Progress in the Treatment of Alzheimer's Disease Is Needed - Position Statement of European Alzheimer's Disease Consortium (EADC) Investigators.

ß-amyloid-targeting antibodies represent the first generation of effective causal treatment of Alzheimer's disease (AD) and can be considered historical research milestones. Their effect sizes, side effects, implementation challenges and costs, however, have stimulated debates about their overall value. In this position statement academic clinicians of the European Alzheimer's Disease Consortium (EADC) discuss the critical relevance of introducing these new treatments in clinical care now. Given the complexity of AD it is unlikely that molecular single-target treatments will achieve substantially larger effects than those seen with current ß-amyloid-targeting antibodies. Larger effects will most likely only be achieved incrementally by continuous optimization of molecular approaches, patient selection and combinations therapies. To be successful in this regard, drug development must be informed by the use of innovative treatments in real world practice, because full understanding of all facets of novel treatments requires experience and data of real-world care beyond those of clinical trials. Regarding the antibodies under discussion we consider their effects meaningful and potential side effects manageable. We assume that the number of eventually treated patient will only be a fraction of all early AD patients due to narrow eligibility criteria and barriers of access. We strongly endorse the use of these new compound in clinical practice in selected patients with treatment documentation in registries. We understand this as a critical step in advancing the field of AD treatment, and in shaping the health care systems for the new area of molecular-targeted treatment of neurodegenerative diseases.

Biological and Cognitive Markers of Presenilin1 E280A Autosomal Dominant Alzheimer's Disease: A Comprehensive Review of the Colombian Kindred.

The study of individuals with autosomal dominant Alzheimer's disease affords one of the best opportunities to characterize the biological and cognitive changes of Alzheimer's disease that occur over the course of the preclinical and symptomatic stages. Unifying the knowledge gained from the past three decades of research in the world's largest single-mutation autosomal dominant Alzheimer's disease kindred - a family in Antioquia, Colombia with the E280A mutation in the Presenilin1 gene - will provide new directions for Alzheimer's research and a framework for generalizing the findings from this cohort to the more common sporadic form of Alzheimer's disease. As this specific mutation is virtually 100% penetrant for the development of the disease by midlife, we use a previously defined median age of onset for mild cognitive impairment for this cohort to examine the trajectory of the biological and cognitive markers of the disease as a function of the carriers' estimated years to clinical onset. Studies from this cohort suggest that structural and functional brain abnormalities - such as cortical thinning and hyperactivation in memory networks - as well as differences in biofluid and in vivo measurements of Alzheimer's-related pathological proteins distinguish Presenilin1 E280A mutation carriers from non-carriers as early as childhood, or approximately three decades before the median age of onset of clinical symptoms. We conclude our review with discussion on future directions for Alzheimer's disease research, with specific emphasis on ways to design studies that compare the generalizability of research in autosomal dominant Alzheimer's disease to the larger sporadic Alzheimer's disease population.

Mild cognitive impairment: differential atrophy in the hippocampal subfields.

BACKGROUND AND PURPOSE: Hippocampus volumetry is a useful surrogate marker for the diagnosis of Alzheimer disease, but it seems insufficiently sensitive for the aMCI stage. We postulated that some hippocampus subfields are specifically atrophic in aMCI and that measuring hippocampus subfield volumes will improve sensitivity of MR imaging to detect aMCI. MATERIALS AND METHODS: We evaluated episodic memory and hippocampus subfield volume in 15 patients with aMCI and 15 matched controls. After segmentation of the whole hippocampus from clinical MR imaging, we applied a new computational method allowing fully automated segmentation of the hippocampus subfields. This method used a Bayesian modeling approach to infer segmentations from the imaging data. RESULTS: In comparison with controls, subiculum and CA2-3 were significantly atrophic in patients with aMCI, whereas total hippocampus volume and other subfields were not. Total hippocampus volume in controls was age-related, whereas episodic memory was the main explanatory variable for both the total hippocampus volume and the subfields that were atrophic in patients with aMCI. Segmenting subfields increases sensitivity to diagnose aMCI from 40% to 73%. CONCLUSIONS: Measuring CA2-3 and subiculum volumes allows a better detection of aMCI.