The past few years have brought some encouraging studies to the forefront in Alzheimer's and Dementia with several drugs in the pipeline that show promise

BIOLOGICAL BASIS

Three major competing hypotheses exist to explain the cause of the disease. The oldest, on which most currently available drug therapies are based, is the cholinergic hypothesis, which proposes that AD is caused by reduced synthesis of the neurotransmitter acetylcholine. The cholinergic hypothesis has not maintained widespread support, largely because medications intended to treat acetylcholine deficiency have not been very effective.

1) The cholinergic hypothesis, which proposes that AD is caused by reduced synthesis of the neurotransmitter acetylcholine. The cholinergic hypothesis has not maintained widespread support, largely because medications intended to treat acetylcholine deficiency have not been very effective. The cholinergic hypothesis is the oldest hypothesis and is what most current drug therapies are based upon.Other cholinergic effects have also been proposed, for example, initiation of large-scale aggregation of amyloid,[1] leading to generalised neuroinflammation [2].

2) In 1991, the amyloid hypothesis postulated that amyloid beta (Aß) deposits are the fundamental cause of the disease.[3][4] Support for this postulate comes from the location of the gene for the amyloid beta precursor protein (APP) on chromosome 21, together with the fact that people with trisomy 21 (Down Syndrome) who thus have an extra gene copy almost universally exhibit AD by 40 years of age.[5][6] Also APOE4, the major genetic risk factor for AD, leads to excess amyloid buildup in the brain before AD symptoms arise. Thus, Aß deposition precedes clinical AD.[43] Further evidence comes from the finding that transgenic mice that express a mutant form of the human APP gene develop fibrillar amyloid plaques and Alzheimer's-like brain pathology with spatial learning deficits.[7]

--Note: An experimental vaccine however was found to clear the amyloid plaques in early human trials, but it did not have any significant effect on dementia.[8] --

Researchers have been led to suspect non-plaque Aß oligomers (aggregates of many monomers) as the primary pathogenic form of Aß. In 2009, it was found that oligomeric Aß exerts a deleterious effect on brain physiology by binding to a specific receptor on neurons. The identity of this receptor is the prion protein that has been linked to mad cow disease and the related human condition, Creutzfeldt-Jakob disease, thus potentially linking the underlying mechanism of these neurodegenerative disorders with that of Alzheimer's disease.[9].

In 2009, this theory was updated, suggesting that a close relative of the beta-amyloid protein, and not necessarily the beta-amyloid itself, may be involved in the disease (see Ref 10). The theory holds that an amyloid-related mechanism that prunes neuronal connections in the brain in the fast-growth phase of early life may be triggered by aging-related processes in later life to cause the neuronal withering of Alzheimer's disease. N-APP, a fragment of APP from the peptide's N-terminus, is adjacent to beta-amyloid and is cleaved from APP by one of the same enzymes. N-APP triggers the self-destruct pathway by binding to a neuronal receptor called death receptor 6 (DR6, also known as TNFRSF21).[10] DR6 is highly expressed in the human brain regions most affected by Alzheimer's, so it is possible that the N-APP/DR6 pathway might be expressed in the aging brain to cause damage. In this model, Beta-amyloid plays a complementary role, by depressing synaptic function.

3) A 2004 study found that deposition of amyloid plaques does not correlate well with neuron loss.[11] This observation supports the tau hypothesis, the idea that tau protein abnormalities initiate the disease cascade. Tau proteins are microtubule-associated proteins that are abundant in neurons in the central nervous system and are less common elsewhere. In this model, hyperphosphorylated tau begins to pair with other threads of tau. Eventually, they form neurofibrillary tangles inside nerve cell bodies.[12] When this occurs, the microtubules disintegrate, collapsing the neuron's transport system.[13] This may result first in malfunctions in biochemical communication between neurons and later in the death of the cells.[14] Herpes simplex virus type 1 has also been proposed to play a causative role in people carrying the susceptible versions of the apoE gene.[15]

Biochemistry

Enzymes act on the APP (amyloid precursor protein) and cut it into fragments. The beta-amyloid fragment is crucial in the formation of senile plaques in AD. Alzheimer's disease has been identified as a protein misfolding disease (proteopathy), caused by accumulation of abnormally folded A-beta and tau proteins in the brain. Plaques are made up of small peptides, 39–43 amino acids in length, called beta-amyloid . Beta-amyloid is a fragment from a larger protein called amyloid precursor protein (APP), a transmembrane protein that penetrates through the neuron's membrane. APP is critical to neuron growth, survival and post-injury repair. In Alzheimer's disease, an unknown process causes APP to be divided into smaller fragments by enzymes through proteolysis. One of these fragments gives rise to fibrils of beta-amyloid, which form clumps that deposit outside neurons in dense formations known as senile plaques.

AD is also considered a tauopathy due to abnormal aggregation of the tau protein. Every neuron has a cytoskeleton, an internal support structure partly made up of structures called microtubules. These microtubules act like tracks, guiding nutrients and molecules from the body of the cell to the ends of the axon and back. A protein called tau stabilises the microtubules when phosphorylated, and is therefore called a microtubule-associated protein. In AD, tau undergoes chemical changes, becoming hyperphosphorylated; it then begins to pair with other threads, creating neurofibrillary tangles and disintegrating the neuron's transport system.

