Targeting Neuroplasticity, Cardiovascular, and Cognitive-Associated Genomic Variants in Familial Alzheimer’s Disease

Abstract

The identification of novel genetic variants contributing to the widespread in the age of onset (AOO) of Alzheimer's disease (AD) could aid in the prognosis and/or development of new therapeutic strategies focused on early interventions. We recruited 78 individuals with AD from the Paisa genetic isolate in Antioquia, Colombia. These individuals belong to the world largest multigenerational and extended pedigree segregating AD as a consequence of a dominant fully penetrant mutation in the PSEN1 gene and exhibit an AOO ranging from the early 1930s to the late 1970s. To shed light on the genetic underpinning that could explain the large spread of the age of onset (AOO) of AD, 64 single nucleotide polymorphisms (SNP) associated with neuroanatomical, cardiovascular, and cognitive measures in AD were genotyped. Standard quality control and filtering procedures were applied, and single- and multi-locus linear mixed-effects models were used to identify AOO-associated SNPs. A full two-locus interaction model was fitted to define how identified SNPs interact to modulate AOO. We identified two key epistatic interactions between the APOE*E2 allele and SNPs ASTN2-rs7852878 and SNTG1-rs16914781 that delay AOO by up to ~ 8 years (95% CI 3.2-12.7, P = 1.83 × 10) and ~ 7.6 years (95% CI 3.3-11.8, P = 8.69 × 10), respectively, and validated our previous finding indicating that APOE*E2 delays AOO of AD in PSEN1 E280 mutation carriers. This new evidence involving APOE*E2 as an AOO delayer could be used for developing precision medicine approaches and predictive genomics models to potentially determine AOO in individuals genetically predisposed to AD.

Familial Alzheimer’s Disease and Recessive Modifiers

“…LOXL4 ECM induced plasticity as well as induction of proliferative activity could lead to a better physiological stability of PSEN1-mutated cells, which results in the ADAOO delaying effect observed in these patients. This effect is in line with the delayer effect of the APOE*E2 allele in this cohort [5,35]. Given the biological relatedness between APOE and LOXL4( Table 3), the synergistic effect of these two genes on ADAOO is yet to be elucidated.…”

“…Individuals included in this study exhibit an extreme phenotype, that is, suffer from AD caused by the PSEN1 E280A fully penetrant mutation, belong to the Paisa genetic isolate and their AD age of onset (ADAOO) ranges from the early 30s to the late 70s [23]. In previous studies [3,5,7,35], we successfully applied this sampling strategy using extreme phenotypes (of major effect phenotypes) [36][37][38][39]. Power estimates are included in the Supplementary Material.…”

“…Gene ontology analyses indicate that CSN1S1 plays an important role in the capacity of milk to transport calcium phosphate. It is intriguing that CSN1S1 is biologically related to the Apolipoprotein E (APOE) and Clusterin (CLU) genes (Table 2), which have been shown to delay ADAOO in PSEN1 E280A mutation carriers and as a mediator of Aβ toxicity with neuroprotective effects, respectively [5,35,44]. Epidemiological studies suggest that intake of milk and fermented dairy products are significantly associated with a decreased risk of AD, cognitive decline, and cognitive-related disorders in the elderly [45][46][47][48][49].…”

Effects of rs958804 and rs7858836 single‐nucleotide polymorphisms of the ASTN2 gene on pain‐related phenotypes in patients who underwent laparoscopic colectomy and mandibular sagittal split ramus osteotomy

“…Together with astrotactin 1, astrotactin 2 plays a key role in glial‐guided neuronal migration during development of the laminar architecture of cortical regions of the mammalian brain 23,24 . Some researchers reported that certain variants of the ASTN2 gene might be associated with the development of neuropsychiatric disorders, such as autism spectrum disorder, attention‐deficit/hyperactivity disorder, anxiety, obsessive‐compulsive disorder, schizophrenia, and Alzheimer's disease, 25–27 although others did not find such associations between ASTN2 gene variants and neuropsychiatric disorders 28 . A substantial number of studies have shown or suggested interactions between these neuropsychiatric disorders and alterations of opioid system function 29–32 .…”

A Comprehensive Machine Learning Framework for the Exact Prediction of the Age of Onset in Familial and Sporadic Alzheimer’s Disease

“…In contrast to f AD, mutations in genes associated with s AD do not directly cause AD but confer susceptibility [ 28 ]. Although f AD and s AD forms are phenotypically similar, the age of onset (AOO) at which signs and/or symptoms of AD appear for the first time in cases of f AD is generally earlier than in cases of s AD, with important predictors of ADAOO in s AD correspond to several genetic variants of small effect [ 29 , 30 ]. Indeed, it is generally established that f AD cases have an AOO before 65 years (ranging from the early 30s to the late 70s), while the AOO in s AD generally starts after 65 years [ 31 , 32 ].…”