Six genetically linked mutations in the CD36 gene significantly delay the onset of Alzheimer's disease

Abstract

The risk of Alzheimer’s disease (AD) has a strong genetic component, also in the case of late-onset AD (LOAD). Attempts to sequence whole genome in large populations of subjects have identified only a few mutations common to most of the patients with AD. Targeting smaller well-characterized groups of subjects where specific genetic variations in selected genes could be related to precisely defined psychological traits typical of dementia is needed to better understand the heritability of AD. More than one thousand participants, categorized according to cognitive deficits, were assessed using 14 psychometric tests evaluating performance in five cognitive domains (attention/working memory, memory, language, executive functions, visuospatial functions). CD36 was selected as a gene previously shown to be implicated in the etiology of AD. A total of 174 polymorphisms were tested for associations with cognition-related traits and other AD-relevant data using the next generation sequencing. Several associations between single nucleotide polymorphisms (SNP’s) and the cognitive deficits have been found (rs12667404 with language performance, rs3211827 and rs41272372 with executive functions, rs137984792 with visuospatial performance). The most prominent association was found between a group of genotypes in six genetically linked and the age at which the AD patients presented with, or developed, a full-blown dementia. The identified alleles appear to be associated with a delay in the onset of LOAD. In silico studies suggested that the SNP’s alter the expression of CD36 thus potentially affecting CD36-related neuroinflammation and other molecular and cellular mechanisms known to be involved in the neuronal loss leading to AD. The main outcome of the study is an identification of a set of six new mutations apparently conferring a distinct protection against AD and delaying the onset by about 8 years. Additional mutations in CD36 associated with certain traits characteristic of the cognitive decline in AD have also been found.

Border-associated macrophages promote cerebral amyloid angiopathy and cognitive impairment through vascular oxidative stress

“…CD36 single nucleotide polymorphisms (SNP) have been linked to AD, some increasing the risk of AD [ 28 , 94 ] and others delaying disease onset [ 94 , 95 ]. In silico studies suggest that the protective SNP may suppress CD36-induced inflammation upon Aβ binding [ 95 ]. To our knowledge it is not known if suppressing CD36 expression reduces CAA in humans.…”

Developmental and age-related synapse elimination is mediated by glial Croquemort

“…SCARB2 mutations are the genetic cause of a rare, progressive form of epilepsy 47 , demonstrating that this gene is somehow important for regulating circuit development, though the cause of this phenotype is unknown. Furthermore, both SCARB2 and CD36 variants have been associated with other diseases characterized by pathological synaptic changes, including autism 48 , Alzheimer’s disease 49,50 and Parkinson’s disease 51,52 . These genetic associations suggest that Crq may have a conserved role in regulating synaptic circuits, and thus we chose to move forward with validating and understanding the function of glial Crq in synapse development.…”

“…Perhaps the excess retention of synapses due to impaired synaptic engulfment by glia underlies this clinical phenotype. In addition, variants in SCARB2 and CD36 are associated with autism 48 , Alzheimer's disease 49,50 and Parkinson's disease 51,52 . Possibly the same mechanisms that these receptors use to regulate appropriate elimination of synapses in development may also contribute to synaptic pathologies that underlie these diseases.…”

Epigenetic and non-epigenetic mechanisms in the accelerated cellular aging in late-onset Alzheimer’s disease

“…One such mutation identified is CD36 gene mutations that are linked with delaying the onset of AD by eight years. CD36 is involved in Aβ clearance by phagocytosing microglia and is involved in reactive oxygen species production and cytokine production [49]. Therefore, alterations in brain morphology, functioning, and oxidative damage are increased extensively in LOAD brain giving rise to mutations and epimutations.…”