Knowledge Center

ALZHEIMER'S DISEASE: RECENT ADVANCES

(0 Rating)
Introduction

Dementia, a chronic and progressive disorder due to the apoptosis of neurons and worsening of cognitive function, has been posing challenges to caregivers as well as medical professionals. Dementia occurs in different forms such as vascular dementia, Lewy body dementia, Alzheimer’s disease and others.

Common symptoms are memory loss, delusions, hallucinations, violence, depression etc.

Alzheimer’s

Fig. 1. Types of dementia
Source: “Guide to Understanding Dementia with Lewy Bodies” (Edited by Kenji Kosaka)

Alzheimer’s disease (AD), a neuro-degenerative disease affecting 50 million people globally, is predicted to be 152 million-strong by 2050. (1) It is the fourth leading cause of death in elderly people over the age of 65 years and the sixth leading cause of death in the US. AD is thought to begin 20 years prior to the appearance of symptoms such as memory loss, challenges in planning or solving problems, difficulty with daily activities, problem with speech, loss of ability to retrace, changes in mood and personality etc. (2)(3).

The main changes taking place in the brain of an Alzheimer’s patient include:

  • Accumulation of beta amyloid plaques outside neurons, causing cell death by stimulating microglia,
  • Accumulation of abnormal forms of tau proteins inside neurons, which block the transport of nutrients and others,
  • Other conditions such as inflammation and atrophy.
Alzheimer's

Fig. 2. Accumulation of amyloid plaques (Source)

Pathogenesis

AD is driven by several hypothesis such as beta amyloid hypothesis, tau hypothesis and inflammation hypothesis. The progression of outcomes from these have further led to a study of cholinergic hypothesis, dendritic hypothesis, mitochondrial cascade hypothesis and others involving oxidative stress occurring in the hippocampus, amygdale association cortices and certain subcortical nuclei of the brain. The starting point of these hypothesis is APP (Amyloid precursor protein). (4)

Overview of APP in the brain

APP belongs to the family of APLP (Amyloid precursor-like proteins) encoded genes. It plays a crucial role in brain development, neuronal plasticity, memory and neuroprotection. It is encoded by a single gene and exists in 3 isoforms, APP695, APP751 and APP770, due to differential splicing. APP695 is more predominant than other isoforms. APP751 and APP770 result from the splicing of exons encoding kunitz-like protease inhibitor domains(KPI) and OX-2 antigen domains that are lacking in APP695.

Structure

  • APP is a type-1 single pass transmembrane protein with a large extracellular domain and short cytoplasmic tail. It consists of E1, E2 and a transmembrane domain (TMD).
  • E1 consists of a growth factor- like domain (GFLD) having a heparin -binding site (HBD) and copper- binding site (CuBD), where GFLD and CuBD are stabilized by disulphide bridges.
  • E2 has a heparin-binding site (HBD) and an RERMS motif (APP328-332), a sequence of five amino acids.
  • TMD directly interacts with cholesterol and modulates processing, which is also influenced by N-glycosylation and O-glycosylation, sialylation and chondroitin sulfate-glycosaminoglycan modifications.
  • Acidic domain (AcD) rich in glutamic acid and aspartic acid is highly flexible and unfolded.
  • APP intracellular domain (AICD) is intracellular.
  • APP contains an Iron-binding site and, therefore, possesses Ferro-oxidase activity and 4 copper binding sites useful in OH- production, APP dimerization and synaptic adhesion.

Cleavage sites

Cleavage sites for α and β secretases are in the juxtamembrane region that links E2 and TMD. γ secretases cuts in TMD.

Alzheimer's

Fig. 3. Structure of APP

APP processing

APP processing includes canonical and non-canonical pathways. Canonical pathways involve cleavage by α or β secretases, followed by γ secretase. APP, upon cleavage by α secretases and β secretases, produces APPsα and APPsβ, respectively; along with corresponding C terminal fragments (CTF), following cleavage with γ secretases. They produce Beta Amyloid (Aβ), P3 due to exoproteolytic cut at N-terminus and AICD (APP intracellular domain) due to endoproteolytic cut at E-site. The Aβ oligomers are cleared by means of proteolytic degradation by neprilysin and insulin-degrading enzymes (IDE).

Table 1 lists the different forms of enzymes that act on APP.

Enzyme Form
α secretases ADAM 10 (disintegrin and metalloproteinase domain containing protein 10)
β secretases BACE1 and BACE2
γ secretases PS1, PS2, NCT, PEN2, APH1 and APH2

Non-canonical pathway involves action of δ- secretases, η- secretases, meprin β and caspases.(5)

Alzheimer's

Fig. 4. APP-processing pathways

Pathogenic pathway

Alzheimer's

Fig. 5. Pathogenic pathway of AD (6)

The exact cause for AD is not known. Due to some unknown changes in the cleavage of APP, there is an imbalance between production and clearance of Aβ peptides, due to which there is a formation of soluble oligomers. This results in aggregation via nucleation-dependent pathways, followed by coalesce, to form fibrils that are insoluble due to beta-sheet conformation, thus resulting in senile plaques.

