Exercise Tied to Delayed Damage in Gene-Driven Young-Onset Dementia

Physical activity was linked to slower progression of plasma neurofilament light chain (NfL), a marker of axonal damage, in people with autosomal dominant frontotemporal lobar degeneration (FTLD), an observational study showed.

Among 160 FTLD variant carriers with a mean age of about 51, those with higher physical activity levels had 14.0% (95% CI -22.7 to -4.3) slower NfL increases over 4 years compared with those whose activity level was average, and 30.3% (95% CI -52.2 to -8.8) slower NfL increases versus those who had low physical activity, reported Kaitlin Casaletto, PhD, of the University of California San Francisco, and co-authors.

On average, NfL increased 45.8% (95% CI 22.5-73.7) over 4 years. Activities associated with higher cardiorespiratory and cognitive demands — like sports, housework, and yard work — were more strongly correlated with slower NfL trajectories than walking and strength training, the researchers reported in JAMA Neurology.

“In this study, we were trying to untangle the importance of lifestyle on brain health by testing its relevance in individuals who have the highest genetic risk for dementia,” Casaletto told MedPage Today.

“We showed for the first time that a modifiable behavior — physical activity — relates to slowing of one of our most sensitive biomarkers of neurodegeneration — neurofilament light chain — in individuals who carry a genetically dominant form of frontotemporal dementia,” she noted.

“Findings support the potential biologic relevance of physical activity as a primary prevention tool against neurodegeneration, even in adults with highest genetic risk for dementia,” she added.

Frontotemporal degeneration is a common cause of young-onset dementia. Prior research in autosomal dominant forms of both Alzheimer’s disease and FTLD have shown positive associations between active lifestyles and cognitive and functional outcomes.

Plasma NfL has high diagnostic and prognostic utility in frontotemporal degeneration, observed Lauren Massimo, PhD, and Katheryn Cousins, PhD, both of the University of Pennsylvania in Philadelphia, in an accompanying editorial.

“Given the lack of treatment for frontotemporal degeneration, research on nonpharmacological strategies that can potentially slow disease is of great importance,” Massimo and Cousins pointed out.

“From a practical standpoint, exercise is often recommended by healthcare professionals to improve cardiovascular health,” they wrote. “Given the current evidence that suggests physical activity appears to be an effective modifier of neurodegeneration, recommending exercise to improve or maintain brain health should also be part of the dialogue between clinicians and patients, including those who are at risk and currently diagnosed with frontotemporal degeneration.”

The study evaluated symptomatic and asymptomatic patients in the ALLFTD Consortium who had pathogenic variants in one of three common genes associated with FTLD — GRN, C9orf72, or MAPT.

Patients came from the U.S. and Canada; they reported baseline physical activity levels, completed yearly blood draws, and were assessed annually for up to 4 years from December 2014 to June 2019.

The researchers used the Physical Activity Scale for the Elderly to assess baseline physical activity levels. One standard deviation (SD) above the mean represented high physical activity, 0 SD was average physical activity, and 1 SD below the mean was low physical activity.

Of the 160 participants, 52.5% were women and 31.8% were symptomatic. Overall, 39 people carried the GRN variant, 77 people carried C9orf72, and 44 carried MAPT.

High physical activity was significantly associated with a 21.0% (95% CI -43.4 to -8.3) slowing of NfL concentration increases in C9orf72 variant carriers and an 18.4% (95% CI -28.1 to -7.2) slowing in MAPT carriers over 4 years compared with average NfL trajectories. Links between physical activity and NfL trajectory were not statistically significant in GRN carriers.

“As an indicator of neuroaxonal degeneration, plasma NfL concentration is among the most robust molecular markers of frontotemporal degeneration disease progression and is predictive of clinical phenoconversion, underscoring the clinical relevance of our findings,” Casaletto and co-authors wrote.

Reverse causality could not be ruled out due to the study’s observational design, the researchers acknowledged. However, associations remained significant after adjusting for functional severity and motor features that might limit activity, they noted. Likewise, effect sizes were similar when assessing only asymptomatic or mildly symptomatic patients.

Another limitation was that physical activity was self-reported and evaluated only at baseline. Sample sizes were relatively small and the follow-up period spanned 4 only years.