Alzheimer’s disease

US Patents for transgenic mice models: U.S. Patent 5,387,742 U.S. Patent No. 5,602,299

Diagnostic Tests: Quest (The calculated ratio of Beta-amyloid 40 and Beta-amyloid 42)

Introduction:

Alzheimer’s disease (AD) is the most common neurodegenerative disorder and the main cuase of dementia. (Rhinn, “Shifting paradigms: The central role of microglia in Alzheimer’s disease” Neurobiology of Disease 143 (2020)). The Alzheier’s treatment space is projected to be wroth 15.5 billion by 2031, accordig to hHealthcareAnalyst.

AD is a progressive disease resulting in senile dementia. It is a progressive disease of the human central nervous system and manifested by dementia in the elderly, by disorientation, loss of memory, diffficulty with language, calculation, or visual spatial skills and by psychiatric manifestations. It is estimated that healthcare spending on Alzheimer’s disease and related age related dementials in 2012 is 200 billion in the US alone.

AD falls into 2 categories: late onset, which occurs in old age (65+ years) and early onset which develops before the senile period (between 35-60). In both types, the pathology is the same but the abnormalities tend to be more severe and widespread in cases beginning in early age.

Pathology and Biomarkers:

Alzheimer’s disease (AD) is a progressive neurodegenerative disease affecting nerve cells located within higher cortical centers that ultimately results in impaired cogntion, including a gradual decline in memory, judgment, and communication. AD is characterized by at least 2 types of lesions in the brain, neurofibrillary tangles and senile plaques. The principal constituent of the plaques is a peptide called “Abeta or beta-amyloid peptide”.

AD shares features with otehr neurodegenerative disorders such as cerebral atrophy, neuron and synapse loss, accumulation of intracellular protein aggregates in neurons, and glial activation, but also other features more specific to AD such as the accumulation of extracellular proteins aggregates, called amyloid plaques. (Rhinn, “Shifting paradigms: The central role of microglia in Alzheimer’s disease” Neurobiology of Disease 143 (2020))

AD is characterized by the presence within the brain of amyloid fibril containing neuritic plaques comprised of proteolytically derived 40-42 resiude fragments of the amyloid precursor protein. Historially, Abeta fibrils have been deemed primarily responsible for neuronal dysfunction and death; however, more recent evidence indicates that oligomers, which includes soluble cross-lined beta-amyloid protein species (CAPS), are the most pathogenic Abeta conformers. (Nuallain, Biochemistry 2008, 47, 12254-12256).

AD is characterized by age-assocaited progressive memory decline. Two hallmarks of AD are amyloid beta and tau.

Amyloid Peptides: (e.g., Amyloid beta protein):

Neuropathological and genetic data stronly supports a primary role for amyloid peptides, particulalry amyloid beta protein, which accumulate as seile plaques in brain parenchyma, in the pathogenesis of AD. The presence of circulating Abeta like antibodies in the peripheral blood of AD pateints is known (Mruthinti, Neurobiology of Aging 25 (2004) 1023-1032).

Abeta peptide is a 4 kDa internal fragment of 39-43 amino acids of a larger transmembrane glycoprotein named amyloid precursor protein (APP). As a result of proteolytic processing of APP by different secretase enzymes, Abeta is primarily found in both a short form, 40 amino acids in lenght, and a long form, rangering from 42-43 amino acids in lenght. Several mutations within the APP protein have been correlated with the presence of AD.

The amyloid hypothesis holds that the accumulation of amyloid-beta (Aβ) is responsible for Alzheimer’s disease. Proponents of this theory believe that when amyloid beta clumps together to form deposits in the brain, it triggers neurodegenerative processes that lead to the loss of memory and cognitive abilities that characterize the disorder. Despite the recent FDA approval of anti-amyloid antibodies for Alzheimer’s disease and new investment in the space, skepticism remains about the value of these first disease-modifying drugs and the validity of the amyloid hypothesis. (“Amyloid Hypothesis in Doubt as Newly Approved Drugs Hit Hurdles” Biospace, 2024)

