Health economic evaluation of treatments for Alzheimer′s disease: impact of new diagnostic criteria

The socio‐economic impact of Alzheimer′s disease (AD) and other dementias is enormous, and the potential economic challenges ahead are clear given the projected future numbers of individuals with these conditions. Because of the high prevalence and cost of dementia, it is very important to assess any intervention from a cost‐effectiveness viewpoint. The diagnostic criteria for preclinical AD suggested by the National Institute on Aging and Alzheimer's Association workgroups in combination with the goal of effective disease‐modifying treatment (DMT) are, however, a challenge for clinical practice and for the design of clinical trials. Key issues for future cost‐effectiveness studies include the following: (i) the consequences for patients if diagnosis is shifted from AD‐dementia to predementia states, (ii) bridging the gap between clinical trial populations and patients treated in clinical practice, (iii) translation of clinical trial end‐points into measures that are meaningful to patients and policymakers/payers and (iv) how to measure long‐term effects. To improve cost‐effectiveness studies, long‐term population‐based data on disease progression, costs and outcomes in clinical practice are needed not only in dementia but also in predementia states. Reliable surrogate end‐points in clinical trials that are sensitive to detect effects even in predementia states are also essential as well as robust and validated modelling methods from predementia states that also take into account comorbidities and age. Finally, the ethical consequences of early diagnosis should be considered.     

Neurochemical enzyme changes in Alzheimer's and Pick's disease

Neurochemical investigations of the whole temporal lobe of cases with Alzheimer's disease (n ? 15; 80.7 ± 1.7 yr). Pick's disease (n = 3; 65 + 1.7 yr), and age-matched controls (n = 18; 74.7 ± 2.6 yr), demonstrate that Alzheimer's and Pick's disease are primary degenerative brain diseases.The activities of glycolytic enzymes, ATPases, carbonic anhydrase, acetylcholinesterase and protein kinase were significantly lower in Alzheimer's and in Pick's disease than in age-matched controls. Pick's disease is characterised by a more pronounced reduction of the enzymes investigated, which is considered to be an expression of a more dramatic degenerative process. The differences between Alzheimer's disease and Pick's disease are quantitative.     

Amyloid‐ß‐directed immunotherapy for Alzheimer's disease

Current treatment options for Alzheimer's disease (AD) are limited to medications that reduce dementia symptoms. Given the rapidly ageing populations in most areas of the world, new therapeutic interventions for AD are urgently needed. In recent years, a number of drug candidates targeting the amyloid‐ß (Aß) peptide have advanced into clinical trials; however, most have failed because of safety issues or lack of efficacy. The Aß peptide is central to the pathogenesis, and immunotherapy against Aß has attracted considerable interest. It offers the possibility to reach the target with highly specific drugs. Active immunization and passive immunization have been the most widely studied approaches to immunotherapy of AD. A favourable aspect of active immunization is the capacity for a small number of vaccinations to generate a prolonged antibody response. A potential disadvantage is the variability in the antibody response across patients. The potential advantages of passive immunotherapy include the reproducible delivery of a known amount of therapeutic antibodies to the patient and rapid clearance of those antibodies if side effects develop. A disadvantage is the requirement for repeated infusions of antibodies over time. After more than a decade of research, anti‐amyloid immunotherapy remains one of the most promising emerging strategies for developing disease‐modifying treatments for AD. In this review, we examine the presently ongoing Aß‐directed immunotherapies that have passed clinical development Phase IIa.     

Pathways to Alzheimer's disease

Recent trials of anti‐amyloid agents have not produced convincing improvements in clinical outcome in Alzheimer's disease; however, the reason for these poor or inconclusive results remains unclear. Recent genetic data continue to support the amyloid hypothesis of Alzheimer's disease with protective variants being found in the amyloid gene and both common low‐risk and rare high‐risk variants for disease being discovered in genes that are part of the amyloid response pathways. These data support the view that genetic variability in how the brain responds to amyloid deposition is a potential therapeutic target for the disease, and are consistent with the notion that anti‐amyloid therapies should be initiated early in the disease process.     

