Curr Allergy Asthma Rep (2014) 14:417 DOI 10.1007/s11882-013-0417-1

BASIC AND APPLIED SCIENCE (M FRIERI AND PJ BRYCE, SECTION EDITORS)

Etiology and Pathogenesis of Late-Onset Alzheimer’s Disease Brian J. Balin & Alan P. Hudson

Published online: 16 January 2014 # Springer Science+Business Media New York 2014

Abstract Alzheimer’s disease (AD) is a neurodegenerative condition that occurs in two forms, an early-onset form that is genetically determined and a far more common late-onset form that is not. In both cases, the disease results in severe cognitive dysfunction, among other problems, and the lateonset form of the disease is now considered to be the most common cause of dementia among the elderly. While a good deal of research has been focused on elucidating the etiology of the late-onset form for more than two decades, results to date have been modest and have not yet engendered useful therapeutic strategies for cure of the disease. In this review, we discuss the prevalent ideas that have governed this research for several years, and we challenge these ideas with alternative findings suggesting a multifactorial etiology. We review promising newer ideas that may prove effective as therapeutic interventions for late-onset AD, as well as providing reliable means of earlier and more specific diagnosis of the disease process. In the discussions included here, we reference relevant clinical and basic science literature underlying research into disease etiology and pathogenesis, and we highlight current reviews on the various topics addressed. Keywords Alzheimer’s disease . Late onset . Amyloid cascade hypothesis . Inflammation . Infection . Neuropathogenesis . Etiology . Pathogenesis . Diagnosis This article is part of the Topical Collection on Basic and Applied Science B. J. Balin Department of Pathology, Microbiology, Immunology, and Forensic Medicine, Philadelphia College of Osteopathic Medicine, 4170 City Avenue, Philadelphia, PA 1913, USA A. P. Hudson (*) Department of Immunology and Microbiology, Wayne State University School of Medicine, Gordon H Scott Hall, 540 East Canfield Avenue, Detroit, MI 48201, USA e-mail: [email protected]

Introduction In 1901, Dr. Alois Alzheimer, a physician at the Frankfurt state asylum in Germany treated and studied a 51-year-old female patient who displayed severe cognitive dysfunction, including memory and language deficits, hallucinations, and paranoia. Upon her death several years later, her brain was sent for neuropathologic analysis to Alzheimer, who had moved to the medical school in Munich in 1903. Microscopic analysis of the brain tissues of the patient identified structures known as plaques and tangles, as well as atherosclerotic changes, all of which had been described by other neurologists in other similar patients prior to the publication of Alzheimer’s 1907 paper describing his study [1]. Although Alzheimer probably had no intention of initiating designation of a new disease with his report, the name Alzheimer’s Disease (AD) was coined by the head of his institute, Dr Emil Kraepelin, in a 1910 publication, and it has remained a recognized clinical entity since that time (www.wellcomecollection.org). Alzheimer died of heart failure in 1915 at the age of 51. It is significant that the individual whose neuropathologic analysis generated the disease designation was relatively young when she was studied initially by Alzheimer—at age 51, she would not have been considered a patient with classic senile dementia, a condition which had been associated by other researchers previous to Alzheimer’s 1907 paper with the above-mentioned brain-related plaques, tangles, and circulatory attenuation. As developed below, neurologists today recognize that AD comes in two distinct forms, an early-onset form that is genetically determined, and a late-onset form that is not (e.g., [2•] and see below). The late-onset form of the disease is far more common than the early-onset form, currently accounting for more than 95 % of all AD cases. Interestingly, recent genetic analysis of remaining brain tissue samples from the woman studied by Alzheimer at the Frankfurt hospital demonstrated that a mutation in one of the genes

417, Page 2 of 10

associated with the early-onset form of the disease (PSEN-1, see below) was responsible for her dementia [3]. Current estimates of the prevalence of AD in the United States indicate that more than 5 million individuals 65 years old or older suffer from the disease; about 200,000 have been diagnosed with the early-onset, familial form (www.alz.org); healthcare costs for the disease are estimated currently at about $200 billion per year. Official sources predict that 13– 14 million people will suffer from all forms of AD in the US by 2050, with a total cost of care rising to more than $1 trillion. In the absence of a breakthrough in cure or therapy, the estimate for prevalence of the disease world-wide surpasses 115 million individuals by 2050 [4•]. Costs for care and treatment of AD world-wide surpassed $604 billion in 2010 and will rise exponentially in coming decades [5, 6••]. Research funding for the disease, however, has been relatively modest—$449 million from the National Institutes of Health in 2013. Funding for AIDS research in the same year is $3 billion from that source; in contrast to the number of patients with late-onset AD, estimates of HIV infection prevalence are given as approximately 1.1 million in the US. Clearly, AD is a major health problem both in the US and abroad and thus constitutes an enormous drain on both affected families and the associated healthcare systems. While it is clear that early-onset AD is primarily genetically determined, the etiology of late-onset disease remains to be elucidated. As outlined below, the prevailing paradigm for causation of lateonset disease, the Amyloid Cascade Hypothesis, has recently been called into question, and in this article we summarize both that idea and others currently emerging from new research. Further, at present, diagnosis of late-onset disease is a post-mortem determination, and we examine recent efforts to provide reliable criteria, and more importantly biomarkers, for earlier and more specific diagnosis. Finally, we discuss current trends and ideas in therapy for late-onset AD, and we identify avenues of approach to therapeutic interventions that we consider potentially valuable. At present, both early- and lateonset AD are incurable, and a cure for the latter most likely will not obtain until its etiology is established. We thus begin with a brief discussion of the neuropathology of AD, and we then examine the current paradigm for its causation.

Neuropathogenesis of Late-Onset Alzheimer’s Disease AD is a neurodegenerative disease associated with atrophy and death of neurons in specific brain regions, and, as mentioned above, it occurs in two general forms: an early-onset familial form that is primarily genetic in origin, and a far more common late-onset form that is not. In the familial form of the disease, patients, who are typically in middle age (as was the woman studied by Alzheimer), initially display minor memory loss but progress to major cognitive dysfunction. The latter