While the exact role of Aβ in Alzheimer’s is up for debate, anti-amyloid antibodies without a doubt have some effect on the disease process. Legembi (see below) for example educed clinical decline by 27% compared to placebo based on the Clinical Dementia Rating-Sum of Boxes (CDR-SB) assessment in patients with mild-to-moderate Alzheimer’s, and Kisunla (see bloew) reduced decline by 29% on the CDR-SB. But “The effect is less than Aricept [an earlier Alzheimer’s drug], and yet they’re moving forward. If the theory was correct, if you remove the amyloid, some patients should get better. Thus while amyloid is “important” to the Alzheimer’s disease process, it is not the driver. Rather, amyloid accumulation may be a response to neural damage, given that antioxidant qualities found in amyloid-beta. With the currently approved anti-amyloid antibodies, the amount of drug that gets into your brain is also about 1%, which is not a very efficient way of treating Alzheimer’s disease. Several companies—including Denali Therapeutics, Voyager Therapeutics and Aliada—are developing technologies to improve on that number. Roche’s anti-amyloid antibody trontinemab is an example of a therapy attempting to get the antibody across the BBB. Developed using the company’s proprietary Brainshuttle platform, trontinemab can cross the BBB and achieve higher levels of brain exposure and broader distribution across the central nervous system. at this point, that Alzheimer’s will have to be treated with multiple drugs attacking multiple mechanisms that are related to the biology of aging. (“Amyloid Hypothesis in Doubt as Newly Approved Drugs Hit Hurdles” Biospace, 2024)

Amyloid Beta Oligomers and Fibrils: Amyloid beta fibrils are been found primarily responsible for neuronal dysfunction and death. In addition, oligomers that include soluble cross-linked beta amyloid protein species (CAPS) have also been found detrimental. (Nuallain, Biochemistry, 2008, 47, pp. 12254-12256).

Receptor for AGEs (RAGE): occur in AD brain within hippocampal pyramidal cells, cortical neurons, glial cells and white matter. Some evidence exists to suggest that RAGE permits the accumulation, supports the aggregate of Abeta, resulting in inflammation and cytotoxicity in neuronal cells. AD individuals are also known to express high levels of anti-RAGE IgGs as shown from purificaiton of RAGE from plasma samples. (Mruthinti, Neurobiology of Aging 25 (2004) 1023-1032).

Tau:

–hyperphosphorylation

Tau is a microtubule (MT) associated protein particularly abundant in neurons, where it mostly localizes to axonal regions. It regulates MT stability and the maintenance of axonal transport. Under physiological conditions, tau binding to MTs is coordinated by phosphorylation, requiring a precise interplay of a multitude of kinases and phosphatases. In pathological conditions such as AD and related neurodegeenrative disorders called tauopathies, increased phosphorylation of tau is associated with a decrease in its binding to microtubules. This in turn results in tau misolding and self-aggregation, eventually leading to the accumulation of insoluble, paired helical filaments and other filamentous structures. Thai pathological tau aggregation is a shared molecular mechanism in more than 20 neurodegenerative conditions, including AD. While tau in the noraml brain contains 2-3 phosporylated residues per tau molecule, it is estimated to be about 3-fold hyper-phosphorylated in AD brain. Accumulating data indicates that phosphorylation alone is not sufficient for aggregation and might even serve a protective role. Several other post-translational modifications such as acetylation, ubiquitination, methylation and glycosylation among others appear to play regulatory roles as well with respect to rates of tau clearance and aggregation and thus contribue to tau pathology. (Steen, WO 2017/053739).

—-Specific patterns of hyperphosphorylation

——T205 and T181:

Barthelemy (US 17/015,985, published as US 2020/0400689; see also US Patent applicaiton No: 17/368403 published as US 2021/0341495) discloses a method for selecting a therapeutic agent that prevents amyloid deposit and reduces amyloid plaque load or targets neurofibrillary tangles based on a specific tau phosphorylation pattern. In one embodiment, a therapeutic agent is administered when the isolated tau sample from a subject contains tau phosphorylation at T181 or p217 at about 1.5 dstand deviations above and tauphosphorylation at T205 that is below about 1.5 standard deviations.

