Protective variant for hippocampal atrophy identified by whole exome sequencing

Abstract

We used whole-exome sequencing to identify variants other than APOE associated with the rate of hippocampal atrophy in amnestic mild cognitive impairment. An in-silico predicted missense variant in REST (rs3796529) was found exclusively in subjects with slow hippocampal volume loss and validated using unbiased whole-brain analysis and meta-analysis across 5 independent cohorts. REST is a master regulator of neurogenesis and neuronal differentiation that has not been previously implicated in Alzheimer’s disease. These findings nominate REST and its functional pathways as protective and illustrate the potential of combining next-generation sequencing with neuroimaging to discover novel disease mechanisms and potential therapeutic targets.

The rs1277306 Variant of the <b><i>REST</i></b> Gene Confers Susceptibility to Cognitive Aging in an Elderly Taiwanese Population

“…Consistent with our findings, several previous studies identified an interaction of the APOE gene with the APP [25,26], PICALM [24], PSEN1 [27], and PSEN2 [26] genes by stratifying APOE ε4 carrier status. Moreover, evidence has been reported for an association of the REST gene with slow hippocampal loss, brain aging, AD pathology, and protection from oxidative stress and amyloid β-protein toxicity [3,4,5,6]. Furthermore, the REST gene may act not only as a primary repressor for normal neurogenesis but also as an essential protector against neurodegeneration [3,4,5,6].…”

“…Moreover, evidence has been reported for an association of the REST gene with slow hippocampal loss, brain aging, AD pathology, and protection from oxidative stress and amyloid β-protein toxicity [3,4,5,6]. Furthermore, the REST gene may act not only as a primary repressor for normal neurogenesis but also as an essential protector against neurodegeneration [3,4,5,6]. Additionally, it should be noted that the A allele frequency of REST rs1277306 varies considerably between different ethnic populations, ranging from 42% in the present Taiwanese population to 75.8% in European subjects, 44.7% in Japanese subjects, 85.3% in African American subjects, and 46.1% in Han Chinese subjects as shown in the public data from the 1000 Genomes Project (http://www.1000genomes.org).…”

“…The protein encoded by the REST gene has been implicated in the regulation of neuronal differentiation, axonal growth, vesicular transport, ion channels, and synaptic plasticity [2,3]. The REST gene has previously been associated with mild cognitive impairment and Alzheimer disease (AD) [4,5,6]. Lu et al [4] showed that the REST protein was almost undetectable in the nucleus of cortical and hippocampal neurons in aging individuals with mild cognitive impairment or AD.…”

“…In an animal study, a conditional deletion of the REST gene can also progressively cause age-related neurodegeneration in the mouse brain [4]. Further, in a whole-exome sequencing study, Nho et al [5] reported that the minor T allele of the REST rs3796529 variant was associated with slow hippocampal volume loss in mild cognitive impairment, suggesting a protective effect of REST rs3796529 T allele on hippocampal loss. On the contrary, it has been identified that the REST rs3796529 variant was not significantly associated with AD susceptibility in a genome-wide association study [7].…”

Clinical workout for the early detection of cognitive decline and dementia

“…Cortical atrophy may be present in preclinical AD 45 years prior to symptom onset. 48 Early detection of cognitive decline and dementia M Tsolaki…”