed Research International · doi:10.1155/2015/172801 · Cited by 173 · cited 2× · see citing works
“Several clinical studies indicate beneficial effects of omega 3 in AD, which have been recently reviewed by Thomas et al (221).”
BackgroundA Single Ascending Dose Study of Bapineuzumab in Patients With Alzheimer Disease
Black, R. S., Sperling, R. A., Safirstein, B., Motter, R. N., Pallay, A., Nichols, A., & Grundman, M. (2010) · Alzheimer Disease & Associated Disorders · doi:10.1097/wad.0b013e3181c53b00 · Cited by 170 · cited 1× · see citing works
“In these initial safety studies, 3/10 patients on the highest dose in the phase I study and 12 patients in the phase II study suffered amyloid-related imaging abnormalities indicative of potential new microhemorrhages, similar to that seen with active immunization (57, 58).”
Phase 3 Trials of Solanezumab and Bapineuzumab for Alzheimer's Disease
Doody, R. S., Farlow, M. R., & Aisen, P. S. S. (2014) · New England Journal of Medicine · doi:10.1056/nejmc1402193 · Cited by 169 · cited 1× · see citing works
“Failure of bapineuzumab to achieve clinical benefit has been attributed to the dose-limiting ARIA-E adverse effect as well as to late-stage treatment (62).”
BackgroundAdachi, N., Numakawa, T., Richards, M. C., Nakajima, S., & Kunugi, H. (2014) · World Journal of Biological Chemsitry · doi:10.4331/wjbc.v5.i4.409 · Cited by 168 · cited 1× · see citing works
“Genetic structure and intracellular mechanisms of BDNF was recently reviewed by Adachi et al (155).”
BackgroundWilkinson, D. G., Windfeld, K., & Colding‐Jørgensen, E. (2014) · The Lancet Neurology · doi:10.1016/s1474-4422(14)70198-x · Cited by 164 · see citing works
Glycogen Synthase Kinase 3 Inhibition Promotes Adult Hippocampal Neurogenesis in Vitro and in Vivo
Morales-Garcia, J. A., Luna‐Medina, R., Alonso‐Gil, S., Sanz-SanCristóbal, M., Palomo, V., Gil, C., Santos, Á., Martı́nez, A., & Pérez‐Castillo, A. (2012) · ACS Chemical Neuroscience · doi:10.1021/cn300110c · Cited by 162 · cited 1× · see citing works
“It acts as an irreversible GSK-3β inhibitor that has been shown to reverse amyloid in brain and prevent cell loss and reduce spatial memory deficits in preclinical studies (106, 107).”
BackgroundSerotonin 5-HT6Receptor Antagonists for the Treatment of Cognitive Deficiency in Alzheimer’s Disease
Benhamú, B., Martín‐Fontecha, M., Vázquez‐Villa, H., Pardo, L., & López-Rodríguez, M. L. (2014) · Journal of Medicinal Chemistry · doi:10.1021/jm5003952 · Cited by 160 · cited 1× · see citing works
“Blockade of 5-HT6 receptors increases synaptic acetylcholine release, improving cholinergic transmission and enhances memory and cognition (137-139).”
BackgroundIncrease of BDNF Serum Concentration in Lithium Treated Patients with Early Alzheimer's Disease
Leyhe, T., Eschweiler, G. W., Stransky, E., Gasser, T., Annas, P., Basun, H., & Laske, C. (2009) · Journal of Alzheimer s Disease · doi:10.3233/jad-2009-1004 · Cited by 158 · cited 1× · see citing works
“However, a recent clinical trial showed no significant effect of donepezil treatment on BDNF levels (166), while a 2009 clinical trial have indicated an increase in BDNF levels in lithium-treated patients with early AD (167).”
BackgroundG-CSF rescues the memory impairment of animal models of Alzheimer's disease
Tsai, K., Tsai, Y.-C., & Shen, C.-K. J. (2007) · The Journal of Experimental Medicine · doi:10.1084/jem.20062481 · Cited by 157 · cited 7× · see citing works
“They also reported that G-CSF administration induced neurogenesis around Aβ aggregates in these acute and chronic animal models of Aβ-driven AD.”
BackgroundInfluentialMartone, R. L., Zhou, H., Atchison, K. P., Comery, T. A., Xu, J. Z., Huang, X., Gong, X., Jin, M., Kreft, A. F., Harrison, B. L., et al. (2009) · Journal of Pharmacology and Experimental Therapeutics · doi:10.1124/jpet.109.152975 · Cited by 155 · cited 1× · see citing works
“However, phase I trials (NCT00959881, NCT00547560) in healthy human volunteers only affected the plasma concentration of Aβ and not its CSF concentration and development was halted (90).”
BackgroundLannfelt, L., Möller, C., Basun, H., Osswald, G., Sehlin, D., Satlin, A., Logovinsky, V., & Gellerfors, P. (2014) · Alzheimer s Research & Therapy · doi:10.1186/alzrt246 · Cited by 152 · cited 1× · see citing works
“197 or neutralize their toxicity based on the discovery of the “artic mutation” in APP, which leads to a form of Alzheimer's disease with particularly high levels of Aβ protofibrils (73).”