Genetic Predisposition to Alzheimer's

There are two categories of genes that can play a role in determining whether a person develops a disease. Alzheimer genes have been found in both categories:

1) Risk genes increase the likelihood of developing a disease, but do not guarantee it will happen.

Scientists have so far identified one Alzheimer risk gene called apolipoprotein E-e4 (APOE-e4).APOE located on chromosome 19, contains the instructions needed to make a protein (apolipoprotein E) that helps carry cholesterol in the bloodstream. APOE comes in several different forms, or alleles. Three forms—APOE e2, APOE e3, and APOE e4—occur most frequently. APOE e2 is relatively rare and may provide some protection against the disease. If AD does occur in a person with this allele, it develops later in life than it would in someone with the APOE e4 gene. APOE e3 is the most common allele. Researchers think it plays a neutral role in AD—neither decreasing nor increasing risk. APOE e4 occurs in about 40 percent of all people who develop late-onset AD and is present in about 25 to 30 percent of the population. People with AD are more likely to have an APOE e4 allele than people who do not develop AD. People who inherit one copy of the APOE e4 allele have an increased chance of developing the disease; those who inherit two copies of the allele are at even greater risk. It is not known how the APOE e4 allele is related to the risk of Alzheimer disease. Researchers have found that this allele is associated with an increased number of protein clumps, called amyloid plaques, in the brain tissue of affected people. It must however be pointed out that many people with AD do not have an APOE e4 allele.

2) Deterministic genes directly cause a disease, guaranteeing that anyone who inherits them will develop the disorder.

Scientists have found rare genes that directly cause Alzheimer’s in only a few hundred extended families worldwide. When Alzheimer’s disease is caused by deterministic genes, it is called "familial Alzheimer’s disease." True familial Alzheimer’s accounts for less than 5 percent of cases.

Some cases of early-onset AD, called familial AD (FAD), are inherited. FAD is caused by a number of different gene mutations on chromosomes 21, 14, and 1, and each of these mutations causes abnormal proteins to be formed. Mutations on chromosome 21 cause the formation of abnormal amyloid precursor protein (APP) -- Alzheimer disease type 1; A mutation on chromosome 14 causes abnormal presenilin 1(PSEN1) to be made --Alzheimers disease type 3, and; mutation on chromosome 1 leads to abnormal presenilin 2 (PSEN2)--Alzheimer disease type 4. Since kindred's with autosomal dominant EOFAD with no identifiable mutations in PSEN1, PSEN2, or APP have been described; thus, it is likely that mutations in other genes are causative. Molecular genetic testing for PSEN1, PSEN2, and APP is available in clinical laboratories.

How does the APOE-4 gene affect Alzheimer's risk?

APOE is 299 amino acids long and transports lipoproteins, fat-soluble vitamins, and cholesterol into the lymph system and then into the blood. It is synthesized principally in the liver, but has also been found in other tissues such as the brain, kidneys, and spleen. In the nervous system, non-neuronal cell types, most notably astroglia and microglia, are the primary producers of APOE, while neurons preferentially express the receptors for APOE. The APOE gene, ApoE, is mapped to chromosome 19. The gene is polymorphic[4] with three major alleles, ApoE2, ApoE3, ApoE4, which translate into three isoforms of the protein: normal - ApoE-3; dysfunctional - ApoE-2 and ApoE-4. These isoforms differ from each other only by single amino acid substitutions at positions 112 and 158,[5].

The E4 variant is the only unequivocal genetic risk factor for late-onset Alzheimer's disease in a variety of ethnic groups. Caucasian and Japanese carriers of 2 E4 alleles have between 10 and 30 times the risk of developing AD by 75 years of age, as compared to those not carrying any E4 alleles.

Apolipoprotein E4 Potentiates Amyloid ? Peptide-induced Lysosomal Leakage and Apoptosis in Neuronal Cells*

..."These findings are consistent with apoE4 forming a reactive molecular intermediate that avidly binds phospholipid and may insert into the lysosomal membrane, destabilizing it and causing lysosomal leakage and apoptosis in response to A?1–42".

Apolipoprotein E fragments present in Alzheimer's disease brains induce neurofibrillary tangle-like intracellular inclusions in neurons.

..."These results suggest that apoE4 preferentially undergoes intracellular processing, creating a bioactive fragment that interacts with cytoskeletal components and induces NFT-like inclusions containing phosphorylated tau and phosphorylated neurofilaments of high molecular weight in neurons".

Apolipoprotein Receptor 2 and X11{alpha}/ß Mediate Apolipoprotein E-Induced Endocytosis of Amyloid-ß Precursor Protein and ß-Secretase, Leading to Amyloid-ß Production

ApoE4 (along with other apolipoproteins) attaches itself to a receptor on the surface of brain cells. That receptor, in turn, adheres to a protein known as amyloid precursor protein. The entire protein mass is then transported inside the cell where cutting enzymes – called proteases – attack the amyloid precursor protein.

