CommentaryAlzheimer's therapeutics: Continued clinical failures question the validity of the amyloid hypothesis—but what lies beyond?
Graphical abstract
Introduction
Alzheimer's disease (AD), the most common form of dementia in the elderly, affects 5.4 million patients in the US alone, with 1 in 8 individuals 65 or older suffering from the disorder. It is the fifth leading cause of death in this group [1]. Particularly sobering is that the number of patients with AD is increasing [2], [3], with predictions of 115 million being affected by 2050 (http://www.alz.co.uk/research/statistics, http://www.alz.org/downloads/facts_figures_2012.pdf) due to: the aging of the population; the continuing lack of progress in identifying effective treatment modalities; and the lack of predictive diagnostic techniques. In 2010, the worldwide prevalence of AD was estimated at approximately 36 million individuals with an annual societal cost of US$604 billion, numbers that probably underestimate AD incidence as approximately 50% of cases are undiagnosed, especially in the early stages of the disease.
At any given time, it has been estimated that 25% of all hospital patients, 65 years or older, have AD. In 2004, these individuals had 828 hospital stays per 1000 Medicare beneficiaries, compared to 266/1000 for patients without AD. Additionally, annualized Medicaid costs for patients over 65 years of age are nine times higher if the patient has AD ($8419 vs. $915). Indeed, provision of care for AD patients has the potential to bankrupt many western healthcare systems if effective treatments are not found [2], [3]. Since drugs to slow or reverse AD progression have been estimated to have a potential market in excess of $20 billion per year, they are a high priority for both the pharmaceutical and biotechnology industries.
The actual pathological process(es) underlying AD causality are thought to begin 20–25 years before overt clinical symptoms become apparent [4], [5], [6], [7] making accurate diagnosis of the disease at as early a stage as possible a critical priority. As current diagnostic tools based on behavioral outcomes [8] and biomarkers (brain volume and metabolism, neuronal loss, brain/CSF amyloid load, CSF tau) have yet to be convincingly validated [9] with AD diagnosis arguably only possible when the disease is well advanced, new diagnostic guidelines proposed in 2011 [10], [11], [12] are currently under validation.
While both familial and sporadic forms of AD have been identified [13], [14], the ability of the familial form, which represents less than 1% of total AD incidence [15], [16] to usefully inform the causality of the sporadic disease state, is debatable. Thus, despite large investments by both academia and the pharmaceutical industry over the past 25 years, the cause(s) of AD remains largely unknown.
Section snippets
Historical drug discovery efforts
Early studies of brain samples from AD patients led to the identification of two key protein aggregates that are considered hallmarks of AD: (i) extracellular amyloid plaques that are mainly comprised of Aβ, a peptide that occurs primarily in 40mer and 42mer forms, designated Aβ40 and Aβ42, that are derived from amyloid precursor protein (APP) in the brain; and (ii) intraneuronal neurofibrillary tangles (NFTs) [13], [14] that contain hyperphosphorylated tau, a protein associated with
Genetics of AD
Genetic factors play a key role in the development and progression of AD, contributing to as much as 80% of the phenotypic variability in the disease [16]. The search for the gene(s) involved in the pathophysiology of AD has been ongoing since 1987 [37] with some 120 AD-associated gene loci identified as either causal or risk factors [38], [39] suggesting a multifactorial causality for the disease with low effect size or the possibility that AD represents more than a single disease. While many
Amyloid and AD therapeutics
Amyloid plaques formed by aggregation and deposition of Aβ are a well-established hallmark of AD neuropathology [13], [14], [70] being widely thought to be causal in disease etiology [66], [67]. Accordingly, current drug discovery approaches in AD have focused on; (i) preventing Aβ formation or improving ‘normal’ APP processing via the inhibition of γ-secretase or β-secretase or activation of α-secretase activity [24], [25], [72] or; (ii) removing existing amyloid deposits using
Alternative hypotheses/approaches to AD therapeutics
Alternative theories to AD causality that have emerged over the past two decades include environmental factors, e.g., the use of aluminum cooking utensils, increased vehicle exhaust in the atmosphere, stress, diet, hormones, diabetes, overuse of antibiotics with attendant alterations in the microbiome [185], intracranial atherosclerosis and the absence of robust intellectual stimuli in present day society. These causes have been complemented by the underlying tissue dysfunction resulting from
Amyloid, AD and the fallacy of low validity environments
With seven therapeutics targeted at ameliorating the amyloid burden in AD now having failed to show robust effects in the clinic, treatment for AD remains limited to four questionably effective palliative drugs. Based on the confounds of the trials and the increasing repetitive chant of “right target, wrong compound” [73], [92] that occurs with each new failure reported, the validity of the amyloid hypothesis remains untested as a result of this remarkable series of failures. Thus the
Is there a logical path forward?
In assessing next steps in AD therapeutics – the laudable road forward [256] – it is appropriate to objectively re-examine the amyloid trial outcomes in the context of the API/DIAN/NAPA initiatives [116], [117], [118], where the gamble [257] will be enhanced exponentially if prodromal studies represent the ultimate path forward [179]. In addition, it is imperative to invest significant research efforts and funding to alternative approaches, e.g., tau, ApoE4, recognizing that the likelihood of
Note added in proof
Shortly after completion of this manuscript, two groups reported that rare variants, e.g., R47H, in the TREM2 gene are another risk factor for LOAD with an odds ratio similar to that observed with ApoE4 [265], [266]. TREM2 encodes for an innate immune receptor present on the cell surface of the EM2 subset of myeloid receptors. In microglia, this receptor is involved in the clearance of neural debris from the CNS, via a process involving phagocytosis and ROS production [267] suggesting that
Conflict of interest
KM is a consultant to the Gladstone Institutes in the area of Alzheimer's disease medications. MW has no conflicts.
Acknowledgments
The authors would like to thank Mike Marino for helpful discussion, Ian Clark for alerting us to his publications in the area of TNF and AD, and would also like to acknowledge the extensive contributions of the late Mark Smith, George Perry and their associates in consistently questioning the many inconsistencies in the amyloid hypothesis of AD.
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