Familial Alzheimer's disease (AD) due to PSEN1 mutations provides an opportunity to examine AD biomarkers in persons in whom the diagnosis is certain. We describe a 55 year-old woman with clinically probable AD and a novel PSEN1 mutation who underwent genetic, clinical, biochemical and magnetic resonance and nuclear imaging assessments. We also describe neuropathological findings in her similarly affected brother. Neuropsychological testing confirmed deficits in memory, visuospatial and language function. CSF t-tau and p-tau181 were markedly elevated and Aβ(42) levels reduced. FDG-PET revealed hypometabolism in the left parietotemporal cortex. FDDNP-PET showed increased binding of tracer in medial temporal and parietal lobes and in the head of the caudate and anterior putamen bilaterally. Neuropathological examination of her brother showed the typical findings of AD and the striatum demonstrated amyloid pathology and marked neurofibrillary pathology beyond that typically seen in late-onset AD. A novel S212Y substitution in PSEN1 was present in the index patient and her affected brother but not in an older unaffected sister. An in vitro assay in which the S212Y mutation was introduced in cell culture confirmed that it was associated with increased production of Aβ(42). We describe biochemical, imaging, and neuropathological changes in a pedigree with a novel PSEN1 mutation. This allows us to validate the pathogenicity of this mutation and the indices used to assess AD.

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