BackgroundM1 muscarinic acetylcholine receptor in Alzheimer’s disease
Jiang, S., Li, Y., Zhang, C., Zhao, Y., Bu, G., Xu, H., & Zhang, Y. (2014) · Neuroscience Bulletin · doi:10.1007/s12264-013-1406-z · Cited by 147 · see citing works
Marlo, J. E., Niswender, C. M., Days, E., Bridges, T. M., Xiang, Y., Rodriguez, A. L., Shirey-Rice, J. K., Brady, A. E., Nalywajko, T., Luo, Q., et al. (2008) · Molecular Pharmacology · doi:10.1124/mol.108.052886 · Cited by 146 · cited 1× · see citing works
“There are several other PAMs that act on M1, such as VU0029767 and VU0090157 which were previously in preclinical development (127).”
BackgroundIncreased plasma levels of BDNF and inflammatory markers in Alzheimer's disease
Faria, M. C., Gonçalves, G. S., Rocha, N. P., de Moraes, E. N., Bicalho, M. A. C., Cintra, M. T. G., de Paula, J. J., de Miranda, L. F. J. R., Ferreira, A. C. D. S., Teixeira, A. L., et al. (2014) · Journal of Psychiatric Research · doi:10.1016/j.jpsychires.2014.01.019 · Cited by 145 · cited 1× · see citing works
“Multiple studies have revealed a drop in BDNF levels in AD patients (156-159), while other reports indicate an increase in BNDF expression compared to control (160), which could be a compensatory repair mechanism during early stages of AD.”
ResultMarksteiner, J., Kemmler, G., Weiss, E. M., Knaus, G., Ullrich, C., Mechtcheriakov, S., OBERBAUER, H., Auffinger, S., Hinterhoelzl, J., Hinterhuber, H., et al. (2009) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2009.03.011 · Cited by 142 · cited 1× · see citing works
“Other researchers have reported an increase in GDNF plasma levels in AD patients (184).”
BackgroundMohajeri, M. H., Troesch, B., & Weber, P. (2015) · Nutrition · doi:10.1016/j.nut.2014.06.016 · Cited by 141 · cited 1× · see citing works
“In fact, insufficient DHA intake has been related to brain aging, and reports suggest a positive effect for DHA in delaying the onset of AD (218).”
BackgroundOptimizing neurotrophic factor combinations for neurite outgrowth
Deister, C., & Schmidt, C. (2006) · Journal of Neural Engineering · doi:10.1088/1741-2560/3/2/011 · Cited by 140 · cited 1× · see citing works
“Glial-Derived Neurotrophic Factor Originally isolated from medium of a rat glioma cell line, glial-derived neurotrophic factor (GDNF) is another important growth factor, especially for survival and maintenance of dopaminergic neurons in midbrain (181).”
BackgroundAdvances in the pathogenesis of Alzheimer’s disease: a re-evaluation of amyloid cascade hypothesis
Dong, S., Duan, Y., Hu, Y., & Zhao, Z. (2012) · Translational Neurodegeneration · doi:10.1186/2047-9158-1-18 · Cited by 139 · see citing works
Neuropathology after active Aβ42 immunotherapy: implications for Alzheimer’s disease pathogenesis
Boche, D., Denham, N., Holmes, C., & Nicoll, J. A. R. (2010) · Acta Neuropathologica · doi:10.1007/s00401-010-0719-5 · Cited by 135 · cited 1× · see citing works
“Phospho-tau analysis showed a reduction of aggregated tau in neuronal processes (44).”
BackgroundMorelli, A. B., Becher, D., Koernig, S., Silva, A., Drane, D. P., & Maraskovsky, E. (2012) · Journal of Medical Microbiology · doi:10.1099/jmm.0.040857-0 · Cited by 134 · cited 2× · see citing works
“Iscomatrix™ was shown to be able to rapidly traffic antigens into the cytosol of multiple dendritic cell subsets, induce the induction of various cytokines and chemokines, and link innate and adaptive immune responses in vivo in a toll-like receptor-independent but MyD99dependent manner to provide enhanced and acceler…”
BackgroundCharacterization of a CNS penetrant, selective M1muscarinic receptor agonist, 77‐LH‐28‐1
Langmead, C. J., Austin, N. E., Branch, C. L., Brown, J. T., Buchanan, K. A., Davies, C. H., Forbes, I. T., Fry, V. A. H., Hagan, J. J., Herdon, H. J., et al. (2008) · British Journal of Pharmacology · doi:10.1038/bjp.2008.152 · Cited by 132 · cited 1× · see citing works
“77-LH-28-1 is another potent, selective and CNS penetrant allosteric M1 agonist which was a structural analog of AC-42 that was reported to improve cognition in animal models (123) as did AC-260584 (124).”
BackgroundEketjäll, S., Janson, J., Kaspersson, K., Bogstedt, A., Jeppsson, F., Fälting, J. M., Haeberlein, S. B., Kugler, A. R., Alexander, R. C., & Cebers, G. (2016) · Journal of Alzheimer s Disease · doi:10.3233/jad-150834 · Cited by 132 · see citing works
Vitamin A exhibits potent antiamyloidogenic and fibril-destabilizing effects in vitro
Ono, K., Yoshiike, Y., Takashima, A., Hasegawa, K., Naiki, H., & Yamada, M. (2004) · Experimental Neurology · doi:10.1016/j.expneurol.2004.05.035 · Cited by 131 · cited 1× · see citing works
“reported vitamin A and β-carotene would inhibit the formation of β-amyloid fibrils in vitro, and even destabilize already formed fibrils in a dosedependent manner (210).”