Curr Allergy Asthma Rep (2014) 14:417

may include behavioral disorders, motor difficulties, language problems, severe memory loss, paranoia, and other attributes, e.g., [7, 8]. While it varies widely among individuals, the rate of progression to cognitive dysfunction can endure for two decades. Incidence of late-onset disease increases with increasing age and is currently thought to be the most significant single cause of dementia in the elderly, e.g., [9, 10]. Unlike the early-onset form of the disease, evidence indicates that lateonset AD is not genetically-determined; although possession of the ε4 allele at the APOE locus on (human) chromosome 19 is a demonstrated and well-accepted risk factor for disease development (see below). Mutations in a small number of other genes associated with early-onset disease are not present in late-onset disease (again, see below). Not all individuals possessing the ε4 allele at the APOE locus will develop lateonset AD, but its presence increases the risk for disease development, promotes earlier onset of symptoms, and somehow facilitates rapid progression. Individuals homozygous for the ε4 allele type, in particular, are at high risk for disease development. The predominant characteristics of neuropathology associated with late-onset AD are neuritic senile plaques (NSP) and neurofibrillary tangles (NFT). The former are comprised of βamyloid peptide (Aβ) deposits, and they have been considered to be critical in the neuronal degeneration process in both early- and late-onset AD [7, 11]. Indeed, as reviewed in the following section, production and deposition of NSP have been considered the predominant causative factors in disease genesis. NFT are comprised of modified tau protein, a normal component of the cytoskeleton. Extensive study has demonstrated that the deposition of NFT follows a profile of various possible unusual post-translational modifications of the protein e.g., [11, 12]. Genetic analyses have identified mutations in several genes that ultimately result in increased production and deposition of Aβ. These mutated genes, associated with early-onset AD, include APP, PSEN-1, and PSEN-2 [13–15]; of these, mutations in PSEN-1 account for most cases of the familial disease (see [16], for review). Aβ takes the form of peptides 40–42 amino acids in length and is derived from cleavage in the C-terminal region of the large amyloid precursor protein, encoded by the gene APP on (human) chromosome 21 [17]; the normal function of this protein has yet to be fully determined. Aβ is generated via cleavage by β-secretase, a membrane-tethered protease, and γ-secretase, a membrane-embedded complex with presenilin as its catalytic component. Available data indicate that approximately 95 % of extracellular Aβ is comprised of a 40amino acid peptide (Aβ1-40); the other 5 % is comprised of a 42-amino acid peptide, Aβ1–42 [18]. Recent studies indicate that the NSP core is composed primarily of Aβ1–42, which now is thought to initiate NSP formation [18, 19]. As developed below, Aβ deposition in NSP and accumulation of modified tau in NFT represent the hallmark

Curr Allergy Asthma Rep (2014) 14:417

pathologies observed in brain tissues of patients with both familial and late-onset AD [7, 20]. Interestingly, death in patients with late-onset AD typically is not caused by the disease itself, but from secondary causes such as pneumonia. Currently, the ultimate diagnosis of late-onset AD comes from post-mortem examination primarily of the density of NSP and NFT in affected brain regions, including the frontal and temporal lobes, and the overall level of neuronal death in those areas. As reviewed next, a number of problems attend the contention that deposition of Aβ in NSP is the primary causative factor in the development of late-onset AD.

The Amyloid Cascade Hypothesis The hallmark neuropathology in AD has been proposed to arise from a cascading event centered on the generation and deposition of Aβ in certain brain regions of affected individuals; accumulation of pathogenic Aβ is thought to be an imbalance between production and degradation/removal of the molecule, e.g., [7, 21]. This explanation for the etiology of the disease is designated the “Amyloid Cascade Hypothesis” and has been the predominant explanation for its causation for more than two decades [22]. Various revisions to the hypothesis have been necessary recently to account for newer findings that suggest that soluble oligomers of Aβ may contribute to early, preclinical stages of disease; these latter are thought to initiate the cascade leading to synaptic dysfunction, atrophy, and neuronal loss [23]. In reality, the amyloid cascade hypothesis may be most applicable (and perhaps exclusively applicable) to familial AD, since it is currently accepted that this version of the disease is caused by mutations in the set of genes discussed briefly above that relate to increased amyloid formation and deposition. However, as mentioned, many studies demonstrate that late-onset AD does not arise from the same genetic defects as have been accepted for familial AD, nor does it necessarily involve, in all cases, dense deposits of Aβ in areas of neurodegeneration [24, 25]. Furthermore, although the Cascade hypothesis has maintained its overall traction for many years, no successful new therapeutic modalities have yet emerged as a function of this explanation for clinical disease ([26, 27]; but see [4•, 28, 29], and below). These and many other observations clearly call into question the generality of Aβ deposition into NSP, and the production of NFT, as the primary causative factors in development of late-onset AD, and several authors have pointed this out in congruence with other possible explanations for that development (e.g., [30••, 31••]; see also [27]). Importantly, the neuropathology, neurodegeneration, and cognitive dysfunction observed in both familial and late-onset AD are essentially identical, indicating that factors other than the genetic lesions currently thought to underlie the former must exist to explain the neurodegeneration, and critically the

Page 3 of 10, 417

neuropathology, of the latter. As mentioned, late-onset disease typically presents in older age; indeed, age is a primary risk factor for its development. Furthermore, other risk factors have been proposed, including: atherosclerosis [32], Type 2 diabetes [33], neurotrauma [34], and infection [35–37]. Interestingly, neuroinflammation is now accepted as a critical component underlying the neurodegeneration process observed in AD, an aspect of disease genesis discussed below [38]. Given these observations, we suggest that a likely scenario for development of late-onset AD includes an as yet poorly understood interplay between genetic risk, as exemplified by possession of the APOE ε4 allele, and a number of environmental factors including toxins and/or bacterial, fungal, and viral pathogens.

The APOE ε4 Allele and the Risk for Late-Onset Disease Development Five alleles have been identified at the APOE locus on chromosome 19. Two of them, ε1 and ε5, are extremely rare, while ε2, ε3, and ε4 are more common, with population frequencies of approximately 8, 75, and 14 %, respectively [39]. Some evidence suggests that the ε4 allele may be the ancestral type, from which the others derived. Many studies have demonstrated that the products of these alleles are critically important for normal cholesterol transport and homeostasis [40, 41]. As mentioned, possession of the ε4 allele has been identified as a significant risk factor associated with late-onset AD ([42]; but see [43, 44]). Possession of the ε4 allele has been associated with multiple sclerosis as well as with late-onset AD (see [45] for discussion). The means by which the ε4 allele product might modulate disease course in multiple sclerosis remains to be elucidated, but current opinion holds that it affects the rate of progression to disability rather than the risk for disease development [46]. As is the case for multiple sclerosis, precisely how the ε4 allelic product promotes AD-related neuropathology remains to be determined. One possibility relates apoE4 interaction with tau to the degenerative process, e.g., [47, 48]. Another potential relationship between this gene product and neurodegeneration postulates its enhancement of Aβ production, e.g., [49]; yet another contends that apoE4 increases the oligomerization of Aβ, which some reports have indicated to be neurotoxic (e.g., [50]; see also [51]). Some observations suggest that the product of the ε4 allele elicits AD-related neuropathology directly at the level of cholesterol metabolism, or that the structure of this gene product itself may not be relevant, but rather its aberrant expression may be involved, e.g., [52]. We have provided results indicating that the ε4 allele product may be involved in neuropathogenesis via its interaction with a bacterial pathogen, Chlamydia pneumoniae ([53], and see below).

