A molecular mechanism has now been proposed that explains why Alzheimer's disease (AD), which typically strikes in 50–80-year olds, is linked with ageing. Reporting in Science, researchers showed that the transcription factors HSF-1 and DAF-16, which are regulated by a central ageing pathway, have opposing disaggregation and aggregation activities that function together to prevent AD.

AD, like other late-onset neurodegenerative diseases, is correlated with toxic aberrant protein aggregation — specifically, amyloid precursor protein breaks down into Aβ1–42 peptides, which aggregate. But why aggregate-mediated toxicity is linked with age has remained unclear.

Cohen, Bieschke and colleagues investigated whether increasing the lifespan (or slowing the ageing) of Caenorhabditis elegans would delay the onset of aggregation. If so, then the late onset of AD could be due to a detoxifying activity that becomes compromised with ageing. If not, a stochastic time-related build-up of toxic aggregates to a threshold could explain the late onset of AD.

To distinguish between these possibilities, researchers disrupted the insulin-signalling pathway, which is central in the regulation of ageing in worms, flies and mammals. In C. elegans, a sole insulin receptor, DAF-2, transduces a signal that reduces the expression of genes that are regulated by the transcription factors DAF-16 and HSF-1, resulting in a shortened lifespan. By knocking down daf-2 in C. elegans that expressed human Aβ1–42, researchers showed that worms with longer lifespans had reduced toxic aggregation — late onset is therefore due to a compromised detoxifying activity rather than a stochastic accumulation. Double knockdown of daf-2 with either daf-16 or hsf-1, however, reversed this effect.

So, how do DAF-16 and HSF-1 inhibit the toxicity of protein aggregation? Examining the amounts of high-molecular-weight Aβ1–42 aggregates and small Aβ1–42 aggregates, Cohen and colleagues made several interesting findings. First, HSF1 regulates the disaggregation of Aβ1–42 aggregates, but DAF-16 does not. By contrast, DAF-16 mediates the formation of high-molecular-weight Aβ1–42 aggregates, but these aggregates do not correlate with toxicity. Last, small Aβ1–42 aggregates correlate with toxicity.

A molecular mechanism has now been proposed that explains why Alzheimer's disease ... is linked with ageing.

Together, these results are indicative of a mechanism that links ageing with late-onset AD. As aggregates develop, HSF-1 activity mediates their disaggregation. DAF-16 activity supports an alternative pathway (which perhaps functions as a back-up pathway) that mediates the formation of low-toxicity, high-molecular-weight aggregates from high-toxicity small aggregates. Because both detoxification pathways are mediated by the ageing-related insulin-signalling pathway, both can become compromised with ageing, leading to aggregate build-up.

Interestingly, as the insulin-signalling pathway is also associated with the formation of other toxic aggregates, such as those responsible for Huntington's disease, further research into this pathway could yield therapeutic targets for the general prevention of late-onset aggregation-linked neurodegenerative diseases.