Heart failure and Alzheimer′s disease

It has recently been proposed that heart failure is a risk factor for Alzheimer′s disease. Decreased cerebral blood flow and neurohormonal activation due to heart failure may contribute to the dysfunction of the neurovascular unit and cause an energy crisis in neurons. This leads to the impaired clearance of amyloid beta and hyperphosphorylation of tau protein, resulting in the formation of amyloid beta plaques and neurofibrillary tangles. In this article, we will summarize the current understanding of the relationship between heart failure and Alzheimer′s disease based on epidemiological studies, brain imaging research, pathological findings and the use of animal models. The importance of atherosclerosis, myocardial infarction, atrial fibrillation, blood pressure and valve disease as well as the effect of relevant medications will be discussed.     

Insulin glargine and receptor-mediated signalling: clinical implications in treating type 2 diabetes

Most patients with type 2 diabetes mellitus will eventually require insulin therapy to achieve or maintain adequate glycaemic control. The introduction of insulin analogues, with pharmacokinetics that more closely mimic endogenous insulin secretion, has made physiologic insulin replacement easier to achieve for many patients. However, there are also concerns regarding alteration of binding affinities for the insulin receptor (IR) or insulin-like growth factor-1 receptor (IGF-1R) may increase the mitogenic potential of some analogues. Therefore, this article will review the relevant preclinical and clinical data to assess the mitogenic potential of insulin glargine, a basal insulin analogue, compared with regular human insulin (RHI).Searches of the PubMed database were performed using terms that included 'IR,' 'insulin-like growth factor-1,' 'IGF-1R,' 'type 2 diabetes mellitus,' and 'insulin glargine.' Original articles and reviews of published literature were retrieved and reviewed.Although one study reported increased binding affinity of insulin glargine for the IGF-1R and increased mitogenic potential in cells with excess IGF-1Rs (Saos/B10 osteosarcoma cells), most in vitro binding-affinity and cell-culture studies have demonstrated behaviour of insulin glargine comparable to that of RHI for both IR and IGF-1R binding, insulin signalling, and metabolic and mitogenic potential.Currently published in vivo carcinogenic studies and human clinical trial data have shown that insulin glargine is not associated with increased risk for either cancer or the development or progression of diabetic retinopathy.     

Cellular and metabolic alterations in the hippocampus caused by insulin signalling dysfunction and its association with cognitive impairment during aging and Alzheimer's disease: studies in animal models

A growing body of animal and epidemiological studies suggest that metabolic diseases such as obesity, insulin resistance, metabolic syndrome and type 2 diabetes mellitus are associated with the development of cognitive impairment, dementia and Alzheimer's disease, particularly in aging. Several lines of evidence suggest that insulin signalling dysfunction produces these metabolic alterations and underlie the development of these neurodegenerative diseases. In this article, we address normal insulin function in the synapse; we review and discuss the physiopathological hallmarks of synaptic insulin signalling dysfunction associated with metabolic alterations. Additionally, we describe and review the major animal models of obesity, insulin resistance, metabolic syndrome and type 2 diabetes mellitus. The comprehensive knowledge of the molecular mechanisms behind the association of metabolic alterations and cognitive impairment could facilitate the early detection of neurodegenerative diseases in patients with metabolic alterations, with treatment that focus on neuroprotection. It could also help in the development of metabolic‐based therapies and drugs for using in dementia and Alzheimer's disease patients to alleviate their symptoms in a more efficient and comprehensive way. Copyright © 2014 John Wiley & Sons, Ltd.     

Brain accumulation of amyloid β protein visualized by positron emission tomography and BF‐227 in Alzheimer's disease patients with or without diabetes mellitus

Aim: Although diabetes mellitus (DM) is considered to be one of the most consistent risks for developing dementia, it is not known if the pathology in dementia patients with DM is similar to or distinct from typical pathological features of Alzheimer's disease (AD). To discover the mechanism of developing dementia in AD patients with DM in a living state, we studied the distribution of amyloid β (Αβ) protein of diabetic AD patients. Methods: To evaluate the accumulation of Aβ, we examined 14 normal controls, four diabetic patients with AD and 11 non‐diabetic patients with AD by positron emission tomography (PET) using BF‐227, a currently developed Aβ tracer. Results: The analysis of PET images among the three groups showed an abundant aggregated Aβ accumulation in the cerebral cortex of both AD patients with and without DM. The extent and distributions of BF‐227 accumulation in diabetic AD patients were not significantly different from these of non‐diabetic AD patients. Conclusion: These results suggest that the degree and extent of Aβ deposition is not significantly different between AD with DM and AD alone. Geriatr Gerontol Int 2013; 13: 215–221.     

