Dr. James Manos (MD)
1 February 2014
Overview of Alzheimer’s disease (AD)
Note: in this text, the writer expresses his point of view. Some advice is empirical, so you should consult your family doctor beforehand.
Alzheimer’s disease (AD) – terminology
Amyloid-beta (Aβ or Abeta) is a 36 – 43 amino acid peptide processed from the amyloid precursor protein (APP). Aβ is the main component of amyloid plaques (extracellular deposits found in the brains of patients with Alzheimer's disease). Similar plaques appear in some variants of Lewy body dementia and in inclusion body myositis (a muscle disease) while Aβ can also form the aggregates that coat cerebral blood vessels in cerebral amyloid angiopathy.
The plaques comprise a tangle of regularly ordered fibrillar aggregates called amyloid fiber, a protein fold shared by other peptides, such as the prions associated with protein misfolding diseases. Recent research suggests that soluble oligomeric forms of the peptide may be causative agents in the development of Alzheimer's disease. It is believed that Aβ oligomers are the most toxic. Brain Aβ is elevated in patients with sporadic Alzheimer’s disease. Aβ is the main constituent of the brain parenchymal (the functional part of the brain) and vascular amyloid. It contributes to cerebrovascular lesions and is neurotoxic.
Some researchers have found that the Aβ oligomers induce some of the symptoms of Alzheimer's disease by competing with insulin for binding sites on the insulin receptor, thus impairing glucose metabolism in the brain. Significant efforts have been focused on the mechanisms responsible for Aβ production, including the proteolytic enzymes alpha- and β-secretases that generate Aβ from its precursor protein, APP (amyloid precursor protein). Aβ circulates in plasma, cerebrospinal fluid (CSF), and brain interstitial fluid (ISF), mainly as soluble Aβ40. Senile plaques contain Aβ40 and Aβ42, while vascular amyloid predominantly is the shorter Aβ40. Several sequences of Aβ were found in both lesions (28).
Tau proteins (τ proteins) are proteins that stabilize microtubules. They are abundant in neurons of the CNS (central nervous system), but less common elsewhere. They are also expressed at very low levels in CNS astrocytes and oligodendrocytes. Pathologies such as dementia (e.g., Alzheimer’s) can result when tau proteins become defective and no longer stabilize microtubules properly. Elevated levels of tau protein in CSF (cerebrospinal fluid) are linked to poor recovery after head trauma. The tau proteins are the product of alternating splicing from a single gene that, in humans, is designated MAPT (microtubule-associated protein tau).
Hyperphosphorylation of the tau protein (tau inclusions, pTau) can result in the self–assembly of tangles of paired helical filaments and straight filaments, which are involved in the pathogenesis of Alzheimer’s disease and other tauopathies. All of the six tau isoforms are present in an often hyperphosphorylated state in paired helical filaments from Alzheimer's disease brain. When misfolded, this otherwise very soluble protein can form extremely insoluble aggregates, contributing to several neurodegenerative diseases.
Recent research suggests that tau may be released extracellularly by an exosome-based mechanism in Alzheimer's disease (the exosome complex is a multiprotein complex capable of degrading various types of RNA (ribonucleic acid) molecules) (27).
Presenilin-1 (PS-1) is a protein that, in humans, is encoded by the PSEN1 gene. Presenilin 1 is one of the four core proteins in the presenilin complex, which mediate the regulated proteolytic events of several proteins in the cell, including gamma-secretase, which is considered to play an especially important role in the generation of beta-amyloid, accumulation of which is related to the onset of Alzheimer’s disease, from the beta-amyloid precursor protein (APP).
Alzheimer’s disease (AD) patients with an inherited form of the disease carry mutations in the presenilin proteins (PSEN1; PSEN2) or the amyloid precursor protein (APP). These disease-linked mutations increase the production of the longer form of amyloid-beta, the main component of amyloid deposits found in AD brains.
Presenilins are postulated to regulate APP processing through their effects on gamma-secretase, an enzyme that cleaves APP. Transgenic mice that overexpressed mutant presenilin-1 show an increase of beta-amyloid-42(43) in the brain, which suggests presenilin-1 plays a significant role in beta-amyloid regulation and can be highly related to Alzheimer’s disease. A further study in neuronal cultures derived from presenilin-1 deficient mouse embryos showed that alpha- and beta-secretase cleavage was still normal without presenilin-1. Also, the cleavage by gamma-cleavage of the transmembrane domain of APP was abolished. A 5-fold drop of the amyloid peptide was observed, suggesting that deficiency of presenilin-1 can downregulate amyloid, and inhibition of presenilin-1 can be a potential method for anti-amyloidogenic therapy in Alzheimer’s disease (29).
Beta-secretase 1 (BACE1) [also known as beta-site APP cleaving enzyme 1(beta-site amyloid precursor protein cleaving enzyme 1), memapsin-2 (membrane-associated aspartic protease 2), and aspartyl protease 2 (ASP2)] is an enzyme that in humans is encoded by the BACE1 gene. Beta-secretase is an aspartic acid protease important for forming peripheral nerve cell myelin sheaths. Generation of the 40 or 42 amino acid–long amyloid-beta - peptides that aggregate in the brain of Alzheimer's disease (AD) patients requires two sequential cleavages of the amyloid precursor protein (APP). Extracellular cleavage of APP by BACE creates a soluble extracellular fragment and a cell membrane-bound fragment called C99. Cleavage of C99 within its transmembrane domain by gamma-secretase (see below) releases the intracellular domain of APP and produces amyloid-beta.
