27 Aug 2019

First, the good news: A healthy lifestyle in your so-called golden years shaves a third off your dementia risk. Now, the bad: If your genetic predisposition for dementia is high, you reap no such reward. In an observational study published August 26 in Nature Medicine, researchers led by Silvan Licher and M. Kamran Ikram at Erasmus MC-University Medical Center in Rotterdam, the Netherlands, stratified participants based on their genetic risk as well as modifiable behavioral, health, and dietary factors. They reported that among ApoE4 noncarriers, living a healthy life protected against dementia. However, among ApoE4 carriers, or people with a high polygenic risk score, those with unhealthy lifestyles had the same 15-year risk of dementia as their salubrious peers.

In people over 55, healthy lifestyle cut dementia risk by a third.

This did not apply to ApoE4 carriers or those with high polygenic risk for dementia.

People with high genetic risk might need to adopt healthy habits earlier in life.

The findings do not negate the numerous known benefits of being healthy, Licher said. Rather, they suggest that people at high genetic risk may need earlier or more intense lifestyle changes to counteract their predisposition for dementia.

Carlos Cruchaga of Washington University in St. Louis focused on the positive, noting the impressive level of protection against dementia a healthy lifestyle bestowed on a majority of participants. While in this study, ApoE4 carriers as a group drew no benefit from healthy living, Cruchaga said it is more complicated than that. Even people who carry two copies of the risk allele present a high amount of clinical variability. “Some E4/E4 carriers never develop AD at all, so there must be modifiable factors,” he said.

Licher told Alzforum that his study was too small to compare the effects of carrying one versus two copies of ApoE4. It is possible that heterozygous carriers might have some lifestyle-mediated protection from dementia that could not be measured, he said.

Promising results from multimodal lifestyle intervention studies have suggested that eating healthy foods, being active, and treating cardiovascular risk factors boost cognition (Nov 2015 conference news; Aug 2017 conference news). Whether the cognitive benefit will extend to reduced dementia risk remains to be seen. The Prevention of Dementia by Intensive Vascular Care (PreDIVA) had negative results for the participants as a group (Aug 2016 conference news). How genetic risk factors—including ApoE and other variants—modify the power of lifestyle interventions is unclear.

To address these unknowns, Licher and colleagues used data from the Rotterdam Study, a prospective observational cohort of people 55 and older who live in the city’s environs. The analysis covered 6,352 participants who were followed for an average of 14 years. At baseline, they were assessed for numerous cardiovascular and lifestyle factors, and then tracked for dementia diagnosis via electronic medical records and follow-up visits.

The researchers grouped the participants based on their genetic and lifestyle characteristics. They separated the cohort into three groups based on ApoE genotype, with E2/E2 and E2/E3 carriers designated as low ApoE risk; E3/E3 carriers as intermediate risk; and E2/E4, E3/E4, and E4/E4 as high risk. They also grouped the participants into tertiles based on their polygenic risk scores, which were calculated by pooling genotypes at 27 SNP positions tied to AD risk in genome-wide association studies. This PRS excluded ApoE. Finally, they stratified the participants based on six health and lifestyle factors thought to alter dementia risk: abstaining from smoking, absence of diabetes, absence of depression, regular physical activity, avoiding social isolation, and healthy diet. People were grouped into unfavorable, intermediate, or favorable modifiable risk categories based on having two or less; three to four; or five to six protective factors.

Over the follow-up period, 915 people were diagnosed with dementia, 739 of them with AD. ApoE4 carriers had triple the risk of dementia, and earlier onset, than people in the low-ApoE-risk group. Among all participants, people with unfavorable lifestyles had a 32 percent higher risk of developing dementia than those with favorable modifiable risk profiles. The strength of this association remained unchanged after adjusting for parental history of dementia, or even for cardiovascular risk factors.

Notably, ApoE genotype held strong sway over how much protection a healthy lifestyle conferred. Only people in the low- and intermediate-ApoE-risk groups—i.e., E4 noncarriers—were protected, having a 2.5- and 1.4-fold decreased risk of dementia, respectively, if they lived with healthy habits. Stratifying by polygenic risk score (PRS) instead of ApoE showed a similar trend. Among people in the lowest PRS tertile, those with unhealthy lifestyles were 1.46 times likelier to have dementia than those with favorable ones. Unhealthy living did not associate with higher dementia risk among people in the mid- or high-PRS groups.

The lifestyle effect generally lessened with age, where the older a participant was at baseline, the weaker his or her benefit for future dementia risk. Still, favorable lifestyle did not protect even the youngest ApoE4 carriers, who were 60 or older. The researchers speculated that people with a genetic predisposition for dementia might benefit from reducing their modifiable risk factors earlier in life. In support of this, other observational studies reported that a healthy lifestyle protected middle-aged ApoE4 carriers—i.e., those younger than 60—against later-life dementia (Rovio et al., 2005; Laitinen et al., 2006; Podewils et al., 2006). Participants in the Rotterdam study averaged 69 years of age at baseline.

The Rotterdam study does not assess whether intensive lifestyle regimens budge dementia risk in ApoE4 carriers. Sixty-four percent of participants were categorized as having favorable modifiable risk profiles, meaning they had at least five of the six protective attributes. However, the bar was low for some of these binary classifications. For example, 40 minutes of exercise per week counted as regular physical activity, and adherence to half of a set of dietary guidelines, including consumption of sufficient fruit, vegetables, whole grains, fish and dairy products, and avoidance of a list of processed and sugary foods, counted as a healthy diet.

Upcoming data from intervention studies, including the seven-year extension follow-up of FINGER in Europe and POINTER in the U.S., will give more insight into whether multimodal interventions can stave off dementia in people at different levels of genetic risk.

The findings could inform the design of future intervention trials that select participants predisposed to dementia. Licher suggested that intervention studies start earlier in people at greater genetic risk. Rather than awaiting a dementia diagnosis, clinicians might use surrogate markers to gauge treatment effects, Licher said. For example, recent data from SPRINT-MIND reported that people taking blood-pressure-lowering treatments had fewer white matter-lesions than the control group (Nasrallah et al., 2019; Aug 2019 news). Other recent studies have identified fluid markers of neurodegeneration, including neurofilament light and a neural pentraxin, NPTX2, that show promise for monitoring responses to intervention (Aug 2019 news).—Jessica Shugart