APOE ε4, white matter hyperintensities, and cognition in Alzheimer and Lewy body dementia

Abstract

ObjectiveTo determine if APOE ε4 influences the association between white matter hyperintensities (WMH) and cognitive impairment in Alzheimer disease (AD) and dementia with Lewy bodies (DLB).MethodsA total of 289 patients (AD = 239; DLB = 50) underwent volumetric MRI, neuropsychological testing, and APOE ε4 genotyping. Total WMH volumes were quantified. Neuropsychological test scores were included in a confirmatory factor analysis to identify cognitive domains encompassing attention/executive functions, learning/memory, and language, and factor scores for each domain were calculated per participant. After testing interactions between WMH and APOE ε4 in the full sample, we tested associations of WMH with factor scores using linear regression models in APOE ε4 carriers (n = 167) and noncarriers (n = 122). We hypothesized that greater WMH volume would relate to worse cognition more strongly in APOE ε4 carriers. Findings were replicated in 198 patients with AD from the Alzheimer's Disease Neuroimaging Initiative (ADNI-I), and estimates from both samples were meta-analyzed.ResultsA significant interaction was observed between WMH and APOE ε4 for language, but not for memory or executive functions. Separate analyses in APOE ε4 carriers and noncarriers showed that greater WMH volume was associated with worse attention/executive functions, learning/memory, and language in APOE ε4 carriers only. In ADNI-I, greater WMH burden was associated with worse attention/executive functions and language in APOE ε4 carriers only. No significant associations were observed in noncarriers. Meta-analyses showed that greater WMH volume was associated with worse performance on all cognitive domains in APOE ε4 carriers only.ConclusionAPOE ε4 may influence the association between WMH and cognitive performance in AD and DLB.

Hippocampal blood–brain barrier permeability is related to the APOE4 mutation status of elderly individuals without dementia

“…33 APOE4 is also a risk factor for vascular cognitive impairment, independent of AD diagnosis. 34 Postmortem studies have indicated that APOE4 exacerbates the intraneuronal accumulation of amyloid beta, plaque deposition, formation of neurotoxic amyloid beta oligomers, and severity of cerebral amyloid angiopathy. 35,36 Accumulating evidence suggests that APOE4 mutation influences amyloid pathology via two pathways in relation to the BBB: anatomical impairment of the BBB with accelerated pericyte loss by the presence of APOE4, 5 and functional impairment of the BBB by transport dysregulation.…”

“…33 APOE4 is also a risk factor for vascular cognitive impairment, independent of AD diagnosis. 34…”

Neuroimaging Advances in Parkinson's Disease and Atypical Parkinsonian Syndromes

“…Recent investigations indicate that APOE -ε4 is related to hippocampal atrophy along with learning and memory performance in DLB as well as across the AD/DLB spectrum, implicating APOE -ε4-associated shared neurodegenerative mechanisms across these disorders ( 9 ). Similarly, MRI-derived WM hyperintensity burden was inversely related to learning/memory, attention/executive and language performances in APOE -ε4 carriers across the AD/DLB spectrum ( 90 ). In addition to the APOE -ε4's influence on amyloidopathy, these results are consistent with the emerging evidence indicating an independent role of APOE -ε4 in modulating α-synucleinopathy in the brain ( 91 ).…”

Apolipoprotein E ε4 Allele-Based Differences in Brain Volumes Are Largely Uniform Across Late Middle Aged and Older Hispanic/Latino- and Non-Hispanic/Latino Whites Without Dementia

“…For example, higher rates of amyloid beta were correlated with lower performance on verbal memory, visual memory, and working memory to a significantly stronger extent among cognitively healthy older ε4 carriers compared to non-carriers (Lim et al, 2013). Similarly, existing evidence suggests that APOE ε4 carriers may be more vulnerable to poor cognition in the presence of white matter hyperintensities, an indicator of small vessel damage, than non-carriers (Mirza et al, 2019). Even less is known about the interactions between the APOE ε4 status and amyloid beta or cerebrovascular damage on cognition among Hispanics/Latinos.…”