APOE/TOMM40 Genetic Loci, White Matter Hyperintensities, and Cerebral Microbleeds

Abstract

BackgroundTwo markers of cerebral small vessel disease are white matter hyperintensities and cerebral microbleeds, which commonly occur in people with Alzheimer's disease.Aim and/or hypothesisTo test for independent associations between two Alzheimer's disease‐susceptibility gene loci – APOE ε and the TOMM 40 ‘523’ poly‐T repeat – and white matter hyperintensities/cerebral microbleed burden in community‐dwelling older adults.MethodsParticipants in the Lothian Birth Cohort 1936 underwent genotyping for APOE ε and TOMM 40 523, and detailed structural brain magnetic resonance imaging at a mean age of 72·70 years (standard deviation = 0·7; range = 71–74).ResultsNo significant effects of APOE ε or TOMM 40 523 genotypes on white matter hyperintensities or cerebral microbleed burden were found amongst 624 participants.ConclusionsLack of association between two Alzheimer's disease susceptibility gene loci and markers of cerebral small vessel disease may reflect the relative health of this population compared with those in other studies in the literature.

Higher prevalence of cerebral white matter hyperintensities in homozygous APOE-ɛ4 allele carriers aged 45–75: Results from the ALFA study

“…In fact, some articles could not find any differences in WMH load between APOE-e4 allele carriers and non-carriers, 40,41 but others have observed a clear correlation. 29,42 These recruited subjects from general population, patients with cerebrovascular disease 43 or patients affected of probable AD. 44 There is, therefore, a great variability on the characteristics of subjects evaluated among studies, including age, ethnicity, comorbidities and other demographic factors that could have an impact on WMH.…”

Associations between APOE genotype and cerebral small-vessel disease: a longitudinal study

“…MBs were defined as areas of signal void on T2*-weighted MRI. The number of MBs in whole cerebral was counted and recorded [ 1 , 7 ].…”

“…There are evidences that they often co-occur and presence of them can increase the future risk of cognitive decline and dementia [ 3 , 4 ]. Although mechanisms underlying association between CSVD and cognition are unclear, previous studies hypothesized that cerebral small-vessel burden may expedite progression of cognitive-related diseases through promoting accumulations of amyloid depositions or increasing vulnerability to these pathology [ 5 – 7 ]. Another known risk factor for age-related cognitive decline is in the APOE gene loci.…”

The Pathogenic Component of the APOE-TOMM40 Region in Alzheimer’s disease: Its Implications in Metabolomics and Pharmacogenomics

“…The 523 VL poly T resulted in significantly higher expression than the S poly T. These results suggest that the 523 locus may contribute to LOAD susceptibility by modulating the expression of TOMM40 and/or APOE transcription [40]. Recent studies also suggest that the TOMM40 gene rs10524523 ("523") variable length poly T repeat polymorphism is associated to a certain extent with similar AD phenotypes as those reported for APOE, such as brain white matter changes [41,42] or different biomarkers [43][44][45][46]. In addition, the TOMM40 rs2075650 G allele may be a risk factor for the development of depression [47] and sporadic inclusion body myositis [48].…”