Additional Genetic Factors

Researchers in the U.K. and France have found three genes that make Alzheimer's disease more likely when certain mutations are present. The genes -- which are called CLU, CR1, and PICALM -- may make good targets for new Alzheimer's disease treatments. Source: Genome-wide association study identifies variants at CLU and PICALM associated with Alzheimer's disease

CLU and Picalm genes account for 9 percent of cases each, and the CR1 gene is responsible for 4 percent. If we were able to remove the detrimental effects of these genes through treatments, we could reduce the proportion of people developing Alzheimer’s by 20 percent,” said Julie Williams, the study’s lead author and a professor of neuropsychological genetics at Cardiff University in Wales.

The CLU gene produces clusterin, which may protect the brain against damage from pathogens or kick in to calm an inflammatory response. Others seem to escort out excess amyloid, the plaque that builds up in patients’ brains.

A second study published in Nature Genetics, by Philippe Amouyel from Institut Pasteur de Lille in France, pinpointed CLU and CR1.

Currently available drugs for Alzheimers

Four medications are currently approved by regulatory agencies such as the US Food and Drug Administration (FDA) and the European Medicines Agency (EMEA) to treat the cognitive manifestations of AD: three are acetylcholinesterase inhibitors and the other is memantine, an NMDA receptor antagonist. No drug has an indication for delaying or halting the progression of the disease.

Drug Name	Molecular Structure	Mechanism of Action	Use
Aricept® (generic name: donepezil) Razadyne®, formerly known as Reminyl (generic name: galantamine)		acetylcholinesterase inhibitor --Prevents the breakdown of acetylcholine in the brain	For people with mild ,moderate or severe AD
Exelon® (generic name: rivastigmine)		acetylcholinesterase inhibitor --Prevents the breakdown of acetylcholine and butyrylcholine (a brain chemical similar to acetylcholine) in the brain	For people with mild or moderate AD
Razadyne®, formerly known as Reminyl (generic name: galantamine)		acetylcholinesterase inhibitors--Prevents the breakdown of acetylcholine and stimulates nicotinic receptors to release more acetylcholine in the brain	For people with mild or moderate AD
Memantine --Memantine is marketed under the brands Axura and Akatinol by Merz, Namenda by Forest, Ebixa and Abixa by Lundbeck and Memox by Unipharm		acting on the glutamatergic system by blocking NMDA glutamate receptors --Blocks the toxic effects associated with excess glutamate and regulates glutamate activation	Used to treat moderate to severe AD

Note: Cognex (generic name: tacrine) also an acetylcholinesterase inhibitors is not commonly used because of a number of side effects.

Cholinesterase inhibitors are the most widely used drugs for Alzheimer's disease. Cholinesterase inhibitors stop the breakdown of acetylcholine, a chemical in the brain used for memory and other mental functions. These types of medications help increase the levels of acetylcholine. In Alzheimer’s disease, there is a deficiency in acetlycholine in some areas of the brain, which accounts for some of the symptoms of the disease.

It is important to remember that these medications only slow the progression of dementia and Alzheimer's disease – they do not stop or reverse their course. These medications typically help for only months to a few years and may not work as well once the disease progresses. In general, individuals who use cholinesterase inhibitors experience few side effects. The most commonly-experienced side effects are gastrointestinal problems, such as nausea, diarrhea, vomiting, and loss of appetite.

Source: http://www.nia.nih.gov/Alzheimers/Publications/medicationsfs.htm

Research Strategies

Intervention strategies Researchers in Alzheimer's disease have identified several strategies as possible interventions against amyloid:

Beta-Secretase inhibitors. These work to block the first cleavage of APP outside of the cell. *

Gamma-Secretase inhibitors (e. g. Semagacestat). These work to block the second cleavage of APP in the cell membrane and would then stop the subsequent formation of Aß and its toxic fragments.

Selective Aß42 lowering agents (e. g. Tarenflurbil). These modulate gamma-secretase to reduce Aß42 production in favor of other (shorter) Aß versions. *

Immunotherapies. These stimulate the host immune system to recognize and attack Aß or provide antibodies that either prevent plaque deposition or enhance clearance of plaques.

Anti-aggregation agents.These prevent Aß fragments from aggregating or clear aggregates once they are formed. There is some indication that supplementation of the hormone melatonin may be effective against amyloid.

______________

Inhibition and Reversal of Tau Fibrils:

Researchers from UC Santa Barbara are investigating a water-soluble extract of cassia cinnamon that contains a class of small organic molecules that inhibit the aggregation of tau and disassembles fibers that have already formed, suggesting that neurofibrillary tangles can possibly be reversed by these compounds. The extract exhibits potent inhibitory activity, is orally available, water-soluble, non-toxic, and the bioactive molecules are likely brain permeable. The extract is readily produced in large quantities and can be encapsulated in powder form for oral administration.