The Aβ42 peptides formed induce oxidative damage, promote tau hyper-phosphorylation and attract microglia that are activated. These produce pro-inflammatory cytokines, resulting in inflammation. This causes neuronal and vascular degeneration, further activating oligodendrocytes and resulting in decreased IDE function. Aβ oligomers bind to α-7nAChRS and astrocytes, which exocytose the glutamate and activate NMDAR-triggering Ca2+, leading to dysfunctional mitochondria, increased NO (nitric oxide) and ROS (reactive oxygen species). This leads to neurotoxicity and AD. (7)

Imbalance in amyloid proteins

There are several reasons for the imbalance in production and clearance of amyloid proteins, some of which are listed below.

New protein aggregation

Disclosure in a recent research project work reported the discovery of new protein aggregation encoded by FAM222A: a protein called aggregatin of molecular weight 47KD and consisting of 452 amino acids, which is expressed in CNS binding to amyloid deposits by interacting with Aβ, was found to be more expressed in AD patients. (8)

Alpha sheet resembling beta sheet

Current studies state that AD is not caused due to β-sheet-rich, insoluble amyloid β-peptide plaques; and plaque burden is not a cause of cognitive impairment, but due to the toxic levels of oligomers. Oligomers share a common conformational structure but not sequence-based epitope. Based on this, scientists proposed a new confirmation on α-sheets resembling β-sheets, called α-sheet hypothesis, suggesting that misfolding of proteins is the cause of cognitive disorders such as AD.(9)

Gut bacteria

Gut microbiome excrete lipopolysaccharides (LPS) that cannot enter the bidirectional communication system of the microbiota-gut-brain; but as age progresses, the gastrointestinal epithelium and the blood brain barrier are more permeable, making the LPS and amyloids engage in bidirectional communication ands resulting in AD. (10)

Mutations

It is already known that early onset of AD is due to the inheritance of mutations in APP of chromosome 21, PSEN1 of chromosome 14 and PSEN2 of chromosome 1, while late onset of AD is due to mutations in APOE gene, e4 allele of chromosome 19, in particular. Researches are focusing on identifying different mutations responsible for early onset of AD through dominantly inherited Alzheimer network (DIAN). The identification of potential biomarkers will help in predicting the development of Alzheimer's disease. (11) By using an approach called genome-wide association study (GWAS), meant for identification of novel complex disease genes, the scientists confirmed three new AD-associated loci: ADAM10, BCKDK/KAT8 and ACE. (12)

Diagnosis

Early diagnosis of AD plays a crucial role in prevention and treatment of the disease. Diagnosis of AD is currently being carried out by brain imaging, also called neuroimaging, which involves structural imaging, functional imaging and molecular imaging.

Structural imaging is performed with magnetic resonance imaging (MRI) and computed tomography (CT), the principle being shrinkage of the brain with the progression of disease. The main drawback is that it can be misled by tumors and other pathological conditions of the brain.

Alzheimer's

Fig. 6. MRI scan of brain - Control vs. Alzheimer patients (Source)

Functional imaging involves the use of positron emission tomography (PET) to detect reduced brain activity resembling the pathological condition of AD; for example, use of fluorodeoxyglucose (FDG)-PET associated with reduced glucose in brain.

alzheimer's

Fig. 7. PET scan image of brain - Control vs. Alzheimer patients (Source)

Molecular imaging involves use of radiotracers to represent the pathological substances involved in AD, i.e., Amyloid and tau proteins. Pittsburgh compound B (PIB) is the first radiotracer used to highlight the Amyloid plaques in the brain. Recently, Amyvid (18F-florbetapir), Vizamyl (18F-flutametamol) and Neuraceq (18F-florbetaben) have been approved by the USFDA as radiotracers.

Apart from neuroimaging, researchers are concentrating on the following for detecting AD:

  • Proteins in CSF
  • Proteins in blood, urine and other biological fluids
  • Genetic risk profile study

Genetic risk profiling involves the identification of mutations, which involve:

  • extra copy of chromosome21, e2, e3 and e4 of gene apolipoprotein (APOe)
  • Mutations in APP gene (presenilin 1 and 2 proteins) (13)

Use of artificial intelligence for diagnosis

More recently, Artificial Intelligence (AI) has seen use in the early diagnosis of AD, which involves developing and training an algorithm to recognize early degradation of the brain; which is otherwise difficult to evaluate.

A deep-learning algorithm developed by Benjamin L. Franc and team at the University of California, San Francisco and the University of California, Berkeley, was trained to predict the onset of AD in the early stages.

