Venue : BBS
IMN
Team: Physiopathology of proteinopathies
Thesis directed by Vincent Planche
Title
Is Alzheimer’s disease unique to humans?
Abstract
Alzheimer’s disease (AD) is a major public health problem in our ageing Western societies. More than a century after it was first described, there is still no consensus on the definition of AD. A purely biological view suggests that the mere presence of extracellular amyloid protein deposits and intracellular tau protein aggregates is sufficient to define the condition, as these abnormalities are considered « causal» according to the amyloid cascade hypothesis. For other authors, biological findings alone are insufficient for diagnosis and must be accompanied by clinical signs suggestive of progression towards dementia, particularly as biological abnormalities may precede symptoms by 10 to 20 years, and many healthy older people with amyloid deposits will never develop the disease. This nosological issue causes the estimated global prevalence to vary from 32 million (clinical-biological definition at the dementia stage) to 315 million people (biological definition), with major implications for future diagnostic and therapeutic strategies (plasma biomarkers, anti-amyloid immunotherapies).
This issue is reflected in the representation of AD within the animal kingdom. Certain characteristic lesions have been reported in rodents, cetaceans and elderly primates, but these species do not develop all the characteristics of human tauopathy, and the cognitive impact of these lesions remains uncertain. The very concept of dementia, based on the loss of independence in everyday activities, remains an anthropocentric definition with no equivalent in the animal kingdom. AD would therefore exist in animals according to a minimalist biological definition centred on amyloid, but not according to a clinical-biological definition.
The first part of this thesis addresses this question through a systematic review of the literature on the presence of amyloid lesions and neurofibrillary tangles in non-human primates (38 articles, 543 brains, four species). Using logistic regression analyses, this study shows that amyloid plaques follow an isometric pattern, proportional to the lifespan of each species, whilst neurofibrillary tangles (NFTs) follow a chronometric pattern, appearing at a fixed time point (30 to 50 years) regardless of life expectancy. This dissociation challenges the hypothesis of the amyloid cascade as a universal mechanism and suggests that the full range of neuropathological lesions associated with AD is only present when a species’ lifespan allows these two independent processes to overlap.
The second part uses quantitative proteomics to compare the molecular signature of the human disease with that observed in macaques that have been injected with pathological tau proteins extracted from patients’ brains, with or without co-injection of oligomeric Aβ. The human signature is not observed in macaques: there is no correlation between the two species, as the model responds to the injection without replicating the molecular program of the human disease.
The third line of inquiry is based on the observation that longevity, a necessary condition for the emergence of a clinically and biologically defined AD, is not the sole factor influencing its manifestation at the population level. We developed an age-structured population model, simulated on an individual-centred basis, which combines demographic dynamics with the social allocation of care. This model shows that longevity alone is sufficient to cause the disease to emerge in a population, and that healthcare does not trigger it but rather perpetuates it, by prolonging the time lived with the disease. The evolutionary reconstruction further shows that the decline in adult mortality necessarily precedes the decline in the age at which people have children.
Key words
Non Human Primate, Alzheimer, care, proteomic