TauRx Therapeutics from Singapore and Allon Therapeutics of Vancouver, presented human trial data for drugs that target tau. In a second-stage trial presented at the conference, one of the doses of the TauRx drug that was tested was able to dramatically slow the progression of the disease; the effect was almost twice as big as typically seen with existing drugs, Wischik says. "We have stopped the progression of AD for 19 months," he claimed. The drug tested is an old chemical that previously has been used for a variety of purposes, including treating urinary tract infections.

ATPZ analogues: These are drug-like inhibitors of AD tau protein clumping, as reported in the Journal Biochemistry---A number of ATPZ analogues were synthesized, and structure-activity relationships were defined. Further characterization of representative ATPZ compounds showed they do not interfere with tau-mediated MT assembly, and they are significantly more effective at preventing the fibrillization of tau than the Abeta(1-42) peptide which forms AD senile plaques. Thus, the ATPZ molecules described here represent a novel class of tau assembly inhibitors that merit further development for testing in animal models of AD-like tau pathology.

Antraquinones inhibit Tau Fibrils -- e.g., emodin which is also a cytotoxic anticancer drug.

ALCAR (acetyl-l-carnitine HCL) in phase III clinical trails, manufactured by Sigma-Tau Pharmaceuticals, attempts to provide a possible protective effect against neuritic tangles.

Drugs in the Pipeline for Alzheimers

A variety of clinical research trials are underway with agents that try either to decrease the amount of Aß1-42 produced or increase the amount of Aß1-42 removed. It is hoped that such therapies may slow down the rate of progression of Alzheimer's disease.

	Molecular Structure	Mechanism of Action	Clinical Trials
Bapineuzumab--Elan and Wyeth	This is a Monoclonal Antibody	Bapineuzumab is an antibody to the beta-amyloid plaques Note: phase II trial, which found that bapineuzumab failed to improve cognitive function in a test of 234 Alzheimer’s patients after 18 months of treatment.	PIII--Bapineuzumab in Patients With Mild to Moderate Alzheimer's Disease (ApoE4 Non-Carrier) -- Estimated Completion Dec. 2010 2014 : Bapineuzumab did not improve clinical outcomes in patients with Alzheimer's disease, despite treatment differences in biomarkers observed in APOE e4 carriers
Semagacestat LY451039 -- Elli Lilly		Gamma secretase inhibitor-- These work to block the second cleavage of APP in the cell membrane and would then stop the subsequent formation of amyloid --Semagacestat blocks the enzyme gamma-secretase which is responsible for APP proteolysis	Phase III --Effect of Gamma-Secretase Inhibition on the Progression of Alzheimer's Disease: LY450139 Versus Placebo in August 2010, a disappointing interim analysis, in which semagacestat performed worse than the placebo, led to the trials being stopped
Solanezumab (Eli Lilly)	This is a Monoclonal Antibody	Solanezumab is a monoclonal antibody that binds specifically to soluble amyloid beta and thereby alters the aggregating characteristics of this peptide.	Phase III Data set to be released in 2012.. see current study Solanezumab, a humanized monoclonal antibody that binds amyloid, failed to improve cognition or functional ability.
Gantenerumab	This is a Monoclonal Antibody	Gantenerumab is a monoclonal antibody that is currently being evaluated in a prodromal Alzheimer's Disease population	Gantenerumab: a novel human anti-Aß antibody demonstrates sustained cerebral amyloid-ß binding and elicits cell-mediated removal of human amyloid-ß. See 2012 study.. see current study
Dimebon -latrepirdine --from Medivation		This drug is an antihistamine used for 25 years in Russia---	Phase III- A Phase 3 Efficacy Study Of Dimebon In Patients With Moderate To Severe Alzheimer's Disease --Estimated Study Completion Date: July 2011
Flurizan (*) Myriad generic name tarenflurbil --“enantiomer,” or mirror-image molecule, of the non-steroidal anti-inflammatory drug flurbiprofen		Lowers toxic Aß42 production by selectively modulating, but not inhibiting, gamma-secretase activity to shift cleavage of amyloid precursor protein (APP) away from Aß42 production toward shorter, less toxic peptide fragments. This drug failed a PIII trial.	Fails PIII -- See Another Alzheimer’s Drug Fails in Large-Scale Trials
rember™-- Tau Aggregation Inhibitor (First and Second Generation) -- TauRx		blocks the formation of Tau oligomers -- ability to dissolve the tau fibers --	Phase II completed.TRx0014 in Patients With Mild or Moderate Alzheimer's Disease Phase II - Ongoing -Open Label Study of TRx0014 in Alzheimer's Disease
PBT2 8-Hydroxyquinoline derivative	Note: Image of 8-Hydroxyquinoline	targets metal-induced aggregation of Aß,	Completed a Phase IIa study in early Alzheimer's Disease patients and has demonstrated safety and tolerability and showed improvement in executive function Plans for PBT2 to Advance to Phase IIb TRIAL FAILED 2014

Note: Why did Flurizan fail? In the past several years, evidence has mounted that amyloid-beta-42, long considered the culprit in the disease, affects memory-related functions only when it has formed multi-protein conglomerations called “oligomers.” In the light of this concept, it is possible that Flurizan affects amyloid-beta-42 production in the brain and reduces the formation of insoluble amyloid deposits but has little or no effect on amyloid oligomer levels.

