Genetic Phenotypes of Alzheimer’s Disease: Mechanisms and Potential Therapy

Abstract

Years of intensive research has brought us extensive knowledge on the genetic and molecular factors involved in Alzheimer's disease (AD). In addition to the mutations in the three main causative genes of familial AD (FAD) including presenilins and amyloid precursor protein genes, studies have identified several genes as the most plausible genes for the onset and progression of FAD, such as triggering receptor expressed on myeloid cells 2, sortilin-related receptor 1, and adenosine triphosphate-binding cassette transporter subfamily A member 7. The apolipoprotein E ε4 allele is reported to be the strongest genetic risk factor for sporadic AD (SAD), and it also plays an important role in FAD. Here, we reviewed recent developments in genetic and molecular studies that contributed to the understanding of the genetic phenotypes of FAD and compared them with SAD. We further reviewed the advancements in AD gene therapy and discussed the future perspectives based on the genetic phenotypes.

Long Non-Coding RNAs: New Insights in Neurodegenerative Diseases

“…The majority of AD cases are sporadic, but it is affected by several genes. Of the genetic variants that are known to cause the AD include presenilin 1 (PSEN1), presenilin 2 (PSEN2), and amyloid precursor protein (APP) [128]. The Apolipoprotein E (APOE) ε4 allele is reported to be the strongest genetic risk factor for SAD [129].…”

“…The Apolipoprotein E (APOE) ε4 allele is reported to be the strongest genetic risk factor for SAD [129]. Additionally, other contributing loci that affect AD include triggering receptors expressed on myeloid cells 2 (TREM2), sortilin-related receptor 1 (SORL1), and adenosine triphosphate-binding cassette transporter subfamily A member 7 (ABCA7) [128,130,131]. Similar to AD, genetic factors also increase the risk for the development of Parkinson's disease (PD).…”

Anti-Amyloid Therapies for Alzheimer’s Disease and the Amyloid Cascade Hypothesis

“…Apolipoprotein E ( APOE ) gene variants follow next, as one copy of the ε4 allele can increase the risk of developing AD by 2–6 times, while two copies increase the risk by 7–21 times. Genetic studies have identified many other AD susceptibility loci and a large number of rare variants associated to AD (e.g., TREM 2, SORL1, ABCA7) [ 3 , 5 , 6 , 7 ]. Moreover, environmental factors (e.g., heavy metals, pesticides), comorbidities (e.g., diabetes, traumatic brain injury) and lifestyle (e.g., smoking, high-fat diet) can impact AD risk [ 5 , 8 ].…”

Are Ischemic Stroke and Alzheimer’s Disease Genetically Consecutive Pathologies?

“…Most researchers suggest that AD may be associated with the accumulation of beta-amyloid and the formation of neurofibrillary tangles in the cerebral cortex and subcortical gray matter [21,[35][36][37]. Specific cases of the disease have been associated with mutations in the amyloid precursor protein gene, in the presenilin genes and some others [38][39][40][41]. Additionally, the presence of the ε4 allele of the APOE gene has found to be significant.…”