Brain β-amyloidosis is an unreliable short-term predictive marker of the clinical progression of Alzheimer disease (AD) in cognitively healthy elderly patients with subjective memory complaints, according to observational study findings published in Lancet Neurology.

In the Investigation of Alzheimer’s Predictors in Subjective Memory Complainers study, investigators enrolled elderly patients (age 70 to 85) from a single center in Paris, France, who were cognitively healthy (Mini-Mental State Examination [MMSE] score ≥27, Clinical Dementia Rating score 0, and Free and Cued Selective Reminding Test [FCSRT] total recall score ≥41) but who reported memory deficits (n=318). Investigators categorized patients as patients with (n=88) vs patients without (n=230) amyloid β deposition as measured by 18F-florbetapir PET (positive or negative) at baseline. Baseline values of amyloid β deposition were compared with those at 24- and 30-month follow-up and were correlated with analyses of progression to prodromal AD.

At baseline, a higher percentage of patients with amyloid β deposition had the APOE ε4 allele (38% vs 13%, P <.0001). Despite this discrepancy, no other patient characteristics, including cognitive function, behavior and mood, or subjective feelings about memory and cognition differed at baseline. In participants who were assessed for biomarkers in cerebrospinal fluid (CSF), the investigators observed a high accuracy associated with Aβ₁-₄₂ concentration and the ratio of Aβ₁-₄₂ to Aβ₁-₄₀ in identifying amyloid β deposition status (mean area under the curve 0.89; 95% CI, 0.80-0.98 and 0.84; 0.72-0.96, respectively).

The investigators observed no differences between patients who were positive or were negative for amyloid β with regard to 30-month MMSE (28.3 [SD 2.0] vs 28.9 [1.2], P =.16) and Clinical Dementia Rating scores (0.06 [0.2] vs 0.05 [0.3]; P =.79). Only 4 patients had progressed to clinical AD during the follow-up period, all of whom rated positive for amyloid β deposition. Compared with participants with amyloid β deposition and without AD progression, patients with disease progression were older (mean age 80.2 [SD 4.1] vs 76.8 [SD 3.4]) and demonstrated greater baseline uptake of 18F-florbetapir (mean standard uptake value ratio 1.46 [SD 0.16] vs 1.02 [SD 0.20]).

In addition, patients who experienced disease progression were more likely to be carriers of the APOE ε4 allele (75% vs 39%). In addition, mild executive dysfunction at baseline was associated with greater disease progression at follow-up (mean Free and Cued Selective Reminding Test free recall score 21.25 [SD 2.75] vs 29.08 [5.44] and Frontal Assessment Battery total score 13.25 [1.50] vs 16.05 [1.68]).

Related Articles

The investigators cite the short follow-up period as well as the strict inclusion criteria as important limitations of this study. Also, the investigators suggest that the exclusion of patients with progression to prodromal AD from analyses may have contributed to the lack of significant decline in patients with amyloid β deposition but no AD diagnosis.

Findings from this small, ongoing study suggest “that compensatory mechanisms maintain brain structure and functioning and that β-amyloidosis alone is insufficient to identify patients at high risk of rapid progression to prodromal AD.”


Dubois B, Epelbaum S, Nyasse F, et al; for the INSIGHT-preAD study group. Cognitive and neuroimaging features and brain β-amyloidosis in individuals at risk of Alzheimer’s disease (INSIGHT-preAD): a longitudinal observational study. Lancet Neurol. 2018;17(4):335-346.