Since alpha-secretase cleaves APP closer to the cell membrane than BACE, it removes a fragment of the amyloid-beta peptide. Initial cleavage of APP by alpha-secretase rather than BACE prevents the eventual generation of amyloid-β. Unlike APP and the presenilin proteins important in gamma-secretase, no known mutation in the gene encoding BACE causes early-onset familial Alzheimer’s disease, a rare disorder. However, levels of this enzyme are elevated in the far more common late-onset sporadic Alzheimer's. The physiological purpose of BACE's cleavage of APP and other transmembrane proteins is unknown. However, a single residue mutation in APP reduces the ability of BACE-1 to cleave it to produce amyloid-beta and reduces the risk of Alzheimer’s disease and other cognitive declines (42).
Note: protease (also termed peptidase or proteinase) is any enzyme that performs proteolysis, namely begins protein catabolism by hydrolysis (the cleavage of chemical bonds by the addition of water) of the peptide bonds that link amino acids together in the polypeptide chain forming the protein (31).
Note: cleavage in molecular biology is the cutting of the 3' signaling region from a newly synthesized pre-messenger RNA (pre-mRNA) molecule in the process of gene transcription (32).
Gamma-secretase is an internal protease that cleaves within the membrane-spanning domain of its substrate proteins, including amyloid precursor protein (APP) and Notch. The gamma-secretase complex is unusual among proteases in having a ‘sloppy’ cleavage site at the C-terminal site in an amyloid-beta generation. Gamma-secretase can cleave APP in multiple sites to generate a peptide from 39 to 42 amino acids long, with Aβ40 the most common isoform and Aβ42 the most susceptible to conformational changes leading to amyloid fibrillogenesis (fibril development). Certain APP and human presenilin types of mutations are associated with increased Aβ42 production and the early-onset genetic form of familial Alzheimer’s disease.
Some evidence has suggested that different forms of the gamma-secretase complex are differentially responsible for generating different amyloid-beta isoforms. However, recent research indicates that the C-terminus of amyloid-beta is produced by a series of single-residue cleavages by the same isoform, beginning with generating Aβ46(30).
Apolipoprotein E (ApoE) is a class of apolipoprotein found in the chylomicron and the IDLs (intermediate–density lipoproteins) that are essential for the normal catabolism of triglyceride (TG) – rich lipoprotein constituents. In peripheral tissues, ApoE is primarily produced by the liver and macrophages and mediates cholesterol metabolism in an isoform-dependent manner. In the CNS (central nervous system), ApoE is mainly produced by astrocytes and transports cholesterol to neurons via ApoE receptors, which are members of the LDL (low-density lipoprotein) receptor gene family.
The E4 variant is the largest genetic risk factor for late-onset sporadic Alzheimer’s disease (AD) in various 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. Evidence has been presented suggesting an interaction between amyloid and E4 alleles. Alzheimer's disease is characterized by build-ups of aggregates of the peptide beta-amyloid.
Apolipoprotein E enhances the proteolytic breakdown of this peptide, both within and between cells. The isoform ApoE-ε4 is not as effective as the others at catalyzing these reactions, resulting in increased vulnerability to AD in individuals with that gene variation. Although 40 – 65% of AD patients have at least one copy of the 4 alleles, ApoE4 is not a determinant of the disease. At least a third of patients with AD are ApoE4 negative, and some ApoE4 homozygotes never develop the disease. There is also evidence that the ApoE2 allele may be protective in AD. Thus, the genotype most at risk for Alzheimer's disease and at an earlier age is ApoE 4,4. The ApoE 3,4 genotype is at increased risk, though not to the degree that those homozygous for ApoE 4 are. The genotype ApoE 3,3 is considered at normal risk for Alzheimer's disease. The genotype ApoE 2,3 is considered at lower risk for Alzheimer's disease. Interestingly, people with both a copy of the two alleles and the four alleles, ApoE 2,4, are at normal risk, like the ApoE 3,3 genotype. The estimated worldwide human allele frequencies of ApoE is:
1) for allele ε2, general frequency of 8.4% and Alzheimer’s disease (AD) frequency of 3.9%.
2) For alleleε3, the general frequency was 77.9%, and the Alzheimer’s disease (AD) frequency was 59.4%.
3) For allele ε4, the general frequency is 13.7%, and the Alzheimer’s disease (AD) frequency is 36.7% (33).
Note: allele, or allele, is one of several alternative forms of the same gene or same genetic locus (generally a group of genes). It is the alternative form of a gene for a character producing different effects (34).
Alzheimer’s disease (AD) – pathogenesis
Alzheimer’s disease (AD) is the most common form of dementia in older people and the 7th leading cause of death in the United States. Deposition of amyloid-beta (Aβ) plaques, hyperphosphorylation of the microtubule-associated protein tau (MAPT), neuroinflammation, and cholinergic neuron loss are the major hallmarks of AD. Deposition of Aβ peptides, which takes place years before the clinical onset of the disease, can trigger hyperphosphorylation of tau proteins and neuroinflammation. The latter is thought to be primarily involved in neuronal and synaptic damage seen in AD (5).