Russel “Comprehensive quantitative profiling of Tau and phosphorylated Tau peptides in cerebrospinal fluid by mass spectrometry provides new biomarker candidates” J of Alzheimer’s disease, 55 (2017) 303-313) disclsoes that aberrant tau phosphorylation is a hallmark in AD and that cerebrospinal fluid (CSF) levels of total tau and tau phosphorylated at threonine resiude 181 (pThr181) are established ore biomarkers for AD.

Vasan (US 2008/0220449) discloses diagnosing, stratifying and monitoring the progression or regression of AD which includes detecting in a sample a level of at least phosphorylated tau pT217, soluble tau oligomer, tau-amyloid-beta 1-42 complex and a combination thereof and comparing the level form the sample to a reference level. Vasan disclsoes that other biomarkers for AD utilize the ratio of p-tau to Abeta1-42 as a senstive marker for discriminating patients with AD form healthy controls and that changes in lvels of tau and Abeta-142, pTau 181 over teh baseline were much higher between groups than in the same groups during the progression of the disease.

——Ser202/Thr205/Ser208:

Despres (PNAS, “Identificaiton of the Tau phosphorylation pattern that drives its aggregation” 2017, 114(34)) discloses using in vitro kinase assays combeind with NMR spefctroscopy to show that the combined phosphorylation at the Ser202/Thr205/Ser208 sites, together with absence of phosphorylation at the Ser262 sites, yeild a Tau sample that readily forms fibers, as observed by thioflavin T fluorescence and electron microscopy.

–Tau kinases and their inhibitors

Multiple protein kinases such as GSK3 (a serine/threonine kinase), CDK5, Akt and PKA can phosphorylate tau. (Xu, US 2009/0233993).

The thousand-and-one amino acid kinases (TAOKs) 1 and 2 phosphorylate tau on more than 40 residues in vitro.. TAOKs are phosphorylated and active in AD brains actions displaying tau patholoy and active TAOKs co-localise with both pre-tange

le and tangle structures. TAOK inhibitors can reduce tau phosphorylation on T123 and T427 and also on additional pathological sites. Such TAOK inhibitors also have been shown to decrease tau phosphorylation in differentiated primary cortical neurons. ((Giacomini, Acta Neuropathologica Communications (2018) 6: 37).

Reagan (US 2009/0104628) discloses a method for measuring phosphorylation of proteins such as tau at specific serine, threonine or tyrosine residues by subjecting the protein to a reaction mixture that includes a phosphokinase which allows the creation of a phosoryalted form of the protein which is then contacted with an antibody specific for the phosphorylation site(s).

Role of Microglia:

Genome-Wide Associattion studies from large European and American consortia identified common genetic polymorphisms at loci harboring gnes with microglia-specific epxrewssion pattern in the CNS, such as ABC7, CD33 and members of the MS4A genes cluster as genetic determinatns of AD risk. The identificaiton of TREM2 R47H and its strong effect size on AD risk association marked a turning point in establshing microglia as a central play in AD pathogenesis. (Rhinn, “Shifting paradigms: The central role of microglia in Alzheimer’s disease” Neurobiology of Disease 143 (2020))

–APOE:

While APOE is predominantly expressed by astrocytes in the healthy brain, it is dramatically upregulated by microglia upon inflammation or injury. Genome-Wide Associattion studies from large European and American consortia identified common genetic polymorphisms at loci harboring gnes with microglia-specific epxrewssion pattern in the CNS, such as ABC7, CD33 and members of the MS4A genes cluster as genetic determinatns of AD risk. (Rhinn, “Shifting paradigms: The central role of microglia in Alzheimer’s disease” Neurobiology of Disease 143 (2020))

–TREM2:

TREM2 is an imune receptor exprewssed in the myeloid lineage, priimarily tissue resident macrophages, including microglia and osteoclasts. TREM2 is a cell surface receptor containing one immunoglobulin domain with no intracellular signaling motifes. Instead TREM2 binds sto the adaptor protin DAP12/TYROBP and to a less extent to DAP10. DAP12 has an immunoreceptor tyrosin-based activating motif (ITAM) that acts as a signal transducer and DAP12 is also essential to traffice TREM2 to the cell surface. A vareity of tREM2 lgiands have been identified, including phospholipids, bacterail surface antigens as well as the AD risk genes APOE and APOJ/CLU. Ligand binding to tREM2 clusters the receptor, which induces DAP12 phosphorylation at the ITAM, recruitment and phosphorylation of SYK and subsequent activation of a downstream signaling cascade that has primarily been studied in osteoclasts, DCs and somewhat in microglia. TREM2 ligation idncues recruitment of SHIP1 and PI3K, which signals through mTOR, as well as activaiton and nuclear transport of beta-cartenin and rapid calcium influx and phosphyrlation of ERK1/2 Human genetics has shown a central role for microglia in AD etiology. The identification of TREM2 as a genetic risk factor marked a turning point in AD genetics. TREM2 R47H was a rare nonsynonymous coding mutation in a known gene, known to be exclusively expressed in microglia in the brain. Mutations in TREM2 and DAP12/TYROBP, its binding partner, were known to cause Nasu-Hakola disease, which is characterized by early onset dementia (among other patholgies in the periphery) and the strong effect size of the mutation that tripled diease risk was proof of its importance. The most prevalent TREM2 mutation associated with AD is the R47H missense mutation. While this variant does not appear to modulate TREM2 expression, maturation or localization, it does reduce ligand binding and ligand mediated TREM2 signaling, suggesting that it is a hypomorphic mutation. Furthermore, people carrying two copies of different TREM2 hypomorphic or loss of funciton mutations develop early onset neurodegenerative diseases, such as leukodystrophy, called Nasu-Hakola Disease or Frontotemperoal dementia. (Rhinn, “Shifting paradigms: The central role of microglia in Alzheimer’s disease” Neurobiology of Disease 143 (2020))

–CD33:

CD33 is a member of the Siglec family of sialic acid bidning receptors. It carries an immunoreceptor tyrosin-based inhibitory motif (ITIM). Siglects generally funciton by engaging specific sialidated glycans on either neighboring cells (trans) or the same cell (cis ) an dwhen engaged, they block the activity of ITAM carrying receptors by recruiting SH2 domain phosphatases that induce dephosphorylation of SYK. CD33 was identified as an AD risk gene by GWAS analysis. SNPs that reduce CD33 expression are assocaited witih a reduced AD risk and reduced CD33 expression correlates with reduced Abeta pathology in human AD patient brains. Later on, the funcitonal SNP was identified to casue alternative splicing of CD33 that reoves its ligand binding domain and reduces cell surface expression. Genome-Wide Associattion studies from large European and American consortia identified common genetic polymorphisms at loci harboring gnes with microglia-specific epxrewssion pattern in the CNS, such as ABC7, CD33 and members of the MS4A genes cluster as genetic determinatns of AD risk. (Rhinn, “Shifting paradigms: The central role of microglia in Alzheimer’s disease” Neurobiology of Disease 143 (2020))

Diagnostics/Detection:

–Amyloid PET imagaging:

Amyloid PET is a well established biomarker that is widely used in clincial trails and observational studies to detmerine brain amyloid plaque burden. (Bateman, “Validation of plasma amyloid-ß 42/40 for detecting Alzheimer Disease amyloid plaques” American Academy of Neurology, 2021).

–Aβ42/Aβ40:

Plasma Aβ42/Aβ40 is a robust measure for detecting amyloid plaques and can be utilized to aid in the diagnosis of AD and identify those at risk for future dementia due to AD. Thea ssay has been developed commercially (PrecivityAD by C2N Diagnostics) and is being used by physicains in the clinic to detect amyloid plaques and assit in diagnosis of AD dementia. (Bateman, “Validation of plasma amyloid-ß 42/40 for detecting Alzheimer Disease amyloid plaques” American Academy of Neurology, 2021).