A database of 2,109 independent Fluorine 18-Fluorodeoxyglucose (F-FDG) PET studies performed between 2005 and 2017 was used for this study.

90 % of the data was used to train the algorithm, while the remaining 10 % was used to test the algorithm.

Researchers also used other 40 (F-FDG) PET scan sets, which the algorithm was not familiar with, to test its accuracy. It was found that the algorithm was predicting AD 6.3 years prior to final diagnosis with 82 % specificity.

Although there is a growing trend of using AI in diagnosis of AD, it will take more research efforts to achieve higher accuracy (14).

Use of navigation in gaming

A game called SEA HERO QUEST, developed by Deutsche Telekom in partnership with Alzheimer's Research UK, University College London (UCL), the University of East Anglia and game developers, has the ability to detect people at risk of Alzheimer’s. It was designed for better understanding of the relation between spatial navigation and the brain.

The game has the ability to distinguish people who are genetically at risk of Alzheimer's from those who are not. People with APOE4 gene demonstrated the worst performance in spatial navigation. (15)

Therapy

There are in all, 4 prescription drugs to treat AD. These include acetylcholinesterase inhibitors (AChEIs) –Rivastigmine, Galantamine, Tacrine and Donepezil and NMDA receptor antagonist–Memantine, and a combination of Donepezil + Memantine. The mode of action of AChEIs is to inhibit the action of cholinesterase to breakdown acetylcholine, a chemical messenger involved in memory. Memantine works by partially blocking NMDA receptors and prevents the overstimulation of these receptors by glutamate, which results in cell death. These drugs only delay or slow the worsening of symptoms, and moreover, their effectiveness changes from person to person. They also have side effects such as seizures, bradycardia and worsening of pulmonary problems.

The list of approved drugs is presented in the table below:

Drug Company Year of approval (US)
Donepezil (16) Eisai Pharmaceuticals 1996
Tacrine (17) Parke-Davis Pharmaceuticals 1995
Galantamine (18) Janssen Research Foundation 2001
Rivastigmine (19) Novartis 2000
Memantine(20) Forest Laboratories 2003

Table 2. List of drugs, the originator company and the year of approval in the US.

Therapeutic approaches

The growing need for new therapeutic approaches is increasing day by day. The following flowchart depicts the different approaches for treating AD:

Alzheimer's

Fig. 8. Approaches in AD treatment(21)

Mode of action

The main approaches for treating AD include the following:

  • Amyloid precursor protein metabolism
  • Approach to target abnormal tau proteins
  • Neurotransmitter approach
  • Others (22)

The mechanism of action involved in new approaches has been depicted in the following flowchart:

Alzheimer's

Fig. 9. Mode of Action

A recent genetic approach of using a gene variant called Christchurch mutation to delay the symptoms of early family onset of AD was discovered accidentally. In a case-study of a family with 6000 members, where everyone carrying a gene mutation called Presenilin 1 (PSEN1) E280A was affected with early AD, there was an exception found of a single woman who had both the variants and yet, did not show any symptom until her 70s. (24)

Biologics

Advances in the understanding of pathogenesis in AD to the molecular level has shifted the attention of the researchers to the use of biologics such as vaccines, recombinant proteins, peptides and other small molecules.

Immunotherapy

Aβ42 stimulates T-cells, B-cells and microglial responses. The present active immunotherapy approach includes the use of synthetic fragments of Aβ conjugated with carrier proteins. Administration of monoclonal antibodies directed against Aβ falls under passive immunotherapy. The main mode of action is plaque breakdown, preventing formation of plaques called peripheral sink and aggregation inhibitors. (25)

Vaccines

Progression of Alzheimer‘s disease could be delayed and prevented with vaccination, based on the following criteria:

  • High concentration of antibodies against the toxic forms of Aβ.
  • Inflammation not to be induced by activating T cells.
  • Treatment initiated before the onset of disease, or at least, during the early stages.

The first-in-human anti Aβ vaccine AN1792 resulted in side effects such as meningoencephalitis, and the Phase 2 trial was quickly terminated. Various peptide/ protein epitope vaccines currently undergoing clinical trials are presented in table 3.

