Better cardiovascular health is associated with slowed clinical progression in autosomal dominant frontotemporal lobar degeneration variant carriers

Anna M VandeBunte^{1

2}, Hyunwoo Lee³, Emily W Paolillo¹, Ging-Yuek Robin Hsiung³, Adam M Staffaroni¹, Rowan Saloner¹, Carmela Tartaglia⁴, Kristine Yaffe¹, David S Knopman⁵, Eliana Marisa Ramos⁶, Katya Rascovsky⁷, Andrea C Bozoki⁸, Bonnie Wong⁹, Kimiko Domoto-Reilly¹⁰, Allison Snyder¹¹, Peter Pressman¹², Mario F Mendez¹³, Irene Litvan¹⁴, Julie A Fields⁵, Douglas R Galasko¹⁴, Ryan Darby¹⁵, Joseph C Masdeu¹⁶, Maria Belen Pasqual¹⁶, Lawrence S Honig¹⁷, Nupur Ghoshal¹⁸, Brian S Appleby¹⁹, Ian R Mackenzie²⁰, Hilary W Heuer¹, Joel H Kramer¹, Adam L Boxer¹, Leah K Forsberg⁵, Brad Boeve⁵, Howard J Rosen¹, Kaitlin B Casaletto¹; ALLFTD Consortium

Affiliations

¹ Department of Neurology, University of California, San Francisco, Memory and Aging Center, San Francisco, California, USA.
² Department of Psychology, Palo Alto University, Palo Alto, California, United States.
³ Division of Neurology, UBC Hospital, University of British Columbia, Vancouver, British Columbia, Canada.
⁴ Tanz Centre for Research in Neurodegenerative Diseases, Division of Neurology, Department of Medicine, University of Toronto, Toronto, Ontario, Canada.
⁵ Department of Neurology, Mayo Clinic, Rochester, Minnesota, USA.
⁶ David Geffen School of Medicine at UCLA, UCLA Semel Institute for Neuroscience and Human Behavior, Los Angeles, California, USA.
⁷ Department of Neurology, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
⁸ Department of Neurology, University of North Carolina, Chapel Hill, North Carolina, USA.
⁹ Harvard Massachusetts General Hospital Frontotemporal Disorders Unit, Charlestown, Massachusetts, USA.
¹⁰ Department of Neurology, University of Washington, Seattle, Washington, USA.
¹¹ National Institute of Neurological Disorders and Stroke, Bethesda, Maryland, USA.
¹² Department of Neurology, University of Colorado School of Medicine, Aurora, Colorado, USA.
¹³ David Geffen School of Medicine at UCLA, Reed Neurological Research Center, Los Angeles, California, USA.
¹⁴ San Diego Department of Neurosciences, University of California, San Diego, La Jolla, California, USA.
¹⁵ Department of Neurology, Vanderbilt University, Nashville, Tennessee, USA.
¹⁶ Houston Methodist Neurological Institute, Houston, Texas, USA.
¹⁷ Department of Neurology, Irving Medical Center, Columbia University, New York, New York, USA.
¹⁸ Department of Neurology, St. Louis School of Medicine, Washington University, St. Louis, Missouri, USA.
¹⁹ Department of Neurology, Case Western Reserve University, Cleveland, Ohio, USA.
²⁰ Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, Canada.

PMID: 39240048
PMCID: PMC11485313
DOI: 10.1002/alz.14172

Better cardiovascular health is associated with slowed clinical progression in autosomal dominant frontotemporal lobar degeneration variant carriers

Anna M VandeBunte et al. Alzheimers Dement. 2024 Oct.

. 2024 Oct;20(10):6820-6833.

doi: 10.1002/alz.14172. Epub 2024 Sep 6.

