Protection against Alzheimer’s may not be as simple as doing a crossword puzzle every day. It turns out that there may be an array of factors — including genes, education level, and activity in middle age — involved in whether one can slow the progression of dementia symptoms, a new study suggests.

People with a specific gene, APOE4, who keep physically and mentally active in middle age, experience a protective effect against Alzheimer’s, the study shows. However, though staying intellectually challenged — reading, working, writing, or playing games — may slow down the symptoms and protein buildup in the brain, it doesn’t stop the disease itself.

Researchers from the Mayo Clinic, using data from the Mayo Clinic Study of Aging, examined 393 people over the age of 70 who didn’t have dementia, though 53 participants had mild cognitive impairment. All 393 people were divided into two groups: Less educated (less than 14 years of education); and higher educated (14 or more years of education). The researchers examined the participants with MRI and PET scans every week, and also had the participants report on their intellectual and physical activity.

The results depended on whether the participants were carriers of the APOE4 gene. It turned out that mentally active people with the gene who also had 14 years or more of education had lower levels of amyloid plaques in the brain, one of the major indicators of Alzheimer's. Mentally active, educated APOE4 carriers had lower levels of buildup than educated people who carried the gene but did not stay mentally active. In short, staying smart and intellectually challenged slowed the symptoms down by about five years in this subgroup of people; a 79-year-old who kept mentally active would be at the same level as a 74-year-old who didn’t.

People who don’t have the APOE4 gene, however, don't benefit from high education levels or high mental activity, the research showed.

“Recent studies have shown conflicting results about the value of physical and mental activity related to the risk of developing Alzheimer’s disease, and we noticed that levels of education differed in those stdies,” Prashanthi Vemuri of the Mayo Clinic, an author of the study, said in the press release. “When we looked specifically at the level of lifetime learning, we found that carriers of the APOE4 gene who had higher education and continued to learn through middle age had fewer amyloid deposition on imaging when compared to those who did not continue with intellectual activity in middle age.”

Past research has hinted that doing crossword puzzles, reading books, staying social, exercising, and eating healthy foods like fish all contribute to a delay in Alzheimer’s symptoms. Some research has even hinted that certain antidepressants may work against the disease. But the Mayo Clinic study is the first to identify a more detailed explanation behind slowed progression — that it may have to be the right mixture of several factors, like the gene, accrued education years, and lifestyle in middle age, in order to happen.

However, the researchers still remain cautious in their conclusion, remarking that they’re still not sure what causes “protection” against the disease and this slowing of symptoms. “It is possible those who did not continue intellectual activity in middle age did so because they had higher levels of amyloid plaques,” Vemuri said in the press release. “While there are many limitations with this study, our findings show further study is needed and suggest that differing education levels in other recent studies may explain the conflicting results seen in the research literature.”

Source: Vemuri P, et al. Neurology, 2016.