New study holds out hope for Alzheimer’s

Kashmir Scroll Webdesk
Kashmir Scroll Webdesk


The fight to counteract Alzheimer’s Disease (AD) just got closer to delaying the onset of confusion and cognitive decline in patients. A large-scale genetic association study, which identified and analysed rare missense variants on a protein, indicative of an individual’s predisposition to AD, has found that a rare mutation changes the protein structure to grant protection against the disease.

The Stanford-led study, published in the monthly JAMA Neurology journal on May 31, analysed datasets comprising 544,384 participants. Meta-analysis was conducted through multiple studies, including 67,896 individuals with AD, 28,484 individuals with proxy-AD, and 340,306 healthy controls.

Existing research on the correlation of Alzheimer’s disease with genetic mutations has established the role of apolipoprotein E — a key protein linked to the pathogenesis of AD. The study has now found that two rare missense variants — V236E in APOE3 and R251G in APOE4 — substantially reduced the risk of AD by more than 60 per cent and 50 per cent respectively.

Notably, in a proof of principle study in March 2014, comprising nearly 9,100 subjects (control and test group combined), it was established that the V236E missense variant was “significantly associated with a markedly decreased risk” of a late onset of AD, independent of the presence of APOE2, APOE3 or APOE4.

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However, the protective effect of R251G is a new development in the field and further studies can lead to a better understanding of the pathology of the disease as well as drug development.

What are missense mutations?

Mutations can be of various types — missense, nonsense, insertion, deletion, frameshift, or duplication — effectively changing the way proteins are synthesised and altering functions at times, depending on the type of mutation.

A missense mutation is a DNA change that results in different amino acids being structured in the resulting protein. Some missense mutations alter the function of the resulting protein — either for the better or for the worse — and some other missense mutations can also be benign and change an amino acid in a protein without altering its function. For example, sickle cell disease is caused by missense mutation.

Missense variants gain significance and importance as they can be readily investigated in model systems to search for novel therapeutic targets. Their association with a disease can also vary or be dependent on ancestry.

What is apolipoprotein E (APOE) and what do the new findings indicate in light of the new study?

It is a protein that is a cholesterol carrier and supports lipid transport between cells and tissues and injury repair in the brain. It also has distinct functions in regulating brain lipid transport, glucose metabolism, neuronal signalling, neuro-inflammation and mitochondrial (akin to a battery of a cell) function in a cell. There are commonly three isoforms or alleles of this protein, that is a variation or mutation, which manifest from the original APOE — APOE2, APOE3 and APOE4. Each of these variants affects the disease risk factor differently.

Previous studies decades ago had already established that the APOE4 is a risk factor for both clinical and neuropathologic Alzheimer’s disease while the APOE2 plays a more protective function. This means that even with advanced age, APOE2 carriers would be less likely to develop dementia and less likely to meet pathologic criteria for Alzheimer’s Disease. APOE3, on the other hand, is the most commonly found isoforms among Caucasians.

Identifying the effect of missense variants, in addition to the protective or risk factor posed by APOE2 and APOE4 respectively, throws more light on Alzheimer’s disease. However, a challenge in identifying patterns in genetic variations and mutations is that of small datasets.

With this latest study, the findings indicate that single amino acid alterations of the APOE3 and APOE4 isoforms can result in substantial risk reduction for AD. Especially with APOE4, which has been otherwise associated with increasing risk of late-onset AD, the rare variant’s presence would effectively mean that an APOE4 carrier can harbour hope.


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