The in vivo detection of biological lesions of Alzheimer's disease has profoundly changed the understanding of its silent phase, known as the preclinical stage. Genetic, experimental, neuropathological, and longitudinal evidence supports a long period during which amyloid and tau lesions may be present before objective cognitive impairment emerges. However, isolated amyloid positivity is not a clinical destiny. It increases the risk of decline, but this risk depends on age, sex, apolipoprotein E (APOE) genotype, amyloid burden, neurodegeneration, comorbidities, and, most importantly, the extent of tau pathology. Longitudinal studies therefore show more frequent progression in amyloid-positive cognitively unimpaired individuals than in amyloid-negative individuals, but absolute risks vary widely across cohorts and time horizons. Models accounting for competing mortality show that many individuals with abnormal biomarkers will not develop dementia during their lifetime, whereas individuals who are both amyloid-and tau-positive constitute a high-risk group over the short term. This review summarizes the concept of the at-risk subject in Alzheimer's disease, its biological foundations, available prognostic estimates, and nosological implications. It supports a cautious formulation: in a cognitively unimpaired person, abnormal biomarkers define an at-risk state, not a predetermined future clinical-biological disease.
Advances in genetic sequencing have profoundly changed our understanding and management of PIK3CA-related diseases. These mutations, first described in cancer, are now recognized in mosaic disorders grouped under the term PROS (PIK3CA-Related Overgrowth Spectrum). Recent research has shed light on their pathophysiology and paved the way for effective targeted therapies. PROS are no longer considered orphan diseases but rather chronic conditions that can be treated, even though many areas of uncertainty remain. This review summarizes the current state of knowledge, from molecular mechanisms to validated therapeutic approaches.
Incretins receptor agonists represent a major therapeutic advance in the management of obesity, a chronic, multifactorial disease with a significant health and socioeconomic impact. By modulating central appetite regulation and digestive physiology, these agents enable an average weight loss of 15 to over 20%, with proven benefits on cardiovascular, metabolic, respiratory comorbidities, as well as on quality of life. Digestive adverse events, particularly nausea and delayed gastric emptying, are common and partly determine adherence to treatment and require careful monitoring. In addition, weight regain after treatment discontinuation underscores the need to establish long-term therapeutic strategies. Concerns persist for muscle loss and for pancreatic, and biliary risks, with no causal link formally established. Marked interindividual variability in weight response complicates patient selection and a clear articulation with bariatric surgery. Finally, the limitations of reimbursement in France accentuate inequalities in access, encourage people to forego treatment, and fuel the development of a parallel market that exposes to misuse. It raises significant ethical, economic and public health challenges because it is associated with spontaneous treatment discontinuation, clinical inertia and the growth of unregulated online markets, thereby highlighting the societal impact of incretin-based obesity therapies.
Blood biomarkers for Alzheimer's disease (AD) represent a major technical advance. In particular, the measurement of tau protein phosphorylated at threonine 217 (ptau217) has been shown to correlate with cerebrospinal fluid biomarkers, to be associated with amyloid PET positivity, to accurately discriminate AD from other neurodegenerative disorders compared with post-mortem neuropathology, and to be associated with AD dementia incidence in patients who still present mild cognitive impairment. Recent studies show that it is now possible to implement their use in memory clinics, in patients whose pre-test probability is known thanks to neuropsychological assessment. Indeed, they would make it possible to establish clinico-biological diagnoses of AD consistent with current international criteria, without requiring invasive procedure such as lumbar puncture or costly, limited-access exams such as amyloid PET imaging. This would broaden access to precise diagnoses for a larger number of patients, with medical and social consequences that are expected to be beneficial, although these will need to be formally evaluated. However, the use of ptau217 in asymptomatic patients or in patients who have been inadequately clinically assessed could lead to numerous diagnostic errors, especially in an international scientific landscape increasingly defining AD by its biology and less by its clinical presentation. It will therefore be essential to provide clear guidance on the appropriate use of these blood biomarkers, to move toward the utopia of an accurate, early, and widely accessible diagnosis, rather than the dystopia of a false positives factory.
The use of brain stimulation to treat symptoms of Parkinson's disease (PD) dates back to the mid-20th century, when it was primarily employed in functional neurosurgery to localize optimal targets prior to irreversible lesioning procedures such as thalamotomy or pallidotomy. Subsequent technological developments enabled a shift from destructive approaches toward chronic, adjustable, and reversible stimulation of specific brain structures. Since the late 1980s, deep brain stimulation (DBS) emerged as a modern and integrated neuromodulation therapy, profoundly transforming the management of advanced PD. Nowadays, DBS has become a well-established surgical option for patients with advanced PD suffering from motor fluctuations and dyskinesias inadequately controlled by medical therapy. Robust evidence from randomized controlled trials and long-term follow-up studies has demonstrated its sustained efficacy on motor symptoms. Nevertheless, DBS remains a symptomatic treatment, with no proven disease-modifying or neuroprotective effects. Moreover, its clinical benefits tend to decline over time for axial symptoms, and its applicability is limited by strict patient selection criteria, as well as by the technical demands of surgery and postoperative programming. In this article, we provide a concise overview of the recent historical development of DBS in PD and review the current state of the art. We highlight its clinical efficacy, limitations, remaining gaps in knowledge, and future perspectives driven by ongoing technological innovations and evolving concepts in neuromodulation.
