Cognitive and neuroimaging features and brain β-amyloidosis in individuals at risk of Alzheimer's disease (INSIGHT-preAD): a longitudinal observational study

Background Improved understanding is needed of risk factors and markers of disease progression in preclinical Alzheimer's disease. We assessed associations between brain beta-amyloidosis and various cognitive and neuroimaging parameters with progression of cognitive decline in individuals with preclinical Alzheimer's disease. Methods The INSIGHT-preAD is an ongoing single-centre observational study at the Salpetriere Hospital, Paris, France. Eligible participants were age 70-85 years with subjective memory complaints but unimpaired cognition and memory (Mini-Mental State Examination [MMSE] score >= 27, Clinical Dementia Rating score 0, and Free and Cued Selective Reminding Test [FCSRT] total recall score >= 41). We stratified participants by brain amyloid beta deposition on F-18-florbetapir PET (positive or negative) at baseline. All patients underwent baseline assessments of demographic, cognitive, and psychobehavioural, characteristics, APOE epsilon 4 allele carrier status, brain structure and function on MRI, brain glucose-metabolism on F-18-fluorodeoxyglucose (F-18-FDG) PET, and event-related potentials on electroencephalo-grams (EEGs). Actigraphy and CSF investigations were optional. Participants were followed up with clinical, cognitive, and psychobehavioural assessments every 6 months, neuropsychological assessments, EEG, and actigraphy every 12 months, and MRI, and F-18-FDG and F-18-florbetapir PET every 24 months. We assessed associations of amyloid beta deposition status with test outcomes at baseline and 24 months, and with clinical status at 30 months. Progression to prodromal Alzheimer's disease was defined as an amnestic syndrome of the hippocampal type. Findings From May 25, 2013, to Jan 20, 2015, we enrolled 318 participants with a mean age of 76.0 years (SD 3.5). The mean baseline MMSE score was 28.67 (SD 0.96), and the mean level of education was high (score >6 [SD 2] on a scale of 1-8, where 1=infant school and 8=higher education). 88 (28%) of 318 participants showed amyloid beta deposition and the remainder did not. The amyloid beta subgroups did not differ for any psychobehavioural, cognitive, actigraphy, and structural and functional neuroimaging results after adjustment for age, sex, and level of education More participants positive for amyloid beta deposition had the APOE e4 allele (33 [38%] vs 29 [13%], p<0.0001). Amyloid beta(1-42) concentration in CSF significantly correlated with mean F-18-florbetapir uptake at baseline (r=-0.62, p<0.0001) and the ratio of amyloid beta(1-42) to amyloid beta(1-40) (r=-0.61, p<0.0001), and identified amyloid beta deposition status with high accuracy (mean area under the curve values 0.89, 95% CI 0.80-0.98 and 0.84, 0.72-0.96, respectively). No difference was seen in MMSE (28.3 [SD 2.0] vs 28.9 [1.2], p=0.16) and Clinical Dementia Rating scores (0.06 [0.2] vs 0.05 [0.3]; p=0.79) at 30 months (n=274) between participants positive or negative for amyloid beta. Four participants (all positive for amyloid beta deposition at baseline) progressed to prodromal Alzheimer's disease. They were older than other participants positive for amyloid beta deposition at baseline (mean 80.2 years [SD 4.1] vs 76.8 years [SD 3.4]) and had greater F-18-florbetapir uptake at baseline (mean standard uptake value ratio 1.46 [SD 0.16] vs 1.02 [SD 0.20]), and more were carriers of the APOE e4 allele (three [75%] of four vs 33 [39%] of 83). They also had mild executive dysfunction at baseline (mean FCSRT 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]). Interpretation Brain beta-amyloidosis alone did not predict progression to prodromal Alzheimer's disease within 30 months. Longer follow-up is needed to establish whether this finding remains consistent.