APP A673T carriers: Lower Aβ levels protective against Alzheimer’s Disease?

While reduced plasma Aβ levels in APP A673T carriers have already been shown in earlier studies, this is the first human population-based randomly selected cohort study to show and confirm evidence that lower Aβ levels throughout the life may be protective against Alzheimer’s Disease. The results support the amyloid cascade hypothesis, which suggests that an accumulation of brain Aβ plays a key role in Alzheimer’s Disease, and therefore these results in itself constitute a significant discovery.

Lately, uncovering the genetic pathogenesis of Alzheimer’s Disease has become one of the  important targets of research, with genome-wide mapping studies leading to significant advances in the field. Thus, these studies have identified not only several new risk genes for Alzheimer’s Disease but also gene variants that protect against the disease, including the APP variant A673T. It was thought that this variant might affect the risk for Alzheimer’s Disease by modulating levels of Aβ. In the present study, researchers used data from the METabolic Syndrome In Men (METSIM), a large population-based study carried out from 2005 to 2010. The study included over 10,000 men aged 45 to 70 years randomly selected from the Population Register of Kuopio, Eastern Finland. None of these men were diagnosed with Alzheimer’s Disease.

Among 8629 genotyped individuals, 47 were heterozygous carriers of the A67T variant; 37 of 4916 genotyped individuals were heterozygous carriers of the ABCA7 rs200538373 gene variant. Researchers compared plasma levels of Aβ40 and Aβ42 in carriers of both gene variants with levels in noncarrier controls from the cohort who were matched for age, body mass index, and similar apolipoprotein E (APOE) genotype distribution. The analysis found that APP A673T carriers had on average 28% lower levels of Aβ compared with controls. A similar reduction was seen in both Aβ42 and Aβ40, while the Aβ42/40 ratio was similar in both the carriers and controls. This indicates an overall reduction in the production of Aβ rather than the γ-secretase-related modulation of the different Aβ peptides. Overall, these data indicate that the APP A673T gene variant protects from Alzheimer’s Disease and that this associates with, or is linked to, reduced plasma Aβ levels providing a direct link between genetic background of an individual and functional outcome, i.e., development of a debilitating disease.

What does this mean for an individual in the general population worldwide? First of all, future studies will have to confirm that the findings in the present study are not in some way specific for a Finnish population, meaning associated to some genetic background of this particular population. Secondly, if confirmed, the study could mean that you as a carrier of the rare APP A673T allelic variant might have a significantly reduced risk to develop Alzheimer’s Disease throughout your lifetime. This would be truly opposite to the widespread assumption that genetic aberrations lead to higher disease risks; in the present case, the “aberration” in a gene, APP in this case, might actually protect you. Thirdly, these findings may help to shift therapy approaches towards targeting low plasma amyloid β levels as measures to prevent the future development of Alzheimer’s Disease in those individuals that are unlucky enough to not carry the protective APP A673T allelic variant. In fact, there are large-scale Alzheimer’s prevention trials ongoing that involve amyloid-targeting drug candidates. You may think of this approach as being similar to taking cholesterol-lowering medication to prevent heart attacks and strokes.