APOE ε4 increases risk for dementia in pure synucleinopathies.

Lewy body disease (LBD) en-compasses a spectrum of clinicopathologic entities that include Parkinson disease (PD), PD with dementia (PDD), and dementia with Lewy bodies (DLB). Dementia with Lewy bodies and PDD are differentiated from one another based on clinical criteria. Dementia with Lewy bodies is diagnosed when dementia occurs before or concurrently with parkinsonism, whereas in PDD, parkinsonism precedes dementia by at least 12 months.1 Lewy body disease neuropathologic changes (NCs) include classic histologic inclusions (Lewy bodies) and α-synuclein immunopositive neuronal inclusions and processes (Lewy neurites) in partially overlapping regions of the brain. However, the pathologic classification of DLB is complex because some cases show LBDNCs with no or low levels of Alzheimer disease (AD) NCs, which we refer to as pure DLB (pDLB), while many other cases show LBDNCs with coexistent high levels of ADNCs (LBDAD). Importantly, the pathophysiologic relationship between LBD-AD, pDLB, and PDD has not been delineated, and whether these disorders share common risk factors remains unclear. Humans are unlike other mammals in that we possess 3 common alleles of the apolipoprotein E (APOE) gene that are determined by 2 single nucleotide polymorphisms located in exon 4 at positions 3937 (T/C; rs429358) and 4075 (C/T; rs7412). The corresponding apoE isoforms (299 amino acids) differ at amino acid positions 112 (Cys for apoE2 and apoE3; Arg for apoE4) and 158 (Cys for apoE2; Arg for apoE3 and apoE4), and these isoforms have different functional and biochemical properties.2 The APOE e4 allele is a well-established risk factor for both early-onset and late-onset AD.3,4 We and others have reported an association between e4 and LBD-AD,5–7 but it is unclear whether e4 is a risk factor for pDLB or PDD because interpretations of existing data are limited by methodologic differences between studies. In particular, studies of DLB have often failed to assess for the presence of coexistent ADNCs, thus they have been unable to differentiate LBD-AD from pDLB.8–10 Therefore, it is possible that all genetic risk for DLB associated with the APOE e4 allele is related to its frequent comorbidity with ADNCs and is unrelated to LBDNCs. Furthermore, no studies have directly compared genetic risk factors between pDLB and PDD. To address this gap in knowledge, we genotyped APOE in a clinically and neuropathologically well-characterized sample of control participants and subjects with AD, LBD-AD, pDLB, and PDD.