BackgroundDevelopment of AFFITOPE vaccines for Alzheimer's disease (AD) — From concept to clinical testing
Schneeberger, A., Mandler, M., Otava, O., Zauner, W., Mattner, F., & Schmidt, W. (2009) · The journal of nutrition health & aging · doi:10.1007/s12603-009-0070-5 · Cited by 130 · cited 1× · see citing works
“This vaccine reached human trials in late 2000s (47, 48) with phase Ia/Ib studies showing favorable safety and tolerability even after 2 years despite some concerns with ARIA-E (NCT00633841, NCT01093664, and NCT00711321).”
BackgroundSchechter, L. E., Smith, D. L., Rosenzweig-Lipson, S. J., Rizzo, S. J. S., Dawson, L. A., Marquis, K. L., Jones, D. P., Piesla, M. J., Andree, T. H., Nawoschik, S. P., et al. (2005) · Journal of Pharmacology and Experimental Therapeutics · doi:10.1124/jpet.105.086363 · Cited by 129 · cited 1× · see citing works
“For instance, lecozotan, a 5-HT1a receptor antagonist which was shown to produce significant improvement in task performance efficiency and reverse learning deficits in animals (144), went as far as phase II/III studies (NCT00277810); however, it was not pursued further for AD development.”
BackgroundMelancon, B. J., Tarr, J. C., Panarese, J. D., Wood, M. R., & Lindsley, C. W. (2013) · Drug Discovery Today · doi:10.1016/j.drudis.2013.09.005 · Cited by 120 · cited 1× · see citing works
“M1 muscarinic receptors are believed to play an important role in the regulation of secretase activities and synthesis of Aβ peptide, and subsequent tau hyperphosphorylation and cognitive dysfunction (117, 118).”
BackgroundCarotenoids and Alzheimer’s Disease: An insight into therapeutic role of retinoids in animal models
Obulesu, M., Dowlathabad, M. R., & Bramhachari, P. V. (2011) · Neurochemistry International · doi:10.1016/j.neuint.2011.04.004 · Cited by 115 · see citing works
Wess, J., Duttaroy, A., Zhang, W.-L., et al. (2003) · Receptors and Channels · doi:10.1080/10606820308262 · Cited by 114 · see citing works
Davtyan, H., Ghochikyan, A., Petrushina, I., Hovakimyan, A., Davtyan, A., Poghosyan, A., Marleau, A. M., Movsesyan, N., Kiyatkin, A., Rasool, S., et al. (2013) · The Journal of Neuroscience · doi:10.1523/jneurosci.4672-12.2013 · Cited by 112 · cited 1× · see citing works
“In animal models, Lu AF20513 was found to induce robust "non-self" T-cell responses and induce production of anti-Aβ antibodies (53).”
BackgroundEarly Life Epidemiology of Alzheimer's Disease - A Critical Review
Seifan, A., Schelke, M. W., Obeng-Aduasare, Y., & Isaacson, R. (2015) · Neuroepidemiology · doi:10.1159/000439568 · Cited by 110 · cited 2× · see citing works
“Other risk factors for AD include head trauma, female gender, learning disabilities, education level, homocysteine levels, socioeconomic status, and previous depression (12).”
BackgroundCardiovascular and cognitive fitness at age 18 and risk of early-onset dementia
Nyberg, J., Åberg, M., Schiöler, L., Nilsson, M., Wallin, A., Torén, K., & Kuhn, H. G. (2014) · Brain · doi:10.1093/brain/awu041 · Cited by 109 · see citing works
Revilla, S., Ursulet, S., Álvarez‐López, M. J., Castro, M., Perpiñá, U., García‐Mesa, Y., Bortolozzi, A. A., Giménez‐Llort, L., Kaliman, P., Cristòfol, R. M., et al. (2014) · CNS Neuroscience & Therapeutics · doi:10.1111/cns.12312 · Cited by 109 · cited 1× · see citing works
“Also, transfection with GDNFexpressing gene using a lentiviral vector has improved cognitive mechanisms in a transgenic mice model of AD (186).”
MethodGrove, R. A., Harrington, C. M., Mahler, A., Beresford, I. J. M., Maruff, P. T., Lowy, M. T., Nicholls, A. J., Boardley, R., Berges, A., Nathan, P. J., et al. (2014) · Current Alzheimer Research · doi:10.2174/1567205010666131212110148 · Cited by 109 · cited 1× · see citing works
“In this 16-week, double-blind, randomized, parallel group study, GSK239512 improved Episodic Memory; however, no improvements were observed in any other domains of cognition or other secondary endpoints indicating that H3 agonists at most, have modest and selective effects on cognitive function in patients with mild-t…”
BackgroundArnt, J., Bang‐Andersen, B., Grayson, B., Bymaster, F. P., Cohen, M. P., DeLapp, N. W., Giethlen, B., Kreilgaard, M., McKinzie, D. L., Neill, J. C., et al. (2010) · The International Journal of Neuropsychopharmacology · doi:10.1017/s1461145710000659 · Cited by 108 · see citing works
Xu, S., Bi, C. W. C., Choi, R., et al. (2013) · Evidence-Based Complementary and Alternative Medicine · doi:10.1155/2013/127075 · Cited by 107 · cited 7× · see citing works
“Loss of BDNF function has been reported in neurodegenerative and psychiatric diseases (153, 154).”
BackgroundInfluentialHarrington, C. R., Storey, J. M. D., Clunas, S., Harrington, K. A., Horsley, D., Ishaq, A., Kemp, S. J., Larch, C. P., Marshall, C., Nicoll, S. L., et al. (2015) · Journal of Biological Chemistry · doi:10.1074/jbc.m114.616029 · Cited by 107 · cited 1× · see citing works
“methylthioninium chloride but was improved for enhanced bioavailability and tolerability (96).”