Serum amyloid A in Alzheimer's disease brain is predominantly localized to myelin sheaths and axonal membrane

Immunohistochemical localization of the injury specific apolipoprotein, acute phase serum amyloid A (A-apoSAA), was compared in brains of patients with neuropathologically confirmed Alzheimer's disease (AD), multiple sclerosis (MS), Parkinson's disease (PD), Pick's disease (Pick's), dementia with Lewy bodies (DLB), coronary artery disease (CAD), and schizophrenia. Affected regions of both AD and MS brains showed intense staining for A-apoSAA in comparison to an unaffected region and non-AD/MS brains. The major site of A-apoSAA staining in both diseases was the myelin sheaths of axons in layers V and VI of affected cortex. A-apoSAA contains a cholesterol binding site near its amino terminus and is likely to have a high affinity for cholesterol-rich myelin. These findings, along with our recent evidence that A-apoSAA can inhibit lipid synthesis in vascular smooth muscle cells suggest that A-apoSAA plays a role in the neuronal loss and white matter damage occurring in AD and MS.     

Selection of peptides binding to the amyloid b-protein reveals potential inhibitors of amyloid formation

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by extracellular amyloid plaques, cerebrovascular amyloid deposits, intracellular neurofibrillary tangles, and neuronal loss. Amyloid deposits are composed of insoluble fibers of a 39–43 amino acid peptide named the amyloid β-protein (Aβ). Neuropathological and genetic studies provide strong evidence of a key role for Aβ amyloidosis in the pathogenesis of AD. Therefore, an obvious pharmacological target for treatment of AD is the inhibition of amyloid growth and/or inhibition of amyloid function. We took an unbiased approach to generate new inhibitors of amyloid formation by screening a FliTrx? combinatorial peptide library for Aβ binding peptides and identified four groups of peptides with different Aβ binding motifs. In addition, we designed and examined peptides mimicking the Aβ binding domain of transthyretin (TTR). Our results showed that Aβ binding peptides selected from FliTrx? peptide library and from TTR-peptide analogs are capable of inhibiting Aβ aggregation and Aβ deposition in vitro. These properties demonstrate that binding of selected peptides to the amyloid β-protein may provide potent therapeutic compounds for the treatment AD.     

A common brain network links development,aging, and vulnerability to disease

Several theories link processes of development and aging in humans. In neuroscience, one model posits for instance that healthy age-related brain degeneration mirrors development, with the areas of the brain thought to develop later also degenerating earlier. However, intrinsic evidence for such a link between healthy aging and development in brain structure remains elusive. Here, we show that a data-driven analysis of brain structural variation across 484 healthy participants (8–85 y) reveals a largely—but not only—transmodal network whose lifespan pattern of age-related change intrinsically supports this model of mirroring development and aging. We further demonstrate that this network of brain regions, which develops relatively late during adolescence and shows accelerated degeneration in old age compared with the rest of the brain, characterizes areas of heightened vulnerability to unhealthy developmental and aging processes, as exemplified by schizophrenia and Alzheimer’s disease, respectively. Specifically, this network, while derived solely from healthy subjects, spatially recapitulates the pattern of brain abnormalities observed in both schizophrenia and Alzheimer’s disease. This network is further associated in our large-scale healthy population with intellectual ability and episodic memory, whose impairment contributes to key symptoms of schizophrenia and Alzheimer’s disease. Taken together, our results suggest that the common spatial pattern of abnormalities observed in these two disorders, which emerge at opposite ends of the life spectrum, might be influenced by the timing of their separate and distinct pathological processes in disrupting healthy cerebral development and aging, respectively.Many phylogenetic or ontogenetic models attempt to relate development and aging at genetic, molecular, or cognitive systems levels (1–4). In neuroscience, one of the most popular hypotheses in this respect postulates that the process of healthy age-related brain decline mirrors developmental maturation. This concept was first introduced in 1881 as a “loi de régression” (Ribot’s law) when Théodule Ribot, a French philosopher, observed that the destruction of memories progresses in reverse order to that of their formation: from the unstable to the stable, from the newly formed memories to older “sensory, instinctive” memories (5). More generally, this hypothesis postulates that the sequence of events associated with brain decline should present itself in reverse order to the series of events related to brain development, with brain regions thought to develop relatively late—at both ontogenetic and phylogenetic levels—also degenerating relatively early (2, 6, 7).One way of tracking this hypothesized mirroring pattern of development and aging in the human brain is to use the information provided at a macroscopic level by structural MRI in large-scale, lifespan human populations. Although structural MRI does not distinguish between the various cellular mechanisms underpinning development and aging processes [e.g., dendritic and synaptic remodeling, neurogenesis and neuronal death, astrogliosis, (de)myelination], this technique is sensitive to detect the overall contribution of these mechanisms to macroscopic age-related changes in brain structure (8–10).In 2000, Raz (11) presented for the first time MRI data suggesting that the chronological order of completion of intracortical fibers myelination was associated with age-related differences in cortical volume. In particular, Raz (12) later noted that “the pattern of differential brain aging suggests that phylogenetically newer and ontogenetically less precocious brain structures such as association cortices and the neostriatum show increased vulnerability to the effects of aging … follow(ing) the rule of (phylogenetically and ontogenetically) last-in, first-out” (12). Direct and intrinsic evidence for a clear link between brain structural development and aging lending support to this evolutionary–developmental “retrogenesis” model [or the “last-in, first-out” model as Raz (12) and others call it] is needed, however. Most of the structural imaging studies investigating relationships between development and aging have so far led to different, and sometimes contradictory, results (13, 14). One possible explanation for this inconsistency is that these studies have tested only one specific pattern of age-related change and have focused on age subgroups or on predefined regions of the brain.Here, we took a purely data-driven approach to assess the intersubject brain structure variability among 484 healthy participants covering most of the lifespan (8–85 y). We analyzed the structural brain images of these healthy subjects using a linked independent component analysis (ICA) (SI Materials and Methods) (15). This approach provides an automatic decomposition of the images into spatial components characterizing the intersubject brain structural variability, i.e., each spatial component represents a mode of variation of brain structure across all participants.     

