Summary: People with a genetic predisposition to frontotemporal dementia (FTD) may preserve function and show resilience to the disease by maintaining regular physical exercise and engaging in mentally stimulating activities.
Source: UCSF
Active physical and cognitive lifestyles are linked to greater resilience against frontotemporal dementia, even for people who carry genetic mutations that greatly increase their risk of developing the disease, according to new research from the UC San Francisco Memory and Aging Center.
This study builds on long-established evidence that physical exercise and cognitive engagement slow or reduce the risk of Alzheimer’s disease, and it is among the first to demonstrate similar benefits for frontotemporal dementia—a distinct neurodegenerative condition with different underlying brain pathology.
Frontotemporal dementia (FTD) is a progressive brain disorder that commonly impairs personality, decision-making, language, or movement. It most often begins between ages 45 and 65 and is the leading cause of dementia in people under 65, accounting for roughly 5–15 percent of all dementia cases. FTD typically progresses rapidly, often leading to severe decline and death within a decade. At present there are no approved medications that stop or reverse FTD, though several clinical trials are underway at UCSF and other research centers.
“FTD is a devastating condition with limited treatment options, but our findings indicate that lifestyle choices—staying physically and mentally active—may help people with genetic risk live longer, more productive lives,” said Kaitlin Casaletto, PhD, assistant professor of neurology at the UCSF Memory and Aging Center and corresponding author of the study, published January 8, 2020 in Alzheimer’s & Dementia.
‘If This Were a Drug, We Would Be Giving it to All Our Patients’
Roughly 40 percent of people with FTD have a family history of the disease. Scientists have identified several dominant gene mutations (such as in MAPT, GRN, and C9orf72) that cause FTD in many familial cases. Even among individuals who carry these mutations, however, symptom onset and disease severity vary widely.
“There is striking variability in how FTD affects people, even among relatives with the same mutation. Some show marked resilience while others decline quickly. We wanted to know whether everyday activities—how physically and mentally active people are—help explain those differences,” said Casaletto, who is also a member of the UCSF Weill Institute for Neurosciences.
To examine this question, the team followed 105 people who carry dominant, disease-causing FTD mutations. Most participants were asymptomatic or had only mild symptoms at enrollment. These individuals were participants in large, multisite longitudinal studies—ARTFL and LEFFTDS—which have since been merged into ALLFTD, coordinated by co-authors Adam Boxer, MD, PhD, and Howie Rosen, MD at UCSF.
At baseline, each participant received MRI scans to assess brain degeneration, completed cognitive testing, and reported how often they engaged in cognitive and physical activities (for example, reading, socializing, walking or jogging). Family members provided structured assessments of participants’ everyday functioning—managing finances, medications, personal care, and other activities of daily living. The study repeated these measures at annual follow-ups to track changes over time.
Within just one to two years of follow-up (two to three study visits), researchers observed clear differences in decline between the most and least active participants. Individuals with the highest levels of combined mental and physical activity showed substantially slower functional decline than those with the lowest activity levels, and the protective pattern was similar whether activity was primarily cognitive or physical.
Specifically, caregivers reported that functional decline in the most active 25 percent of participants was 55 percent slower than in the least active five percent. “That magnitude of effect so early in the study is remarkable,” Casaletto said. “If this were a drug, we would be giving it to all of our patients.”
The investigators found that lifestyle activity did not significantly change the rate of measurable brain atrophy on MRI during the first year of follow-up. Nonetheless, among participants whose scans already showed atrophy, those with the most active lifestyles continued to perform about twice as well on cognitive tests compared with the least active participants. These findings suggest that activity may enhance cognitive resilience—helping people maintain function despite underlying brain degeneration.
Findings Could Illuminate Biology of Brain Resilience Across Dementias
The research team expects to see larger and more definitive differences as the ALLFTD study follows participants over more years. “We are already observing significant effects in people with very mild disease. If these patterns persist, an active lifestyle could set individuals on a substantially different clinical trajectory,” Casaletto said.
Next steps include collecting more objective activity measures, such as wearable fitness trackers, to quantify the amount and intensity of activity that best supports cognitive resilience. Precise measurement will help researchers estimate how much exercise and mental engagement may be required to produce meaningful benefits.
Casaletto emphasized caution: the study describes an association and cannot yet prove causation. It remains possible that participants who were already on a more aggressive disease course tended to be less active because symptoms had begun to limit their behavior. Randomized clinical trials that deliberately increase cognitive and physical activity in carriers of FTD mutations will be necessary to determine whether lifestyle interventions can change disease outcomes.
Even so, Casaletto hopes these results will encourage clinicians, families, and people with a family history of FTD to adopt healthier daily routines that include regular exercise and cognitive engagement. The findings also open new avenues for research into the biological mechanisms that underlie resilience in the face of neurodegeneration.
“We can now begin to ask how lifestyle behaviors influence brain biology to confer resilience. Understanding those mechanisms could point to pharmaceutical or other interventions that mimic the protective effects of an active life,” Casaletto said.
Authors: The study’s co-senior authors were Howie Rosen, MD, professor of neurology at the UCSF Memory and Aging Center, and Kristine Yaffe, MD, professor of psychiatry, neurology and epidemiology and Vice Chair of Research in Psychiatry at UCSF. Other UCSF contributors included Adam Staffaroni, Amy Wolf, Fanny Elahi, Jamie Fong, Hilary Heuer, John Kornak, Joel Kramer, Bruce Miller, and Adam Boxer, among others.
Funding: The LEFFTDS and ARTFL studies were supported by grants from the National Institute on Aging (U01AG045390, U54NS092089). Dr. Casaletto’s work was additionally supported by NIA awards (K23AG058752, L30AG057123) and the Larry L. Hillblom Fellowship (2017-A-004-FEL).
Disclosures: Dr. Casaletto reports no conflicts of interest. Full disclosures for all authors are available in the published study.
Source:
UCSF
Media Contacts:
Nicholas Weiler – UCSF
Image Source:
The image is in the public domain.
Original Research: Open access. Title: “Assessment of executive function declines in presymptomatic and mildly symptomatic familial frontotemporal dementia: NIH‐EXAMINER as a potential clinical trial endpoint” (Kaitlin Casaletto et al.). Published in Alzheimer’s & Dementia, DOI: 10.1016/j.jalz.2019.01.012.
Abstract
Introduction:
Identifying clinical measures that track early-stage frontotemporal lobar degeneration (FTLD) is critical for designing and evaluating trials. Familial FTLD offers a unique model for studying early disease. Executive dysfunction is a core clinical feature and may serve as an early marker of progression.
Methods:
Ninety-three mutation carriers with no or minimal symptoms (MAPT, n = 31; GRN, n = 28; C9orf72, n = 34) and 78 noncarriers enrolled in ARTFL/LEFFTDS completed the NIH‑EXAMINER executive function assessment and a standard neuropsychological battery. Linear mixed-effects models examined baseline and longitudinal cognitive differences and associations with clinical functioning and MRI volumes.
Results:
NIH‑EXAMINER scores detected baseline differences and divergent slopes between carriers and noncarriers, including carriers who appeared asymptomatic at baseline. Declines on NIH‑EXAMINER related to worse clinical function and brain volume loss.
Discussion:
The NIH‑EXAMINER is sensitive to cognitive change in presymptomatic familial FTLD and shows promise as a clinical trial endpoint.