BackgroundSB-742457 and donepezil in Alzheimer disease: a randomized, placebo-controlled study
Maher‐Edwards, G., Dixon, R., Hunter, J. A., Gold, M., Hopton, G., Jacobs, G., Hunter, J., & Williams, P. M. (2010) · International Journal of Geriatric Psychiatry · doi:10.1002/gps.2562 · Cited by 105 · cited 1× · see citing works
“In the studies evaluating SB-742457 alone, no benefit was seen in cognition, but a significant improvement in global function was seen in those studies that evaluated patients also receiving donepezil (143).”
ResultPasquier, F., Sadowsky, C., Holstein, A. R., Prince, G. L., Peng, Y., Jackson, N. M., Fox, N. C., Ketter, N., Liu, E., Ryan, J. M., et al. (2016) · Journal of Alzheimer s Disease · doi:10.3233/jad-150376 · Cited by 105 · cited 1× · see citing works
“Further exploratory cognitive evaluations, volumetric brain MRI, and CSF biomarkers, however, did not show differences between treatment groups and placebo although some trends were seen including less brain amyloid accumulation in vaccinated patients as assessed by PET imaging and slight reductions in CSF phosphoryla…”
BackgroundStem cell factor is a chemoattractant and a survival factor for CNS stem cells.
Erlandsson, A., Larsson, J., & Forsberg-Nilsson, K. (2004) · Experimental Cell Research · doi:10.1016/j.yexcr.2004.08.009 · Cited by 103 · cited 2× · see citing works
“Along with G-CSF it helps bone marrow-derived progenitor cells differentiate to microglial cells or neuronal stem cells (192).”
BackgroundAscorbic Acid and the Brain: Rationale for the Use against Cognitive Decline
Harrison, F. E., Bowman, G. L., & Polidori, M. C. (2014) · Nutrients · doi:10.3390/nu6041752 · Cited by 99 · cited 1× · see citing works
“It easily reacts with reactive oxygen species to neutralize their activity, and become ascorbate free radical, which is then recycled (203).”
BackgroundSafety profile of semagacestat, a gamma-secretase inhibitor: IDENTITY trial findings
Henley, D. B., Sundell, K. L., Sethuraman, G., Dowsett, S. A., & May, P. C. (2014) · Current Medical Research and Opinion · doi:10.1185/03007995.2014.939167 · Cited by 98 · cited 13× · see citing works
“The amyloidogenic pathway is initiated through cleavage of APP by β-secretase (also known as beta-site APP cleaving enzyme; BACE1), and again processed by γ-secretase (22).”
BackgroundInfluentialBMS-708,163 Targets Presenilin and Lacks Notch-Sparing Activity
Crump, C. J., Castro, S. V., Wang, F., Pozdnyakov, N., Ballard, T. E., Sisodia, S. S., Bales, K. R., Johnson, D. S., & Li, Y. (2012) · Biochemistry · doi:10.1021/bi301137h · Cited by 95 · cited 1× · see citing works
“Avagacestat was reported to selectively block processing of the enzyme's APP substrate with 137-fold selectivity for APP over Notch in cell culture, and to reduce CSF Aβ levels without causing Notch-related toxicity in animals (87, 88).”
BackgroundNeuroprotection by stem cell factor in rat cortical neurons involves AKT and NFκB
Dhandapani, K. M., Wade, F. M., Wakade, C. G., Mahesh, V. B., & Brann, D. W. (2005) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.2005.03319.x · Cited by 93 · cited 1× · see citing works
“This suggests a protective role towards neurons, which might be exerted via PI3K/Akt or MEK/ERK pathways (193).”
BackgroundLanden, J. W., Zhao, Q., Cohen, S., BORRIE, M. J., Woodward, M., Billing, C. B., Bales, K. R., Alvey, C. W., McCush, F., Yang, J., et al. (2013) · Clinical Neuropharmacology · doi:10.1097/wnf.0b013e31827db49b · Cited by 88 · cited 1× · see citing works
“Ponezumab (PF-04360365) is a humanized IgG2δA monoclonal antibody that unlike the other monoclonal antibodies binds the free carboxyl terminal of amino acids 33-40 of the Aβ 1-40 peptide (72).”
BackgroundTargeting Beta Amyloid: A Clinical Review of Immunotherapeutic Approaches in Alzheimer's Disease
Lobello, K., Ryan, J. M., Liu, E., Rippon, G. A., & Black, R. S. (2012) · International Journal of Alzheimer s Disease · doi:10.1155/2012/628070 · Cited by 86 · cited 1× · see citing works
“V-950 is an Aβ amino terminal peptide formulated on an aluminum-containing adjuvant along with IscomatrixTM an improved saponin adjuvant with antigen delivery and presentation properties as well as immunomodulatory capabilities (49).”
BackgroundMelatonin redox activity. Its potential clinical applications in neurodegenerative disorders.
Miller, E., Morel, A., Saso, L., & Saluk, J. (2015) · Current Topics in Medicinal Chemistry · doi:10.2174/1568026615666141209160556 · Cited by 86 · cited 1× · see citing works
“Melatonin, a pineal gland hormone with well-known role in sleep regulation, easily passes BBB, is a scavenger of hydroxyl, carbonate, alkoxyl, peroxyl and aryl cation radicals, and stimulates activities of antioxidative enzymes, which suggests a protective role in neurodegenerative disorders (224).”