Alzheimer’s disease related single nucleotide polymorphisms and correlation with intracerebral hemorrhage incidence

Apolipoprotein E alleles have been associated with both Alzheimer’s disease (AD) and intracerebral hemorrhage (ICH). In addition, ICH is associated with a markedly high risk of subsequent dementia compared to other subtypes of stroke. We sought to evaluate if other genetic markers for AD were also associated with ICH. We examined whether published AD risk single nucleotide polymorphisms (SNPs) and haplotypes were associated with ICH utilizing genome-wide association study data from 2 independent studies (genetic and environmental risk factors for hemorrhagic stroke [GERFHS] study and genetics of cerebral hemorrhage with anticoagulation [GOCHA]). Analyses included evaluation by location of ICH. GERFHS and GOCHA cohorts contained 745 ICH cases and 536 controls for analysis. The strongest association was on 1q32 near Complement receptor type 1 (CR1), where rs6701713 was associated with all ICH (P = .0074, odds ratio [OR] = 2.07) and lobar ICH (P = .0073, OR = 2.80). The 51 most significant 2-SNP haplotypes associated with lobar ICH were identified within the Clusterin (CLU) gene. We identified that variation within CR1 and CLU, previously identified risk factors for AD, and are associated with an increased risk for ICH driven primarily by lobar ICH. Previous work implicated CR1 and CLU in cerebral amyloid clearance, the innate immune system, and cellular stress response.     

Type 2 Diabetes and Alzheimer's Disease: From Common Pathologies to Potential New Therapeutics

Type 2 diabetes constitutes a major health risk in the United States, with over 20% of individuals over the age of 60 currently suffering from this disease and an additional 1.5 million new cases diagnosed in patients over 20 years of age in 2005. Similarly, Alzheimer''s disease represents a major risk to the aging population, with recent statistics estimating up to 16 million people diagnosed by 2050 in the United States alone. As type 2 diabetes and Alzheimer''s disease are now recognized as members of the broader class of amyloid diseases and because the pathologies of disease progression between these indications is similar, common strategies focused on the design of next-generation therapeutics can be envisioned and are discussed herein.     

