Investigating Functional Impairment in Preclinical Alzheimer’s Disease

Very little is known about functional change in persons in the preclinical stage of AD. As currently conceptualized, functional impairment in Alzheimer’s disease (AD) is the final and somewhat remote downstream outcome of a cascade of preceding pathophysiological and clinical events characterizing AD: amyloid deposition, neurodegenerative cellular, metabolic and network pathway changes, tissue loss and atrophy, and significant cognitive decline. Given this prevailing conceptual framework, possible functional change in preclinical AD, and related clinical trial methodology, have received relatively little attention. For example, the 2013 draft guidance of the FDA for treatment of early stage Alzheimer’s disease anticipates that persons in the preclinical phase will only show subtle cognitive deficits “in the absence of any detectable functional impairment” (1), and that in these circumstances the field may be allowed to pursue valid and reliable cognitive assessments as a single primary efficacy measure (1). This prevailing framework notwithstanding, a new perspective has recently begun to emerge concerning functional change and outcome measures in preclinical AD. The intriguing possibility that detectable functional change actually commences much earlier in the AD disease process, possibly as early as the preclinical stage, has recently been suggested (2, 3). In support of this proposition is the now well-established finding that functional impairment is clearly present in prodromal AD. Prior research by several groups (3–7) has shown that complex functional skills (Independent Activities of Daily Life, or IADLs) show impairment in patients with mild cognitive impairment (MCI) and continue to decline over time (5). In particular, financial capacity is a higher order functional skill that is highly sensitive and vulnerable to MCI and mild AD (4, 5, 8), which raises the possibility that measurable financial decline may also occur in persons with preclinical AD. It should be noted that current diagnostic criteria for preclinical AD explicitly contemplate and posit incipient subtle cognitive changes emerging in the third or “late” stage of the preclinical phase (9). Consistent with this theoretical view, recent studies have shown episodic memory impairments in older individuals with abnormal levels of brain amyloid (10, 11). The presence of detectable albeit subtle cognitive impairments in individuals with preclinical AD raises the possibility that associated subtle changes in complex functional activities may also be present and detectable. A critical factor here is the sensitivity of the functional measure employed. Detection of functional impairment in cognitively normal individuals with preclinical AD will require instruments sensitive to subclinical cognitive and functional changes. Informant report measures commonly used to characterize functional decline in late MCI and AD type dementia likely lack sensitivity to detect these very subtle functional changes. In contrast, performance based assessment measures may have sufficient sensitivity as they can support finely grained quantitative measurement using performance and task completion time variables. In the author’s view, in order to maximize detection of functional impairment in preclinical AD, proposed functional assessment measures should incorporate the following features: Assess cognitively complex functional abilities relevant to independent living and sensitive to early decline in AD. Assess the functional ability using an interval scaled, direct performance measure that evaluates performance variables in a highly detailed and granular manner. Include time limitations for performance items in order to enhance item difficulty. In addition to performance items, include task completion time variables in order to capture subtle processing speed changes.