Alzheimer's Disease: Past, Present, and Future

Abstract

Although dementia has been described in ancient texts over many centuries (e.g., "Be kind to your father, even if his mind fail him." - Old Testament: Sirach 3:12), our knowledge of its underlying causes is little more than a century old. Alzheimer published his now famous case study only 110 years ago, and our modern understanding of the disease that bears his name, and its neuropsychological consequences, really only began to accelerate in the 1980s. Since then we have witnessed an explosion of basic and translational research into the causes, characterizations, and possible treatments for Alzheimer's disease (AD) and other dementias. We review this lineage of work beginning with Alzheimer's own writings and drawings, then jump to the modern era beginning in the 1970s and early 1980s and provide a sampling of neuropsychological and other contextual work from each ensuing decade. During the 1980s our field began its foundational studies of profiling the neuropsychological deficits associated with AD and its differentiation from other dementias (e.g., cortical vs. subcortical dementias). The 1990s continued these efforts and began to identify the specific cognitive mechanisms affected by various neuropathologic substrates. The 2000s ushered in a focus on the study of prodromal stages of neurodegenerative disease before the full-blown dementia syndrome (i.e., mild cognitive impairment). The current decade has seen the rise of imaging and other biomarkers to characterize preclinical disease before the development of significant cognitive decline. Finally, we suggest future directions and predictions for dementia-related research and potential therapeutic interventions. (JINS, 2017, 23, 818-831).

Keywords: Alzheimer’s disease; Biomarkers; Clinical trials; Cognition; Mild cognitive impairment; Neuroimaging; Neuropsychology; Neuroscience.

Fig. 1

Photographs of Alois Alzheimer (left) and his patient Auguste Deter (right).

Fig. 2

Sketches of Auguste Deter’s histopathologic preparations of early and late stage neurofibrillary tangle pathology as drawn by Alzheimer from his 1911 paper entitled “Über eigenartige Krankheitsfälle des späteren Alters.”

Fig. 3

Mean plaque count plotted against the summary cognitive test score constructed by Blessed, Tomlinson, & Roth (1968). The “Blessed” test score was computed from “a number of simple psychological tests of orientation, remote memory, recent memory, and concentration,” resulting in a total score ranging from 0 (complete failure) to 37 (perfect score). The scatterplot resulted in a highly significant correlation coefficient of −0.59 (p <.001) (from Blessed, Tomlinson, & Roth, 1968).

Fig. 4

Receiver operating characteristic curves demonstrating excellent sensitivity and specificity for the accurate diagnosis of early AD achieved with neuropsychological tests of memory (California Verbal Learning Test), language (category fluency: animals, fruits, and vegetables) and executive functions (Trail-Making Test: Part B) (adapted from Salmon et al., 2002).

Fig. 5

A representative number of publications with the search term “mild cognitive impairment” in the title or abstract from 1990 through part of 2008. Note the exponential rate of increase in the numbers of publications during the 2000s (from Petersen et al., 2009).

Fig. 6

Nelson et al.’s (2011) contrasting depictions of the epidemiology of dementia. Panel (a) is the schematic representation of the prevailing view of Alzheimer neuropathology by age, whereas panel (b) depicts distinct brain diseases other than AD that may contribute to cognitive impairment in late life (adapted from Nelson et al., 2011).

Fig. 7

Regional cortical thickness maps of the left and right lateral and medial pial surfaces for each neuropsychological MCI subtype relative to normal control (NC) participants (Edmonds et al., 2016). The scale indicates group differences in cortical thickness at p< .0001. The cyan/blue shades represent areas where the MCI subgroup has significantly thinner cortex than the NC group. Cluster-derived normal (CDN) = those participants who performed normally across the neuropsychological tests but whom ADNI diagnosed as MCI. Their maps show no areas of cortical thinning relative to the NC group, suggesting they are false-positive diagnostic errors. Our prior work showing the CDN subgroup to have normal CSF AD biomarkers and low progression rates adds to the inference that they received false-positive MCI diagnoses (Bondi et al., 2014).