Welcome to the AD/PD™ 2024 Interactive Program
The conference will officially run on Western European Standard Time (Lisbon, UTC+0)
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THE GENETICS OF NEURODEGENERATIVE DISEASES – FROM RARE POPULATIONS TO COMMON VARIANTS
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Understanding the genetics of neurodegenerative diseases has already opened promising avenues for early diagnosis, risk prediction, and targeted therapeutic interventions. These results stem from the application of different genetic technologies enabling the investigation of both rare and common variants within the genome.
Interestingly, the application of exome and genome sequencing to the study of neurodegenerative diseases across various populations has revealed not only novel genes linked to these conditions but also an extensive array of pleiotropic phenomena. TREM2 is a prime example of this: initially identified as the causative genetic factor for the mendelian Nasu-Hakola disease, subsequent research revealed its role in familial frontotemporal dementia within an understudied population. More recently, it has emerged as one of the most significant genetic risk factors for Alzheimer's disease across diverse populations. The same type of pleomorphic risk can be seen for other genes and phenotypes, often crossing from monogenic to complex diseases.
The presence of shared genetic factors among distinct clinical conditions and phenotypes introduces an added layer of complexity to the diagnostic process. It also offers insights into common molecular mechanisms and potential shared drug targets across these diseases. Equally vital is recognizing the substantial contribution of genetic studies in underrepresented populations, which have significantly enriched our comprehension of Alzheimer's disease, dementia, and other neurodegenerative disorders.
In summary, the convergence of genetic insights obtained across the spectrum from rare to common variants, populations, and phenotypes has the potential to give us an integrated roadmap to fully understand the genetic architecture of neurodegenerative diseases.
ESCAPING DEMENTIA UNTIL EXTREME AGES: WHAT CAN COGNITIVELY HEALTHY CENTENARIANS TEACH US?
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A Dutch woman who died at age 115 without any symptoms of cognitive decline proved that cognitive decline is not inevitable. This leads to the question: how can cognitive health be maintained during human aging? To learn about the molecular mechanisms underlying this extraordinary phenomenon, we set up the 100-plus Study, a longitudinal cohort study of cognitively healthy centenarians with the primary aim to identify protective genetic and biomolecular factors that associate with the escape of cognitive decline.
Currently the cohort includes more than 450 healthy centenarians whom we subject annually to an extensive neuropsychological testing battery. We collect medical, family and life history, and various biomaterials including blood samples, faeces samples, and ~30% of the centenarians agrees to post-mortem brain donation.
Compared to individuals born in the same birth-year, centenarians are mostly from the higher social economic classes, have a relatively high education, and slightly more children, and they are mostly optimistic individuals. After reaching 100 years in cognitive health, many centenarians remain cognitively healthy until death. Centenarians are depleted with genetic elements associated with increased risk of Alzheimer's Disease, while they are enriched with protective genetic elements. This genetic protection is especially focused on maintaining a functional immune- and endolysosomal system. Amyloid-beta is widely spread in centenarian-brains, while loads stay low. Some centenarians are resistant, while others are resilient to tau and/or other neuropathological hallmarks of neurodegenerative disease. Based on specific aspects of their brain proteome, centenarian-brains are up to decades younger than expected according to their age, which pinpoints important proteomic determinants of maintaining brain health.
In my presentation, I will cover the latest results of the 100-plus Study, covering neuropsychological, genetic, neuropathological, brain proteomic, and immunological findings.
MS TECHNOLOGIES FOR PLASMA BIOMARKER DEVELOPMENT
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The mass spectrometer (MS) originated in Europe, near the beginning of the 20th century. The main application at the time was for analyzing the isotopes of elements. Later, related technologies, such as for sample pretreatment, ionization, separation, and trace amount detection methods were developed remarkably. Today, MS systems can be used to analyze a wide variety of organic compounds, such as lipids, carbohydrates, nucleic acids, peptides and proteins.
In particular, proteomics, the comprehensive analysis of all proteins in a specimen, is large-scale research that developed along with MS from around the year 2000 and has had a major role in researching disease biomarkers.
Our team participated in the "Funding Program for World-Leading Innovative R&D on Science and Technology (FIRST),” an industry-academia-government collaboration that started in Japan in 2010. That collaboration successfully detected trace amounts of Aβ in plasma using a MALDI-TOFMS system (Kaneko et al. 2014a) and showed that those amounts correlate to amyloid accumulations in the brain (Kaneko et al. 2014b). Furthermore, we engaged in international joint research and published the results in Nature, in an article entitled “High performance plasma amyloid-β biomarkers for Alzheimer’s disease” (Nakamura et al. 2018).
In my presentation, I intend to explain mainly the history of how such MS techniques developed into biology and medical fields, particularly for establishing a variety of biomarkers for brain disorders.