417, Page 4 of 10

Inflammation as a Component of Alzheimer’s Neuropathogenesis Although it has not always been the case, inflammation is now considered an important factor contributing to the neurodegeneration characteristic in late-onset AD [27, 54]. Generally, neuroinflammation in AD is thought to be a direct result of Aβ deposition via activation of astocytes and microglia ([38]; see [55••] for review). Clinical trials investigating the effects of non-steroidal anti-inflammatory drugs in older populations support inflammation as a factor in late-onset disease, since some studies have shown that individuals who regularly use such drugs can exhibit delayed disease onset ([56]; see also [57]); disappointingly, however, a number of clinical trials indicate that NSAIDS and related drugs are ineffective as therapeutic agents for the disease once cognitive impairment has become manifest. As indicated, the resident cells in the brain responsible for inflammation are typically microglia and to a lesser extent astroglia. Both of these are activated in the late-onset AD brain and often are identified in and around amyloid plaques [58]. As developed below, microglia and astroglia respond to insult by producing pro-inflammatory cytokines and reactive oxygen species.

Alternative Ideas Regarding the Etiology of Late-Onset Alzheimer’s Disease Given the significant and increasingly recognized shortcomings of the Amyloid Cascade Hypothesis, as well as the issue of whether NSP and NFT are the primary causes underlying the neurodegeneration process, a number of alternative explanations have been put forward to account for development of late-onset AD. As indicated above, it is clear that the agerelated version of the disease cannot be a straightforward result of mutations in APP and/or the small number of other genes thought to be responsible for early-onset (familial) AD. Regardless, the idea that late-onset disease genesis must have some, probably quite complex, genetic underpinning has been a relative constant in AD research for many years, e.g., [59••]. For that reason, a great deal of effort and resources have been expended in performing genome-wide searches on affected families to identify loci that confer risk. These studies routinely identify the APOE locus with high scores, of course, and they have pointed to a relatively large number of additional loci as being potentially involved (see [59••, 60–62] for reviews). However, while many of the identified loci have been found in multiple independently conducted studies, none of them provide much in the way of useful diagnostic criteria either singly or in combination, e.g., [63]. These genes probably do provide some insight into various biochemical and metabolic aspects related to disease development, although

Curr Allergy Asthma Rep (2014) 14:417

how useful that information may be for development of new therapies remains to be seen. Various environmental factors have been investigated as contributors to the development of late-onset AD. The general idea behind many studies of such factors is based on the normally extended period of time required for progression between disease onset and significant cognitive dysfunction. This well-documented disease phenotype is thought to be consistent with gradual accumulation of an environmental toxin, such as aluminum, in the relevant portions of the central nervous system (e.g., [64] for recent review). Early ideas regarding the detailed role this metal might play in AD included interaction with NFT and, more recently, disruption of calcium homeostasis ([65, 66]; see [67] for additional discussion). Other environmental factors that have been considered include air pollution and natural radiation, among others, e.g., [68, 69]. None of these is generally regarded at present as a proximal cause of late-onset AD, although research is continuing to assess whether any of these influences might exacerbate disease development or progression. Several infectious agents have been investigated for a role in the genesis of late-onset AD, again with the underlying idea that long-term, largely subclinical, bacterial, viral, fungal, or parasitic infection might engender the characteristic neurodegeneration of the disease. In this regard, we identified the obligate intracellular bacterial pathogen Chlamydia pneumoniae in a high proportion of tissue samples from affected but not unaffected regions of the late-onset AD brain a decade and a half ago [35]. Infected microglia, astroglia, and perivascular macrophages, as well as neurons, were observed in our studies in areas of amyloid deposition [35, 70, 71]. Activation of microglia and astroglia in response to the presence of infected, activated monocytes could promote increased production of a variety of cytokines and chemokines thereby contributing to the inflammation characteristic of the AD brain [72, 73]. Indeed, in a recent in vitro study, production of several proinflammatory molecules including MCP-1, IL-6, and TNFα was significantly higher in supernatant fluids of C. pneumoniae-infected murine microglial cells compared with controls [74]. Infected murine astrocytes also displayed higher levels of MCP-1 and IL-6 compared to controls. Neurons exposed to conditioned supernatant from infected murine microglial cells displayed an increase in cell death compared with supernatants from mock infected cells; addition of neutralizing antibodies to IL-6 and TNFα to the conditioned supernatant reduced neuronal cell death by ~50 %. These data suggest that C. pneumoniae infection plays a role in neuroinflammation by stimulating a strong pro-inflammatory response resulting in neurodegeneration. Additionally, the normal developmental cycle of this ubiquitous intracellular pathogen often ends in host cell lysis, which would also contribute to neurodegeneration ([75] for review). In subsequent studies, we demonstrated that the load of infecting C. pneumoniae in

Curr Allergy Asthma Rep (2014) 14:417

the late-onset AD brain varies with the APOE genotype, with the heaviest burden born by those homozygous for the ε4 allele [53]. We also showed that possession of that allele enhances host cell infection by this pathogen [76]. Further, in a mouse model of AD, C. pneumoniae appeared to elicit amyloid plaque formation [77]. Several pathogens in addition to C. pneumoniae have been identified in the late-onset AD brain, or relevant circulating antibodies to them, including H.pylori, T. gondii, HSV-1, CMV, and others [78–81, 82•, 83]. Interestingly, one recent article suggested that AD itself might be an infectious disease [84]. The universal problem with identification of pathogens of any sort in this context has been the lack of confirmatory evidence from additional, independent studies. For just one of many examples, some laboratories have failed to find the pathogen we identified, C. pneumoniae, in relevant AD brain tissue samples, e.g., [85–87]. Thus, at this point, Koch’s postulates dictate that none of the potential infectious initiators of late-onset disease can be accepted as causative among relevant researchers and clinicians, and indeed none are. We suggest, though, that another explanation for late-onset disease genesis should be considered, one that is consistent in large part with the evidence of infection summarized above. That explanation for causality specifies that the neurodegeneration characteristic of late-onset AD does not have a single, unique cause; rather, it is a common endpoint for a number of different starting points or causal inputs. Those inputs, which can include environmental toxins of many types, infectious agents, and others either singly or in combination, interact in some as yet unknown manner with various specific aspects of the genetic background of each at-risk individual, including genotype at APOE, to produce the neuronal loss, synaptic dysfunction, and other characteristics of late-onset disease. While this argument for multifactorial causality significantly complicates the approaches available for elucidation of disease initiation and development, ultimately it may prove a more productive approach to understanding late-onset AD than those currently employed. Understanding the detailed biochemistry and metabolic aspects of such complex disease causality will also answer the question of whether NSP and NFT, common to both familial and late-onset disease, are truly of primary importance in the neuropathogenesis process or simply a terminal, epiphenomenal, result. As reviewed next, elucidation of the detailed causes of late-onset AD will provide for the first time meaningful access to therapeutic strategies to treat and cure the disease.