BackgroundHickman, D. T., López-Deber, M. P., Ndao, D. M., Silva, A. B., Nand, D., Pihlgren, M., Giriens, V., Madani, R., St-Pierre, A., Karastaneva, H., et al. (2011) · Journal of Biological Chemistry · doi:10.1074/jbc.m110.186338 · Cited by 83 · see citing works
AF710B, a Novel M1/σ1 Agonist with Therapeutic Efficacy in Animal Models of Alzheimer's Disease
Fisher, A., Борисович, Б. И., Wu, L., Ryskamp, D. A., Bar-Ner, N., Natan, N., Brandeis, R., Elkon, H., Nahum, V., Gershonov, E., et al. (2015) · Neurodegenerative Diseases · doi:10.1159/000440864 · Cited by 82 · cited 1× · see citing works
“AF710B was a potent and safe cognitive enhancer in animal models, while also reportedly decreasing BACE1, GSK3β activity, neuro-inflammation, soluble and insoluble Aβ40, Aβ42, plaques and tau pathologies (125).”
BackgroundPerović, M., Tešić, V., Mladenović, A., Smiljanić, K., Lončarević‐Vasiljković, N., Ruždijić, S., & Kanazir, S. (2012) · AGE · doi:10.1007/s11357-012-9495-6 · Cited by 81 · cited 1× · see citing works
“A drop in NGF levels with aging has been reported in many animal models (175-177), which could be an indication of the beneficial effects of NGF in AD patients.”
BackgroundComplex Relationships of Nicotinic Receptor Actions and Cognitive Functions
Levin, E. (2013) · Biochemical Pharmacology · doi:10.1016/j.bcp.2013.07.021 · Cited by 80 · cited 1× · see citing works
“Nicotinic agonists The role of nicotinic receptors in AD is less clear than muscarinic agonists, but it is known that nicotinic acetylcholine receptors (nAChRs) play diverse roles in cognition, memory, and neuroprotection (129).”
BackgroundBharadwaj, P. R., Bates, K. A., Porter, T., Teimouri, E., Perry, G. L., Steele, J., Gandy, S., Groth, D., Martins, R. N., & Verdile, G. (2013) · Translational Psychiatry · doi:10.1038/tp.2013.97 · Cited by 80 · cited 1× · see citing works
“A mechanism of action for cognitive benefit has never been conclusively established; however, a broad spectrum of effects has been proposed including modulation of NMDA glutamate receptors, α-adrenergic receptors, and serotonergic or dopaminergic receptors (149).”
BackgroundDeardorff, W., Shobassy, A., & Grossberg, G. (2015) · Expert Review of Neurotherapeutics · doi:10.1586/14737175.2015.995639 · Cited by 79 · cited 1× · see citing works
“As such, a 24-week phase II trial (NCT01073228) was conducted in 409 people using higher doses in mild to moderate AD patients and met most of its primary and secondary endpoints, including cognitive measures (134).”
BackgroundSopova, K., Gatsiou, K., Stellos, K., & Laske, C. (2014) · Current Alzheimer Research · doi:10.2174/1567205010666131120100743 · Cited by 79 · cited 1× · see citing works
“However, recent studies have not revealed a significant difference in blood, CSF, and brain levels of NGF in AD patients compared to healthy subjects (178).”
ResultA Randomized Study of H3 Antagonist ABT-288 in Mild-To-Moderate Alzheimer's Dementia1
Haig, G. M., Pritchett, Y., Meier, A., Othman, A. A., Hall, C. M., Gault, L. M., & Lenz, R. A. (2014) · Journal of Alzheimer s Disease · doi:10.3233/jad-140291 · Cited by 71 · cited 1× · see citing works
“Unfortunately, the trial was terminated early, as no statistical changes in cognitive function was found and because futility criteria were met (147).”
BackgroundDiniz, B. S., Reynolds, C. F., Begley, A. E., Dew, M. A., Anderson, S., Lotrich, F. E., Erickson, K. I., López, O. L., Aizenstein, H. J., Sibille, E. L., et al. (2013) · Journal of Psychiatric Research · doi:10.1016/j.jpsychires.2013.11.004 · Cited by 69 · cited 1× · see citing works
“However, a recent clinical trial showed no significant effect of donepezil treatment on BDNF levels (166), while a 2009 clinical trial have indicated an increase in BDNF levels in lithium-treated patients with early AD (167).”
BackgroundBradley, S. R., Lameh, J., Ohrmund, L., Son, T., Bajpai, A., Nguyen, D., Friberg, M., Burstein, E. S., Spalding, T. A., Ott, T. R., et al. (2009) · Neuropharmacology · doi:10.1016/j.neuropharm.2009.10.003 · Cited by 68 · cited 1× · see citing works
“77-LH-28-1 is another potent, selective and CNS penetrant allosteric M1 agonist which was a structural analog of AC-42 that was reported to improve cognition in animal models (123) as did AC-260584 (124).”
BackgroundCarman, A. J., Dacks, P. A., Lane, R. F., Shineman, D. W., & Fillit, H. M. (2014) · The journal of nutrition health & aging · doi:10.1007/s12603-014-0021-7 · Cited by 68 · cited 1× · see citing works
“However, the results of observational studies vary significantly, and are therefore inconclusive (222).”
BackgroundClinical Trials of Intravenous Immunoglobulin for Alzheimer’s Disease
Relkin, N. R. (2014) · Journal of Clinical Immunology · doi:10.1007/s10875-014-0041-4 · Cited by 67 · cited 1× · see citing works
“Some positive results were noted in subgroups, especially among APOE-e4 carriers and moderately impaired AD patients and recruitment is ongoing for further phase III trials (NCT01561053) in these populations (74, 75).”
