Alz Res Therapy: Genetic variation may reveal the underlying mechanism of AD

Alzheimer's disease (AD) is highly heritable, and the heritability of late-onset AD (LOAD) is 58-79%
.

Previous large-scale genome-wide association studies ( GWAS s) have found more than 20 AD gene variants, which endow the risk of LOAD

GWAS

APOE remains the strongest genetic risk factor for LOAD, resulting in a 3 to 15-fold increase in risk
.

However, these confirmed variants account for only a small part of the heritability of the disease

Although most of the non-APOE-related AD-related gene variants described so far are located in introns or non-coding regions, these variants may still affect nearby gene expression and play a protective or disease-inducing role
.

In addition, the development of AD has gone through a long preclinical stage with abnormal neuropathological biomarkers
.

Recently, the National Institute of Aging and Alzheimer’s Association (NIAAA) released a new research framework that provides a flexible platform for generating or testing hypotheses about different pathological processes in AD.

Amyloidosis biomarkers, especially cortical amyloidosis-PET ligand binding or low CSF Aβ42; tauopathy biomarkers, especially CSF phosphorylated tau (pTau) elevated or cortical tau-PET ligand binding; and nerve Degeneration biomarkers, especially CSF total tau (ttau) increased, 18F-fluorodeoxyglucose (FDG)-PET decreased, or brain structure atrophy on MRI
.

Many early AD variants are related to the expression levels of genes near them, and are related to brain amyloidosis and neurodegeneration
.

Relatively speaking, few studies have reported the association of these top AD risk gene variants with brain tauopathy, and most of these studies have focused on one variant or several variants

More importantly, the precise disease-related mechanisms of the new gene variants discovered in the recent GWAS meta-analysis are still unknown
.

In this way, Meng-Shan Tan of Fudan University et al.
analyzed the relationship between variants in the top 30 non-APOE AD risk genes and transcript expression levels in the current large-scale GWAS research, as well as brain amyloidosis, tauopathy and The comprehensive analysis of the pathological process of neurodegeneration uses baseline and follow-up data of CSF, PET, and MRI related to AD
.

The human brain gene expression data comes from the British Brain Expression Consortium (UKBEC), while other data used in its study comes from the Alzheimer's Disease Neuroimaging Initiative (ADNI) cohort
.

They studied the association of AD risk allele carrier status with blood and brain gene expression levels, and used a multivariate linear regression model to test the association with baseline brain amyloidosis, tauopathy, and neurodegeneration
.

They used a mixed-effects model to analyze the longitudinal effects of these variants on the rate of pathological change

They detected a total of 27 variants related to changes in the expression of 21 nearby genes in the blood and brain regions
.

11 variants (especially the new variants of ADAM10, IGHV1-68 and SLC24A4/RIN3) are related to brain amyloidosis, 7 variants (especially INPP5D, PTK2B) are related to brain tauopathy, 8 variants (especially It's ECHDC3, HS3ST1) and cranial nerve degeneration

Variants of ADAMTS1, BZRAP1-AS1, CELF1, CD2AP and SLC24A4/RIN3 are involved in more than one brain pathological process
.

Variants of ADAMTS1, BZRAP1-AS1, CELF1, CD2AP and SLC24A4/RIN3 are involved in more than one brain pathological process
.

They found that genetic variation may play a functional role in the pathogenesis of AD and proposed potential mechanisms
.

Genetic variation may play a functional role in the pathogenesis of AD and propose potential mechanisms
.

 

Original source:
Alzheimer's Disease Neuroimaging Initiative, Tan MS, Yang YX, et al.

A ssociations of Alzheimer's disease risk variants with gene expression, amyloidosis, tauopathy, and neurodegeneration.
  Alz Res Therapy.
2021;13(1):15.
doi: 10.

ssociations of Alzheimer's disease risk variants with gene expression, amyloidosis, tauopathy, and neurodegeneration.
 

 

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