The main characteristic feature of Alzheimer’s disease (AD) is the presence of beta-amyloid plaques. These plaques are an accumulation of small fibers called beta-amyloid fibrils. The deposition of beta-amyloid protein is a consistent pathological hallmark of brains affected by AD (4).
An increasing body of evidence indicates that the accumulation of soluble oligomeric assemblies of a β-amyloid polypeptide (Aβ) plays a key role in Alzheimer’s disease (AD) pathology. Specifically, 56 kDa oligomeric species were shown to be correlated with impaired cognitive function in AD model mice (3).
Alzheimer’s disease (AD) is characterized by two histopathological hallmarks: the senile plaques, or extracellular deposits mainly composed of amyloid-beta peptide (Abeta), and the neurofibrillary tangles, or intraneuronal inclusions composed of hyperphosphorylated tau protein. Since Abeta aggregates are found in pathological cases, several strategies are underway to develop drugs that interact with Abeta to reduce its assembly (6).
Gain-of-function mutations in the presenilin-1 (PS-1) promote Alzheimer's disease (AD) by increasing reactive oxygen species (ROS), at least part of which is derived from an accompanying increase in the generation of amyloid-beta (Abeta). Additional studies indicate that impaired Apolipoprotein E function, which increases oxidative stress and is also associated with AD, potentiates the deleterious (negative) activity of PS-1. Folate deficiency is also associated with AD and potentiates the impact of ApoE deficiency and beta exposure. More recently, folate deficiency has been shown to increase PS-1 expression. Prior studies demonstrate that impaired DNA methylation resulting from a deficiency in S-adenosylmethionine (SAM, rapidly depleted following folate deprivation) leads to PS-1 overexpression, and direct supplementation with SAM attenuates PS-1 overexpression (1).
The toxicity of the amyloid-beta peptide is mediated through the generation of hydrogen peroxide (H2O2). The actions of H2O2 include oxidative modifications of proteins, lipids, and DNA, as observed in AD (2).
Alzheimer's disease (AD) is one of the neurodegenerative diseases characterized by the deposition of amyloid-β-protein (Aβ) as senile plaques in the brain parenchyma and phosphorylated-tau accumulation as neurofibrillary tangles in the neurons. Although details of the disease pathomechanisms remain unclear, Aβ likely acts as a key protein for AD initiation and progression, followed by abnormal tau phosphorylation and neuronal death (amyloid-cascade hypothesis) (20).
The exact mechanisms leading to Alzheimer's disease (AD) are largely unknown, limiting the identification of effective disease-modifying therapies. The two principal neuropathological hallmarks of AD are extracellular β-amyloid (Aβ), peptide deposition (senile plaques), and intracellular neurofibrillary tangles containing hyperphosphorylated tau protein (21).
PPIs (such as lansoprazole) and correlation with Alzheimer’s disease – Published studies
Proton-pump inhibitors (PPIs) are a group of medications whose main action is a pronounced and long-lasting reduction of gastric–acid production and used for conditions such as peptic ulcer disease (PUD), gastritis, gastroesophageal reflux disease (GERG or GORG). They are the most potent inhibitors of acid secretion available. The group followed and has largely superseded another group of pharmaceuticals with similar effects but a different mode of action called H2 – receptor antagonists. Most of these drugs are benzimidazole derivatives, but promising new research indicates that imidazopyridine derivatives may be a more effective treatment. High-dose or long-term use of PPIs can increase bone fracture risk (39).
A key event in the pathogenesis of Alzheimer's disease (AD) is the accumulation of amyloid-β (Aβ) species in the brain, derived from the sequential cleavage of the amyloid precursor protein (APP)by beta- and gamma-secretases. Based on a systems biology study to repurpose drugs for AD, a study explored the effect of lansoprazole, and other proton-pump inhibitors (PPIs), on Aβ production in AD cellular and animal models. The study found that lansoprazole enhances Aβ37, Aβ40, and Aβ42 production and lowers Aβ38 levels in amyloid cell models. Interestingly, acute lansoprazole treatment in wild-type and AD transgenic mice promoted higher Aβ40 levels in the brain, indicating that lansoprazole may also exacerbate Aβ production in vivo. Overall, this data presents for the first time that proton-pump inhibitors (PPIs) can affect amyloid metabolism in vitro and in vivo (40).
The authors of a study describe the interactions of two benzimidazole derivatives, astemizole (AST) and lansoprazole (LNS; a PPI (Proton-pump inhibitor)), with anomalous aggregates of tau protein (neurofibrillary tangles). Interestingly, these compounds, with important medical applications in treating allergies and gastrointestinal disorders, respectively, specifically bind to aggregated variants of tau protein and to paired helical filaments isolated from the brains of Alzheimer's disease (AD) patients (41).
Diagnosis of dementia
According to the Mayo Clinic, the diagnosis of dementia includes a) Cognitive and neuropsychological tests. In these tests, doctors will evaluate the person’s thinking (cognitive) function. Several tests measure thinking skills such as memory, orientation, reasoning and judgment, language skills, and attention. Doctors use these tests to determine whether someone has dementia, how severe it is, and what part of the brain is affected. b) Neurological evaluation. In a neurological evaluation, doctors will evaluate the person’s movement, senses, balance, reflexes, and other areas. Doctors may use neurological evaluation to diagnose other conditions. c)Brain image scans.
Doctors may order brain scans, such as a CT or MRI, to check for evidence of stroke or bleeding and to rule out the possibility of a tumor. d) Laboratory tests. Simple blood tests can rule out physical problems affecting brain function, such as vitamin B-12 deficiency or an underactive thyroid gland (hypothyroidism) (9).
