Genetics and Neuropathology of Neurodegenerative Dementias

This article provides an overview of the current understanding of the genetic and pathologic features of neurodegenerative dementias, with an emphasis on Alzheimer disease and related dementias.

In recent years, there has been substantial progress in genetic research, contributing significant knowledge to our understanding of the molecular risk factors involved in neurodegenerative dementia syndromes. Several genes have been linked to monogenic forms of dementia (eg, APP, PSEN1, PSEN2, SNCA, GRN, C9orf72, MAPT) and an even larger number of genetic variants are known to influence susceptibility for developing dementia. As anti-amyloid therapies for patients with early-stage Alzheimer disease have entered the clinical arena, screening for the apolipoprotein E ε4 high-risk allele has come into focus, emphasizing the importance of genetic counseling. Similarly, advances in the pathologic classifications of neurodegenerative dementia syndromes and molecular pathology highlight their heterogeneity and overlapping features and provide insights into the pathogenesis of these conditions.

Recent progress in neurogenetics and molecular pathology has improved our understanding of the complex pathogenetic changes associated with neurodegenerative dementias, facilitating improved disease modeling, enhanced diagnostics, and individualized counseling. The hope is that this knowledge will ultimately pave the way for the development of novel therapeutics.