How early can we diagnose Alzheimer disease (and is it sufficient)? The 2017 Wartenberg lecture

Abstract

A seismic shift in our understanding of the ability to diagnose Alzheimer disease (AD) is occurring. For the last several decades, AD has been a clinical-pathologic diagnosis, and this conceptualization of the disease has served the field well. Typically, the clinician would identify a syndrome such as mild cognitive impairment or dementia, and label the condition as "probable AD" since the diagnosis of definite AD could not be made until an autopsy revealed the presence of amyloid plaques and tau-based neurofibrillary tangles. However, with the advent of biomarkers for AD including neuroimaging and CSF, the identification of AD pathology can be made in life, which greatly enhances the ability of clinicians to be precise about the underlying etiology of a clinical syndrome. Hypothetical models of the temporal relation among the pathologic elements and the clinical symptoms have been proposed and have influenced the field enormously. This has enabled clinicians to be specific about the underlying cause of a given clinical syndrome. As such, the diagnostic capability of the clinician is evolving. However, AD pathology is only a component of the puzzle describing the causes of cognitive changes in aging. Most often, there is a multitude of pathologic entities contributing to the neuropathologic explanation of cognitive changes in aging. AD changes contribute important elements to the diagnosis, but the final answer is more complex. The field of aging and dementia will have to incorporate these additional elements.

Figure 1. Theoretical portrayal of the temporal development of pathologic and clinical events leading to Alzheimer disease dementia

Aβ = β-amyloid; CN = cognitively normal; MCI = mild cognitive impairment. Reproduced with permission from Elsevier. Copyright © 2010 Elsevier Ltd. All rights reserved.

Figure 2. Temporal evolution of criteria and research frameworks for Alzheimer disease

Aβ = β-amyloid; MCI = mild cognitive impairment. Reproduced with permission of Mayo Foundation for Medical Education and Research. All rights reserved.

Figure 3. Interrelations of various criteria for mild cognitive impairment using a combination of clinical features and biomarkers for Alzheimer disease

NIA-AA = National Institute on Aging–Alzheimer's Association; NINCDS-ADRDA = National Institute of Neurological and Communicative Disorders and Stroke–Alzheimer’s Disease and Related Disorders Association. Reproduced with permission from Wiley. Copyright © 2014 The Association for the Publication of the Journal of Internal Medicine.

Figure 4. Correspondence of clinical syndromes and stages for Alzheimer disease (AD) in the National Institute on Aging–Alzheimer's Association research framework

Aβ = β-amyloid; DSM-5 = Diagnostic and Statistical Manual of Mental Disorders, 5th edition; MCI = mild cognitive impairment. Reproduced with permission of Mayo Foundation for Medical Education and Research. All rights reserved.

Figure 5. Clinical spectrum of cognitively unimpaired–mild cognitive impairment–dementia with its multiple potential etiologies

The contribution of Alzheimer disease (AD) is expressed by β-amyloid (Aβ) and tau. However, the other protein abnormalities, including TDP-43 and α-synuclein, as well as vascular disease may also contribute to cognitive impairment. The ring of yellow symbols indicates the biomarkers that exist or are being developed for each pathologic entity. Ultimately, treatments will developed for each pathologic component based on its biomarker. Reproduced with permission of Mayo Foundation for Medical Education and Research. All rights reserved.