—-The AD-Detect Test for Alzheimer’s Disease (Quest Diagnostics): is a blood test for Alzheimer’s disease, measures A-beta 42 and A-beta 40 biomarkers (a biological marker of a molecule found in the body that may be used in evaluating a disease state) in the blood and provides the A-beta 42/40 ratio. The ratio between these two molecular biomarkers may help to detect risk of Alzheimer’s disease in an individual.

Treatment:

The FDA has approved two types of medications for the maangement of Alzheimer’s disease: cholinesterase inhibitors and the NMDA-type glutamate receptor inhibitor memantine. These therapies serve to alleviate cognitive symptoms such as memory loss, confusion and loss of critical thinking abilities in subjects diagnosed with age related dementia. In addiition to these approved therapies, several sutdies have suggested that poole intravenous immunoglbulin is effective in slowing the progression fo symptoms. (Hofbauer, US2014/0271669).

Under certain circumstances, immune cells in the brain, known as microglia, promote the inflammatory and destructive process that can lead to Alzheimer’s disease. It has been reported that once a specific molecule on the surface of microglia, CD40, get activated by its partner, CD40 ligand, the scene is set for microglial injury to the main cells in the brain; the neurons.

Researchers are currently administering anti-CD40 ligand antibody to mice so as to develop symptoms similar to Alzheimer’s disease. The mice can then be immunized with an investigational anti-Alzheimer’s vacine shown to remove beta amyloid plaques that accumulate in the brain, thereby leading to nerve damage and memory loss (Morgan).

Chlinesterase inhibitors: include Aricept (donepezil), Exelon (rivastigmine), Razadyn (galantamine) and Cognek (tacrine)

NMDA-type glutamate receptor inhibitor memantine:

Anti-amyloid Beta Antibodies:

Treatments that focus on amyloid-beta plaque, which is tightly linked to AD include ad

–Aducanumab and BAN2401: (Biogen) After poor results in 2019, the company presented positive date from a phase-3 trial. The durg robustly removes amyloid, possible clears tau tangles and at sustained high doses may modestly slow decline.

–Bepranemab (UCB0107): Roche’s Genetech had a collaboration in 2020 with UCB to develop an anti-tau antibody and gave over 120 million upfront to UCB with the Belgia company eligible for 2 billion based on certain regulatory approvals. However, Roche terinated the partnership.

–Crenezumab: Roche terminated its collaboration with AC Immune over the anti-amyloid beta antibody crenezumab beause it failed Phase II and III clinical trails in 2019 and 2022.

–Gantenerumab: failed wo phase III studies in November 2022.

Leqembi (Lecanemab): targets Alzheimer’s disease protein that are thought to be the most toxic to brain cells. It reduces clumps of amyloid-beta proteins, which play a key role in Alzheimer’s disease. However, lecanemab is not helpful for people with full cognitive function or later stages of Alzheimer’s. Lecanemab is manufactured by the Japanese pharmaceutical company Eisai and its U.S. partner Biogen. The drug is not a miracle drug in that it does not stop, reverse or cure the disorder. It can slwo mental decline by 5 months over an 1ucanumab and lecanemab, which were approved in 2021 and 2023, respetively, for mild cognitive impairment adn early AD. These treatments are beleived to reduce plaque in the brain, but they do not bring about cures. There are cases in which the plaque has been completely removed, but the people are still declining, so additional therapeis are needed. 8 month treatment period. But it comes with side effects including the risk of brain swelling and blooding. Despite all these drawbacks, it represetns a breakthrough.