Initially, it was thought that the insoluble amyloid plaques were the pathologic culprits in AD. However, emerging evidence implicates soluble Aß aggregates as the mediators of neurotoxicity. The Aß rapidly aggregates by two separate pathways. The first leads to soluble oligomers, referred to as Aß-derived diffusible ligands (ADDLs), referred to as ADDLs. In a separate pathway, monomers can also form protofibrils that eventually generate fibrillar aggregates that coalesce into the characteristic insoluble amyloid. Several lines of in vivo evidence suggest that ADDLs and protofibrils , rather than monomeric Aß or insoluble amyloid plaques, mediate neurotoxicity.

LATEST NEWS UPDATES

Update July 31, 2017- Dementia: BACE inhibitor improves brain function

The protein amyloid beta is believed to be the major cause of Alzheimer's disease. Substances that reduce the production of amyloid beta, such as BACE inhibitors, are therefore promising candidates for new drug treatments. Scientists have recently demonstrated that one such BACE inhibitor reduces the amount of amyloid beta in the brain. By doing so, it can restore the normal function of nerve cells and significantly improve memory performance. read more

Update January 25, 2017 --Drug compound halts Alzheimer's Related Damage

Now, a new drug that could treat Alzheimer's disease, SAK3, has been developed by a Japanese research group led by Tohoku University Professor Kohji Fukunaga.In their study, the researchers found that the T-type calcium channel enhancer, SAK3, stimulates the release of acetylcholine in the brain and improves cognition by activating the memory molecule CaMKII. read more...

Update July 25, 2016 --Antibiotic-induced perturbations in gut microbial diversity influences neuro-inflammation and amyloidosis in a murine model of Alzheimer’s disease

..."We show that prolonged shifts in gut microbial composition and diversity induced by long-term broad-spectrum combinatorial antibiotic treatment regime decreases Aβ plaque deposition...These findings suggest the gut microbiota community diversity can regulate host innate immunity mechanisms that impact Aβ amyloidosis.. Abstract and Article

Update March 18, 2016 --Tryptophan-2,3-dioxygenase (TDO) inhibition ameliorates neurodegeneration by modulation of kynurenine pathway metabolites

Genetic inhibition of two KP enzymes—kynurenine-3-monooxygenase and tryptophan-2,3-dioxygenase (TDO)—improved neurodegeneration and other disease symptoms in fruit fly models of AD, PD, and HD, and that alterations in levels of neuroactive KP metabolites likely underlie the beneficial effects. Furthermore, it was found that inhibition of TDO using a drug-like compound reverses several disease phenotypes, underscoring the therapeutic promise of targeting this pathway in neurodegenerative disease... See Article in PNAS).

Update November 14, 2015 --Experimental drug J147 targeting Alzheimer's disease shows anti-aging effects

The Salk team expanded upon their previous development of a drug candidate, called J147 (see information and molecular structure of J147) , which takes a different tack by targeting Alzheimer's major risk factor–old age. In the new work, the team showed that the drug candidate worked well in a mouse model of aging not typically used in Alzheimer's research. When these mice were treated with J147, they had better memory and cognition, healthier blood vessels in the brain and other improved physiological features, as detailed. Salk Institute says Human Trials to begin in 2016. Journal Aging November 12, 2015 in the See previous research-- Abstract.. Full Article...The neurotrophic compound J147 reverses cognitive impairment in aged Alzheimer's disease mice --

Update July 20, 2015 --Novel antibodies show promise for Alzheimer's disease treatment--

NeuroPhage's NPT088 --Universally Targets Misfolded Proteins in Preclinical Studies Highlighted in Oral Session at the Alzheimer's Association International Conference-- (Fusion Protein -- antibody--) -- See The Virus that could cure Alzheimers.

See also: Scientists at NYU have evidence that monoclonal antibodies they developed may provide the blueprint for effective treatments for Alzheimer's disease and other neurodegenerative diseases, such as Parkinson's disease. Read news release

Update June 11,2015 --Axovant goes publc --main product candidate, RVT-101, aims to treat dementia in patients with Alzheimer’s disease --

RVT-101 has demonstrated statistically significant results on cognition as measured by the ADAS-cog and on function as measured by the ADCS-ADL in a randomized, placebo-controlled 684-subject study spanning 48 weeks of therapy, administered once-daily on a background of stable donepezil therapy. RVT-101 was well-tolerated by subjects in all 13 clinical trials conducted by GSK. We intend to commence a confirmatory phase 3 study in 2015.

Update Sept 11,2014 --In mouse model of Alzheimer's disease, targeted immune booster removes toxic proteins

Alzheimer's disease experts at NYU Langone Medical Center and elsewhere are reporting success in specifically harnessing a mouse's immune system to attack and remove the buildup of toxic proteins in the brain that are markers of the deadly neurodegenerative disease. Researchers say the immune booster reduced both amyloid beta plaques and tau tangles. Clinical Trial could begin in 2015... see full text of news release see Abstract of study.