Alzheimer's disease and epigenetic diet
Sezgin, Z., & Dinçer, Y. (2014) · Neurochemistry International · doi:10.1016/j.neuint.2014.09.012 · Cited by 67 · cited 1× · see citing works
“However, it has been suggested that curcumin could also inhibit DNA methyltransferase, histone acetyltransferase and histone deacetylase, and modulate miRNA in hippocampus, which are associated with an increase in BDNF levels (164).”
BackgroundSivilia, S., Lorenzini, L., Giuliani, A., Gusciglio, M., Fernández, M., Baldassarro, V. A., Mangano, C., Ferraro, L., Pietrini, V., Baroc, M. F., et al. (2013) · BMC Neuroscience · doi:10.1186/1471-2202-14-44 · Cited by 64 · cited 1× · see citing works
“Subsequent preclinical studies proposed other mechanisms of action, such as restoring neurogenesis, reorganizing the astrocytic cytoskeleton, reducing tau, rescuing synaptic plasticity, or acting on microglia to counteract inflammation (91).”
BackgroundSano, M., Ernesto, C., Klauber, M. R., Schafer, K. A., Woodbury, P., Thomas, R. G., Grundman, M., Growdon, J. H., & Thal, L. J. (1996) · Alzheimer Disease & Associated Disorders · doi:10.1097/00002093-199601030-00004 · Cited by 62 · cited 1× · see citing works
“reported a randomized double-blind, placebocontrolled clinical study, which showed some benefit for vitamin E administration to AD patients (58% chance of death, institutionalization, change to a Clinical Dementia Rating of three, or loss of two basic activities of daily living within two years for recipients of 2000…”
BackgroundBirdsall, N., Farries, T., Gharagozloo, P., et al. (1997) · Life Science · doi:10.1016/s0024-3205(97)00046-5 · Cited by 61 · cited 1× · see citing works
“Brucine was one of the first PAMs identified and was capable of selectively enhancing the effects of acetylcholine at M1 receptors by an allosteric mechanism (126).”
BackgroundArai, H., Suzuki, H., & Yoshiyama, T. (2015) · Current Alzheimer Research · doi:10.2174/1567205012666150302154121 · Cited by 60 · cited 1× · see citing works
“Further exploratory cognitive evaluations, volumetric brain MRI, and CSF biomarkers, however, did not show differences between treatment groups and placebo although some trends were seen including less brain amyloid accumulation in vaccinated patients as assessed by PET imaging and slight reductions in CSF phosphoryla…”
BackgroundLaske, C., Stellos, K., Stransky, E., Leyhe, T., & Gawaz, M. (2009) · Journal of Alzheimer s Disease · doi:10.3233/jad-2009-1017 · Cited by 60 · cited 1× · see citing works
“A decrease in G-CSF blood levels in early AD patients has been reported by Laske et al, with no data available for the CSF or brain level of this growth factor (188).”
MethodRosenbloom, M. H., Barclay, T. R., Pyle, M., Owens, B. L., Cagan, A., Anderson, C. P., Frey, W. H., & Hanson, L. R. (2014) · CNS Drugs · doi:10.1007/s40263-014-0214-y · Cited by 58 · cited 1× · see citing works
“cognition in ApoE4 carriers with AD (113).”
5-HT6 Receptor: A New Player Controlling the Development of Neural Circuits
Dayer, A. G., Jacobshagen, M., Chaumont‐Dubel, S., & Marin, P. (2015) · ACS Chemical Neuroscience · doi:10.1021/cn500326z · Cited by 58 · cited 1× · see citing works
“Blockade of 5-HT6 receptors increases synaptic acetylcholine release, improving cholinergic transmission and enhances memory and cognition (137-139).”
BackgroundTan, C.-C., Wang, C., & Tan, L. (2014) · Current Alzheimer Research · doi:10.2174/1567205011666141001114140 · Cited by 56 · cited 1× · see citing works
“performed a systematic review and metaanalysis on efficacy of vitamin B supplementation in AD (217).”
BackgroundSamson, S., Clément, S., Narme, P., Schiaratura, L., & Ehrlé, N. (2015) · Annals of the New York Academy of Sciences · doi:10.1111/nyas.12621 · Cited by 52 · cited 1× · see citing works
“Therapeutic Approaches The non-pharmacological approaches to prevent AD include relaxing activities, such as listening to music or cooking that are speculated to improve the neural efficacy of cognitive processing and emotional and behavioral functioning (42).”
BackgroundRuiz, J., Gil-Bea, F., Bustamante-Ara, N., et al. (2014) · International Journal of Sports Medicine · doi:10.1055/s-0034-1375693 · Cited by 52 · cited 1× · see citing works
“in other clinical trials conducted on AD treatment, especially in trials on the effect of physical activity and exercise on AD (168-170).”
BackgroundBarbier, A. J., Hilhorst, M., Vliet, A. V., Snyder, P., Palfreyman, M. G., Gawryl, M., Dgetluck, N., Massaro, M., Tiessen, R., Timmerman, W., et al. (2015) · Clinical Therapeutics · doi:10.1016/j.clinthera.2014.09.013 · Cited by 51 · cited 1× · see citing works
“Secondary efficacy endpoints at that time suggested that EVP-6124 could improve attention, verbal fluency, and executive function, when given in conjunction with acetylcholinesterase inhibitors (133).”