Cognitive and neuropsychological tests
The Clinical Dementia Rating (CDR), the Mini-Mental State Examination (MMSE), and the Alzheimer's Disease Assessment Scale (ADAS) are used to assess the severity of dementia and cognitive impairment (15).
The early detection of dementia is the key to the best patient care. In addition to his clinical approach, the general practitioner can use a certain number of screening tools to detect and diagnose dementia with acceptable specificity and sensitivity (around 80%). Amongst these tools, the authors describe a four-question questionnaire to the informants, the Mini-Mental State Examination, the clock drawing test, and the Mementool.
A supplementary screening task, the 5 words test can orientate the diagnosis towards an Alzheimer's disease or another form of dementia (35).
Brain image scans
The aim of a study was to review, summarize and analyze recent findings relevant to the contribution of neuroimaging to the diagnosis of Alzheimer's disease (AD) and vascular dementia (VaD).
Computerized tomography (CT) or magnetic resonance imaging (MRI) accurately demonstrates the location and rate of progression of atrophic changes affecting the brain in AD and the different types of vascular lesions observed in mixed dementias and in pure VaD. Quantification of cortical thickness allows early diagnosis and rate of progression of mild cognitive impairment (MCI) to dementia. White matter involvement can also be quantified with diffusion tensor imaging (DTI) and functional methods, including fMRI (functional MRI), functional connectivity, and MR spectroscopy (MRS). Isotope-based techniques such as positron emission tomography (PET) allow measurement of regional cerebral glucose metabolism using (18)F-2-fluoro-deoxy-D-glucose (FDG). Cerebral blood flow can be measured using PET with H(2)(15)O or with single-photon emission computerized tomography (SPECT) with technetium (99m)Tc-HMPAO) or, more recently, arterial spin-label (ASL) imaging. There are isotope markers for amyloid-beta (11)O-PIB, (18)F-florbetapir), tau (18) FDDNP), and activated microglia (11)C-PK11195).
Neuroimaging markers are particularly useful in the early symptomatic and preclinical asymptomatic phases of Alzheimer's disease (AD) and serve as endpoints in clinical trials (16).
Adverse effects of gadolinium-based contrast agent on MRI brain imaging
Published studies
Magnetic resonance imaging (MRI) contrast agents have been used routinely for more than 20 years to increase the sensitivity and specificity of lesion detection. MRI contrast agents (CAs) are usually categorized according to their magnetic behavior, bio-distribution, and effect on the MR image. Typically, small-molecular-weight gadolinium-based CAs are examples of T1 agents, while magnetic nanoparticle (MNP) based CAs are examples of T2 agents. In addition to differences in magnetic relaxation behavior, small-molecular-weight gadolinium-based CAs and MNP-based CAs show significantly different toxicity profiles. In the case of small-molecular-weight gadolinium-based CAs, many previous toxicological studies have reported favorable safety profiles of gadolinium-based CAs. However, a delayed, serious adverse reaction known as nephrogenic systemic fibrosis (NSF) has recently been reported in patients, with a marked reduction in renal function after administering certain types of gadolinium-based CAs. For MNP-based CAs, in addition to a wide spectrum of nanotoxicity common in nanomaterials, the emerging unexpected cytotoxicity (toxicity on cells) of MNPs has become a new concern. Specifically, the combination of magnetic nanoparticles (MNPs) and strong static magnetic field (SMF) within MRI may give rise to potential adverse effects of MNPs in the clinical application (38).
Nephrogenic systemic fibrosis (NSF)is a multisystem disease seen exclusively in patients with renal (kidney) impairment. It can be severely debilitating and sometimes fatal. There is a strong association with gadolinium-based contrast agents used in magnetic resonance imaging (MRI). Risk factors include renal impairment and proinflammatory conditions, e.g., major surgery and vascular events. Although there is no single effective treatment for NSF, the most successful outcomes are seen following the restoration of renal function, either following recovery from acute kidney injury or following renal transplantation. There have been ten biopsy-proved pediatric cases of NSF, with no convincing evidence that children have a significantly altered risk compared with the adult population. After implementing guidelines restricting the use of gadolinium-based contrast agents in at-risk patients, there has been a sharp reduction in new cases and no new reports in children. Continued vigilance is recommended: screening for renal impairment, using more stable gadolinium chelates, and considering non-contrast-enhanced MRI or alternative imaging modalities where appropriate (37).
Nephrogenic systemic fibrosis (NSF) has been related to using gadolinium-based contrast agents (GBCAs) in patients undergoing dialysis. The Prospective Fibrose Nephrogenic Systemic study, a French prospective study supported by the French drug regulatory agency and the French Societies of Nephrology, Dermatology, and Radiology, aimed at determining the incidence of NSF in patients undergoing long-term dialysis. Adult patients undergoing long-term dialysis receiving a magnetic resonance imaging (MRI) examination with or without GBCA were included in the study. The study concluded that the incidence of nephrogenic systemic fibrosis (NSF) after a single dose of a macrocyclic gadolinium-based contrast agent (GBCA) is null in the sample of 268 patients undergoing dialysis (hemodialysis and peritoneal dialysis). This incidence is just lower than 0.5%. When contrast-enhanced MRI can be essential, or even decisive, to the diagnosis, these results are important and reassuring if physicians need to perform contrast-enhanced MRI in patients undergoing dialysis (36).