Amyloidogenic and anti-amyloidogenic properties of recombinant transthyretin variants

Most transthyretin (TTR) mutations lead to TTR amyloid depositions in patients with familial amyloidotic polyneuropathy and familial amyloidotic cardiomyopathy. However, though an amyloidogenic protein itself, TTR inhibits aggregation of Alzheimer's amyloid beta protein (Aβ) in vitro and in vivo. The pathogenic relationship between two amyloidogenic processes remains unclear. To understand how TTR mutations influence the ability of TTR to inhibit Aβ amyloidosis, forty-seven recombinant TTR variants were produced and analyzed. We showed that all recombinant proteins formed tetramers and were functional in thyroxine binding. Acid denaturation at pH?3.8 resulted in aggregation and fibril formation of all TTR variants. However, only TTR G42 and TTR P55 formed fibrils at pH?6.8. Most TTR variants bound to Aβ and inhibited Aβ aggregation in vitro. TTR variants S64, A71, Q89, V107, H114 and I122 revealed decreased binding to Aβ and decreased inhibition of Aβ aggregation. Only TTR G42 and TTR P55 completely failed to bind Aβ and to inhibit Aβ aggregation. We suggest that TTR variants characterized by decreased binding to Aβ or by decreased inhibition of Aβ aggregation in vitro may contribute to Aβ amyloid formation in vivo. These TTR variants might be important targets for epidemiological studies in Alzheimer's disease.     

Patterns of Cerebrospinal Fluid Alzheimer’s Dementia Biomarkers in People Living with HIV: Cross-Sectional Study on Associated Factors According to Viral Control,Neurological Confounders and Neurocognition

People living with HIV (PLWH) age with an excess burden of comorbidities that may increase the incidence of age-related complications. There is controversy surrounding the hypothesis that HIV can accelerate neurodegeneration and Alzheimer’s dementia (AD). We performed a retrospective study to analyze the distribution of cerebrospinal fluid (CSF) AD biomarkers (beta amyloid 1–42 fragment, tau, and phosphorylated tau) in adult PLWH (on cART with undetectable viremia, n = 136, with detectable viremia, n = 121, and with central nervous system CNS disorders regardless of viremia, n = 72) who underwent a lumbar puncture between 2008 to 2018; HIV-negative controls with AD were included (n = 84). Five subjects (1.5%) presented CSF biomarkers that were compatible with AD: one was diagnosed with AD, whereas the others showed HIV encephalitis, multiple sclerosis, cryptococcal meningitis, and neurotoxoplasmosis. Regardless of confounders, 79.6% of study participants presented normal CSF AD biomarkers. Isolated abnormalities in CSF beta amyloid 1–42 (7.9%) and tau (10.9%) were associated with age, biomarkers of intrathecal injury, and inflammation, although no HIV-specific feature was associated with abnormal CSF patterns. CSF levels of AD biomarkers very poorly overlapped between HIV-positive clinical categories and AD controls. Despite the correlations with neurocognitive performance, the inter-relationship between amyloid and tau proteins in PLWH seem to differ from that observed in AD subjects; the main driver of the isolated increase in tau seems represented by non-specific CNS inflammation, whereas the mechanisms underlying isolated amyloid consumption remain unclear.     

Lithium therapy and cerebrospinal fluid biomarker levels in Alzheimer's disease

Recent studies suggest that lithium may retard pathological deterioration by inhibiting aberrant phosphorylation of tau in Alzheimer's disease (AD). Here, we describe three cases of AD who were treated with lithium for agitation. However, there was no obvious improvement either in global cognition, agitation or cerebrospinal fluid markers that were thought to reflect Alzheimer's pathology. Increased dosages of lithium were not tolerated by the patients because of adverse effects. It is likely that AD patients do not benefit from lithium therapy as an alternative choice of treatment.     

The possible role of the immune system in Alzheimer’s disease

—Currently, there is little doubt that the immune system plays a role in the neurodegenerative process in Alzheimer’s disease (AD). Inflammatory proteins such as complement components, enzymes, eicosanoids, and cytokines are found in association with cerebral amyloid plaques and may exacerbate the fundamental pathology of AD, by stimulating Amyloid β (Aβ) production, supporting its aggregation and increasing its cytotoxicity. Activated microglia and astrocytes are the main source of these proteins, and Aβ may trigger their release. Interestingly, there are also indications that the immune system may play a protective role against the development of AD. Microglial cells have been shown to degrade Aβ, and recent evidence suggests that autoreactive Aβ-specific T cells may be relevant to the elimination of the peptide. This mechanism seems, however, impaired in the majority of patients with AD. The immune system seems thus to represent a natural line of defense against the accumulation of dangerous amyloidogenic substances. Impairment of this specific immunological defense mechanism and the failure to eliminate a toxic metabolite can be the basis for a chronic nonspecific inflammatory process in the brain, as described above. AD is a good example how an immune response initially aiming at maintaining the integrity of the body may fail and consequently lead to tissue destruction and neuronal loss.