INSIGHT study highlights compensation mechanisms in patients with Alzheimer’s disease lesions

The INSIGHT-preAD study, directed by Professor Bruno Dubois, was carried out by teams at Institut du Cerveau - ICM (Brain and Spine Institute – Inserm/CNRS/Sorbonne University) and the Memory and Alzheimer’s Disease Institute (IM2A) at AP-HP Pitié-Salpêtrière Hospital in Paris, in collaboration with the MEMENTO cohort. It aims at identifying factors underlying Alzheimer’s Disease development in healthy subjects over 70 with no current cognitive disorders.

The INSERM-sponsored study shows that at a 30-month follow-up, amyloid lesions (also called Alzheimer’s lesions) did not impact cognition or behaviour in affected subjects.

Results of the study were published on February 27th, 2018 in Lancet neurology and suggest that subjects with amyloid lesions may implement compensatory mechanisms.

Drugs currently under development to treat Alzheimer’s Disease demonstrate significant efficacy on brain lesions without a joint decrease in symptoms. Drug trials may be undertaken too late, with patients who are at an advanced stage of the disease. This led to the idea of testing treatment efficacy at an earlier stage, right at the start or even before onset of symptoms in patients with Alzheimer’s disease lesions. This implies extensive knowledge of disease progression markers at pre-clinical stage.

The INSIGHT-preAD study, short for “INveStIGation of AlzHeimer’s PredicTors in subjective memory complainers - Pre Alzheimer’s disease” was supervised by Professor Bruno Dubois and aimed at identifying these progression factors. Professor Dubois is Director of the Cognitive and Behavioural Diseases Center at AP-HP Pitié-Salpêtrière Hospital and Professor of Neurology at Sorbonne University.

The study is based on longitudinal monitoring of an active cohort launched in May 2013 at AP-HP Pitié-Salpêtrière of 318 volunteer patients over 70 years of age, with perceived memory problems despite normal cognitive and memory performance during testing.

Participants agreed to imaging examinations to determine whether or not their brain presented Alzheimer’s disease lesions (also called “amyloid” lesions). 28% of participants were found to have lesions although no factors were identified at this stage.

Amyloid-positive and amyloid-negative patients did not present any differences in cognitive (memory, language, orientation), functional, and behavioural testing when they entered the cohort. Additionally, sub-groups based on severity of perceived memory problems did not present any differences, whether in structural neuro-imaging (MRI) or metabolic neuro-imaging (PET-FDG).

As part of the INSIGHT-preAD study, patients passed a neuropsychological assessment, an electroencephalogram and actigraphy testing on a yearly basis as well as undergoing blood testing (to test for biomarkers) and neuro-imaging exams (MRI, PET-FDG and PET-amyloid) every two years.

The teams involved in the study analysed the data collected at its launch and two years later, as well as a 30-month follow-up clinical assessment of volunteer subjects. They did not find any significant evolution between amyloid-positive and amyloid-negative patients either for the full set of markers monitored (behavioural, cognitive, functional) or in in neuro-imaging testing. Electroencephalogram data, however, highlighted that patients with lesions displayed modified electrical activity in anterior regions of the brain, especially frontal areas, to maintain intellectual and memory performance.

At a 2.5-year follow-up, only four patients have developed Alzheimer’s Disease. When they entered the study, they displayed predictive factors including older age, higher concentration of amyloid lesions, and decreased hippocampal volume.

Results show that amyloid lesions in the brain do not translate into cognitive, morphological, metabolic or functional modifications in affected patients. Results of the study pertaining to electroencephalographic variations also suggest that a compensation mechanism may exist.

Progression towards Alzheimer’s Disease in these patients, with an average age of 76, is low, highlighting the existence of significant cognitive reserve in this type of population. Ongoing monitoring if necessary to determine whether these findings are verified over a longer time span.

The next INSIGHT-preAD study update will take place in 2022.

This research has received financial support from the French Ministry of Research (Investment for the Future), the Plan-Alzheimer Foundation, and Pfizer.