Vaccine Company + collaborator Constituents Clinical trail
Targeting Aβ
ACC-001 Pfizer+JANSSEN Alzheimer Immunotherapy Research & Development, LLC 1-7 +diphtheria toxoid protein Terminated at low doses Completed Phase II at high dose
CAD-106 Novartis Pharmaceuticals 1-6+QB virus like particle Phase-III
V950 Merck Sharp & Dohme Corp 1-15 + ISCOMATRIX Completed Phase I
Targeting tau proteins
UBITh /UB-311 United Neuroscience Ltd 1-14+Th2 biased delivery Completed Phase I
AADvac1 Axon Neuroscience SE Synthetic peptide derived from amino acids 294 to 305 of the tau sequence Phase 2

Table 3. Peptide/ protein epitope vaccines currently under trials

Clinical trials

Past trials

Although there were more than 130 entities undergoing clinical trials, not a single entity has been approved since 2003 after Menatine. Some of the failures are listed below:

  • In 2018, Janssen Pharmaceuticals terminated Phase 2 and Phase 2b/3 trial of Atabecestat (which acts by inhibiting beta-amyloid cleaving enzyme 1, causing low levels of beta amyloid levels) reportedly after finding elevated liver enzyme levels in study participants.
  • In 2018, Eli lily and AstraZeneca discontinued Phase 3 trials of Lanabecestat, a beta-secretase-cleaving enzyme (BACE) inhibitor, due to lack of efficacy. (27)
  • In 2019, Merck announced discontinuation of Phase 3 clinical trials of its drug, Verubecestat, a beta-secretase-cleaving enzyme (BACE) inhibitor, as many patients on the drug presented progressing dementia. (28)
  • In 2019, Genentech discontinued phase 3 trial of Crenezumab as the high dosage used in the trial produced side effects. It is continuing with phase 2 trial of its API for primary prevention. (29)
  • In 2019, Allergan withdrew the Phase 1 trial evaluating the safety and tolerance of AGN-242071.
  • Novartis (along with Amgen and the Banner Alzheimer's Institute) discontinued its Phase 2/3 trials of Umibacestat due to deteriorating cognitive functions.
  • In 2019, Intracellular therapies terminated Phase 3 trial of ITI-007 (Lumateperone) due to lack of efficacy.
  • In 2019, Eisai and Biogen discontinued their Phase 3 trial of Elenbecestat.(30)

Ongoing trials

A few on-going clinical trials are presented in Table 4 below.

Drug Phase Company and Collaboration Mode of action Date of start to estimated end date
BIIB076 1 Biogen Anti-tau antibody February 17, 2017 to March 3, 2020
Aducanumab 2 Biogen and Eisai Anti-β-amyloid antibody September 30, 2015 to August 5, 2019
AL002 1 AL002 Targets immune system receptors November 12, 2018 to March, 2020
S-equol (AUS-131) 1/2 Ausio Pharmaceuticals Estrogen receptor activator May 5, 2017 to March 30,2020
COR388 >sup>(24) 1& 2/3 Cortexyme, Inc. Bacterial protease inhibitor March 28, 2019 to December 31, 2021
Neflamapimod (VX-745) 2, 2b & 3 EIP Pharma Inhibits p38 MAPKα July 8, 2019 to June 2020
Xanamem 2 Actinogen Medical Inhibits a cortisol-producing enzyme Mar 23, 2017 to mar 15, 2019
Piromelatine 2 Neurim Pharmaceuticals Binds to and activates melatonin and serotonin receptors November 2015 to November 30, 2019
Lemborexant 2 Eisai and Purdue Pharma Orexin receptor antagonist December 20, 2016 to July 26, 2018
ALZT-OP1 (inhaled cromolyn and oral ibuprofen) 3 AZTherapies, Inc. Anti-inflammatory September 2015 to December 2020

table 4. On-going drug trials

* Biogen and Eisai, its Tokyo-based collaboration partner, announced discontinuation of clinical trials of Aducanumab, but later on, announced that high doses of the drug had shown positive results and that after discussions with FDA, they would pursue regulatory approval. At the conference on Clinical Trials on Alzheimer’s disease held in San Diego, Biogen disclosed data to explain the reason to restart the clinical trials of aducanumab. (37) (38)

Recent announcement

China’s GV-971

Conditionally approved by China National Medical Products Administration (NMPA), Sodium oligomannate is the first new drug in the last 17 years with the potential to treat AD. Invented by a team of scientists from Geng Meiyu [Shanghai institute of Materia medica under Chinese Academy of Sciences], it is derived from a seaweed-based brown algae that is reported to treat mild to moderate AD. In the journal, Cell Research, the authors described how a sugar moiety in a sea weed can suppress certain bacteria contained in the gut that can cause AD. The mechanism was later confirmed by a clinical trial carried out by Green Valley, a Shanghai-based pharmaceutical company. The team now wishes to gain full approval from USFDA by initiating phase-III study by the spring of 2020. (33) (34)

Start-ups

With increase in failure of treatment options, many startups are adopting different approaches for the treatment of Alzheimer’s disease.