Diagnosis Historically, confirmational diagnosis of late-onset AD has been available only at autopsy, at which time the density, distribution, and localization of NSP and NFT in the affected

Page 5 of 10, 417

brain are determined. Prior to death, presumed diagnosis is made on the basis of age, cognitive ability as determined by observation and testing, and the presence of a number of other accepted phenotypic aspects of the disease. However, a longterm goal of the research community has been to define rational and reliable means for early diagnosis, thereby allowing earlier, and presumably more effective, therapeutic intervention. In this context, it has become clear over the last 10 years or more that inception of the disease process takes place at a point long before the onset of observable cognitive deficit or other symptoms, e.g., [27]. The current practice for pre-mortem diagnosis of the disease targets the presence and levels of Aβ 1–40/1–42 peptides and modified and total tau proteins in cerebrospinal fluid of patients at issue, often in conjunction with PET, MRI, or other imaging methods ([88–90] for review; but see [91]). Olfactory symptoms are frequently observed in patients relatively early in the AD disease process, and tests of olfactory function have been examined with some success as an additional means of premortem diagnosis, e.g., [92, 93]. Regardless, given the predicted increase in patient numbers and costs for late-onset AD, the search continues for more reliable early disease biomarkers, as well as for effective means of treating patients at extremely early stages of disease development (see also below). A promising and potentially important area in the search for useful early disease biomarkers in AD is that involving miRNAs. MicroRNAs are highly conserved small, noncoding RNAs that suppress gene expression following binding to the 3′-untranslated region of target mRNAs. These miRNAs have been implicated in a variety of cancers and neurodegenerative diseases including late-onset AD [94, 95]. Wide arrays of biological functions are altered following both up- and down-regulation of expression of several miRNAs in the AD neurodegenerative process (for review, see [96]). These functions include inflammation and oxidative stress, innate immunity, apoptosis, amyloid processing and expression, and tau expression. For example, miR-9 may be upregulated as a response to induction by IL-1β and Aβ42, thus implicating it in inflammatory and oxidative stress pathways [97]. Up-regulation of miR-125b has also been demonstrated in various regions of the AD brain [96–99]. Interestingly, this miRNA may be important in suppressing immune and inflammatory pathways in the brain, which would contribute to the neuropathological changes observed in late-onset AD [100, 101]. Down-regulation of some miRNAs also appears to have a dramatic effect on AD neuropathology. For just one example, miR-29 expression has been shown to be inversely correlated with amyloid plaque density in the AD brain [102]. Down-regulation of expression of this miRNA has been linked to increased β-secretase expression [103]. More investigation is required to elucidate the precise roles of the many miRNA species that may influence gene and

417, Page 6 of 10

protein regulation events in the genesis of late-onset AD. Understanding those diverse roles will engender a far better understanding of the underlying mechanisms leading to disease. Definition of predictive changes in expression for an array of miRNAs may well be a critical component of an earlier and more reliable diagnosis of the inception of neuropathology in late-onset AD.

Treatments and Their Delivery to the Alzheimer’s Brain The current treatments for late-onset AD are aimed solely at ameliorating symptoms and/or attenuating disease progression. The primary drugs commonly employed include those acting as acetylcholinesterase inhibitors, with the idea that impaired synaptic transmission due to attrition of cholinergic neurons is an important aspect of neuropathogenesis leading to memory loss (see [104•] for an excellent review). These agents are donepezil, rivastigmine, and galantamine, and they have been shown to function effectively primarily in patients early in disease development. A second drug in current use is memantine, attenuating glutamatergic neurotransmission which also is thought to be involved in AD-related neurodegeneration. Unlike the acetylcholinesterase inhibitors, this latter drug is approved for use in patients with moderate to severe AD. To our knowledge, no new drugs for the treatment of late-onset AD have been approved for a decade; although several compounds have been examined in clinical trials, none have proved to be efficacious to date (again, see [4•, 104•] for detailed reviews). Interestingly, some studies employing combination therapies of donepezil or other acetylcholinesterase inhibitors with memantine are underway, but at present results appear to be equivocal [4•]. Several other strategies are currently being examined for their efficacy in treatment of late-onset AD, including modulation of GABAbased transmission, serotonin receptor function, and modulation of amyloid production/processing, among others [4•]. As outlined briefly above, neuroinflammation is now thought to be a significant aspect of the pathogenic process obtaining in late-onset AD; however, while the incidence of disease development has been reported to be lower in regular NSAIDS users, the use of these drugs in affected patients has proved to be relatively ineffective therapeutically, e.g., [55••]. NSAIDS are known to attenuate inflammation generally by attenuating cyclooxygenase activity. Interestingly, one recent report indicated that in an in vitro model system, ibuprofen altered the structure of Aβ with a consequent attenuation of the putative synapto-toxicity exerted by this molecule [105]. Examination of the several NSAIDS available, however, has demonstrated that only a small proportion of these drugs display any useful Aβ-modifying or other activity relevant to therapeutic use for patients with lateonset AD, e.g., [57, 105–107]. Nonetheless, studies of other antiinflammatory compounds and strategies are ongoing and may yet yield therapeutically useful results (see [108] for review).

Curr Allergy Asthma Rep (2014) 14:417

Given the preponderance of the Amyloid Cascade Hypothesis and its contention that NSP and NFT are the root causes of the neurodegeneration and consequent cognitive dysfunction in late-onset AD, it is not surprising that therapeutic approaches targeting Aβ production/accumulation have been major goals in the search for treatments for this disease. Therapies intended to elicit immune-mediated clearance of Aβ from affected brain regions have been among the most prominent in clinical trials to date. The initial attempt, which utilized the full-length Aβ as immune target, was terminated due to adverse reactions in some patients [109]. Later vaccine trials targeted smaller regions of the Aβ peptide, and some of these, using humanized monoclonal antibodies targeting those smaller peptide regions, have shown promise (see [4•] for review). Other strategies under development focus on modulation of the secretase enzymes that produce Aβ from the APP gene product, attenuation of the aggregation of Aβ into NSP, increasing efflux of Aβ from the CNS to impede its aggregation into NSP, and others; to date, none of these strategies has progressed to a standard treatment regimen. Similarly, strategies targeting clearance of NFT, inhibition of tau modification (e.g., by phosphorylation), attenuating aggregation of modified tau into NFT, and others have not reached clinical practice, although some such strategies have shown initial promise (see [4•] for detailed review). A major issue in designing strategies for the treatment of late-onset AD using chemical, immunologically-based, or other means lies in how to provide access and optimal targeting into the CNS for therapeutic molecules. The blood brain barrier has proved to be an effective means of excluding molecules of most types from such access, and getting therapeutics across it (or “around” it) effectively and without degradation of the molecules at issue or damage to the barrier is under active, indeed highly aggressive, investigation. One strategy for therapeutics delivery to the CNS is to administer the drug intranasally, which functionally avoids having to cross the barrier, e.g., [110, 111]. Nanodevices, including nanoparticles of various compositions, liposomes, and others, have been studied for effective delivery of therapeutics across the barrier. Liposomes do not appear to be especially effective for this purpose, unless the blood brain barrier has been damaged somehow (e.g., [112•] for review; see also [113]). In contrast, various types of nanoparticles have given promise of effective CNS delivery of diverse therapeutics in a number of studies (see [112•, 114–116] for reviews). These devices were developed initially for delivery of anti-neoplastic compounds to the CNS and have been investigated for more effective delivery of therapeutics relevant to neurodegeneration and neuroinflammation, e.g., reviewed in [114, 115]. Attaching relevant ligands to the nanoparticle surface has provided a means not only of enhancing transport across the blood–brain barrier but also of targeting of the nanodevice to the CNS. Studies to date have identified little in the way of

Curr Allergy Asthma Rep (2014) 14:417

neuro- or other toxicities associated with the use of nanodevices for CNS delivery of therapeutics, although this is an area that requires extensive confirmation prior to any standard use in clinical situations.

