Variable phenotype of Alzheimer's disease with spastic paraparesis

• Published in: Journal of neurochemistry Vol. 104; no. 3; pp. 573 - 583
• Main Authors: Karlstrom, Helena, Brooks, William S, Kwok, John B.J, Broe, G. Anthony, Kril, Jillian J, McCann, Heather, Halliday, Glenda M, Schofield, Peter R
• Format: Journal Article
• Language: English
• Published: Oxford, UK Oxford, UK : Blackwell Publishing Ltd 01.02.2008; Blackwell Publishing Ltd; Blackwell
• Subjects: Adult and adolescent clinical studies; Alzheimer disease; Alzheimer Disease - complications; Alzheimer Disease - genetics; Alzheimer's disease; Animals; Biochemistry; Biological and medical sciences; cotton wool plaques; Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases; Genotype & phenotype; Humans; Medical sciences; Medicin och hälsovetenskap; Mutation; Neurology; Neurosciences; Organic mental disorders. Neuropsychology; Paraparesis, Spastic - complications; Paraparesis, Spastic - genetics; Pedigree; Phenotype; Plaque, Amyloid - pathology; Presenilin-1 - genetics; Psychology. Psychoanalysis. Psychiatry; Psychopathology. Psychiatry; spastic paraparesis; Peptides; Motor system disorder; Alzheimer disease; Variability; Lower limb; Heterogeneity; Familial disease; Gene; Degenerative disease; Neurological disorder; Alzheimer's disease; Nervous system diseases; Spasticity; Muscle tonus alteration; Paraparesia; Cerebral disorder; cotton wool plaques; spastic paraparesis; Striated muscle disease; Phenotype; Paresis; Central nervous system disease; Dystrophy; Mutation; Subtype
• ISSN: 0022-3042; 1471-4159; 1471-4159
• DOI: 10.1111/j.1471-4159.2007.05038.x

Pedigrees with familial Alzheimer's disease (AD) show considerable phenotypic variability. Spastic paraparesis (SP), or progressive spasticity of the lower limbs is frequently hereditary and exists either as uncomplicated (paraparesis alone) or complicated (paraparesis and other neurological features) disease subtypes. In some AD families, with presenilin-1 (PSEN1) mutations, affected individuals also have SP. These PSEN1 AD pedigrees frequently have a distinctive and variant neuropathology, namely large, non-cored plaques without neuritic dystrophy called cotton wool plaques (CWP). The PSEN1 AD mutations giving rise to CWP produce unusually high levels of the amyloid β peptide (Aβ) ending at position 42 or 43, and the main component of CWP is amino-terminally truncated forms of amyloid β peptide starting after the alternative β-secretase cleavage site at position 11. This suggests a molecular basis for the formation of CWP and an association with both SP and AD. The SP phenotype in some PSEN1 AD pedigrees also appears to be associated with a delayed onset of dementia compared with affected individuals who present with dementia only, suggesting the existence of a protective factor in some individuals with SP. Variations in neuropathology and neurological symptoms in PSEN1 AD raise the prospect that modifier genes may underlie this phenotypic heterogeneity.