Amyloid imaging in cognitively normal individuals, at-risk populations and preclinical Alzheimer's disease

Abstract

Recent developments of PET amyloid ligands have made it possible to visualize the presence of Aβ deposition in the brain of living participants and to assess the consequences especially in individuals with no objective sign of cognitive deficits. The present review will focus on amyloid imaging in cognitively normal elderly, asymptomatic at-risk populations, and individuals with subjective cognitive decline. It will cover the prevalence of amyloid-positive cases amongst cognitively normal elderly, the influence of risk factors for AD, the relationships to cognition, atrophy and prognosis, longitudinal amyloid imaging and ethical aspects related to amyloid imaging in cognitively normal individuals. Almost ten years of research have led to a few consensual and relatively consistent findings: some cognitively normal elderly have Aβ deposition in their brain, the prevalence of amyloid-positive cases increases in at-risk populations, the prognosis for these individuals is worse than for those with no Aβ deposition, and significant increase in Aβ deposition over time is detectable in cognitively normal elderly. More inconsistent findings are still under debate; these include the relationship between Aβ deposition and cognition and brain volume, the sequence and cause-to-effect relations between the different AD biomarkers, and the individual outcome associated with an amyloid positive versus negative scan. Preclinical amyloid imaging also raises important ethical issues. While amyloid imaging is definitely useful to understand the role of Aβ in early stages, to define at-risk populations for research or for clinical trial, and to assess the effects of anti-amyloid treatments, we are not ready yet to translate research results into clinical practice and policy. More researches are needed to determine which information to disclose from an individual amyloid imaging scan, the way of disclosing such information and the impact on individuals and on society.

Keywords: Amyloid PET imaging; ApoE4; Cognitively normal elderly; Longitudinal studies; Preclinical Alzheimer's disease; Subjective cognitive decline.

Fig. 1

Illustration of positive, negative, and intermediate cases within the cognitively normal elderly. These data are issued from the IMAP study (Inserm U1077, Caen, France). Each circle represents the mean neocortical ¹⁸F-florbetapir SUVR from an individual. The majority (67%) of healthy controls older than 60 years (HC > 60 yrs) is clearly negative (i.e. their SUVR value is within 2SD of the controls younger than 60 years = HC < 60 yrs). Three cases were clearly positive (i.e. classified as positive both compared to younger controls and using the iterative outlier approach). There were 25% of intermediate cases, i.e. cases classified as positive or negative according to the method.

Fig. 2

Illustration of the brain distribution of ¹⁸F-florbetapir in six cases from the IMAP project (Inserm U1077, Caen, France). The figure shows disproportionate binding of ¹⁸F-florbetapir in the caudate nucleus in the asymptomatic and symptomatic mutation carriers for the early-onset familial form of AD compared to both sporadic AD cases and amyloid-positive cognitively normal elderly.