Update August 22, 2014 - Creating pomegranate drug to stem Alzheimer's, Parkinson's
Research will look to produce compound derivatives of punicalagin for a drug that would treat neuro-inflammation and slow down the progression of Alzheimer's disease, scientists report. see Abstract in Molecular Nutrition

New Update Jan 2014 --Dominantly Inherited Alzheimer Network Trial: An Opportunity to Prevent Dementia (DIAN TU)

This international study will assess the safety, tolerability, and biomarker efficacy of the drugs gantenerumab and solanezumab in individuals who have a genetic mutation for autosomal-dominant Alzheimer's disease. see full text

New Update -- June 18, 2013 ---Reversing the loss of brain connections in Alzheimer’s disease -

A New Drug --NitroMemantine-- Reverses Loss of Brain Connections in Alzheimer's by shutting down hyperactive eNMDA receptors on diseased neurons, NitroMemantine restores synapses between those neurons...."The Food and Drug Administration-approved drug memantine offers some beneficial effect, but the improved eNMDAR antagonist NitroMemantine completely ameliorates Aß-induced synaptic loss, providing hope for disease-modifying intervention in AD. "..- See abstract in PNAS.

Molecular structure for NitroMemantine ---- Source: Talantova et al. 10.1073/pnas.1306832110

New Update - March 26, 2012 --PLoS ONE Journal Publishes Mechanistic Model of Alzheimer's Disease Endorsing Prana's PBT2 .

"This paper builds on Prana’s previously published findings that as we age our ability to maintain normal zinc distribution deteriorates. Abeta forms amyloid by capturing and holding zinc, which in turn further reduces our ability to maintain normal zinc distribution. “This is a vicious pathological cycle. PBT2 interrupts this cycle, re-distributing zinc needed for healthy brain function..”

See Full Article: The Zinc Dyshomeostasis Hypothesis of Alzheimer's Disease.

New Update - March 13, 2012 Potential Alzheimer's Disease Drug Slows Damage and Symptoms in Animal Model

A compound that previously progressed to Phase II clinical trials for cancer treatment slows neurological damage and improves brain function in an animal model of Alzheimer's disease, according to a new study. Summary from ScienceDaily

The Microtubule-Stabilizing Agent, Epothilone D, Reduces Axonal Dysfunction, Neurotoxicity, Cognitive Deficits, and Alzheimer-Like Pathology in an Interventional Study with Aged Tau Transgenic Mice

New Update - February 14, 2012 --Turmeric-Based Drug Effective On Alzheimer Flies

"Curcumin, a substance extracted from turmeric, prolongs life and enhances activity of fruit flies with a nervous disorder similar to Alzheimers, according to new research. The study conducted at Linköping University, indicates that it is the initial stages of fibril formation and fragments of the amyloid fibrils that are most toxic to neurons..." Summary from ScienceDaily

Source: Curcumin Promotes A-beta Fibrillation and Reduces Neurotoxicity in Transgenic Drosophila

**New Update February 9, 2012 --Alzheimer's Disease Symptoms Reversed in Mice --The cancer drug bexarotene given to mice eliminates brain-damaging proteins, leading to improved cognition.

The cancer drug was given to mice and eliminated brain-damaging proteins, leading to improved cognition within days, but it is not known if it will work in humans. See review article in Scientific American Online

**New Update -- December 12, 2011 --The Journal of Biological Chemistry published a study offering powerful validation of PBT2 as a treatment for a number of neurodegenerative diseases, including Alzheimer's, Parkinson's and Huntingtons diseases

PBT2 is Prana Biotechnology's lead drug for treating dementia in Alzheimer's and Huntington's disease. It is a specific type of 8-OHQ. Prana designed and selected PBT2 therapy for its enhanced efficacy and tolerability.

See the full publication: , "Different 8-OHQ's Protect Models of TDP-43, alpha-synuclein, and Polyglutamine Proteotoxicity through Distinct Mechanisms".

***New Update -- December 14, 2011 --Alzheimer's drug candidate may be first to prevent disease progression Salk scientists develop new drug that improves memory and prevents brain damage in mice --

A new drug candidate may be the first capable of halting the devastating mental decline of Alzheimer's disease, based on the findings of a study published today in PLoS one. When given to mice with Alzheimer's, the drug, known as J147, improved memory and prevented brain damage caused by the disease. The new compound, developed by scientists at the Salk Institute for Biological Studies, could be tested for treatment of the disease in humans in the near future. "J147 enhances memory in both normal and Alzheimer's mice and also protects the brain from the loss of synaptic connections," says David Schubert, the head of Salk's Cellular Neurobiology Laboratory, whose team developed the new drug. "No drugs on the market for Alzheimer's have both of these properties." Although it is yet unknown whether the compound will prove safe and effective in humans, the Salk researchers' say their results suggest the drug may hold potential for treatment of people with Alzheimer's. read more...

