Identification of genes in which mutations cause autosomal dominant Alzheimer disease (ADAD) has opened up the opportunity to explore both human and animal models of the exponentially more common sporadic form of the disease (typically of later onset and therefore sometimes referred to as late-onset AD [LOAD]). Demonstration that such pathogenic mutations lead to aberrant cleavage or aggregation of the amyloid precursor protein (APP)1 has provided impetus to the prevailing amyloid cascade hypothesis of the disease, simply put, that certain cleavage products of APP (eg, β-amyloid [Aβ] 42) are initiating factors or otherwise central to the pathogenesis of all forms of AD. However, such abnormalities of Aβ production are less evident in LOAD, and altered clearance due to other genetic variants, environmental or lifestyle factors, or other age-related phenomenon are thought to play key roles2 in the development of the disease. Although there are more commonalities than differences in the clinical and neuropathologic features between ADAD and LOAD,3 in addition to presenting at a younger age, ADAD can have distinctive features including spastic paraparesis, early myoclonus and seizures, dysarthria, pseudobulbar affect, more extensive cerebral amyloid angiopathy,3 and atypical amyloid plaque morphology,4 chemical make-up,5 and distribution.6 Such atypical features occur more often in young-onset ADAD cases, particularly those associated with presenilin 1 (PSEN1) mutations,6,7 leaving open the question as to whether any differences between these forms of the disease arise from their different underlying biochemical mechanisms or principally as a function of age.