  • Alector: Founded in 2013, Alector is working towards the development of antibody drug technologies that target immune system receptors rather than the pre-existing plaques. Alector, in collaboration with AbbVie (ABBV), is developing AL002, a monoclonal antibody that targets the triggering receptor expressed on myeloid cells 2 (TREM2); which is the strongest genetic link for Alzheimer’s after the recent phase 1 entry of APOE4. (31)
  • Cortexyme: Founded in 2012, Cortexyme is developing COR388-targeting bacteria responsible for developing Alzheimer’s. The company recently completed the phase 1 trial of COR388 and is currently running phase 2/3. (31)
  • Alzheon: Founded in 2013, Alzheon is developing a Phase 3-ready oral drug candidate: ALZ-801, a prodrug of active ingredient tramiprosate that dissolves amyloid beta plaques by targeting its precursor. (31)
  • Cognito Therapeutics: Founded in 2014, Cognito Therapeutics is developing a device based therapy, such as Gamma stimulation, for reducing amyloid beta plaques and tau tangles in the brain. It is actively enrolling participants for multiple clinical studies. (31)
  • Pinteon: Founded in 2014, Pinteon has started a Phase 1 trial for its drug candidate (PNT001) to target tau proteins, specifically cis-pT231 tau epitope, for the treatment of Alzheimer’s.(32)
AAIC 2019

Alzheimer’s Association International Conference (AAIC) is the largest and most influential annual international meeting focusing on dementia. In 2019, it was more focused on life style changes, clinical trial results and new targets for treating AD.A few highlights are presented below:

Staging system

Researchers Niklas Mattsson and Oskar Hansson of Lund University presented data on a new staging system of amyloid accumulation that could help in detecting AD way before the positive identification through PET scans. They conducted a study using the longitudinal data of cerebrospinal fluid Aβ42, along with PET scans of 741 participants, under the Alzheimer’s disease Neuroimaging Initiative. They categorized the progression of AD into 4 stages based on amyloid accumulation which is presented in Table 5 below. (39)

Stage Rate of Progression Amyloid accumulation
0 15% Low risk of developing plaques.
1 71% Precuneus, posterior and isthmus cingulate, insula, and medial and lateral orbitofrontal cortices.
2 53% Parahippocampus, medial and inferior temporal lobes, inferior parietal lobe, and superior parietal, temporal, and frontal regions
3 Precentral, postcentral, paracentral, lingual, and pericalcarine cortices

Table 5. The 4 stages of AD progression

PET scans showed positive for AD only at later stages when the disease progressed to the next stage. The staging system will help identify people with risk of AD progression in the early stages itself, which may be useful to detect disease pathology and also identify the stage of progression. (40)

Life style changes

Healthy lifestyle reduces the risk of AD even in a population that is genetically at risk of Alzheimer’s. Five research studies based on life style interventions were presented at AAIC-19. Topics discussed include the following:

  • Multiple healthy lifestyle habits: Adopting at least 4-5 healthy life style habits help in reducing cognitive decline. Healthy life style habits include 150min/week of physical exercise, engaging the brain in mental activities, healthy diet, abstaining from smoking and moderate alcohol intake.
  • Healthy life style and genetic factors of Dementia: A research conducted at the University of Exeter Medical School showed that sticking to a healthy life style may decrease risk of Alzheimer’s, irrespective of underlying genetic factors.
  • Protecting brain against air pollution with active lifestyle: Higher the air pollution, higher is the risk of Alzheimer’s, as air pollution results in damage and shrinkage of brain. A study conducted on women aged 65-79 years, by Diana Younan and team at the University of Southern California, showed that women who were engaged in physical and mental activities with years of education and job status (cognitive reserve) were less likely to develop Alzheimer’s than those with lower cognitive reserve. Women with more cognitive reserve who stayed in air-polluted surroundings were at 21% increased risk of AD, as compared to women with lower cognitive reserve under the same circumstances at 113% increased risk of AD. This study suggests that cognitive reserve acts as a shield against brain damage resulting from environmental risk factors.
  • Cigarette Smoking: Heavy stable smokers were more likely to show cognitive impairment than non-smokers, whereas quitters and mild smokers showed no increased risk, as per a study conducted by Amber Bahorik from the University of California, San Francisco.
  • Alcohol Use Disorder: A study conducted by Drs. Bahorik and Yaffe from the University of California, San Francisco, suggests that alcohol-use disorders lead to increased risk of AD in older women. (41)

CSF – p Tau as early detector of AD

Amyloid accumulation in the brain results in the over-production of Tau proteins by neurons. These Tau proteins are modified at certain sites such as threonine 181 and serine 217, and the resultant isoforms of p-tau can be detected in CSF and plasma. This suggests that a positive blood test for presence of p-tau may indicate the presence of amyloid plaques in the brain, which can be an early detector of AD. These markers (p181, p217) can be detected before the PET scans show positive results. (42)

Update on clinical trials

Clinical data with an innovative approach towards AD was discussed.