Conclusions Both the clinical and scientific communities clearly recognize that, in the absence of effective means for diagnosis and treatment, the steeply increasing prevalence and costs associated with late-onset AD in an aging population will become an overwhelming burden over the next 3–4 decades. While research into biochemical, genetic, and pathophysiologic issues related directly or indirectly to disease genesis and progression have been pursued vigorously over the last 40 years or so, effective treatment regimens and diagnostic procedures have not kept pace. We and others have suggested that, to a large extent, this lack of progress in advancing both our understanding of, and consequently treatment of, this important disease can be traced to an inappropriate long-term focus on a single hypothesis for disease genesis. Other ideas to explain the origin of the characteristic neurodegeneration and its consequent cognitive dysfunction associated with late-onset AD are now being actively explored by many laboratories. While the picture emerging from those other ideas indicates a far more complex process for disease initiation and development than that of the Amyloid Cascade Hypothesis, we suspect that this new focus will provide insights for generating meaningful progress in diagnosis and treatment. Specifically, it is clear that a cure for late-onset AD must be founded on a firm understanding of the cause(s) of the disease, and, given what appears to be the increasingly complex ideas regarding etiology under current investigation, that etiology will be a challenge to elucidate. Regardless, progress in the development of new therapeutic approaches should result from increased understanding of the genetic, biochemical, and neurologic components, and of environmental insults, such as infection, related to disease development and progression. Along this same line, advances in earlier detection as well as more efficient and more highly targeted delivery of therapeutic molecules should improve symptomatic treatment of late-onset AD even in the absence of a cure.

Page 7 of 10, 417

References Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance 1. 2.•

3. 4.•

5. 6.••

7.

8. 9. 10. 11.

12.

13.

14.

15. Compliance with Ethics Guidelines Conflict of Interest Brian J. Balin and Alan P. Hudson declare that they have no conflict of interest. Human and Animal Rights and Informed Consent With regard to the authors’ research cited in this paper, all institutional and national guidelines for the care and use of laboratory animals were followed. In addition, all procedures were followed in accordance with the ethical standards of the responsible committee on human experimentation and with the Helsinki Declaration of 1975, as revised in 2000 and 2008.

16.

17.

Alzheimer A. Über eine eigenartige Erkrankung der Hirnrinde. Allg Zeitschr Psychiatr. 1907;64:146–8. Defina PA, Moser RS, Glenn M, Lichtenstein JD, Fellus J. Alzheimer's Disease clinical and research update for health care practitioners. J Aging Res. 2013 in press. A thorough and readable summary of clinical aspects, as well as some promising research aspects, of disease characteristics. Muller U, Winter P, Graeber MB. A presenilin 1 mutation in the first case of Alzheimer’s disease. Lancet Neurol. 2013;12:129–30. Anand R, Gill KD, Mahdi AA. Therapeutics of Alzheimer’s disease: past, present and future. Neuropharmacology. 2013;in press. As above, a timely summary of the present state of therapeutics as available and in use for this disease. Alzheimer’s Disease International, World Alzheimer’s Report 2010. Dorsey ER, George BP, Leff B, Willis AW. The coming crisis: obtaining care for the growing burden of neurodegenerative conditions. Neurology. 2013;80:1989–96. In our view, an important summary of the impending problem with regard to the care, costs, and therapy of Alzheimer’s Disease. Schellenberg GD. Genetic dissection of Alzheimer Disease, a heterogeneous disorder. Proc Natl Acad Sci U S A. 1995;92: 8552–9. Tanzi RE, Bertram L. New frontiers in Alzheimer’s disease genetics. Neuron. 2001;32:181–4. Madeo J, Frieri M. Alzheimer’s disease and immunotherapy. Aging Dis. 2013;4:210–20. Keefover RW. The clinical epidemiology of Alzheimer’s disease. Neurol Clin. 1996;14:337–51. Scheuner D, Eckman C, Jensen M, Song X, Citron M, Suzuki N, et al. Secreted amyloid β peptide similar to that in the senile plaques of Alzheimer’s disease is increased in vivo by the presenilin 1 and 2 mutations linked to familial Alzheimer’s disease. Nature Med. 1996;2:864–70. Alonso AC, Grundke Iqbal I, Iqbal R. Alzheimer’s disease hyperphosphorylated tau sequesters normal tau into tangles of filaments and disassembles microtubules. Nature Med. 1996;2:783–7. Goate A, Chartier-Harlin MC, Mullan M, Brown J, Crawford F, Fidani L, et al. Segregation of a missense mutation in the amyloid precursor protein gene with familial Alzheimer's disease. Nature. 1991;349:704–6. Levy-Lahad E, Wijsman EM, Nemens E, Anderson L, Goddard KA, Weber JL, et al. A familial Alzheimer's disease locus on chromosome 1. Science. 1995;269:970–3. Rogaev EI, Sherrington R, Rogaeva EA, Levesque G, Ikeda M, Liang Y, et al. Familial Alzheimer's disease in kindreds with missense mutations in a gene on chromosome 1 related to the Alzheimer's disease type 3 gene. Nature. 1995;376:775–8. Wolfe MS. When loss is gain: reduced presenilin proteolytic function leads to increased Abeta42/Abeta40. Talking Point on the role of presenilin mutations in Alzheimer disease. EMBO Rep. 2007;8:136–40. Selkoe DJ, Podlisny MB, Joachim CL, Vickers EA, Lee G, Fritz LC, et al. Beta-amyloid precursor protein of Alzheimer disease occurs as 110- to 135-kilodalton membrane-associated proteins in neural and nonneural tissues. Proc Natl Acad Sci U S A. 1988;85: 7341–5.

417, Page 8 of 10 18.

19.

20.

21.

22. 23.

24.

25.

26.

27.

28.

29.

30.•• 31.••

32. 33. 34.

35.

36.

37. 38.

