Summary
Pedigrees with familial Alzheimer's disease (FAD), caused by mutations in either the amyloid precursor protein (APP) or the presenilin 1 (PS1) or presenilin 2 (PS2) genes, show considerable phenotypic variability. Monogenic diseases typically exhibit variations in biological features, such as age of onset, severity, and multiple clinical and cellular phenotypes. This variation can be due to specific alleles of the disease gene, environmental effects, or modifier genes.
Spastic paraparesis (SP), or progressive spasticity of the lower limbs, is frequently hereditary, with over 20 loci being identified for uncomplicated (paraparesis alone) and complicated (paraparesis and other neurological features) disease subtypes. Moreover, over 10 different genes have been identified with mutations that lead to SP. While dementia is a common feature of complicated SP, a reciprocal observation has also been made since the earliest clinical reports of FAD: namely, that a number of AD families have been reported in which some individuals have SP. In 1997, the key observation was made that PS1 mutations were associated with the presence of SP, suggesting that there was a complex relationship between SP and AD. In addition, in 1998, it was also shown that PS1 AD/SP pedigrees frequently have variant, large, non-cored plaques without neuritic dystrophy, named cotton wool plaques (CWP). The PS1 mutations associated with CWP secrete unusually high levels of the amyloid β 42 peptide, suggesting a molecular basis for the formation of this distinctive plaque type.
The SP phenotype in PS1 pedigrees appears to be associated in some cases with a delayed onset of dementia, compared with affected individuals who present with dementia only. Some individuals who present with SP have remained dementia-free for up to 10 years. Variations seen in neuropathology and neurological symptoms in PS1 FAD suggest that modifier genes may underlie this phenotypic heterogeneity. As PS1 mutations are almost always associated with a particularly aggressive form of presenile dementia, these findings suggest the existence of a protective factor in some individuals with SP.
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Karlstrom, H., Brooks, W.S., Kwok, J.B.J., Kril, J.J., Halliday, G.M., Schofield, P.R. (2005). Variable Phenotype of Alzheimer's Disease with Spastic Paraparesis. In: Cummings, J.L., Poncet, M., Hardy, J., Christen, Y. (eds) Genotype — Proteotype — Phenotype Relationships in Neurodegenerative Diseases. Research and Perspectives in Alzheimer's Disease. Springer, Berlin, Heidelberg. https://doi.org/10.1007/3-540-26522-8_7
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