Kisunla (donanemab-azbt) (Ili Lilly): is a once monthly injection greatment indicated for adults with early symptomatic Alzheimer’s dieaes (AD) including mild cognitve impariment (MCI) or mild dementia stage of disease with confirm amyloid pathology. Kisunla is the first amyloid plaque targeting therapy with evidence to support stopping therapy when amyloid plaques are removed, which according to Lilly can reduce both the number of infusions needed as well as the treatment cost. The FDA based its approval of Kisunla on positive data form Phase III TRAILBLAZER-ALZ 2 trail (NCT04437511), in which people elast advanced in the disease showed the strongest results 18 months after receiving the drug. Treatment with Kisunla significantly slowed clinical decline in two groups: pateints with low to medium levels of tau protein adn patients mirroring the overall popuation, which also inluded participants with high tau levels. Lilly has set a list price of of about 32,000 for a year of treatment which is about 21% above the $26,500 annual list price for Leqembi, an Alzhiemr’s treatment marketed by Isai and Biogen.

Gantenerumab: (Chugai Pharmaceutical Co., Ltd., Hoffmann-LaRoche): is a fully human IgG1 antibody designed to bind with subnanomlar affnity to a conformational epitope on amyloid-beta fibrils. It encompasses both N-temrinal and central amino acids of amyloid-beta. The therapetuic rationale is that it acts to disassemble and degrade amyloid plaques by recuiting microglia and activating phagocytosis. Gantenerumab preferentially interacts with aggregated brain amyloidbeta, both parenchymal and vascular.

–Patents:

Du (US 2002/0009445) discloses infusion of human IgG anti-amyloid beta antibodies for treatment of AD patients. The Anti-amyloid beta antibodies were recovered form a body fluid such as plasma using amyloid beta affinity chromatography.

Hyman (Ann Neurol, 2001, 49, pp. 808-810) discloses analysis of the plasma of 365 individuals for the presence of antibodies to amyloid-beta. There were detectable but very low levels of anti-amyloid-beta antibodies in just over 50% of all samples and modest levels in under 5% of all samples. However, neither the presence nor the level of anti-amyloid-beta antibodies correlated with the likelihood of developing demential or with plasma levels of amyloid-beta peptide.

Math (Neuromolecualr Med. 2003; 3(1): 29-39) disclose that AD patietns exhibit an enhanced immune response to Abeta adn that, contrary to expectation, Abeta antibodies enhance the neurotoxic activity of the peptide. Serum titers to Abeta were significantly elevated in AD patients and Abeta antibodies were found in association with amyloid plques in their brains, but there was no evidence of cell mediated immune responses to Abeta in the patents.

–IVIG administration:

It has been shown that antibodies against beta-amyloid (Abeta) are present in human immunoglobuilin preprations (IVIgG). Commerically available IVIG preparations contain IgGs that specifically recognize epitopes of varous conformers of amyloid beta (e.g., amyloid beta monomers, amyloid beta fibrils and cross-linked amyloid beta protein species CAPS). Form example, GAMMAGARD LIQUID (10% immune globulin infusion (humna) contain 0.1% anti-amyloid beta fibril IgG, 0.04% anti-CAPS IgG and 0.02% anti-amyloid beta monomer IgG.

Dodel (J Nuerol Nuerosurg Psychiatry, 2004, 75(10) 1472-4) reports that in a study of 5 patients with AD who received monthly IVIgG over 6 month period, total Abeta levels in the CSF decreased by 30.1% and imporvement was deetected using an ADAS-cog.

Eggenburg (US 15/385721, published as US 2017/0218051) discloses a high titer anti-amyloid beta pooled immunogloublin G composiiton that contains at least 0.1 antiamyloid beta IgG. In one embodiment, the composition contains at least 1% anti-amyloid beta fibril IgG, at least 0.4% anti-amyloid beta oligomer immunogloublin G, at least 0.2% anti-amyloid beta monomer IgG and a pharmaceutically acceptable stablizing agent. In some embodiments, the composition further includes anti-RAGE IgGor anti-alpha-synuclein IgG. Methods for administering a therapeutically effective amoun of the IgG compostions for the treatment of a disorder such as Alzheimer’s disease are also disclosed.

Puli (J Neuroinflammation, 2012, 9:105) disclose that treatment of transgenic and WT mice with hIVIG provided no reduction in amyloid beta pathology but rather increased soluble levels of AB40 adn AB42.