Gandy S. The role of cerebral amyloid beta accumulation in common forms of Alzheimer disease. J Clin Invest. 2005;115: 1121–9. Iwatsubo T, Odaka A, Suzuki N, Mizusawa H, Nukina N, Ihara Y. Visualization of A beta 42(43) and A beta 40 in senile plaques with end-specific A beta monoclonals: Evidence that an initially deposited species is A beta 42(43). Neuron. 1994;13:45–53. Lee VM, Balin BJ, Otvos Jr L, Trojanowski JQ. A68: a major subunit of paired helical filaments and derivatized forms of normal Tau. Science. 1991;251:675–8. Claeyson S, Cochet M, Donegar R, Dumuis A, Bockaert J, Giannoni P. Alzheimer culprits: cellular crossroads and interplay. Cell Signal. 2012;24:1831–40. Hardy JA, Higgins GA. Alzheimer’s disease: the amyloid cascade hypothesis. Science. 1992;256:184–5. Jack Jr CR, Wiste HJ, Vemuri P, Weigand SD, Senjem ML, Zeng G, et al. Brain beta-amyloid measures and magnetic resonance imaging atrophy both predict time-to-progression from mild cognitive impairment to Alzheimer's disease. Brain. 2010;133:3336–48. Hsia AY, Masliah E, McConlogue L, Yu GQ, Tatsuno G, Hu K, et al. Plaque-independent disruption of neural circuits in Alzheimer's disease mouse models. Proc Natl Acad Sci U S A. 1999;96:3228–33. Mucke L, Yu GQ, McConlogue L, Rockenstein EM, Abraham CR, Masliah E. Astroglial expression of human alpha(1)antichymotrypsin enhances alzheimer-like pathology in amyloid protein precursor transgenic mice. Am J Pathol. 2000;157:2003–10. Nalivaeva NN, Turner AJ. The amyloid precursor protein: a biochemical enigma in brain development, function, and disease. FEBS Lett. 2013;587:2046–54. McGeer PL, McGeer EG. The amyloid cascade-inflammatory hypothesis of Alzheimer disease: implications for therapy. Acta Neuropathol. 2013;in press. Carreiras MC, Mendes E, Perry MJ, Francisco AP, Marco-Contellas J. The multifactorial nature of Alzheimer’s disease for developing potential therapeutics. Curr Top Med Chem. 2013;13:1745–70. Okura Y, Matsumoto Y. Recent advances in immunotherapy for Alzheimer’s disease: with special reference to DNA vaccination. Hum Vaccin. 2009;5:373–80. Bishop GM, Robinson SR. The amyloid hypothesis: let sleeping dogmas lie? Neurobiol Aging. 2002;23:1101–5. Krstic D, Knuesel I. The airbag problem – a potential culprit for bench-to-bedside translational efforts: relevance for Alzheimer’s disease. Acta Neuropathol Comm. 2013;1:62–9. An interesting and timely re-examination of the underlying premises of the Amyloid Cascade Hypothesis. de la Torre JC. How do heart disease and stroke become risk factors for Alzheimer's Disease? Neurol Res. 2006;28:637–44. Revill P, Moral MA, Prous JR. Impaired insulin signaling and the pathogenesis of Alzheimer's disease. Drugs Today. 2006;42:785–90. Szczygielski J, Mautes A, Steudel WI, Falkai P, Bayer TA, Wirths O. Traumatic brain injury: cause or risk of Alzheimer's disease? A review of experimental studies. J Neural Transm. 2005;112:1547–64. Balin BJ, Gerard HC, Arking EJ, Appelt DM, Branigan PJ, Abrams JT, et al. Identification and localization of Chlamydia pneumoniae in the Alzheimer's brain. Med Microbiol Immunol. 1998;187:23–42. Itzhaki RF, Lin WR, Shang D, Wilcock GK, Faragher B, Jamieson GA. Herpes simplex virus type 1 in brain and risk of Alzheimer's disease. Lancet. 1997;349:241–4. Miklossy J. Alzheimer's Disease–a spirochetosis? Neuroreport. 1993;4:841–88. Lue LF, Brachova L, Civin WH, Rogers J. Inflammation, A beta deposition, and neurofibrillary tangle formation as correlates of Alzheimer's Disease neurodegeneration. J Neuropathol Exp Neurol. 1996;55:1083–108.

Curr Allergy Asthma Rep (2014) 14:417 39.

Ordovas JM, Litwack-Klein L, Wilson PW, Schaefer MM, Schaefer EJ. Apolipoprotein E isoform phenotyping methodology and population frequency with identification of apoE1 and apoE5 isoforms. J Lipid Res. 1987;28:371–80. 40. Mahley RW. Apolipoprotein E: cholesterol transport protein with an expanding role in cell biology. Science. 1988;240: 622–30. 41. Strittmatter WJ. Apolipoprotein E, and Alzheimer's disease: signal transduction mechanisms. Biochem Soc Symp. 2001;67:101–9. 42. Roses AD. Apolipoprotein E, alleles as risk factors in Alzheimer’s disease. Annu Rev Med. 1996;47:387–400. 43. Deary IJ, Whiteman MC, Pattie A, Starr JM, Hayward C, Wright AF, et al. Cognitive change and the APOE epsilon 4 allele. Nature. 2002;418:932. 44. Bennett DA, Wilson RS, Schneider JA, Evans DA, Aggarwal NT, Arnold SE, et al. Apolipoprotein E epsilon4 allele, AD pathology, and the clinical expression of Alzheimer's disease. Neurology. 2003;60:246–52. 45. Swanborg RH, Whittum-Hudson JA, Hudson AP. Infectious agents and multiple sclerosis: are human herpes virus 6 and Chlamydia pneumoniae involved? J Neuroimmunol. 2003;136:1–8. 46. Fazekas F, Strasser-Fuchs S, Kollegger H, Berger T, Kristoferitsch W, Schmidt H, et al. Apolipoprotein E epsilon 4 is associated with rapid progression of multiple sclerosis. Neurology. 2001;57:853–7. 47. Lovestone S, Anderton B, Betts J, Dayanandan R, Gibb G, Ljungberg C, et al. Apolipoprotein E gene and Alzheimer's disease: is tau the link? Biochem Soc Symp. 2001;67:111–20. 48. Huang Y, Liu XQ, Wyss-Coray T, Brecht WJ, Sanan DA, Mahley RW. Apolipoprotein E fragments present in Alzheimer's disease brains induce neurofibrillary tangle-like intracellular inclusions in neurons. Proc Natl Acad Sci U S A. 2001;98:8848–53. 49. Hartman RE, Laurer H, Longhi L, Bales KR, Paul SM, McIntosh TK, et al. Apolipoprotein E4 influences amyloid deposition but not cell loss after traumatic brain injury in a mouse model of Alzheimer's disease. J Neurosci. 2002;22:10083–7. 50. Hashimoto T, Serrano-Pozo A, Hori Y, Adams KW, Takeda S, Banerji AO, et al. Apolipoprotein E, especially apolipoprotein E4, enhances the oligomerization of amyloid β peptide. J Neurosci. 2012;32:15181–92. 51. Carter DB. The interaction of amyloid-beta with apoE. Subcell Biochem. 2005;38:255–72. 52. Puglielli L, Tanzi RE, Kovacs DM. Alzheimer’s disease: the cholesterol connection. Nat Neurosci. 2003;6:345–51. 53. Gerard HC, Wildt KL, Whittum-Hudson JA, Lai Z, Ager JL, Hudson AP. The load of Chlamydia pneumoniae in the Alzheimer’s brain varies with APOE genotype. Microbiol Pathog. 2005;39:19–26. 54. Sastra M, Richardson JC, Gentleman SM, Brooks DJ. Inflammatory risk factors and pathologies associated with Alzheimer’s disease. Curr Alzheimers Res. 2011;8:132–41. 55.•• Meraz-Ríos MA, Toral-Rios D, Franco-Bocanegra D, VilledaHernández J, Campos-Peña V. The inflammatory process in Alzheimer disease. Front Integr Neurosci. 2013;7:59. doi:10. 3389/fnint.2013.00059. An important examination of the role of inflammation in the pathogenesis of Alzheimer’s disease. 56. Breitner JC. The role of anti-inflammatory drugs in the prevention and treatment of Alzheimer’s disease. Annu Rev Med. 1996;47:401–11. 57. Pasinetti GM. From epidemiology to therapeutic trials with antiinflammatory drugs in Alzheimer's disease: the role of NSAIDs and cyclo-oxygenase in beta-amyloidosis and clinical dementia. J Alzheimers Dis. 2002;4:435–45. 58. Wood PL. Role of CNS macrophages in neurodegeneration. In: Wood PL, editor. Neuroinflammation mechanisms and management. Totowa: Humana Press; 1998. p. 1–59. 59.•• Tanzi RE. The genetics of Alzheimer’s disease. Cold Spring Harb Perspect Med. 2012;2:doi:10.1101/cshperspect.a006296. A

