The National Institute on Aging and the Alzheimer's Association charged a workgroup with the task of revising the 1984 criteria for Alzheimer's disease (AD) dementia. The workgroup sought to ensure that the revised criteria would be flexible enough to be used by both general healthcare providers without access to neuropsychological testing, advanced imaging, and cerebrospinal fluid measures, and specialized investigators involved in research or in clinical trial studies who would have these tools available. We present criteria for all-cause dementia and for AD dementia. We retained the general framework of probable AD dementia from the 1984 criteria. On the basis of the past 27 years of experience, we made several changes in the clinical criteria for the diagnosis. We also retained the term possible AD dementia, but redefined it in a manner more focused than before. Biomarker evidence was also integrated into the diagnostic formulations for probable and possible AD dementia for use in research settings. The core clinical criteria for AD dementia will continue to be the cornerstone of the diagnosis in clinical practice, but biomarker evidence is expected to enhance the pathophysiological specificity of the diagnosis of AD dementia. Much work lies ahead for validating the biomarker diagnosis of AD dementia.

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The diagnosis of dementia due to Alzheimer’s disease: Recommendations from the National Institute on Aging-Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer's disease

The pathophysiological process of Alzheimer's disease (AD) is thought to begin many years before the diagnosis of AD dementia. This long "preclinical" phase of AD would provide a critical opportunity for therapeutic intervention; however, we need to further elucidate the link between the pathological cascade of AD and the emergence of clinical symptoms. The National Institute on Aging and the Alzheimer's Association convened an international workgroup to review the biomarker, epidemiological, and neuropsychological evidence, and to develop recommendations to determine the factors which best predict the risk of progression from "normal" cognition to mild cognitive impairment and AD dementia. We propose a conceptual framework and operational research criteria, based on the prevailing scientific evidence to date, to test and refine these models with longitudinal clinical research studies. These recommendations are solely intended for research purposes and do not have any clinical implications at this time. It is hoped that these recommendations will provide a common rubric to advance the study of preclinical AD, and ultimately, aid the field in moving toward earlier intervention at a stage of AD when some disease-modifying therapies may be most efficacious.

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Toward defining the preclinical stages of Alzheimer's disease: Recommendations from the National Institute on Aging-Alzheimer's Association workgroups on diagnostic guidelines for Alzheimer's disease

In 2011, the National Institute on Aging and Alzheimer's Association created separate diagnostic recommendations for the preclinical, mild cognitive impairment, and dementia stages of Alzheimer's disease. Scientific progress in the interim led to an initiative by the National Institute on Aging and Alzheimer's Association to update and unify the 2011 guidelines. This unifying update is labeled a "research framework" because its intended use is for observational and interventional research, not routine clinical care. In the National Institute on Aging and Alzheimer's Association Research Framework, Alzheimer's disease (AD) is defined by its underlying pathologic processes that can be documented by postmortem examination or in vivo by biomarkers. The diagnosis is not based on the clinical consequences of the disease (i.e., symptoms/signs) in this research framework, which shifts the definition of AD in living people from a syndromal to a biological construct. The research framework focuses on the diagnosis of AD with biomarkers in living persons. Biomarkers are grouped into those of β amyloid deposition, pathologic tau, and neurodegeneration [AT(N)]. This ATN classification system groups different biomarkers (imaging and biofluids) by the pathologic process each measures. The AT(N) system is flexible in that new biomarkers can be added to the three existing AT(N) groups, and new biomarker groups beyond AT(N) can be added when they become available. We focus on AD as a continuum, and cognitive staging may be accomplished using continuous measures. However, we also outline two different categorical cognitive schemes for staging the severity of cognitive impairment: a scheme using three traditional syndromal categories and a six-stage numeric scheme. It is important to stress that this framework seeks to create a common language with which investigators can generate and test hypotheses about the interactions among different pathologic processes (denoted by biomarkers) and cognitive symptoms. We appreciate the concern that this biomarker-based research framework has the potential to be misused. Therefore, we emphasize, first, it is premature and inappropriate to use this research framework in general medical practice. Second, this research framework should not be used to restrict alternative approaches to hypothesis testing that do not use biomarkers. There will be situations where biomarkers are not available or requiring them would be counterproductive to the specific research goals (discussed in more detail later in the document). Thus, biomarker-based research should not be considered a template for all research into age-related cognitive impairment and dementia; rather, it should be applied when it is fit for the purpose of the specific research goals of a study. Importantly, this framework should be examined in diverse populations. Although it is possible that β-amyloid plaques and neurofibrillary tau deposits are not causal in AD pathogenesis, it is these abnormal protein deposits that define AD as a unique neurodegenerative disease among different disorders that can lead to dementia. We envision that defining AD as a biological construct will enable a more accurate characterization and understanding of the sequence of events that lead to cognitive impairment that is associated with AD, as well as the multifactorial etiology of dementia. This approach also will enable a more precise approach to interventional trials where specific pathways can be targeted in the disease process and in the appropriate people.

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NIA-AA Research Framework: Toward a biological definition of Alzheimer's disease

1. Introduction and Overview. 2. Detecting Influential Observations and Outliers. 3. Detecting and Assessing Collinearity. 4. Applications and Remedies. 5. Research Issues and Directions for Extensions. Bibliography. Author Index. Subject Index.