New Update Novemember 29,2011 Surprisingly Few U.S. Physicians and Payers Surveyed Are Familiar with Late-Stage Emerging Alzheimer's Disease Therapies -- Resources, one of the world's leading research and advisory firms for pharmaceutical and healthcare issues, finds that, in the United States, surprisingly few surveyed neurologists are familiar with key emerging therapies for Alzheimer's disease on which they were surveyed.Less than one-quarter of surveyed neurologists were familiar with the anti-beta-amyloid monoclonal antibodies solanezumab (Eli Lilly) and bapineuzumab (Janssen Alzheimer Immunotherapy/Pfizer) and less than 10 percent of PCPs were familiar with these emerging disease-modifying drugs. .. read more

New Update March 3, 2011 Scripps Research study points to liver, not brain, as origin of Alzheimer's plaques

Unexpected results from a Scripps Research Institute and ModGene, LLC study could completely alter scientists' ideas about Alzheimer's disease—pointing to the liver instead of the brain as the source of the "amyloid" that deposits as brain plaques associated with this devastating condition. The findings could offer a relatively simple approach for Alzheimer's prevention and treatment. read more

New Update Jan 27, 2011 Stimulating The Brain's Immune Response May Provide Treatment For Alzheimer's Disease

A new target for the prevention of adverse immune responses identified as factors in the development of Alzheimer's disease (AD) has been discovered by researchers at the University of South Florida's Department of Psychiatry and the Center of Excellence for Aging and Brain Repair. read more

New Update Jan 6, 2011 -- Blood Test for Alzheimers

Using a new technology that relies on thousands of synthetic molecules to fish for disease-specific antibodies, researchers have developed a potential method for detecting Alzheimer's disease with a simple blood test. The same methodology might lead to blood tests for many important diseases, according to the report in the January 7th issue of the journal Cell, a Cell Press publication. read more

New Update -- Jan 8 2010 --New approach to fighting Alzheimer's shows potential in clinical trial Nutrient mix shows promise in improving memory

In a clinical trial of 225 Alzheimer's patients, researchers found that a cocktail of three naturally occurring nutrients believed to promote growth of those connections, known as synapses, plus other ingredients (B vitamins, phosopholipids and antioxidants), improved verbal memory in patients with mild Alzheimer's. -- read more

New Update Oct. 16, 2009 -- IL-6 (Interleukin-6) shown to remove plaque from Alzheimer's mouse model

Published online in The FASEB Journal, data is based on the unexpected finding that when the brain's immune cells (microglia) are activated by the interleukin-6 protein (IL-6), they actually remove plaques instead of causing them or making them worse. read Abstract (Massive gliosis induced by interleukin-6 suppresses A deposition in vivo: evidence against inflammation as a driving force for amyloid deposition Paramita Chakrabarty, Karen Jansen-West, Amanda Beccard, Carolina Ceballos-Diaz, Yona Levites, Christophe Verbeeck, Abba C. Zubair, Dennis Dickson, Todd E. Golde, and Pritam Das)

New Update Jul 15, 2009 Significant Increase in Overall Executive Function With PBT2

The presentation was entitled "PBT2 ameliorates cognitive impairment in Alzheimer's disease transgenic and aged mice: Evidence for a common mechanism of action." New data indicates PBT2 benefits not only Alzheimer's disease patients, but also could treat the cognitive loss commonly associated with the normal ageing process. PBT2 lowers amyloid burden in the brain and also corrects metal imbalances that occur in the aged brain. Plans for PBT2 to Advance to Phase IIb Clinical Trial Testing. See News Release.

New Update April 16, 2009 -- Depletion of circulating SAP and , almost complete, disappearance of SAP from the CSF

Here, in this unique study in Alzheimer's disease from the Journal PNAS, the bis(d-proline) compound, (R)-1-[6-[(R)-2-carboxy-pyrrolidin-1-yl]-6-oxo-hexanoyl]pyrrolidine-2-carboxylic acid (CPHPC), was shown to deplete circulating SAP and almost complete, disappearance of SAP from the CSF. Kolstoe et.al., demonstrate that SAP depletion in vivo is caused by CPHPC cross-linking pairs of SAP molecules in solution to form complexes that are immediately cleared from the plasma. Article Title: Molecular dissection of Alzheimer's disease neuropathology by depletion of serum amyloid P component, See Abstract.

Note: Pentraxin Therapeutics Ltd, has acquired the full rights to CPHC. In February 2009 Pentraxin Therapeutics Ltd licensed CPHPC to GlaxoSmithKline for treatment of systemic amyloidosis, a rare fatal disease.

References

1 - Shen ZX (2004). "Brain cholinesterases: II. The molecular and cellular basis of Alzheimer's disease". Med Hypotheses 63 (2): 308–21. doi:10.1016/j.mehy.2004.02.031. PMID 15236795.

2 - a b Wenk GL (2003). "Neuropathologic changes in Alzheimer's disease". J Clin Psychiatry 64 Suppl 9: 7–10. PMID 12934968.