Curr Allergy Asthma Rep (2014) 14:417

60.

61.

62.

63.

64. 65.

66.

67.

68.

69.

70.

71.

72.

73.

74.

75.

76.

77.

78.

current and thorough review of genome studies relating to the underlying genetics of Alzheimer’s disease. Ebbert MT, Ridge PG, Wilson AR, Sharp AR, Bailey M, Norton MC, Tschanz JT, Munger RG, Corcoran CD, Kauwe JS. Population-based analysis of Alzheimer's Disease risk alleles implicates genetic interactions. Biol Psychiatry. 2013;in press. Kamboh MI, Demirci FY, Wang X, Minster RL, Carrasquillo MM, Pankratz VS, et al. Genome-wide association study of Alzheimer’s disease. Transl Psychiatry. 2012;2:e117. Kauwe JS, Cruchaga C, Karch CM, Sadler B, Lee M, Mayo K, et al. Fine mapping of genetic variants in BIN1, CLU, CR1 and PICALM for association with cerebrospinal fluid biomarkers for Alzheimer's disease. PLoS One. 2011;6:e15918. Hu X, Pickering E, Liu YC, Hall S, Fournier H, Katz E, et al. Meta-analysis for genome-wide association study identifies multiple variants at the BIN1 locus associated with late-onset Alzheimer's disease. PLoS One. 2011;6:e16616. Walton JR. Aluminum involvement in the progression of Alzheimer’s disease. J Alzheimers Dis. 2013;35:7–43. Perl DP, Pendlebury WW. Aluminum neurotoxicity – potential role in the pathogenesis of neurofibrillary tangle formation. Can J Neurol Sci. 1986;13:441–5. Perl DP, Moalem S. Aluminum and Alzheimer’s disease: a personal perspective after twenty-five years. J Alzheimers Dis. 2006;9:291–300. Walton JR. Aluminum disruption of calcium homeostasis and signal transduction resembles change in aging and Alzheimer’s disease. J Alzheimers Dis. 2012;29:255–73. Moulton PV, Yang W. Air pollution, oxidative stress, and Alzheimer’s disease. J Environ Pub Health. 2012:472751. doi: 10.1155/2012/472751. Cherry JD, Liu B, Frost JL, Lemere CA, Williams JP, Olschowka JA, et al. Galactic cosmic radiation leads to cognitive impairment and increased aβ plaque accumulation in a mouse model of Alzheimer's disease. PLoS One. 2012;7:e53275. Gérard HC, Dreses-Werringloer U, Wildt KS, Oszust C, Balin BJ, Frey WH, et al. Chlamydia (Chlamydophila) pneumoniae in the Alzheimer’s brain. FEMS Immunol Med Microbiol. 2006;48: 355–66. Hammond CJ, Hallock LR, Howanski RJ, Appelt DM, Little CS, Balin BJ. Immunohistological detection of Chlamydia pneumoniae in the Alzheimer's disease brain. BMC Neurosci. 2010;11:121. Hu J, Van Eldik L. Glial-derived proteins activate cultures astrocytes and enhance beta amyloid-induced glial activation. Brain Res. 1999;842:46–54. Simpson JE, Newcombe J, Cuzner ML, Woodroofe MN. Expression of monocyte chemoattractant protein-1 and other beta-chemokines by resident glia and inflammatory cells in multiple sclerosis lesions. J Neuroimmunol. 1998;84: 238–49. Boelen E, Steinbusch HW, van der Ven AJ, Grauls G, Bruggeman CA, Stassen FR. Chlamydia pneumoniae infection of brain cells: an in vitro study. Neurobiol Aging. 2007;28:524–32. Roulis E, Polkinghome A, Timms P. Chlamydia pneumoniae: modern insights into an ancient pathogen. Trends Microbiol. 2013;21:120–8. Gérard HC, Fomicheva E, Whittum-Hudson JA, Hudson AP. Apolipoprotein E4 enhances attachment of Chlamydophila (Chlamydia) pneumoniae elementary bodies to host cells. Microb Pathog. 2008;44:279–85. Little CS, Hammond CJ, MacIntyre A, Balin BJ, Appelt DM. Chlamydia pneumoniae induces Alzheimer-like amyloid plaques in brains of BALB/c mice. Neurobiol Aging. 2004;25:419–25. Kountouras J, Boziki M, Zavos C, Gavalas E, Giartza-Taxidou E, Venizelos I, et al. A potential impact of chronic Helicobacter

Page 9 of 10, 417

79.

80.

81.

82.•

83.

84.

85.

86. 87.

88.

89.

90.

91.

92. 93.

94. 95. 96.

97. 98.

99.

