Rare Amyloid Precursor Protein Point Mutations Recapitulate Worldwide Migration and Admixture in Healthy Individuals: Implications for the Study of Neurodegeneration

Abstract

Genetic discoveries related to Alzheimer’s disease and other dementias have been performed using either large cohorts of affected subjects or multiple individuals from the same pedigree, therefore disregarding mutations in the context of healthy groups. Moreover, a large portion of studies so far have been performed on individuals of European ancestry, with a remarkable lack of epidemiological and genomic data from underrepresented populations. In the present study, 70 single-point mutations on the APP gene in a publicly available genetic dataset that included 2504 healthy individuals from 26 populations were scanned, and their distribution was analyzed. Furthermore, after gametic phase reconstruction, a pairwise comparison of the segments surrounding the mutations was performed to reveal patterns of haplotype sharing that could point to specific cross-population and cross-ancestry admixture events. Eight mutations were detected in the worldwide dataset, with several of them being specific for a single individual, population, or macroarea. Patterns of segment sharing reflected recent historical events of migration and admixture possibly linked to colonization campaigns. These observations reveal the population dynamics of the considered APP mutations in worldwide human groups and support the development of ancestry-informed screening practices for the improvement of precision and personalized approaches to neurodegeneration and dementia.

Apolipoprotein E (APOE) Haplotypes in Healthy Subjects from Worldwide Macroareas: A Population Genetics Perspective for Cardiovascular Disease, Neurodegeneration, and Dementia

“…Nonetheless, the data suggest that individuals of African ancestry may be more likely to simultaneously carry multiple variants linked to cardiovascular ailments and lipid metabolism dysfunction in the sequence of APOE, on the background of potentially neurodegenerative alleles, while individuals from other macroareas may predominantly carry mutations related to AD and dementia in different positions along the gene. Indeed, it is very telling that groups of different local ancestry showcase different risk-associated mutations, remarking the necessity to acquire extensive knowledge around putatively causative mutations [ 34 ]. Thanks to the relatively recent introduction of paleoanthropology, it has been revealed that several genetic changes associated with adaptive phenotypes and diseases in the current populations have been inherited from ancestral inhabitants of Europe and Asia that were present there before the arrival of our species.…”

Using the Theory of Planned Behavior and Past Behavior to Explain the Intention to Receive a Seasonal Influenza Vaccine among Family Caregivers of People with Dementia

“…Some types of dementia are classifiable as "primary" (e.g., Alzheimer's disease, dementia with Lewy bodies, frontotemporal dementia) and others as "secondary" to other conditions (e.g., vascular dementia) [5]. Although most cases of dementia are sporadic-the causes of which have not yet been fully understood-there are also forms with a high familial recurrence and/or with autosomal dominant transmission of causative mutations from the parent to the offspring [6][7][8][9][10]. The prevalence of dementia is on the rise in the general population, and this evidence prompted the World Health Organization and Alzheimer Disease International to consider dementia as a global public health priority [11].…”