Drug treatment of Alzheimer’s disease (AD)
Alzheimer's dementia (AD) is a major cause of debility and economic strain in aging societies worldwide. The only 2 medication classes approved specifically for treating AD are the cholinesterase inhibitors (donepezil, rivastigmine, and galantamine) and memantine (10).
Alzheimer's disease (AD) is a progressive, degenerative brain disease. The mainstay of managing patients with AD is drugs that provide symptomatic therapy. Two classes of medications have been approved by the US FDA for the treatment of AD: the cholinesterase inhibitors (ChEIs), which include galantamine and rivastigmine (both approved for use in mild to moderate AD) and donepezil (approved for use in mild to severe AD); and the non-competitive NMDA receptor antagonist memantine (approved for use in moderate to severe AD). The European and Asian regulatory bodies have also approved ChEIs as monotherapy in mild to moderate AD (11).
According to the Mayo Clinic, treatment of dementia may help slow or minimize the development of symptoms. Treatment options include:
a) Cholinesterase inhibitors.
These drugs – donepezil (Aricept), rivastigmine (Exelon), and galantamine hydrobromide (Razadyne) – are Alzheimer's drugs that work by boosting levels of a chemical messenger involved in memory and judgment. Side effects can include nausea, vomiting, and diarrhea. Although primarily used as Alzheimer's drugs, they're also used to treat vascular, Parkinson's, and Lewy body dementias.
b) Memantine (Namenda). This drug for Alzheimer's disease works by regulating the activity of glutamate, another chemical messenger involved in all brain functions, including learning and memory. Its most common side effect is dizziness. Some research has shown that combining memantine with a cholinesterase inhibitor may have beneficial results.
c) Other medications. A doctor may prescribe medications to treat other symptoms or conditions, such as a sleep disorder.
d) Occupational therapy. A doctor may suggest occupational therapy to help the patient adjust to living with dementia. Therapists may teach the patient coping behaviors and ways to adapt movements and daily living activities as the condition changes (9).
Published studies about the combination of drugs already used for Alzheimer’s disease (AD)
The effectiveness of adding memantine to an Alzheimer's dementia treatment regimen which already includes donepezil
Evidence that the use of memantine in a patient already on cholinesterase inhibitor therapy can provide a clinically significant benefit is limited. A review searched for evidence supporting the addition of memantine therapy in patients with moderate-to-severe AD who are already receiving treatment with a cholinesterase inhibitor. One article was selected for review. Patients receiving memantine for 24 weeks experienced a statistically significant change from baseline on a modified 19-item AD Cooperative Study-Activities of Daily Living Inventory and on the Severe Impairment Battery (P=0.001) when compared with placebo. The change in mean scores in the memantine group versus placebo on the 19-item AD Cooperative Study-Activities of Daily Living Inventory were -2.0 versus -3.4 and on the Severe Impairment Battery 0.9 versus -2.5 which indicates an improved performance or reduced deterioration in the memantine group. The number needed to treat, and the effect size could not be calculated from the data provided.
The review concluded that adding memantine to donepezil in patients with moderate-to-severe Alzheimer’s disease (AD)AD provides a statistically significant improvement in several AD-oriented outcome measures. However, the clinical relevance of this benefit remains unclear (10).
Combination therapy for Alzheimer's disease
Alzheimer's disease (AD) is a progressive, degenerative brain disease. The mainstay of managing patients with AD is drugs that provide symptomatic therapy. Two classes of medications have been approved by the US FDA for the treatment of AD: the cholinesterase inhibitors (ChEIs), which include galantamine and rivastigmine (both approved for use in mild to moderate AD) and donepezil (approved for use in mild to severe AD); and the non-competitive NMDA receptor antagonist memantine (approved for use in moderate to severe AD). The European and Asian regulatory bodies have also approved ChEIs as monotherapy in mild to moderate AD. Future research directions are mostly focusing on disease modification and prevention.
A review shows that combination therapy for Alzheimer’s disease (AD) seems to be safe, well-tolerated and may represent the current gold standard for treating moderate to severe AD and possibly mild to moderate AD (11).
Effect of memantine treatment on patients with moderate-to-severe Alzheimer's disease treated with donepezil
A prospective, randomized, parallel-group study investigated memantine's behavioral and cognitive effect in moderate to severe patients with Alzheimer's disease receiving donepezil. In the study, 43 patients were enrolled in this study. There were no significant imbalances between the treatment groups in demographic and baseline clinical characteristics. Cognitive and global measures were collected at baseline and at the end of weeks 4, 8, 12, and 24. Behavioral measures were collected at baseline, at the end of week 12, and at week 24. The results showed that memantine-treated patients showed significantly less deterioration in their functionality. Of patients who exhibited agitation/aggression at baseline, those treated with memantine, and donepezil showed a significant reduction of symptoms compared with donepezil-treated patients.
The study concluded that treatment with memantine was well tolerated. It reduced agitation/aggression, irritability, and appetite-eating disturbances in patients who were agitated at baseline and delayed its emergence in those who were free of agitation at baseline (12).
