The complex relationship between genotype, pathology and phenotype in familial dementia

Causative genes involved in familial forms of dementias, including Alzheimer's disease (AD), frontotemporal lobar degeneration (FTLD) and dementia with Lewy bodies (DLB), as well as amyotrophic lateral sclerosis and prion diseases where dementia is present as a significant clinical feature, are associated with distinct proteinopathies. This review summarizes the relationship between known genetic determinants of these dementia syndromes and variations in key neuropathological proteins in terms of three types of heterogeneity: (i) Locus Heterogeneity, whereby mutations in different genes cause a similar proteinopathy, as exemplified by mutations in APP, PSEN1 and PSEN2 leading to AD neuropathology; (ii) Allelic Heterogeneity, whereby different mutations in the same gene lead to different proteinopathies or neuropathological severity, as exemplified by different mutations in MAPT and PRNP giving rise to protein species that differ in their biochemistry and affected cell types; and (iii) Phenotypic Heterogeneity, where identical gene mutations lead to different proteinopathies, as exemplified by LRRK2 p.G2019S being associated with variable Lewy body presence and alternative AD neuropathology or FTLD-tau. Of note, the perceived homogeneity in histologic phenotypes may arise from laboratory-specific assessment protocols which can differ in the panel of proteins screened. Finally, the understanding of the complex relationship between genotype and phenotype in dementia families is highly relevant in terms of therapeutic strategies which range from targeting specific genes, to a broader strategy of targeting a downstream, common biochemical problem that leads to the histopathology.