pylori infection on Alzheimer's disease pathobiology and course. Neurobiol Aging. 2012;33:e3–4. Jung BK, Pyo KH, Shin KY, Hwang YS, Lim H, Lee SJ, et al. Toxoplasma gondii infection in the brain inhibits neuronal degeneration and learning and memory impairments in a murine model of Alzheimer's disease. PLoS One. 2012;7:e33312. Itzhaki RF, Wozniak MA. Herpes simplex virus type 1 in Alzheimer's disease: the enemy within. J Alzheimers Dis. 2008;13:393–405. Lurain NS, Hanson BA, Martinson J, Leurgans SE, Landay AL, Bennett DA, et al. Virological and immunological characteristics of human cytomegalovirus infection associated with Alzheimer disease. J Infect Dis. 2013;208:564–72. Miklossy J. Emerging roles of pathogens in Alzheimer’s disease. Exp Rev Mol Med. 2011;13:e30. An interesting review of the possible role of infectious agents in the genesis of Alzheimer’s disease. Krstic D, Madhusudan A, Doehner J, Vogel P, Notter T, Imhof C, et al. Systemic immune challenges trigger and drive Alzheimer-like neuropathology in mice. J Neuroinflammation. 2012;9:151–9. Reis HJ, Mukhamedyarov MA, Rizvanov AA, Palotás A. A new story about an old guy: is Alzheimer’s disease infectious? Neurodegener Dis. 2011;7:272–8. Nochlin D, Shaw CM, Campbell LA, Kuo CC. Failure to detect Chlamydia pneumoniae in brain tissues of Alzheimer's disease. Neurology. 1999;53:1888. Ring RH, Lyons JM. Failure to detect Chlamydia pneumoniae in the late-onset Alzheimer’s brain. J Clin Microbiol. 2000;38:2591–4. Gieffers J, Reusche E, Solbach W, Maass M. Failure to detect Chlamydia pneumoniae in brain sections of Alzheimer’s disease patients. J Clin Microbiol. 2000;38:881–2. Prvulovic D, Hampel H. Amyloid β (Aβ) and phosphor-tau (ptau) as biomarkers in Alzheimer’s disease. Clin Chem Lab Med. 2011;49:367–74. Hampel H, Mitchell A, Blennow K, Frank RA, Brettschneider S, Weller L, et al. Core biological marker candidates of Alzheimer's disease - perspectives for diagnosis, prediction of outcome and reflection of biological activity. J Neural Transm. 2004;111:247–72. Risacher SL, Saykin AJ, West JD, Shen L, Firpi HA, McDonald BC, et al. Baseline MRI predictors of conversion from MCI to probable AD in the ADNI cohort. Curr Alzheimers Res. 2009;6: 347–61. Teipel SJ, Grothe M, Lista S, Toschi N, Garaci FG, Hampel H. Relevance of magnetic resonance imaging for early detection and diagnosis of Alzheimer’s disease. Med Clin North Am. 2013;97: 399–424. 95 Stamps JJ, Bartoshuk LM, Heilman KM. A brief olfactory test for Alzheimer’s disease. J Neurol Sci. 2013;in press. Djordjevic J, Jones-Gotman M, De Sousa K, Chertkow H. Olfaction in mild cognitive impairment and Alzheimer’s disease. Neurobiol Aging. 2008;29:693–706. Lau P, de Strooper B. Dysregulated microRNAs in neurodegenerative disorders. Semin Cell Dev Biol. 2010;21:768–73. Sonntag KC. MicroRNAs and deregulated gene expression networks in neurodegeneration. Brain Res. 2010;1338:48–57. Holohan KN, Lahiri DK, Schneider BP, Foroud T, Saykin AJ. Functional microRNAs in Alzheimer’s disease and cancer: differential regulation of common mechanisms and pathways. Front Gen. 2013;3:323. Lukiw WJ. NF-ΚB-regulated micro RNAs (miRNAs) in primary human brain cells. Exp Neurol. 2012;235:484–90. Sethi P, Lukiw WJ. Micro-RNA abundance and stability in human brain: specific alterations in Alzheimer’s disease temporal lobe neocortex. Neurosci Lett. 2009;459:100–4. Cogswell JP, Ward J, Taylor IA, Waters M, Shi Y, Cannon B, et al. Identification of miRNA changes in Alzheimer’s disease brain and

417, Page 10 of 10

100.

101.

102.

103.

104.•

105.

106.

107.

CSF yields putative biomarkers and insights into disease pathways. J Alzheimers Dis. 2008;14:27–41. Lukiw WJ, Zhao Y, Cui JG. An NF-KB-sensitive micro RNA146a-mediated inflammatory circuit in Alzheimer disease and in stressed human brain cells. J Biol Chem. 2008;283:31315–22. Lukiw WJ, Alexandrov PN. Regulation of complement factor H (CFH) by multiple miRNAs in Alzheimer’s disease (AD) brain. Mol Neurobiol. 2012;46:11–9. Wang WX, Huang Q, Hu Y, Stromberg AJ, Nelson PT. Patterns of microRNA expression in normal and early Alzheimer’s disease human temporal cortex: white matter versus gray matter. Acta Neuropathol. 2011;121:193–205. Hebert SS, Horre K, Nicolai L, Papadopoulou AS, Mandemakers W, Silahtaroglu AN, et al. Loss of microRNA cluster miR-29a/b-1 in sporadic Alzheimer’s disease correlates with increased BACE1/betasecretase expression. Proc Natl Acad Sci U S A. 2008;105:6415–20. Rafii MS. Update on Alzheimer’s disease therapeutics. Rev Recent Clin Trials. 2013;in press. As the title indicates, a review on the current and potential therapeutics for the disease. Zurita MP, Muñoz G, Sepúlveda FJ, Gómez P, Castillo C, Burgos CF, et al. Ibuprofen inhibits the synaptic failure induced by the amyloid-β peptide in hippocampal neurons. J Alzheimers Dis. 2013;35:463–73. Gasparini L, Rusconi L, Xu H, del Soldato P, Ongini E. Modulation of beta-amyloid metabolism by non-steroidal antiinflammatory drugs in neuronal cell cultures. J Neurochem. 2004;337–48. Ho L, Qin W, Stetka BS, Pasinetti GM. Is there a future for cyclooxygenase inhibitors in Alzheimer's disease? CNS Drugs. 2006;20:85–98.

Curr Allergy Asthma Rep (2014) 14:417 108.

Walker D, Lue LF. Anti-inflammatory and immune therapy for Alzheimer's disease: current status and future directions. Curr Neuropharmacol. 2007;5:232–43. 109. Orgogozo JM, Gilman S, Dartigues JF, Laurent B, Puel M, Kirby LC, et al. Subacute meningoencephalitis in a subset of patients with AD after Abeta42 immunization. Neurology. 2003;61:46e54. 110. Hanson LR, Frey WH. Intranasal delivery bypasses the blood– brain barrier to target therapeutic agents to the central nervous system and treat neurodegenerative disease. BMC Neurosci. 2008;9:S5. 111. Dhuria SV, Hanson LR, Frey WH. Intranasal delivery to the central nervous system: mechanisms and experimental considerations. J Pharm Sci. 2010;99:1654–53. 112.• De Rosa G, Salzano G, Caraglia M, Abbruzzese A. Nanotechnologies: a strategy to overcome blood–brain barrier. Curr Drug Metab. 2012;13:61–9. A good review of current thinking regarding nanotechnological approaches to the delivery of therapeutic molecules to the central nervous system. 113. Michelia M-R, Bovab R, Maginib A, Polidorob M, Emiliani C. Lipid-based nanocarriers for CNS-targeted drug delivery. Recent Patients CNS Drug Discov. 2012;7:71–86. 114. Silva GA. Nanotechnology approaches to crossing the blood brain barrier and drug delivery to the CNS. BMC Neurosci. 2008;9:S4. 115. Silva GA. Nanotechnology applications and approaches for neuroregeneration and drug delivery to the central nervous system. Ann N Y Acad Sci. 2010;99:221–30. 116. Syed S, Zubair A, Frieri M. Immune response to nanomaterials: implications for medicine and literature review. Curr Asthma Allergy Rep. 2012;13:50–7.