Cost-effectiveness of memantine in moderate-to-severe Alzheimer's disease patients receiving donepezil
The efficacy and safety of memantine in patients with moderate-to-severe Alzheimer's disease (AD) receiving stable doses of donepezil were recently demonstrated in a phase III trial. The cost-effectiveness of such therapy is unknown. A microsimulation model was developed to depict AD progression and associated clinical and economic outcomes. AD progression was measured in terms of decline in cognitive function, as assessed by the Severe Impairment Battery (SIB). At model entry, patients were assumed to have moderate-to-severe AD, to be on stable doses of donepezil, and to begin combination therapy with memantine or continue to receive donepezil alone; the duration of therapy was assumed to be 1 year. Drug efficacy was based on data from a phase III trial. The study concluded that in patients with moderate-to-severe Alzheimer's disease (AD) already receiving donepezil, memantine treatment improved clinical outcomes and reduced total costs of care (13).
Analysis of the treatment effects of memantine in patients receiving stable donepezil treatment
In moderate-to-severe Alzheimer's disease (AD), there are significant losses of activities of daily living (ADL). In a recent prospective, randomized, placebo-controlled trial, memantine treatment lessened the overall functional decline in AD patients already on stable donepezil therapy. In a trial, patients (n=404 subjects) with Mini-Mental State Examination scores of 5 to 14 receiving stable donepezil treatment were randomized to double-blind treatment with memantine (10 mg b.i.d. (twice daily); n=203 subjects) or placebo (n=201 subjects). A primary outcome measure was the 19-item Alzheimer's Disease Cooperative Study--Activities of Daily Living Inventory (ADCS-ADL (19)). To further evaluate the treatment effects of memantine on function, we performed post hoc analyses of ADCS-ADL (19) data from this trial, including ADL items and new subscales derived from factor analysis. Using mixed model analyses, patients receiving memantine had statistically significantly less decline in total ADCS-ADL (19) scores than placebo. Item analysis revealed statistically significant benefits of memantine on grooming, toileting, conversing, watching television, and being left alone. Statistically, significant improvements were noted in subscales evaluating higher-level functions and connectedness/autonomy with memantine compared with placebo. in conclusion, these post hoc analyses in moderate-to-severe Alzheimer's disease (AD) patients receiving stable donepezil treatment suggest that memantine may impact overall functional levels and some cognitive processing underlying ADL performance (14).
Alzheimer’s disease (AD) and new treatments under research
Bapineuzumab & solanezumab immunotherapy for Alzheimer's disease
Published studies
Bapineuzumab and solanezumab for Alzheimer's disease
The 'amyloid cascade hypothesis' remains the leading hypothesis to explain the pathophysiology of Alzheimer's disease (AD). Immunotherapeutic agents have been developed to remove the neurotoxic amyloid β42 protein and prevent the hypothesized amyloidβ42-induced neurotoxicity and neurodegeneration. The most notable of these immunotherapies is bapineuzumab and solanezumab.
Phase III trials showed that bapineuzumab failed to improve cognitive and functional performances in AD patients and was associated with a high incidence of amyloid-related imaging abnormalities (ARIA). Solanezumab's two Phase III trials in AD patients failed to meet endpoints when analyzed independently. However, analysis of pooled data from both trials showed a significant reduction in cognitive decline in mild AD patients. The improvement was associated with increased plasma amyloid-β (Aβ) levels and a low incidence of ARIA in solanezumab-treated patients. The marginal benefits of solanezumab are encouraging to support a continued evaluation in future studies and offer small support in favor of the ongoing viability of the 'amyloid cascade hypothesis of AD (17).
The case for soluble Aβ oligomers as a drug target in Alzheimer's disease (AD)
Soluble Aβ oligomers are now widely recognized as key pathogenic structures in Alzheimer's disease. They inhibit synaptic function, leading to early memory deficits and synaptic degeneration, and they trigger the downstream neuronal signaling responsible for phospho-tau Alzheimer's pathology. The marginal effects observed in recent clinical studies of solanezumab, targeting monomeric Aβ, and bapineuzumab, targeting amyloid plaques, prompted expert comments that drug discovery efforts in Alzheimer's disease should focus on soluble forms of Aβ rather than fibrillar Aβ deposits found in amyloid plaques (18).
Passive anti-amyloid immunotherapy in Alzheimer's disease (AD)
Alzheimer's disease (AD) is strongly associated with Amyloid-beta (Aβ) protein aggregation, resulting in brain extracellular plaques. According to the amyloid cascade hypothesis, it is a promising target for developing AD therapeutics. Within the past decade, convincing data has arisen, positioning the soluble prefibrillar Aβ-aggregates as the prime toxic agents in AD. However, different Aβ aggregate species are described, but their remarkable metastability hampers the identification of a target species for immunization.
Passive immunotherapy with monoclonal antibodies (mAbs) against Aβ is in late clinical development. Still, recently, the two most advanced mAbs, Bapineuzumab and Solanezumab, targeting an N-terminal or central epitope, respectively, failed to meet their target of improving or stabilizing cognition and function. Preliminary data from off-label treatment of a small cohort for 3 years with intravenous polyclonal immunoglobulins (IVIG) that appear to target different conformational epitopes indicate cognitive stabilization. Thus, it might be a more promising strategy to reduce the spectrum of Aβ-aggregates than to focus on a single aggregate species for immunization (19).
