Journal
JPAD-JOURNAL OF PREVENTION OF ALZHEIMERS DISEASE
Volume 6, Issue 2, Pages 112-120Publisher
EDITIONS SERDI
DOI: 10.14283/jpad.2019.6
Keywords
Autosomal dominant Alzheimer's disease; dementia; biomarkers; cognitive markers
Categories
Funding
- NIH Office of the Director [DP5OD019833]
- NIH National Institute on Aging [R01AG054671, 1RF1AG041705, 1R01AG055444, AG058805-01]
- Massachusetts General Hospital ECOR [1200-228010, 1200-228767]
- Rappaport Fellowship
- Alzheimer's Association Clinical Fellowship [AACF-16-440965]
- Alzheimer's Association
- Administrative Department of Science, Technology, and Innovation (Colciencias Colombia) [111565741185]
- European Union's Horizon 2020 Research and Innovation Programme (Marie Sklodowsk
- a-Curie Grant agreement) [IF-2015-GF, 706714]
- Belgian Foundation for Scientific Research (FNRS) [SPD28094292]
- Belgian Foundation for Alzheimer Research (SAO-FRA grant) [P16.008]
- Banner Alzheimer's Foundation
- GHR Foundation
- F-Prime Biosciences Research Initiative
- NOMIS Foundation
- FIL Foundation
- Fidelity Biosciences
- Harvard Neurodiscovery Center
- Marr Foundation
- Phi Kappa Phi Graduate Student Fellowship
- AstraZeneca
- Avanir
- Biogen
- Cognoptix
- Eli Lilly
- H. Lundbeck A/S
- Merck and Company
- Roche
- Takeda
- Amgen
- Avid
- Functional Neuromodulation
- GE Healthcare
- Genentech
- Novartis
- Targacept
- National Institute on Aging
- Arizona Department of Health Services
- National Institutes of Health
- Lilly
- National Institute on Aging [U19AG10483, U01AG024904-S1]
- Michael J. Fox Foundation
- National Institutes of Health [U01 AG032438, U01 AG024904, R01 AG037497, R01 AG034556, U19 AG010483]
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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 noncarriers 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.
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