Conceptual evolution in Alzheimer's disease: implications for understanding the clinical phenotype of progressive neurodegenerative disease

Abstract

Over the past several decades, our understanding of Alzheimer's disease (AD) has seen an evolution from the dichotomous concept of normal versus AD in the dementia state to a more accurate and complete appreciation of AD as a progressive disorder with clinical, biological, and pathological features occurring along a continuum from normal to end-stage disease. Integrating our understanding of the relationships and interplay between the clinical, biological, and pathological features of AD may allow the identification of AD at even preclinical, completely asymptomatic stages of the disease. This review attempts to summarize the clinical stages of AD in terms of epidemiology, historical evolution of disease stage diagnoses, cognitive/neuropsychologic features, psychiatric/behavioral manifestations, and functional decline in the context of our developing understanding of the biological processes responsible for the pathogenesis of AD described in detail in the accompanying articles.

Figure 1

Simplified schematic of the Papez circuit. Early Alzheimer’s disease (AD) pathological changes start in the entorhinal cortex, spreading through the perforant pathway to involve the CA1 & 3 hippocampal subfields leading to anterograde amnesia. Later involvement includes pathological spread into the cingulate cortex and eventually the entire neocortex leading to both short-term and long-term memory impairment (retrograde amnesia). Limbic systems involved in emotion, behavior, arousal, and cortical activation including the amygdala and nucleus basalis of Meynert converge on this pathway and are heavily involved in the early stages of biological AD. This simplified schematic does not imply a linear or regimented progression for all cases of AD, but rather a generalization schema for understanding the typical progression of disease.

Figure 2

Diagrammatic algorithm for the diagnosis of MCI subtypes proposed by the 2^nd International Working Group on MCI [68, 75]. Subgroup classification may allow for the formulation of a differential diagnosis for the cognitive profile characteristic of each group that remains unproved at present. Abbreviations: MCI, mild cognitive impairment; AD, Alzheimer’s disease; HS, hippocampal sclerosis; VaD, vascular dementia; FTD, frontotemporal dementia; DLB, dementia with Lewy bodies.