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PHILADELPHIA -- The Lancet Commission on dementia prevention, intervention, and care has raised the number of modifiable risk factors definitively linked to cognitive loss to 14, based on research conducted since its last update in 2020.

Vision loss and high levels of low-density lipoprotein (LDL) cholesterol are now added to the commission's list, which stood at 12 in the previous version. The new 57-page update, from Gill Livingston, MD, of University College London in England, and colleagues, was published Wednesday in and presented simultaneously at the Alzheimer Association International Conference here.

The 14 factors include:

• Education
• Hearing loss
• Depression
• Head trauma from sports and bike riding
• Physical activity
• Smoking
• Hypertension
• Obesity
• Type 2 diabetes
• Alcohol drinking
• Social isolation
• Air pollution
• Vision loss
• High LDL

If all of these were fully addressed -- providing higher education to everyone, ending obesity, making helmet use mandatory for youth, eliminating air pollution, etc. -- worldwide risk for dementia would fall by 45%, the commission found in its review of nearly 600 scientific publications.

About 7% of dementia risk can be attributed to high LDL, according to the report, making it one of the most powerful risk factors. Also accounting for 7% is unaddressed hearing loss; social isolation and low education are tied for third on the list, at 5% of the population-attributable risk each. Other factors account for 3% or less (the authors put the effect of untreated vision loss at 2%).

The commission also examined a number of other factors with research linking them to dementia risk, including diet, reduced sleep, and neuropsychiatric conditions such as bipolar and psychotic disorders. Ultimately the authors found that the research was insufficient to establish population-attributable risks for them. Nor is there solid evidence that interventions targeting these factors do indeed reduce dementia risk.

As well, the review took on the difficult question of direct interventions -- including diagnostic screens and scans, symptomatic treatments such as anticholinesterase inhibitors, and anti-amyloid biologic drugs -- though mainly in narrative rather than quantitative terms. The commission looked favorably on current symptomatic treatments, citing "short-term, modest positive effects and that stopping this treatment is associated with worse outcomes in the long term."

But the authors were not especially enthusiastic for anti-amyloid drugs such as donanemab (Kisunla) and lecanemab (Leqembi). "Currently, the effects of all [anti-amyloid] drugs are small. The resources required to support early biomarker-based diagnosis, supervision of administration and safety, and buying the drugs will mean that roll-outs into many health systems will be slow or non-existent in some," they wrote. (Motivated at least partly by these considerations, as well as the potential for adverse effects, the European Medicines Agency recently .)

Several of the same authors, including Livingston, helped author a separate report, published at the same time in , on a cost-benefit analysis of policies addressing six risk factors as applied to England. These included drinking, dietary salt and sugar, pollution from automobiles, smoking, and youth head trauma. The analysis then examined interventions already tested in various settings: i.e., raising alcohol and cigarette prices, reducing salt and sugar in commercial foods, banning cars from certain areas, and mandating use of bike helmets. The authors then estimated the monetary costs and associated quality-adjusted life years (QALYs) gained if implemented in the English population.

So, for example, raising the price of alcohol by an amount that, in Scotland, cut weekly consumption by 1-2 units on average would lead to some 15,000 fewer Britons age 45 subsequently developing dementia linked to drinking. Overall costs over time would decline by £280 million ($360 million), and 4,767 QALYs would be gained.

The most dramatic effect was seen with reduction in salt intake. The authors modeled a policy that would cut mean daily intake by 1.68 g per person, with an accompanying decrease of 1.59 mm Hg in systolic blood pressure. Given the relationship previously found between hypertension and dementia risk, Livingston's group estimated that more than 43,000 people age 45 would not suffer dementia later on, and the associated cost saving would reach £2.37 billion ($3.04 billion); QALYs gained would top 39,000.

Acknowledging the real-world political landscape, "[i]t is possible that policy makers are hesitant to put these interventions into place given the long lead time before the benefits of cognitive decline could be expected," the investigators wrote.

"However, given the effect of these interventions on vascular or brain health in general, benefits in terms of other non-communicable diseases would be expected sooner. Our analysis further strengthens the argument for implementation of effective population-level policies as soon as practicably possible."

Similarly, Livingston and colleagues on the commission argued that "policy makers should prioritize resources to enable risk reduction to prevent or delay dementia and interventions to improve symptoms and life for people with dementia and their families."