Introduction: The role of TOMM40-APOE 19q13.3 region variants is well documented in Alzheimer's disease (AD) but remains contentious in dementia with Lewy bodies (DLB) and Parkinson's disease dementia (PDD). Methods: We dissected genetic profiles within the TOMM40-APOE region in 451 individuals from four European brain banks, including DLB and PDD cases with/without neuropathological evidence of AD-related pathology and healthy controls. Results: TOMM40-L/APOE-ε4 alleles were associated with DLB (ORTOMM40 -L = 3.61; P value = 3.23 × 10−9; ORAPOE -ε4 = 3.75; P value = 4.90 × 10−10) and earlier age at onset of DLB (HRTOMM40 -L = 1.33, P value =.031; HRAPOE -ε4 = 1.46, P value =.004), but not with PDD. The TOMM40-L/APOE-ε4 effect was most pronounced in DLB individuals with concomitant AD pathology (ORTOMM40 -L = 4.40, P value = 1.15 × 10−6; ORAPOE - ε 4 = 5.65, P value = 2.97 × 10−8) but was not significant in DLB without AD. Meta-analyses combining all APOE-ε4 data in DLB confirmed our findings (ORDLB = 2.93, P value = 3.78 × 10−99; ORDLB+AD = 5.36, P value = 1.56 × 10−47). Discussion: APOE-ε4/TOMM40-L alleles increase susceptibility and risk of earlier DLB onset, an effect explained by concomitant AD-related pathology. These findings have important implications in future drug discovery and development efforts in DLB.

Original languageEnglish
JournalAlzheimer's and Dementia: Translational Research and Clinical Interventions
Pages (from-to)814-824
Number of pages11
Publication statusPublished - 2019


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