BackgroundLaske, C., Stellos, K., Stransky, E., Seizer, P., Akcay, Ö., Eschweiler, G. W., Leyhe, T., & Gawaz, M. (2008) · Journal of Alzheimer s Disease · doi:10.3233/jad-2008-15311 · Cited by 50 · cited 1× · see citing works
“A decrease in plasma and cerebrovascular fluid levels of SCF has been reported in AD patients (194).”
BackgroundZandi, P. P. (2004) · Archives of Neurology · doi:10.1001/archneur.61.1.82 · Cited by 47 · cited 1× · see citing works
“More interestingly, the 2004 Cache County study indicates that only the combination of vitamins C and E could reduce the risk of AD (206).”
BackgroundPilot Study of Granulocyte-Colony Stimulating Factor for Treatment of Alzheimer's Disease
Sanchez‐Ramos, J., Cimino, C. R., Ávila, R. T., Rowe, A. R., Ren, C., Whelan, G. J., Lin, X., Cao, C., & Ashok, R. (2012) · Journal of Alzheimer s Disease · doi:10.3233/jad-2012-120196 · Cited by 46 · cited 1× · see citing works
“In 2012, a pilot clinical study in 8 patients with mild to moderate stages of AD did not show a serious adverse effect for five days of subcutaneous G-CSF administration, but did provide evidence for positive changes in hippocampal-dependent cognitive tasks (190).”
BackgroundMicronutrients and Alzheimer's disease
Staehelin, H. B. (2005) · Proceedings of The Nutrition Society · doi:10.1079/pns2005459 · Cited by 44 · cited 1× · see citing works
“Reports show antioxidants could contribute to breaking down superoxide radicals and hydrogen peroxide compounds, and prevent them from damaging the neurons (197).”
BackgroundComparing the efficacy and neuroinflammatory potential of three anti-abeta antibodies
Fuller, J. P., Stavenhagen, J. B., Christensen, S., Kartberg, F., Glennie, M. J., & Teeling, J. L. (2015) · Acta Neuropathologica · doi:10.1007/s00401-015-1484-2 · Cited by 44 · cited 1× · see citing works
“Crenezumab is an IgG4 monoclonal antibody which is expected to reduce pro-inflammatory activity and limit risk of vasogenic edema due to reduced effector functions on microglia (71).”
BackgroundGault, L. M., Lenz, R. A., Ritchie, C. W., Meier, A., Othman, A. A., Tang, Q., Berry, S. M., Pritchett, Y., & Robieson, W. (2016) · Alzheimer s Research & Therapy · doi:10.1186/s13195-016-0210-1 · Cited by 43 · see citing works
Bennett, R. E., Esparza, T. J., Lewis, H. A., Kim, E., Donald, C. L. M., Sullivan, P. M., & Brody, D. L. (2013) · Journal of Neuropathology & Experimental Neurology · doi:10.1097/nen.0b013e31828e24ab · Cited by 42 · cited 1× · see citing works
“It has also been shown that ApoE ɛ4 is associated with increased tau accumulation (28).”
BackgroundMemory Complaints in Mild Cognitive Impairment, Worried Well, and Semantic Dementia Patients
Ahmed, S., Mitchell, J., Arnold, R. J., Dawson, K., Nestor, P. J., & Hodges, J. R. (2008) · Alzheimer Disease & Associated Disorders · doi:10.1097/wad.0b013e31816bbd27 · Cited by 42 · cited 1× · see citing works
“display other subtle symptoms of cognitive impairment (34, 35).”
Backgroundde Bruin, N., & Kruse, C. (2015) · Current pharmaceutical design · doi:10.2174/1381612821666150605112105 · Cited by 42 · cited 1× · see citing works
“Blockade of 5-HT6 receptors increases synaptic acetylcholine release, improving cholinergic transmission and enhances memory and cognition (137-139).”
BackgroundTarr, J. C., Turlington, M., Reid, P. R., Utley, T. J., Sheffler, D. J., Cho, H. P., Klar, R., Pancani, T., Klein, M. T., Bridges, T. M., et al. (2012) · ACS Chemical Neuroscience · doi:10.1021/cn300068s · Cited by 41 · cited 1× · see citing works
“ML169 is a M1 PAM which has more recently been in preclinical developed (128).”
BackgroundHasenöhrl, R. U., Söderström, S., Mohammed, A. H., Ebendal, T., & Huston, J. P. (1997) · Experimental Brain Research · doi:10.1007/pl00005629 · Cited by 41 · cited 1× · see citing works
“A drop in NGF levels with aging has been reported in many animal models (175-177), which could be an indication of the beneficial effects of NGF in AD patients.”
BackgroundTailoring the Antibody Response to Aggregated Aß Using Novel Alzheimer-Vaccines
Mandler, M., Santic, R., Gruber, P., Cinar, Y., Pichler, D., Funke, S. A., Willbold, D., Schneeberger, A., SCHMIDT, W. A., & Mattner, F. (2015) · PLoS ONE · doi:10.1371/journal.pone.0115237 · Cited by 38 · cited 1× · see citing works
“This vaccine reached human trials in late 2000s (47, 48) with phase Ia/Ib studies showing favorable safety and tolerability even after 2 years despite some concerns with ARIA-E (NCT00633841, NCT01093664, and NCT00711321).”
BackgroundHardman, R. J., Kennedy, G., Macpherson, H., Scholey, A. B., & Pipingas, A. (2015) · Nutrition Journal · doi:10.1186/s12937-015-0042-z · Cited by 38 · cited 1× · see citing works
“in other clinical trials conducted on AD treatment, especially in trials on the effect of physical activity and exercise on AD (168-170).”