Authors

Affiliations

¹ Department of Neurology, University of California, San Francisco, Memory and Aging Center, San Francisco, California, USA.
² Department of Psychology, Palo Alto University, Palo Alto, California, United States.
³ Division of Neurology, UBC Hospital, University of British Columbia, Vancouver, British Columbia, Canada.
⁴ Tanz Centre for Research in Neurodegenerative Diseases, Division of Neurology, Department of Medicine, University of Toronto, Toronto, Ontario, Canada.
⁵ Department of Neurology, Mayo Clinic, Rochester, Minnesota, USA.
⁶ David Geffen School of Medicine at UCLA, UCLA Semel Institute for Neuroscience and Human Behavior, Los Angeles, California, USA.
⁷ Department of Neurology, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
⁸ Department of Neurology, University of North Carolina, Chapel Hill, North Carolina, USA.
⁹ Harvard Massachusetts General Hospital Frontotemporal Disorders Unit, Charlestown, Massachusetts, USA.
¹⁰ Department of Neurology, University of Washington, Seattle, Washington, USA.
¹¹ National Institute of Neurological Disorders and Stroke, Bethesda, Maryland, USA.
¹² Department of Neurology, University of Colorado School of Medicine, Aurora, Colorado, USA.
¹³ David Geffen School of Medicine at UCLA, Reed Neurological Research Center, Los Angeles, California, USA.
¹⁴ San Diego Department of Neurosciences, University of California, San Diego, La Jolla, California, USA.
¹⁵ Department of Neurology, Vanderbilt University, Nashville, Tennessee, USA.
¹⁶ Houston Methodist Neurological Institute, Houston, Texas, USA.
¹⁷ Department of Neurology, Irving Medical Center, Columbia University, New York, New York, USA.
¹⁸ Department of Neurology, St. Louis School of Medicine, Washington University, St. Louis, Missouri, USA.
¹⁹ Department of Neurology, Case Western Reserve University, Cleveland, Ohio, USA.
²⁰ Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, Canada.

PMID: 39240048
PMCID: PMC11485313
DOI: 10.1002/alz.14172

Abstract

Introduction: Cardiovascular health is important for brain aging, yet its role in the clinical manifestation of autosomal dominant or atypical forms of dementia has not been fully elucidated. We examined relationships between Life's Simple 7 (LS7) and clinical trajectories in individuals with autosomal dominant frontotemporal lobar degeneration (FTLD).

Methods: Two hundred forty-seven adults carrying FTLD pathogenic genetic variants (53% asymptomatic) and 189 non-carrier controls completed baseline LS7, and longitudinal neuroimaging and neuropsychological testing.

Results: Among variant carriers, higher baseline LS7 is associated with slower accumulation of frontal white matter hyperintensities (WMHs), as well as slower memory and language declines. Higher baseline LS7 associated with larger baseline frontotemporal volume, but not frontotemporal volume trajectories.

Discussion: Better baseline cardiovascular health related to slower cognitive decline and accumulation of frontal WMHs in autosomal dominant FTLD. Optimizing cardiovascular health may be an important modifiable approach to bolster cognitive health and brain integrity in FTLD.

Highlights: Better cardiovascular health associates with slower cognitive decline in frontotemporal lobar degeneration (FTLD). Lifestyle relates to the accumulation of frontal white matter hyperintensities in FTLD. More optimal cardiovascular health associates with greater baseline frontotemporal lobe volume. Optimized cardiovascular health relates to more favorable outcomes in genetic dementia.

Keywords: Life's Simple 7; aging; cardiovascular health; frontotemporal dementia; genetic dementia; lifestyle behaviors; modifiable risk; neuropsychology.

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Conflict of interest statement