Inhaled Insulin in mild cognitive impairment (MCI) and AD

A phase 2/3 clinical trial involved 289 participants with MCI and AD, in which the control group received 40 IU of placebo and the test group received Insulin (humulin-RU100, Eli Lilly) a day for 12 months, and an open label extension for 6 months. Two devices were used for inhaling the insulin. The first 49 participants received insulin using Kurve Technology/Device 1, whereas the remaining 240 participants used Impel NeuroPharma/Device 2, due to the varying reliability of Device 1. Outcomes were measured using Alzheimer's Disease Assessment Scale for Cognition-12 (ADASCog-12) at 15 and 18 intervals. Activities of Daily Living Scale for MCI (ADL-MCI), and Alzheimer's biomarkers in cerebrospinal fluid (CSF) were also measured. Device 1 showed good results, whereas device 2 showed no significant difference when compared with the placebo.

Porphyromonas gingivalis: Cortexyme is targeting the inhibition of toxic virulence factor Gingipains secreted by Porphyromonas gingivalis in its phase 2/3 study of COR388 (GAIN trial, called GingipAIN inhibitor for treatment of AD).(43)

Biomarkers in AD

Measuring amyloid and tau in CSF and PET scans can be expensive and invasive. A few easily available, simple and inexpensive testing technologies that are currently under development were presented at AAIC19.

Plasma amyloid levels: Scientists at the National Center for Geriatrics and Gerontology in Japan suggested that measuring plasma levels of amyloid peptides (Aβ1-42, Aβ1-40 and APP669-711) and generating a combined ratio of results in a blood biomarker has the potential to identify people who are likely to develop AD in future. The blood biomarkers, when compared with amyloid PET scans, structural MRI, FDG-PET and behavioral tests, showed significant correlation. This test will be able to detect amyloid deposits even before onset of dementia-related symptoms.

Plasma Neurofilament Light: A neurofilament light (NfL) chain is being considered as a biomarker for neurodegenerative disorders, including AD. NfL is able to distinguish between different neurodegenerative diseases based on the blood NfL levels. A cut-off point of NfL is established to differentiate among several neurodegenerative disease and health controls. (44)

Patents

A few interesting patents have been presented below:

Diagnosis

US20200080132A1 from Alisch Reid Spencer, Hogan Kirk Jeffrey and Madrid Andy titled Test for detecting Alzheimers disease deals with a method for measuring the methylation level of differentially methylated positions (DMPs) sites in B3GALT4 and/or ZADH2 using the following steps:

a) extracting genomic DNA from a blood sample of a human individual suspected of/ already having AD;

b) treating the extracted genomic DNA with bisulfite;

c) amplifying it with primers specific for B3GALT4 and a pair of primers specific for ZADH2; and

d) measuring the methylation level using methylation-specific PCR, DNA restriction enzyme analysis, microarray analysis, pyrosequencing, bisulfite genomic sequencing PCR or whole methylome sequencing.

Treatment

WO2020061150A1 from Biogen MA INC. titled 0-Glycoprotein-2-Acetamido-2-Deoxy-3-D-Glucopyranosidase inhibitors deals with pharmaceutical salts involving method of inhibiting 0-GlcNAcase to treat neurodegenerative diseases such as AD

Alzheimer's

The patent deals with a method of treating a disease such as AD characterized by hyper phosphorylation of tau in the brain, by administering an effective amount of the compound.

WO2020028290A1 from Alzheon Inc. titled Methods for treating neurodegenerative disorders deals with a method of treating a patient suffering from AD by selecting a patient with levels of 3-sulfopropaonoic acid (3-SPA) lower than a predetermine level and administering a metabolite of Tramiprosate for treatment which will inhibit the aggregation of Aβ42 into small oligomers.

Drug targeting

CN110841062A from China Pharmaceutical University titled SER34 LMTK1 and its phosphorylated protein as alzheimer drug target applications deals with LMTK1 and its Ser34 phosphorylated protein as drug targets in screening drugs for prevention and treatment of Alzheimer's disease. The drug inhibits synaptic atrophy by regulating Rab11.

Monoclonal antibodies

EP3521308A1 from Probiodrug A titled Humanized and de-immunized antibodies deals with the use of monoclonal antibodies for diagnosis and, treatment of amyloidosis. The antibodies bind to pyroglutamated amyloid beta peptide in plasma, brain, and cerebrospinal fluid and prevent the accumulation or reverse the deposition of Aβ N3pE within the brain and in various tissues in the periphery, and thus alleviate amyloidosis.

EP2994160B1 from Baxalta titled Treatment of Alzheimer's disease subpopulations with pooled immunoglobulin G deals with pooled human immunoglobulin IgG composition to treat a subject with moderately severe Alzheimer's disease or carrier of at least one APOE4 allele.

Stabilization of microtubules in the neurons

IN201811020565A from Indian Institute of Chemical Biology titled Nonapeptide of formula i, Pharmaceutical compositions and methods for preparation thereof deals with peptide-based microtubule stabilizer working on the principle of Taxol binding pocket of P-tubulin and hydrophobic region of amyloid beta. This leads to a potential nonapeptide, which strongly binds with taxol pocket of P-tubulin and serves as an excellent microtubule stabilizer, Ap aggregation inhibitor and neuroprotective agent.