BackgroundUenaka, K., Nakano, M., Willis, B., et al. (2012) · Clinical neuropharmacology · doi:10.1097/wnf.0b013e31823a13d3 · Cited by 37 · cited 1× · see citing works
“Later phase II single dose studies (NCT00329082, NCT00749216) completed in 2008 and 2009 (64, 65) and an additional phase II, randomized, doubleblind, placebo-controlled trial evaluating patients exposed to repeated doses completed in 2012 (NCT01148498), confirmed the antibody's safety and tolerability.”
BackgroundStraten, G., Saur, R., Laske, C., et al. (2011) · Current Alzheimer Research · doi:10.2174/156720511798192754 · Cited by 37 · cited 1× · see citing works
“The CSF levels of GDNF has shown a significant increase in AD patients (despite a decrease in serum levels of this growth factor), which has been explained as an adaptive process to enhance neurotrophic effect (183).”
BackgroundWatt, M. L., Schober, D. A., Hitchcock, S. A., Liu, B., Chesterfield, A. K., McKinzie, D. L., & Felder, C. C. (2011) · Journal of Pharmacology and Experimental Therapeutics · doi:10.1124/jpet.111.182063 · Cited by 37 · cited 1× · see citing works
“LY593093 is a newer M1AChR orthosteric agonist that demonstrates modest to no activity at the other muscarinic subtypes and displays efficacy in the in vivo models of cognition (121).”
BackgroundCallaghan, C. K., Hok, V., Della-Chiesa, A., Virley, D. J., Upton, N., & O’Mara, S. M. (2012) · Neuropharmacology · doi:10.1016/j.neuropharm.2012.06.034 · Cited by 35 · cited 1× · see citing works
“In animals, SB-742457 has been reported to not only have beneficial effects in AD models, but also in age-related cognitive decline in rats (142).”
BackgroundFlorian, H., Meier, A., Gauthier, S., et al. (2016) · Journal of Alzheimer's Disease · doi:10.3233/jad-150978 · Cited by 32 · cited 1×
“However, although ABT126 was generally well tolerated with the most common adverse events were agitation, constipation, diarrhea, fall, and headache, ABT-126 did not demonstrate significant improvement in the primary efficacy endpoint and a treatment effect was not observed for any secondary efficacy measures of cogni…”
BackgroundNumakawa, T. (2014) · Neural Regeneration Research · doi:10.4103/1673-5374.139474 · Cited by 29 · cited 2× · see citing works
“Overall, it has been hypothesized that activating BDNF intracellular signaling could be a promising strategy in AD treatment (151).”
BackgroundPassani, M. B., & Blandina, P. (1998) · Methods and Findings in Experimental and Clinical Pharmacology · doi:10.1358/mf.1998.20.8.487510 · Cited by 25 · cited 1× · see citing works
“Blockage of the pre-synaptic H3 receptor leads to increased release of acetylcholine, dopamine, GABA, noradrenaline and histamine into the synaptic cleft, indirectly improving cholinergic neurotransmission (146).”
BackgroundLi, Y., Liu, Y., Wang, Z., & Jiang, Y. (2013) · Expert Opinion on Biological Therapy · doi:10.1517/14712598.2013.838555 · Cited by 21 · cited 1× · see citing works
“Solanezumab binds soluble Aβ in both the periphery and the brain thereby driving the equilibrium toward the soluble form, putatively resulting in resolution of Aβ plaques (63).”
BackgroundIntravenous immunoglobulin for Alzheimer's disease.
Holmes, C. (2013) · Lancet Neurology · doi:10.1016/s1474-4422(13)70015-2 · Cited by 19 · cited 1×
“Some positive results were noted in subgroups, especially among APOE-e4 carriers and moderately impaired AD patients and recruitment is ongoing for further phase III trials (NCT01561053) in these populations (74, 75).”
Fleiner, T., Zijlstra, W., Dauth, H., & Häussermann, P. (2015) · Trials · doi:10.1186/s13063-015-0758-2 · Cited by 14 · cited 1× · see citing works
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Background
Flagged first, then by citations
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Cited by
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- Authors
- Amirrad, F., Bousoik, E., Shamloo, K., Al-Shiyab, H., Nguyen, V.-H. V., & Montazeri Aliabadi, H.
- Affiliations
- Chapman University (US)
- Venue
- Journal of Pharmacy & Pharmaceutical Sciences
- Publisher
- Frontiers Media SA
- Published
- 2017-07-26
- Volume
- 20
- Issue
- 0
- Pages
- 184
- ISSN
- 1482-1826 (ISSN-L)
- OpenAlex
- W2737697705
- Cited by
- 21
- References
- 219
- Citations by year
- 2026: 1 · 2025: 4 · 2024: 1 · 2023: 1 · 2021: 4 · 2020: 4 · 2019: 3 · 2018: 3
- FWCI
- 2.03
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- cc-by
- Locations
- Journal of Pharmacy & Pharmaceutical Sciences (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Chapman University Digital Commons (Chapman University) (submittedVersion, cc-by-sa)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Health Sciences › Medicine › Pharmacology › Cholinesterase and Neurodegenerative Diseases
- Keywords
- Alzheimer's disease, dementia, neurodegeneration, cognitive impairment, drug development, immunotherapy, tau-targeted therapy, growth factors, antioxidant therapy, clinical trials, disease pathology, diagnosis
- MeSH terms
- Alzheimer Disease, Animals, Cognition, Humans
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
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