One of the causes of Alzheimer’s disease is the build-up of amyloid and tau in and around brain cells. In this disease, different areas of the brain shrink.
Alzheimer’s disease is associated with a specific pattern of pathological changes in the brain that result in neurodegeneration. However, this case is not the same in all patients. Also, the disappointing results from recently marketed drugs have highlighted the need to reconsider this disease.
In Switzerland, a European consortium of physicians and scientists, led by the University of Geneva (UNIGE) and the University Hospitals of Geneva (HUG), which also includes INSERM in France, has analyzed the data presented in nearly 200 previously published studies. Far from being a monolithic disease where the same causes produce the same effects, this analysis proposes a categorization of patients into three groups, each with its dynamics.
Giovanni Frisoni, Professor in the Department of Readaptation and Geriatrics at the UNIGE Faculty of Medicine and Director of the HUG Memory Centre, who directed this work, said, “Yet if we consider Alzheimer’s disease as a sequential cascade of biological events, it should have been much more effective. Stopping the production of beta-amyloid with a drug should logically interrupt neuronal loss and, therefore, memory loss, which has not been massively observed. Furthermore, we have found that some people with amyloid do not develop cognitive symptoms. What does protect their brain from neurotoxicity?”
Scientists wanted to determine why the deterministic model of the disease is found in some cases but not in others. They conducted a systematic literature review; some articles tend to confirm this model, while others refute it.
Daniele Altomare, a researcher in Giovanni Frisoni’s group, said, “Our interpretive framework showed that Alzheimer’s disease is more complex than it appears. Three groups of patients can be distinguished according to their risk factors, the characteristics of their disease, and their clinical fate.”
The cascade prediction is only confirmed in one of these three groups, where patients carry an inherited genetic mutation known as “autosomal dominant.”
Fortunately, this mutation is uncommon, as it causes the systematic development of an early cognitive deficit (between 30 and 50 years of age). The presence or absence of a genetic variant, the e4 allele of the APOE gene, which appears to be an essential risk factor, affects the development of cognitive deficit symptoms in the sporadic form: two-thirds of carriers will develop Alzheimer’s disease symptoms sooner or later. The third group includes those who do not have a genetic mutation but for whom neurotoxic proteins appear to be a significant but not unique risk factor.
Giovanni Frisoni said, “Half of our patients belong to this third group. Our probabilistic model, therefore, suggests that all genetic and environmental risk factors should be considered. Cognitive impairment develops when their weight overcomes the resilience of the brain, which is itself determined by protective factors of genetic and environmental origin.”
In the case of patients with cardiovascular disease, preventing risks (hypertension, obesity, etc.) in people who have never had a heart attack or stroke results in a very significant reduction in the number of cases in the following years. In contrast, such treatment after a stroke or heart attack brings only minimal benefits in recovery.
Frisoni said, “In our view, the same reasoning should apply to Alzheimer’s disease: it is essential to treat people at risk before symptoms appear.”
The recent development of instruments that allowed precise detection of beta-amyloid and hyperphosphorylated tau in the blood is about to change this. It could allow the inclusion of such screening in routine check-ups.
Scientists noted, “Although patient management will not change overnight, a more detailed understanding of the biological mechanisms at work will make it possible to develop more precise research protocols that take into account the different forms of Alzheimer’s disease. In the years to come, we hope to adopt preventive and therapeutic strategies to each individual, rather than according to a standardized protocol that has already shown its limits.”
- Frisoni, G.B., Altomare, D., Thal, D.R. et al. The probabilistic model of Alzheimer disease: the amyloid hypothesis revised. Nat Rev Neurosci (2021). DOI: 10.1038/s41583-021-00533-w