Future trends

The search for biomarkers is promising in diagnosis, such as, for example, the use of tyrosine phosphorylation-signaling modulation in erythrocytes. Using AI in diagnosis is definitely set to grow; and with availability of more and more data, the accuracy will indeed get better. As treatment options are getting fewer, with no new drugs on the horizon, scientists are working on techniques to catch the disease in the initial stages. The focus of AD treatment has so far been in treating the symptoms through release of chemical messengers from the cells, without addressing the underlying cause, leading to destruction of cells and progression of AD.

The current focus has also been to understand the mechanisms involved, especially the role of different proteins in the formation of plaque. Efforts are in progress to develop biologics such as monoclonal antibodies that will destroy the plaques and stop the aggregation of proteins. Influence of hormones such as insulin is gaining importance. The effect of oxidative stress and inflammatory factors; such as the influence of interleukin and glycosidase inhibition, along with signaling pathways such as amylin, insulin dependence etc.; are being studied. Scientists are also trying to understand the key proteins, such as involvement of translocator proteins and their modulation by respective agonists or antagonists to prevent or treat AD. In the near future, the direction will be towards early diagnosis and slow progression of disease.

References
  1. Alzheimer’s disease: Facts & Figures- BrightFOcus Foundation; cure in mind. Cure in sight
  2. Alzheimer’s Therapeutics Market to Reach USD 12.43 Billion By 2026 | Reports and Data- May 02, 2019 12:00 ET | Source: Reports and Data
  3. Alzheimer’s disease and Other Dementias-source: Department of Aging MARYLAND ACCESS POINT your link to health and support services
  4. Current Research Therapeutic Strategies for Alzheimer's Disease Treatment-Jaume Folch, Dmitry Petrov, Miren Ettcheto, Sonia Abad, Elena Sánchez-López, M. Luisa García, Jordi Olloquequi, Carlos Beas-Zarate, Carme Auladell, and Antoni Camins ; Neural Plast. 2016; 2016: 8501693; Published online 2016 Jan 3. doi: 10.1155/2016/8501693; PMCID: PMC4735913; PMID: 26881137
  5. Not just amyloid: physiological functions of the amyloid precursor protein family. -Müller UC, Deller T, Korte M; Nat Rev Neurosci. 2017 May; 18(5):281-298. doi: 10.1038/nrn.2017.29. Epub 2017 Mar 31.
  6. Reviewing reasons for the decreased CSF Abeta42 concentration in Alzheimer disease -Petra E. Spies, Marcel M. Verbeek, Thomas van Groen, Jurgen A.H.R. Claassen; [Frontiers in Bioscience 17, 2024-2034, June 1, 2012]
  7. A review on Alzheimer's disease pathophysiology and its management: an update. - Pharmacol Rep. 2015 Apr;67(2):195-203. doi: 10.1016/j.pharep.2014.09.004. Epub 2014 Sep 22; Kumar A, Singh A, Ekavali
  8. FAM222A encodes a protein which accumulates in plaques in Alzheimer’s disease- Tingxiang Yan, Jingjing Liang, Ju Gao, Luwen Wang, Hisashi Fujioka, The Alzheimer Disease Neuroimaging Initiative, Xiaofeng Zhu, and Xinglong Wang
  9. α-Sheet secondary structure in amyloid β-peptide drives aggregation and toxicity in Alzheimer’s disease; Dylan Shea, Cheng-Chieh Hsu, Timothy M. Bi, Natasha Paranjapye, Matthew Carter Childers, Joshua Cochran, Colson P. Tomberlin, Libo Wang, Daniel Paris, Jeffrey Zonderman, Gabriele Varani, Christopher D. Link, Mike Mullan, and Valerie Daggett; PNAS April 30, 2019 116 (18) 8895-8900; first published April 19,2019 https://doi.org/10.1073/pnas.1820585116
  10. The Gut Microbiota and Alzheimer's Disease.; Jiang C, Li G, Huang P, Liu Z, Zhao B; J Alzheimers Dis. 2017;58(1):1-15. doi: 10.3233/JAD-161141.
  11. Dominantly Inherited Alzheimer Network (DIAN) (DIAN)-U.S. National Library of Medicine Clinicaltrials .gov
  12. GWAS on family history of Alzheimer’s disease-Riccardo E. Marioni, Sarah E. Harris, Qian Zhang, Allan F. McRae, Saskia P. Hagenaars, W. David Hill, Gail Davies, Craig W. Ritchie, Catharine R. Gale, John M. Starr, Alison M. Goate, David J. Porteous, Jian Yang, Kathryn L. Evans, Ian J. Deary, Naomi R. Wray, and Peter M. Visscher