3 - Hardy J, Allsop D (October 1991). "Amyloid deposition as the central event in the aetiology of Alzheimer's disease". Trends Pharmacol. Sci. 12 (10): 383–88. doi:10.1016/0165-6147(91)90609-V. PMID 1763432.

4- a b Mudher A, Lovestone S (January 2002). "Alzheimer's disease-do tauists and baptists finally shake hands?". Trends Neurosci. 25 (1): 22–26. doi:10.1016/S0166-2236(00)02031-2. PMID 11801334.

5 -Nistor M, Don M, Parekh M, et al. (October 2007). "Alpha- and beta-secretase activity as a function of age and beta-amyloid in Down syndrome and normal brain". Neurobiol Aging 28 (10): 1493–1506. doi:10.1016/j.neurobiolaging.2006.06.023. PMID 16904243.

6 - Lott IT, Head E (March 2005). "Alzheimer disease and Down syndrome: factors in pathogenesis". Neurobiol Aging 26 (3): 383–89. doi:10.1016/j.neurobiolaging.2004.08.005. PMID 15639317.

43- Polvikoski T, Sulkava R, Haltia M, et al. (November 1995). "Apolipoprotein E, dementia, and cortical deposition of beta-amyloid protein". N Engl J Med 333 (19): 1242–47. doi:10.1056/NEJM199511093331902. PMID 7566000.

7- Transgenic mice: Games D, Adams D, Alessandrini R, et al. (February 1995). "Alzheimer-type neuropathology in transgenic mice overexpressing V717F beta-amyloid precursor protein". Nature 373 (6514): 523–27. doi:10.1038/373523a0. PMID 7845465.

Masliah E, Sisk A, Mallory M, Mucke L, Schenk D, Games D (September 1996). "Comparison of neurodegenerative pathology in transgenic mice overexpressing V717F beta-amyloid precursor protein and Alzheimer's disease". J Neurosci 16 (18): 5795–811. PMID 8795633.

Hsiao K, Chapman P, Nilsen S, et al. (October 1996). "Correlative memory deficits, Abeta elevation, and amyloid plaques in transgenic mice". Science (journal) 274 (5284): 99–102. doi:10.1126/science.274.5284.99. PMID 8810256.

Lalonde R, Dumont M, Staufenbiel M, Sturchler-Pierrat C, Strazielle C. (2002). "Spatial learning, exploration, anxiety, and motor coordination in female APP23 transgenic mice with the Swedish mutation.". Brain Research (journal) 956: 36–44,year=2002. doi:10.1016/S0006-8993(02)03476-5. PMID 12426044.

8 - Holmes C, Boche D, Wilkinson D, et al. (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): 216–23. doi:10.1016/S0140-6736(08)61075-2. PMID 18640458. ^ Lauren J, Gimbel D, et al. (February 2009). "Cellular prion protein mediates impairment of synaptic plasticity by amyloid-beta oligomers". Nature 457 (7233): 1128-32. PMID 19242475.

9 Lauren J, Gimbel D, et al. (February 2009). "Cellular prion protein mediates impairment of synaptic plasticity by amyloid-beta oligomers". Nature 457 (7233): 1128-32. PMID 19242475.

10- a b Nikolaev, Anatoly; Todd McLaughlin, Dennis O'Leary, Marc Tessier-Lavigne (19 February 2009). "N-APP binds DR6 to cause axon pruning and neuron death via distinct caspases". Nature 457 (7232): 981–989. doi:10.1038/nature07767. ISSN 0028-0836. PMID 19225519.

11- Schmitz C, Rutten BP, Pielen A, et al. (April 2004). "Hippocampal neuron loss exceeds amyloid plaque load in a transgenic mouse model of Alzheimer's disease". Am J Pathol 164 (4): 1495–1502. PMID 15039236.

12- Goedert M, Spillantini MG, Crowther RA (July 1991). "Tau proteins and neurofibrillary degeneration". Brain Pathol 1 (4): 279–86. doi:10.1111/j.1750-3639.1991.tb00671.x. PMID 1669718.

13 - Iqbal K, Alonso Adel C, Chen S, et al. (January 2005). "Tau pathology in Alzheimer disease and other tauopathies". Biochim Biophys Acta 1739 (2-3): 198–210. doi:10.1016/j.bbadis.2004.09.008. PMID 15615638.

14 - Chun W, Johnson GV (2007). "The role of tau phosphorylation and cleavage in neuronal cell death". Front Biosci 12: 733–56. doi:10.2741/2097. PMID 17127334.

15 - Itzhaki RF, Wozniak MA (May 2008). "Herpes simplex virus type 1 in Alzheimer's disease: the enemy within". J Alzheimers Dis 13 (4): 393–405. ISSN 1387-2877. PMID 18487848. http://iospress.metapress.com/openurl.asp?genre=article&issn=1387-2877&volume=13&issue=4&spage=393.

16 - Moan R (July 20, 2009). "MRI software accurately IDs preclinical Alzheimer’s disease". Diagnostic Imaging. http://www.diagnosticimaging.com/news/display/article/113619/1428344.