Short Article on Alzheimer's Disease: #2 Amyloid beta accumulation, imbalance of the production and clearance of Abeta

Alzheimer’s disease is an incurable and progressive neurodegenerative illness with the two commonly accepted hallmarks being the deposition of insoluble amyloid plaques and the aggregation of neurofibrillary tangles in the brain. There are mainly two types, early-onset Alzheimer’s which affects people as young as 30 and late-onset Alzheimer’s which begins after the age of 65. Late-onset Alzheimer’s (sporadic) is the most common form of the disorder affecting about 90% of AD sufferers. The causes are possibly a combination of genetic, lifestyle and environmental factors.

Accumulation of Amyloid beta
One hypothesis is that the accumulation of amyloid beta arises from an imbalance of the production and clearance of Abeta.[1] Increased production of amyloid beta is associated with pathogenic mutations in three genes, AAP gene on chromosome 21, presenilin1 (PSEN1) on chromosome 14, and presenilin 2 (PSEN2) on chromosome 1 and is most common in early-onset Alzheimer’s and familial Alzheimer’s.[2] However, recent data suggests that in most cases/sporadic AD, imbalance occurs as a result of amyloid beta clearance impairment.[1]

APOE E4, A major genetic risk factor in late-onset Alzheimer’s.
One of the major genetic risk factors known for late-onset AD is the E4 isoform of apolipoprotein E (APOE). The APOE gene has three major allelic variants, E2, E3, E4 with E3 the most common allele. Each individual possesses two alleles inherited from both parents and it is known that having one or two alleles e4 of APOE gene increases by 3-fold and 12-fold respectively the risk of developing AD.[2] However, the possession of the E4 allele is not sufficient enough nor necessary to develop AD as only half of APOE E4 carriers will develop AD by age 85 (compare to 10% of non-carriers).[3]

Function of APOE in Lipid Metabolism
The APOE gene code for APOE apolipoprotein-E lipid-transport protein, a regulator of lipid metabolism that allows lipids and cholesterol to be transported into cells via cell-surface lipoprotein receptors such as the low-density lipoproteins receptors (LDL) or LDL receptor related proteins (LRP) etc..[4] This is particularly important as cholesterol and lipids are essential for central nervous system (CNS) functions, such as neuronal growth, synaptic plasticity and neuronal maintenance and repair.

It is still not yet fully understood how APOE E4 increases AD risk but emerging data show that there is a correlation between APOE4 and increased levels of neurotoxic soluble oligomeric amyloid beta.[5] It is thought that in the CNS, the ability of APOE4 in clearing beta-amyloid across the blood brain barrier is impaired (while APOE3 and APOE2 are more efficient in performing this task), consequently contributing to the accumulation of amyloid beta in the brain. [3,4]

Newmarket Scientific is a distributor in the UK and Ireland of life science reagents with a strong focus in neuroscience research. It provides several antibodies, ELISA kits (Oligomeric amyloid-beta; apolopoprotein E/Beta-amyloid complex) and peptides for Alzheimer's research:

Further reading:
- Amyloid beta plaque staining
- Short Articles on Alzheimer’s Disease:
#1 Amyloid beta Formation
#3 Microglia
#4 Tau Phosphorylation
#5 Tau Aggregation and Propagation

References:
[1] Evidence for impaired amyloid β clearance in Alzheimer's disease, Wildsmith KR et al,  Alzheimers Res Ther. 2013 Jul 12;5(4):33
[2] Alzheimer’s Disease, Masters C. et al. Nature reviews Disease Primers 1, article number 15056, 2015
[2] APOE genotype and cognition in healthy individuals at risk of Alzheimer's disease: A review, O'Donoghue MC et al, Cortex. 2018 Jul;104:103-123.
[3] Apolipoprotein E: Structure and Function in Lipid Metabolism, Neurobiology, and Alzheimer’s Diseases Huang Y et al, Neurobiol Dis. 2014 Dec; 72PA: 3–12. 
[4] Soluble apoE/Aβ complex: mechanism and therapeutic target for APOE4-induced AD risk, Tai LM et al, Mol Neurodegener. 2014; 9: 2.

Written by Magalie Dale
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