Abstract
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.
Highlights
Alzheimer’s disease (AD) is a progressive neurodegenerative disorder that is associated with the accumulation of amyloid-beta (Aβ1-42) plaques and intra-neuronal tau tangles which are hypothesized to damage brain structures, impair brain metabolism, and result in the clinical15 manifestation of the disease [1,2]
The age of onset of dementia and rate of disease progression in this kindred was found to be variable [15], but a large, retrospective study of 449 mutation carriers identified a median age of 15 onset of mild cognitive impairment (MCI) of 44 years old, with a symptomatic disease course averaging 15 years thereafter
20 addition, subjective memory complaint (SMC) scores based on study-partner report began to differ from non-carriers approximately -6 estimated years until onset (EYO) and followed a linear function, correlating with hippocampal volume in these carriers in the preclinical stage of the disease [21]
Summary
Alzheimer’s disease (AD) is a progressive neurodegenerative disorder that is associated with the accumulation of amyloid-beta (Aβ1-42) plaques and intra-neuronal tau tangles which are hypothesized to damage brain structures, impair brain metabolism, and result in the clinical15 manifestation of the disease [1,2]. Most individuals develop the sporadic form AD, which for the purpose of this review we operationally define as the form of AD with a late onset of clinical. A small percentage of AD cases, are caused by autosomal dominant mutations that typically result in an earlier onset of clinical symptoms Beyond aiming to find treatments that benefit mutation-carriers, ADAD investigators work to elucidate the trans-diagnostic disease mechanisms between ADAD and the more common sporadic form of the disease. As ADAD kindreds provide a quasi-experimental framework to investigate AD mechanisms and treatments, to the degree which ADAD and sporadic AD are similar it is possible through ADAD research to generate testable research hypotheses for new ways to identify and treat individuals at risk for the sporadic form of AD
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