  13. Alzheimer’s and Dementia Testing for Earlier Diagnosis- alzheimer’s association; alz.org | research center, advancing Alzheimer’s research worldwide
  14. AI tool predicts Alzheimer’s more than 6 years ahead of diagnosis; Anicka Slachta | November 06, 2018 | Artificial Intelligence
  15. The mobile game that can detect Alzheimer's risk by University of East Anglia- APRIL 24, 2019
  16. ARICEPT (donepezil hydrochloride)-WCG CenterWatch
  17. Therapeutics-Tacrine; Alzforum networking for a cure
  18. Drug Approval Package: Razadyne (Galantamine Hydrobromide) ; U.S. FOOD & DRUG ADMINISTRATION
  19. Drug Approval Package: Exelon (Rivastigmine Tartrate) Capsules; U.S. FOOD & DRUG ADMINISTRATION
  20. Therapeutics -Memantine; ALZFORUM NETWORKING FOR A CURE
  21. Treatment Combinations for Alzheimer’s disease: Current and Future Pharmacotherapy Options- J Alzheimers Dis. 2019; 67(3): 779–794.; Published online 2019 Feb 12.
  22. Current Research Therapeutic Strategies for Alzheimer's Disease Treatment- Neural Plast. 2016; Published online 2016 Jan 3.
  23. A review on Alzheimer's disease pathophysiology and its management: an update- Volume 67, Issue 2, April 2015, Pages 195-203
  24. Unique case of disease resistance reveals possible Alzheimer's treatment-Study identifies gene variant as potential drug target; November 4, 2019; NIH/National Institute on Aging
  25. 'Clinical trials in Alzheimer's disease': immunotherapy approaches.- J Neurochem. 2012 Jan;120 Suppl 1:186-93. Epub 2011 Nov 28.
  26. Immunogenicity of DNA- and recombinant protein-based Alzheimer disease epitope vaccines.- Hum Vaccin Immunother. 2014;10(5):1248-55Epub 2014 Feb 13
  27. Update on Phase III clinical trials of lanabecestat for Alzheimer’s disease-AstraZeneca, published on 12 june 2018
  28. Results from Verubecestat APECS Trial Published- 11 Apr 2019 ; ALZFORUM NETWORKING FOR A CURE
  29. A Long Line of Alzheimer's Failures: Roche Drops Two Drug Trials; Published: Jan 30, 2019 By BioSpace
  30. Alzheimer’s Disease Insight Report: Current Therapies, Drug Pipeline and Outlook-Published: Sep 23, 2019 ; BioSpace
  31. 6 Startups Searching for a Cure for Alzheimer’s- September 10, 2018; nanalyze
  32. Cambridge Startup Targets Alzheimer's With A New Approach To An Old Idea; October 31, 2019; Bostonomix
  33. Sodium oligomannate therapeutically remodels gut microbiota and suppresses gut bacterial amino acids-shaped neuroinflammation to inhibit Alzheimer’s disease progression- Cell Research volume 29, pages787–803(2019)
  34. Alzheimer’s drug Oligomannate gets conditional approval in China-4 NOVEMBER 2019; Pharmaceutical technology
  35. Alzheimer’s Disease Insight Report: Current Therapies, Drug Pipeline and Outlook; Sep 23, 2019 ; BioSpace
  36. Clinicaltrials .gov
  37. Biogen explains how its Alzheimer’s drug went from poor to promising-December 6, 2019; Time
  38. A new hope: Biogen's Aducanumab headed to Regulators for treating Alzheimer's Disease; Oct 22, 2019 ; BioSpace
  39. Staging β-Amyloid pathology with Amyloid Positron Emission Tomography- July 17, 2019; JAMA network
  40. New PET staging scheme for Amyloid?; Alzheimer's Association International Conference 2019; 25 Jul 2019; ALZFORUM NETWORKING FOR A CURE
  41. Lifestyle interventions provide maximum memory benefit when combined; And may offset elevated Alzheimer's risk due To genetics, pollution; Alzheimer's Association International Conference 2019; P&T community
  42. Move over Aβ, CSF P-Tau Tells Us There’s plaque in the Brain; Series - Alzheimer's Association International Conference 2019; ALZFORUM NETWORKING FOR A CURE
  43. Clinical Trial Results At AAIC 2019 Focus on new ideas and new targets- P&T community
  44. Advances In the global search for blood markers for Alzheimer's Disease and other Dementias; FROM THE ALZHEIMER'S ASSOCIATION INTERNATIONAL CONFERENCE 2019- P&T community
Disclaimer:
  • This document has been created for educational and instructional purposes only
  • Copyrighted materials used have been specifically acknowledged
  • We claim the right of fair use as ascertained by the author

Authors

Ms. Dilekha Vikruthi

Ms. Parupugalla Swetha