Regression Diagnostics: Identifying Influential Data and Sources of Collinearity

2016 Alzheimer's disease facts and figures

denatured and treated with a detergent. The lack of sensitivity of the seLDI-TOF method was clearly demonstrated by the fact that it was barely able to detect the approximately 3,500 pM endogenous plasma Aβ1–40 found in the TG2576 App transgenic mice, which is approximately 70-fold greater than the levels present in human plasma [14]. secondly, the group performed seLDI-TOF on human brain extracts that were prepared under conditions that yielded primarily aggregated/oligomer Aβ, a structural form of Aβ to which solanezumab does not bind [17]. The abundance of oligomeric Aβ species in the human brain extracts is demonstrated in the bapineuzumab capture data. They showed that bapineuzumab captured more truncated forms of Aβ (5–42, 4–42, p3–42, 2–42) than full-length Aβ1–42 and since bapineuzumab does not recognize aminoterminally truncated forms, a likely way the truncated forms could be bound would be as part of an aggregate/ oligomer. The group did demonstrate that all the antibodies bound to multiple full-length forms of Aβ (1–42, 1–40, 1–39, 1–38) when similar extractions were performed on cortical tissue from 15-month-old TG2576 mice; however, prior studies have demonstrated that deposited Aβ from these transgenic mice is very easily solubilized as compared to Alzheimer’s disease tissue [13]. since solanezumab is selective for soluble monomeric forms of Aβ, the Watt et al. brain extraction experiments were not properly designed to detect target engagement for this antibody. Thirdly, the authors present no negative control experiments for their immunoprecipitation—mass spectrometry experiments using tagged Fab fragments of the antibodies. Appropriate controls would have been one or more tagged Fab fragments of unrelated antibodies and also omitting any primary antibody. Considering the very high amount of proteins in plasma (range 35–50 g/L), there is a very high risk of unspecific binding to the beads used for We read with interest the recent publication by Watt et al. [21] describing the properties of three anti-Aβ antibodies, bapineuzumab, solanezumab, and crenezumab in particular, with regard to target engagement. While the authors reported in vitro binding of the antibodies to synthetic Aβ, the ex vivo studies carried out on plasma and brain lysates led the authors to conclude that all three antibodies failed to engage the intended molecular targets. We believe the data represented do not justify the conclusions for the following reasons. First, surface-enhanced laser desorption/ionization timeof-flight mass spectrometry (seLDI-TOF Ms) used by Watt et al. to investigate this question does not possess a dynamic range sufficient to measure endogenous Aβ peptides in murine and human plasma. While the authors state that their method is capable of measuring 50 pM concentrations, detection at this level was demonstrated only after synthetic Aβ peptide was spiked into tissues that had already been

Anti-Aβ antibody target engagement: commentary regarding Watt et al. Acta Neuropathol 127:803–810 (2014)

also assessed the specificity of E2012 for different gamma-secretase substrates. Results: E2012 was shown to decrease Ab(x-40) and Ab(x-42) and to increase Ab(1-38) without changing total Ab(1-x) levels. MALDITOF analysis also revealed that E2012 reduced Ab40 and Ab42 and increased shorter Ab peptides, such as Ab37 and Ab38. E2012 did not induce the accumulation of APP-CTFs, suggesting that E2012 modulates, but does not inhibit, the cleavage of APP-CTF by gamma-secretase. Production of Notch intracellular domain (NICD) was not inhibited by E2012. Conclusions: We have profiled E2012, a compound from a new chemical class of GSMs, and found that it preferentially reduced gamma-secretase mediated Ab40 and Ab42 production over Notch cleavage via a different mechanism from that of classical GSIs. These results provide the basis for the development of E2012 as a new therapeutic agent for Alzheimer’s disease.

Characterization of amino-terminally truncated Abeta-42 peptides in plasma from Alzheimer's patients receiving solanezumab immunotherapy treatment

Pet biomarkers in the expedition 3 trial of patients with mild ad

was not used in the original derivation of iADRS, it can provide additional information on the performance of iADRS. Methods: EXPEDITION3 was an 80-week, placebo-controlled study of solanezumab (400mg/4 weeks). The study enrolled individuals with mild AD dementia. Mixed model repeated measure (MMRM) was used for treatment group comparisons. iADRS scores were computed using the ADAS-Cog13(iADRS 1⁄4[-1(ADASCog13)+85]+iADL). Results: A statistically significant difference between placebo and active drug was observed for change iADRS score (change from baseline) at Week 28 (p1⁄40.028) through Week 80 (p1⁄40.015) (Figure 1). Spearman rank correlations between iADRS and MMSE for baseline scores and baseline to endpoint changes were 0.533 and 0.611, respectively; correlations between iADRS and CDR were -0.644 and -0.600, respectively. Baseline iADRS and sociodemographic variable correlations were -0.130 for age and 0.002 (p>0.05) for gender. All correlations were statistically significant (p<0.001) unless stated otherwise. Conclusions: These EXPEDITION3 findings suggest that the combination of cognitive and functional measures in the iADRS provide an important measure of both cognition and function in a treatment trial of individuals with mild AD dementia. The correlations of iADRS score with MMSE and CDR scores support convergent validity, and age and gender did not greatly influence iADRS scores. The iADRS may provide a useful integrated measurement tool for the AD research community.

Eric Siemers

Papers

Anti-Aβ antibody target engagement: commentary regarding Watt et al. Acta Neuropathol 127:803–810 (2014)

Characterization of amino-terminally truncated Abeta-42 peptides in plasma from Alzheimer's patients receiving solanezumab immunotherapy treatment

Pet biomarkers in the expedition 3 trial of patients with mild ad

The patient voice: exploring treatment preferences in participants with mild cognitive concerns to inform regulatory decision making

O4-03-04