Lifestyle benefits tended to be greater in younger participants
“APOE genotype significantly modified the association between protective factors and dementia,” the authors said. Compared with participants with protective modifiable risk profiles, participants with unfavorable modifiable risk profiles had greater risk for dementia in the low–APOE risk group (hazard ratio, 2.51) and intermediate–APOE risk group (HR, 1.39), but not in the high–APOE risk group.
“Protective associations of favorable risk profiles against dementia tended to be stronger in younger individuals than in older individuals and were most pronounced for younger individuals at low APOE risk,” Dr. Licher and colleagues said. In a sensitivity analysis that used a polygenic risk score for Alzheimer’s disease based on 27 variants other than APOE to determine participants’ genetic risk, the patterns were “attenuated yet largely comparable,” they wrote. Patterns also remained consistent when the researchers used an ideal cardiovascular health score to indicate modifiable health profiles.
“Our results confirm that individuals with a favorable profile have a lower risk of dementia than those with intermediate or unfavorable profiles based on modifiable risk factors,” they said. Unlike in a subgroup analysis of data from the FINGER study, however, “this study found that a favorable profile could not offset high APOE risk.”
The findings may have implications for clinical trial design and suggest that APOE4 carriers may need to be targeted earlier in the disease process to influence their risk for dementia.
“On the positive side, results from this study show that avoiding an unhealthy lifestyle could potentially prevent or postpone the onset of dementia in most individuals in the population (73%), namely those at low and intermediate genetic risk,” the investigators wrote. “Among these, the majority were categorized has having a favorable profile (66%), yet room for improvement is still substantial.”
The study lacked data on hearing impairment and did not capture shifts to more adverse or optimal lifestyles during follow-up. In addition, the results are based on relatively small samples in each risk category, and the estimates had wide confidence intervals. The population was older and mostly of European descent, which limits the generalizability of the findings, the authors noted.
Lifestyle factors may benefit only people with low genetic risk
“The authors’ key finding was that modifiable lifestyle risk factors were able to reduce dementia risk only in people who did not have an APOE4 allele and hence were at lower genetic risk,” said Kenneth Rockwood, MD, professor of geriatric medicine and neurology at Dalhousie University in Halifax, N.S., and his coauthors, in an accompanying editorial.
Dr. Kenneth Rockwood
The findings contrast with those of another recent population-based study using data from the UK Biobank (JAMA. 2019;322[5]:430-7. doi: 10.1001/jama.2019.9879), which suggested that modifiable factors affect dementia risk regardless of genetic risk.
Together, these studies “tell us that ... we must better understand outcomes in those most at risk,” they said. “We might begin by recognizing that aging is essential, rather than incidental, to dementia disease expression.” Future research should focus on people living with frailty, who often are excluded from trials and are at high risk for dementia. Older adults who develop delirium also may be an ideal target group of patients at increased risk for dementia.
“Reducing the extent of disease expression in people prone to developing dementia late in life is difficult. Studies investigating whether dementia can be prevented at all, such as the Rotterdam study, and then whether it can be prevented in the people at greatest risk, can be commended for their clear-eyed approach,” Dr. Rockwood and colleagues said.
The Rotterdam Study is funded by Erasmus Medical Center and University, as well as a variety of Dutch organizations, institutes, and government ministries, and the European Commission. The authors had no competing interests.
Dr. Rockwood is president and chief science officer of DGI Clinical, which has contracts with pharmaceutical and device manufacturers related to individualized outcome measurement.
SOURCES: Licher S et al. Nat Med. 2019 Aug 26. doi: 10.1038/s41591-019-0547-7; and Rockwood K et al. Nat Med. 2019 Aug 26. doi: 10.1038/s41591-019-0575-3.