Aβ immunotherapy for Alzheimer's disease
Alzheimer's disease (AD) is one of the neurodegenerative diseases characterized by the deposition of amyloid-β-protein (Aβ) as senile plaques in the brain parenchyma and phosphorylated-tau accumulation as neurofibrillary tangles in the neurons. Although details of the disease pathomechanisms remain unclear, Aβ likely acts as a key protein for AD initiation and progression, followed by abnormal tau phosphorylation and neuronal death (amyloid-cascade hypothesis). According to this hypothesis, Aβ immunization therapies are created to eliminate Aβ from the brain and to prevent the neurons from being damaged by these pathogenic proteins. There are two methods for Aβimmunotherapies: active and passive immunization. Previous studies have shown Aβ removal and improved cognitive function in animal models of AD. Clinical trials on various drugs, including AN1792, bapineuzumab, and solanezumab, have been carried out; however, all trials have failed to demonstrate apparent clinical benefits.
On the contrary, side effects emerged, such as meningoencephalitis, and vasogenic edema, currently called amyloid-related imaging abnormalities (ARIA)-E, and microhemorrhage (ARIA-H). In neuropathological studies of immunized cases, Aβ was removed from the brain parenchyma, and phosphorylated tau was reduced in the neuronal processes. Moreover, deterioration of cerebral amyloid angiopathy (CAA) and increased microhemorrhages and microinfarcts were described. Aβ is cleared from the brain mainly via the lymphatic drainage pathway. ARIA could stem from severe CAA due to dysfunction of the drainage pathway after immunotherapy. Aβ immunization has the potential of a cure for Alzheimer's disease (AD) patients, although the above-described problems must be overcome before applying this therapy in clinical treatment (20).
Immunotherapy for Alzheimer's disease (AD)
The exact mechanisms leading to Alzheimer's disease (AD) are largely unknown, limiting the identification of effective disease-modifying therapies. AD's two principal neuropathological hallmarks are extracellular β-amyloid (Aβ), peptide deposition (senile plaques), and intracellular neurofibrillary tangles containing hyperphosphorylated tau protein. During the last decade, most of the pharmaceutical industry's efforts were directed against the production and accumulation of Aβ. The most innovative of the pharmacological approaches was the stimulation of Aβ clearance from the brain of AD patients via the administration of Aβ antigens (active vaccination) or anti-Aβ antibodies (passive vaccination). Several active and passive anti-Aβ vaccines are under clinical investigation. Unfortunately, the first active vaccine (AN1792, consisting of pre-aggregate Aβ and an immune adjuvant, QS-21) was abandoned because it caused meningoencephalitis in approximately 6% of treated patients. Anti-Aβ monoclonal antibodies (bapineuzumab and solanezumab) are now being developed. The clinical results of the initial studies with bapineuzumab were equivocal regarding cognitive benefit. The occurrence of vasogenic edema after bapineuzumab and, more rarely, brain microhemorrhages (especially in Apo E ε4 carriers) has raised concerns about the safety of these antibodies directed against the N-terminus of the Aβ peptide.
Solanezumab, a humanized anti-Aβmonoclonal antibody directed against the mid-region of the Aβ peptide, was shown to neutralize soluble Aβ species. Phase II studies showed a good safety profile of solanezumab, while studies on cerebrospinal and plasma biomarkers documented good signals of pharmacodynamic activity. Although some studies suggested that active immunization may be effective against tau in animal models of AD, very few studies regarding passive immunization against tau protein are currently available. Based on the new diagnostic criteria for AD and on recent major failures of anti-Aβ drugs in mild-to-moderate AD patients, one could argue that clinical trials on potential disease-modifying drugs, including immunological approaches, should be performed in the early stages of Alzheimer's disease (AD) (21).
Bapineuzumab captures the N-terminus of the Alzheimer's disease (AD) amyloid-beta peptide in a helical conformation
Bapineuzumab is a humanized antibody targeting the amyloid (Aβ) plaques that underlie Alzheimer's disease neuropathology. The authors report the crystal structure of a Fab-Aβ peptide complex that reveals Bapineuzumab surprisingly captures Aβ in a monomeric helical conformation at the N-terminus. Microscale thermophoresis suggests that the Fab binds soluble Aβ(1-40) with a K(D) of 89 (±9) nM. The structure explains the antibody's exquisite selectivity for particular Aβ species and why it cannot recognize N-terminally modified or truncated Aβ peptides (22).
Effect of immunotherapy with bapineuzumab on cerebrospinal fluid Biomarker levels in patients with mild to moderate Alzheimer's disease (AD)
Given the slow and variable clinical course of Alzheimer's disease (AD), large and extended clinical trials are needed to identify the beneficial clinical effect of disease-modifying treatments. Therefore, biomarkers are essential to prove that an anti-β-amyloid (Aβ) drug candidate affects both Aβ metabolism, plaque load, and downstream pathogenic mechanisms. Two-phase 2, multicenter, randomized, double-blind, placebo-controlled clinical trials of 12-month duration evaluated the effect of the anti-Aβ monoclonal antibody bapineuzumab on cerebrospinal fluid (CSF) biomarkers reflecting Aβ homeostasis, neuronal degeneration, and tau-related pathology in patients with Alzheimer disease. Forty-six patients with mild to moderate Alzheimer's disease participated. Patients received either placebo (n = 19 subjects) or bapineuzumab (n = 27 subjects) in 3 or 4 ascending dose groups. The results showed that passive Aβ immunotherapy with bapineuzumab decreases cerebrospinal fluid (CSF) T-tau and P-tau, which may indicate downstream effects on the degenerative process. Cerebrospinal fluid biomarkers may be useful for monitoring the effects of novel disease-modifying anti-Aβ drugs in clinical trials (23).
