Very early detection of Alzheimer neuropathology and the role of brain reserve in modifying its clinical expression

Abstract

Numerous studies show that the pathology of Alzheimer's disease is present decades before a clinical diagnosis of dementia can be made. Given the likelihood that agents will become available that reliably delay onset and/or slow progression of Alzheimer's disease, it will be important to detect preclinical Alzheimer's disease as early as possible for maximal treatment effect. Detection of individuals by sensitive cognitive measures provides one way to identify people who are at high risk of developing clinical Alzheimer's disease. However, it is likely that those with considerable brain or cognitive reserve will be able to mask cognitive deficits until very close to the onset of the dementia, rendering such cognitive measures insensitive. Optimum biomarkers for Alzheimer's disease therefore need to target the severity of underlying brain pathology independently of brain reserve. Findings are presented showing the importance of higher education and larger brain size in masking the underlying disease pathology.

Figure 1

Mean scores on the Cognitive Abilities Screening Instrument (CASI) mental status exam by head circumference categories in a sample of 1985 Japanese Americans age 65 and over (the Kame Study). Copyright 1996 from “Head Circumference as a Measure of Cognitive Reserve: Association With Severity of Impairment in Alzheimer's Disease” by Graves et al. Adapted and reprinted with permission of the Royal College of Psychiatrists.

Figure 2

Percentage of Catholic sisters demented in six groups defined by educational attainment (high = bachelor's degree or more, low = less than a bachelor's degree) and head circumference tertile. Copyright 2003 from “Head Circumference, Education and Risk of Dementia: Findings From the Nun Study” by Mortimer et al. Reproduced by permission of Taylor & Francis Group, LLC., http://www.taylorandfrancis.com.

Figure 3

Percentages of non-demented Catholic sisters by educational attainment (high = bachelor's degree or more, low = less than a bachelor's degree) and Braak neurofibrillary stage at autopsy.

Figure 4

Percentages of Catholic sisters with dementia and mild cognitive impairment (MCI) by Braak neurofibrillary stage.