Relkin (Nuerobiology of Aging 30 (2009) 1728-1736) discloses that antibodies against beta-amyloid which are contained in IVIg which was infused into AD patients decreased cerebrospinal fluid AB and also led to improvement indicators such as mini-mental state scores.

Anti-Tau antiodies:

–Semorinemab: Roche ended its partnership with AC Immune regarding its anti-tau antibody semorinemab becaseu semorinemab failed to hit its priary endpoint, as well as two secondary endpoints.

Peptides/small molecuels:

–Companies: NervGen

–Protein tyrosine Phosphatase signma (PTPsigma): (NervGen): Their lead product NVG-291 provides a potential therapy for Alzehimer’s. The peptide binds preferentially to the PTPsignma receptor and effectively present inhibition from happening. Scar romation is a would healing process that takes place thorugh the body, including the nervous system. After an injury, more chonditin sulfate proteolycans (CSPs) is produced in its location. These sticky proteins act as a potent barrier to protect a wound and creat a wall to constrain inflammation and isolate it form healthy tissue. Unfortuantley, CSPs are the main reason why a nervous system does not repair itself by regrowing nerves. It was disocvered that a specific receptor on nerve cells (PTPsignma) recognizes CSPGs wihtin scar tissue and binds to them. Their interaction forms a very strong bond that effectively traps nerves permanetly within the scar. NervGen’s peptide binds preferentially to the PTPsigma receptor and effectvely present inhibition from occuring. The end result is release of trapped axons and presention of new ones form getting trapped in the scar. That enalbles the nervous system to regrow and repair itself in those previously inhibited area.

NVG-291 (NerGene): Their core technology targets PT

Fosgonimeton (Athira): is a small molecule that can cross the blood-brain varreir and apepars to protect neuronal cells and extend their lives, thus improving patients’ congition and funciton. The molecule is, basically, a grwoth factor enhancer for nerve cells. It promtoes nuron grwoth and creates new connections. This molecuel was also evaluated in a Phase II trail for Parkinson’s disease dementia and dementia with Lewy bodeis. Taht 28 person Phase II study measrued conitive improvement from baseline, using the Alzhimer’s Diease Assessment Scale for cognitive impairment (ADAS-Cog13). Resutls form 5 patients treated with 40 mg fosgonimeton in a modified intent to treat population showed a 7.2 point improvement by week 26, whcih suggets that fosgonimeton may be valuable therapeutic for patients with neurodegeenrative diseases.

Orexin-2 Receptor Blockers:

–Seltorexant: is a human orexin-2 receptor blocker intended for treatment of agitation or aggression i Alzheimers which is being studied in a Phase II trail. However, J&J will no longer develop the drug for this indication but will continue to evaluate seltorexant for a treatment for major depressive disorder with insomina symptoms.

Tetrahydrocannabinol (THC):

–TCH+ Melatonin + insulin:

(Cao (WO 2021/011421) discloses compositions which include THC, melatonin and insulin for treating Alzheimer’s diease. In some embodiments, the THC is organic THC, synthetic THC, Dronabinol, delta9-THC or THC-A. The inventors disclose that the composition is useful in reducing amyloid beta (amyloid beta 40 and/or amyloid beta-42).

Insulin:

Boosting brain insulin action could be a therapeutic option for people at an increased risk of developing metabolic and cognitive diseases such as AD and T2DM. Insulin action is critically important in the developing nervous system, directing differentiation, proliferation, and neurite growth. (Fisher, ” Insulin action in the brain regulates both central and peripheral functions” Am J. Phsy Endocri. Path., 2021 Jul 1; 321(1): E156–E163)

Models:

Neurons presenting hallmarks of AD:

Sun et al. developed a microRNA-based direct reprogramming approach using fibroblasts from individuals with late-onset Alzheimer’s disease ()LOAD). The authors generated neurons presenting the major hallmarks of the disease, including depositions of the proteins Aβ and tau and dysregulation of age-associated transposable elements. Preventing transposable element dysregulation rescued neurodegeneration and reduced Aβ deposition. Sun et al. “Modeling late-onset Alzheimer’s disease neuropathology via direct neuronal reprogramming” Science, 2024.