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.
