Alzheimer's disease pathology explains association between dementia with Lewy bodies and APOE-ε4/TOMM40 long poly-T repeat allele variants

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 (OR_{TOMM40 -L} = 3.61; P value = 3.23 × 10⁻⁹; OR_{APOE -ε4} = 3.75; P value = 4.90 × 10⁻¹⁰) and earlier age at onset of DLB (HR_{TOMM40 -L} = 1.33, P value =.031; HR_{APOE -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 (OR_{TOMM40 -L} = 4.40, P value = 1.15 × 10⁻⁶; OR_{APOE - 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 (OR_DLB = 2.93, P value = 3.78 × 10⁻⁹⁹; OR_DLB+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.