Objective: To identify the association of apolipoprotein E ɛ4-allele (APOE-ε4) with hippocampal volumes across the spectrum of Alzheimer’s disease (AD) and dementia with Lewy bodies (DLB).

Background: APOE-ε4 is a well-recognized susceptibility factor for late-onset AD. Recent pathology-proven studies demonstrate an overrepresentation of APOE-ε4 not only in AD but also α-synucleinopathies (i.e., mixed AD/DLB, pure DLB, and Parkinson’s disease dementia) (Guerreiro et al., 2018; Tsuang et al., 2013). Thus, the association of APOE-ε4 with neuroimaging and cognitive phenotypes across the spectrum of AD and DLB, irrespective of the discrete diagnostic categories, may elucidate shared pathophysiological mechanisms. One such extensively-studied brain phenotype in AD and DLB is the hippocampus, which is intimately involved in learning and memory.

Methods: We studied 298 patients [AD=250, DLB=48; 38 pathology-confirmed] using comprehensive neuropsychological testing, volumetric MRI, and APOE genotyping (Table 1).

Results: Across the AD and DLB spectrum, (1) hippocampal volumes were smaller with increasing APOE-ε4 dosage (β=-0.20, P<0.0001), with no genotype x diagnosis interaction (Table 2), (2) learning performance as assessed by total recall scores of the California verbal learning test (CVLT) was positively associated with hippocampal volumes only among APOE-ε4 carriers (β=0.17, P<0.01) but not among non-carriers, and (3) APOE-ε4 carriers performed worse on CVLT long-delay free word recall (Mann-Whitney U=6715.0, P<0.05). The APOE-ε4 dose was also inversely associated with hippocampal volumes when the analyses were performed within the DLB (β=-0.28, P<0.05) and AD (β=-0.20, P<0.001) diagnostic groups (Table 3), or when the analysis was restricted to the pathology-confirmed sub-sample (β=-0.32, P<0.05) (Figure 1).

Conclusions: These findings suggest that APOE-ε4 is linked to hippocampal atrophy and associated learning and memory phenotypes across the AD and DLB spectrum, possibly via shared mechanisms of neurodegeneration. Given that the AD and DLB pathologies frequently coexist and share genetic risk, the development of effective treatments will depend upon targeting shared pathophysiological pathways. In this regard, hippocampal volume in APOE-ε4 carriers may have utility as biomarker of treatment effectiveness in clinical trials of AD, DLB, and mixed disease.

References: Guerreiro, R., Ross, O.A., Kun-Rodrigues, C., Hernandez, D.G., Orme, T., Eicher, J.D., Shepherd, C.E., Parkkinen, L., Darwent, L., Heckman, M.G., et al. (2018). Investigating the genetic architecture of dementia with Lewy bodies: a two-stage genome-wide association study. Lancet Neurol. 17, 64–74. Tsuang, D., Leverenz, J.B., Lopez, O.L., Hamilton, R.L., Bennett, D. a, Schneider, J. a, Buchman, A.S., Larson, E.B., Crane, P.K., Kaye, J.A., et al. (2013). APOE ε4 increases risk for dementia in pure synucleinopathies. JAMA Neurol. 70, 223–228.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/the-shared-risk-of-apolipoprotein-e-%c9%9b4-allele-on-hippocampal-volume-across-the-spectrum-of-alzheimers-disease-and-dementia-with-lewy-bodies-evidence-from-the-sunnybrook-dementia-study/