Molecular Genetics of Neurodegenerative Dementias

Abstract

Neurodegenerative dementias are clinically heterogeneous, progressive diseases with frequently overlapping symptoms, such as cognitive impairments and behavior and movement deficits. Although a majority of cases appear to be sporadic, there is a large genetic component that has yet to be fully explained. Here, we review the recent genetic and genomic findings pertaining to Alzheimer's disease, frontotemporal dementia, Lewy body dementia, and prion dementia. In this review, we describe causal and susceptibility genes identified for these dementias and discuss recent research pertaining to the molecular function of these genes. Of particular interest, there is a large overlap in clinical phenotypes, genes, and/or aggregating protein products involved in these diseases, as well as frequent comorbid presentation, indicating that these dementias may represent a continuum of syndromes rather than individual diseases.

Figure 1.

Frequency of specific neurodegenerative dementias. The inner circle shows the frequency of specific neurodegenerative dementias (indicated by different colors) as an approximate percentage of all cases of disease. The middle circle shows the percentage of patients that show familial or sporadic patterns of inheritance for each disease. The outer circle depicts the approximate percent of patients with familial inheritance patterns that harbor mutations in specific known causal genes.

Figure 2.

Neurodegenerative dementias as a spectrum disorder. Genes (left) and their pathologically aggregating protein products (right) and the neurodegenerative disorders (center) in which they have been implicated are shown.