Safety and biomarker effects of solanezumab in patients with Alzheimer's disease (AD)
A study assessed the safety, tolerability, pharmacokinetics, and pharmacodynamics of 12 weekly infusions of solanezumab, an anti-β-amyloid (Aβ) antibody, in patients with mild-to-moderate Alzheimer's disease (AD). Cognitive measures were also obtained.
In this phase 2, randomized, double-blind, placebo-controlled clinical trial, 52 patients with Alzheimer's disease received a placebo or antibody (100 mg every 4 weeks, 100 mg weekly, 400 mg every 4 weeks, or 400 mg weekly) for 12 weeks. Safety and biomarker evaluations continued until 1 year after randomization. Both magnetic resonance imaging and cerebrospinal fluid (CSF) examinations were conducted at baseline and after the active treatment period. The results showed that antibody administration was well tolerated with doses up to 400 mg weekly. The dose-dependent increase in unbound CSF Aβ(1-42) suggests that this antibody may shift Aβ equilibria sufficiently to mobilize Aβ(1-42) from amyloid plaques (24).
Prevalence of asymptomatic vasogenic edema in pretreatment Alzheimer's disease (AD) study cohorts from phase 3 trials of semagacestat and solanezumab
Cerebral vasogenic edema (VE)has been reported to occur during anti-amyloid immunotherapy. VE may be associated with central nervous system pathology with blood-brain barrier disruptions; however, less is known about the prevalence of naturally occurring VE in patients with Alzheimer's (AD).
Fluid-attenuated inversion recovery imaging sequences were obtained from four ongoing multicenter, randomized, double-blind, placebo-controlled, phase 3 trials in patients with mild-to-moderate AD. The first set of baseline scans was from patients in volumetric magnetic resonance imaging addenda in the Interrupting Alzheimer's Dementia by EvaluatiNg Treatment of Amyloid PaThologY (IDENTITY) studies examining semagacestat, a γ-secretase inhibitor (cohort 1, n = 621 subjects). The second set of baseline scans was from the EXPanding Alzheimer's Disease InvestigaTIONs (EXPEDITION) studies examining solanezumab, an anti-Aβ monoclonal antibody (cohort 2, n = 2 141 subjects). The conclusion was that cerebral vasogenic edema (VE) seems rare at baseline in patients with Alzheimer's disease (AD) in clinical trials, 2 of 2 762 associated with AD. Additional cohorts should be evaluated to support these findings (25).
Amyloid-related imaging abnormalities in patients with Alzheimer's disease treated with bapineuzumab
Amyloid-related imaging abnormalities (ARIA) have been reported in patients with Alzheimer's disease treated with bapineuzumab, a humanized monoclonal antibody against amyloid β. ARIA includes MRI signal abnormalities suggestive of vasogenic edema and sulcal effusions (ARIA-E), microhemorrhages, and haemosiderin deposits (ARIA-H). A study investigated the incidence of ARIA during treatment with bapineuzumab, and evaluated associated risk factors. Two neuroradiologists independently reviewed 2 572 fluid-attenuated inversion recovery (FLAIR) MRI scans from 262 participants in two phase-2 bapineuzumab studies and an open-label extension study. The conclusion was that Amyloid-related imaging abnormalities (ARIA) consist of a spectrum of imaging findings with variable clinical correlates. Some patients with ARIA-E remain asymptomatic even if treatment is continued. The increased risk of ARIA among APOE ɛ4 carriers, its association with high bapineuzumab dose, and its time course in relation to dosing suggest an association between ARIA and alterations in vascular amyloid burden (26).
MRI – guided focused ultrasound as a novel treatment
A study assessed whether repeated magnetic resonance (MR) imaging-guided focused ultrasound treatments targeted to the hippocampus, a brain structure relevant to Alzheimer's disease (AD), could modulate pathologic abnormalities, plasticity, and behavior in a mouse model. Seven-month-old transgenic (TgCRND8) (Tg) mice and their nontransgenic (non-Tg) littermates were entered into the study. Mice were treated weekly with MR (magnetic resonance) imaging-guided focused ultrasound in the bilateral hippocampus. After a month, spatial memory was tested in the Y maze with the novel arm before sacrifice and immunohistochemical analysis. The study concluded that repeated MRI (magnetic resonance imaging)-guided focused ultrasound treatments led to spatial memory improvement in a transgenic (Tg) mouse model of Alzheimer's disease (AD). The behavior changes may be mediated by decreased amyloid pathologic abnormalities and increased neuronal plasticity (43).
Note: The hippocampus is a major component of the brains of humans and other vertebrates. Humans and other mammals have two hippocampi on each side of the brain. It belongs to the limbic system and is important for consolidating information from short-term to long-term memory and spatial navigation. The hippocampus is located under the cerebral cortex (the outer layer of the neural tissue of the cerebrum (brain)). It is in the medial temporal lobe, underneath the cortical surface in primates. It contains two main interlocking parts: Ammon's horn and the dentate gyrus. In Alzheimer’s disease, the hippocampus is one of the first regions of the brain to suffer damage. Memory loss and disorientation are some of the early symptoms. People with extensive, bilateral hippocampal damage may experience anterograde amnesia, i.e., the inability to form or retain new memories (44).
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