CORDIS - EU research results

Non-amyloid-related hippocampal network dysfunction as an early biomarker of Alzheimer’s disease

Final Report Summary - OSCILL_A (Non-amyloid-related hippocampal network dysfunction as an early biomarker of Alzheimer’s disease)

Alzheimer's disease (AD) is a progressive neurodegenerative disorder that begins with mild short-term memory deficits before progressively culminating in total loss of cognitive and executive functions. Genetic studies have identified mutations in the genes of amyloid precursor protein (APP) and presenilin 1 and 2 that cause rare (less than 5% of AD patients), dominantly inherited familial AD (FAD). Proteolytic processing of APP generates amyloid-β (Aβ) peptides that deposit in amyloid plaques. Genetic and cell biological studies show increased production of more amyloidogenic Aβ peptides associated with FAD-linked mutations, providing strong support for the amyloid hypothesis. In this conceptual framework, early accumulation of soluble Aβ in specific brain regions elicits abnormal patterns of neuronal activity which leads to cognitive deficits. Indeed, information processing and storage by brain networks, especially within the hippocampus and hippocampo-cortical circuits, requires a highly coordinated operation of multiple neuronal groups. One likely mechanism is through the coordinated, rhythmic activity of neuronal populations, which gives rise to oscillations in local field potentials. Among these brain rhythms, the hippocampal theta (3-12 Hz) and gamma (slow gamma; SG; 25-50 Hz and fast gamma; FG; 60-150Hz) oscillations have been described as a critical player in memory consolidation. Theta and gamma frequency oscillations occur in the same brain regions and interact with each other, the phase of the ongoing theta oscillation modulating the amplitude of gamma rhythms. Recent studies suggest that this phenomenon, known as cross-frequency coupling, might play a key role in learning and memory. In particular, the magnitude of the coupling (or coupling strength) is positively associated with cognitive processes in humans, monkeys, mice and rats. Currently, and in accordance with the amyloid hypothesis, nearly all the research on AD is focused on Aβ and its hazardous effect on brain network functioning. In contrast, we have recently shown in a mouse model of AD that hippocampal cross-frequency coupling is altered in the absence of detectable Aβ but correlates with the levels of β-CTF, its immediate precursor. While we do not call into question the deleterious role of Aβ on neuronal functioning, our general objective was to complement the current theory by showing that β-CTF represents the first hazardous step in the amyloid cascade, well before Aβ. We were able to show that that young pre-pl aque mouse model of AD exhibit early behavioral alterations only in a subset of hippocampal-dependent tasks. Further, we showed that these specific memory impairments were likely related to alterations in hippocampal inhibitory networks, gamma oscillations and theta-gamma coupling. Finally, to assess the respective role, if any, of each APP cleavage product detected in the reported memory deficits, we opted for a pharmacological approach. We were able to show that different APP metabolites were likely responsible for different cognitive deficits. To summarize, we have shown in a mouse model of AD that the earliest memory impairments arise concomitantly with the first hippocampal network alterations and are detectable before Aβ overproduction. Interestingly, in patients, signs of memory impairments may arise more than 10 years before the diagnosis of the disease. We therefore propose that the first alterations in brain oscillatory activity (i.e. mainly in cross-frequency coupling) may arise concomitantly with the first memory deficits observed in patients. Thus, cross-frequency coupling alterations might represent an early biomarker of the disease. Recent evidence indicates that oscillatory coupling might be recorded in humans using non-invasive technique such as high-density EEG (128 or 256 electrodes) or MEG recordings. However, high-density EEGs are not routinely used in clinical practice, and therefore dampen the use of such theta-gamma coupling as an easily accessible early biomarker of AD. In collaboration with Pr. André Dufour’s Team at the LNCA, we analyzed “10/20 montage” EEG recordings (32 electrodes; routinely used in clinical practice) performed in 10 young and 20 nondemented senior subjects during a navigational task. We were able to show that a type of cross-frequency coupling (namely beta-gamma coupling) was clearly detectable using this approach in young subjects. Even if decreased, this type of coupling was still present in the high performing seniors but completely absent in the low performing ones. Therefore, in addition to being a marker of aging, cross frequency coupling seems also related to the level of cognitive performances.
As current medication offer symptomatic benefits only if given early in the time course of the disease, the possible validation of a new (cost-efficient and easily accessible in humans) early biomarker for AD will be of a fantastic interest to increase life quality of patients with AD. Further, several drugs for the treatment of AD have met endpoints in Phase 2 and 3 trials, as they paradoxically worsened or had no effect on cognitive functions. One of the explanations was that patients were treated too late in the time course of the disease, when neuronal damages were already too extensive. As the field inches toward treating AD at the preclinical stage, the characterization of coupling state might also represent a way to recruit patients at the earliest possible stage and to assess therapies effectiveness. Additionally, with predictions of a coming global avalanche of dementia cases, clinicians are turning their attention to prevention strategies. For example, it is well known that individuals engaged in higher levels of mental and physical activities are at lower risk of developing AD, a phenomenon known as “cognitive reserve”. However, these physical and social enhancements have to occur before amyloidogenesis to be effective. Therefore, the systematic characterization of the coupling state in mildly-cognitively impaired patients might lead to the development of new therapeutic approaches (based on increase mental and physical activity together with AD therapeutics) dedicated to revert or prevent memory deficits and therefore increase life quality of patients.