Anna M. VandeBunte, Hyunwoo Lee, Emily W. Paolillo, Rowan Saloner, Katya Rascovsky, Allison Snyder, Mario F. Mendez, Ryan Darby, Hilary Heuer, and Kaitlin B. Casaletto have nothing to disclose. Ging‐Yuek Robin Hsiung received grant support from CIHR, NIH, and Alzheimer Society of BC; participated in clinical trials sponsored by Anavax, Biogen, Cassava, Eli Lilly, and Roche; and served as a consultant to Biogen, Novo Nordisk, and Roche. Adam Staffaroni is a co‐inventor of four ALLFTD mApp tasks and receives licensing fees. Datacubed Health was not involved with the analysis or reporting of study data. He has also received research support from the NIA/NIH, Bluefield Project to Cure FTD, the Alzheimer's Association, the Larry L. Hillblom Foundation, the Rainwater Charitable Foundation, and has provided consultation to Alector, Lilly/Prevail, Passage Bio, and Takeda. Carmela Tartaglia has served as an investigator for clinical trials sponsored by Biogen, Avanex, Green Valley, Roche/Genentech, Bristol Myers Squibb, Eli Lilly/Avid Radiopharmaceuticals, and Janssen. She receives research support from the Canadian Institutes of Health Research. Kristine Yaffe is on the board for Alector Inc. David S. Knopman serves on the data and safety monitoring board of the DIAN‐TU study; is a site principal investigator for clinical trials sponsored by Biogen, Lilly, and the University of Southern California; and is funded by the NIH. Eliana Marisa Ramos, Peter Pressman, and Julie A. Fields receive research support from NIH. Andrea C. Bozoki receives research funding from the NIH, Alector Inc., Cognition Therapeutics, EIP Pharma, and Transposon, Inc. She is a consultant for Eisai Pharmaceuticals and Creative Biopeptides and a member of the data safety monitoring board for AviadoBio. Bonnie Wong receives research support from the NIH. Kimiko Domoto‐Reilly receives research support from the NIH, and serves as an investigator for a clinical trial sponsored by Lawson Health Research Institute. Irene Litvan receives research support from NIH 1U19AG063911‐01 2R01AG038791‐06A, U01NS100610, U01NS80818, and 1R21NS114764‐01A1; the Michael J Fox Foundation, Parkinson Foundation, Lewy Body Association, CurePSP, Roche, Abbvie, Lundbeck, Novartis, Transposon, and UCB. She is a member of the scientific advisory board for the Rossy PSP Program at the University of Toronto, and of the scientific advisory board for Amydis but does not receive funds. She is the chief editor of Frontiers in Neurology. Douglas R. Galasko receives NIH research funding, clinical trial funding from Alector and Esai, and is a consultant to Esai, General Electric Health Care, Fujirebio, DSMB for Cyclo Therapeutics. Joseph C. Masdeu is a consultant and received research funding from Eli Lilly, parent co. of Avid Radiopharmaceuticals, manufacturer of 18F‐flortaucipir; receives personal fees from GE Healthcare; grants and personal fees from Eli Lilly; and grants from Acadia, Avanir, Biogen, Eisai, Janssen, NIH, Novartis, with no relation to the submitted work. Maria Belen Pasqual and Leah K. Forsberg receive research support from the NIH. Lawrence S. Honig receives research funding from Abbvie, Acumen, Alector, Biogen, BMS, Eisai, Genentech/Roche, Janssen/J&J, Transposon, UCB, Vaccinex. Consulting fees from Biogen, Cortexyme, Eisai, Medscape, and Prevail/Lilly. Nupur Ghoshal has participated or is currently participating in clinical trials of anti‐dementia drugs sponsored by the following companies: Bristol Myers Squibb, Eli Lilly/Avid Radiopharmaceuticals, Janssen Immunotherapy, Novartis, Pfizer, Wyeth, SNIFF (The Study of Nasal Insulin to Fight Forgetfulness) study, and A4 (The Anti‐Amyloid Treatment in Asymptomatic Alzheimer's Disease) trial. She receives research support from Tau Consortium and the Association for Frontotemporal Dementia and is funded by the NIH. Brian S. Appleby receives research support from CDC, NIH, Ionis, Alector, and the CJD Foundation. He has provided consultation to Acadia, Ionis, and Sangamo. Ian R. Mackenzie receives research funding from Canadian Institutes of Health Research, Alzheimer's Association US, NIH, and Weston Brain Institute. Joel H. Kramer receives research support from NIH and royalties from Pearson Inc. Adam Boxer is a co‐inventor of four of the ALLFTD mApp tasks and has previously received licensing fees. He also receives research support from the NIH (U19AG063911, R01AG038791, R01AG073482), the Tau Research Consortium, the Association for Frontotemporal Degeneration, Bluefield Project to Cure Frontotemporal Dementia, Corticobasal Degeneration Solutions, the Alzheimer's Drug Discovery Foundation, and the Alzheimer's Association. He has served as a consultant for Aeovian, AGTC, Alector, Arkuda, Arvinas, AviadoBio, Boehringer Ingelheim, Denali, GSK, Life Edit, Humana, Oligomerix, Oscotec, Roche, Transposon, TrueBinding and Wave, and received research support from Biogen, Eisai, and Regeneron. Brad Boeve has served as an investigator for clinical trials sponsored by Alector, Biogen, and Transposon. He receives royalties from the publication of a book entitled Behavioral Neurology of Dementia (Cambridge Medicine, 2009, 2017). He serves on the scientific advisory board of the Tau Consortium. He receives research support from the NIH, the Mayo Clinic Dorothy and Harry T. Mangurian Jr. Lewy Body Dementia Program, and the Little Family Foundation. Howard Rosen has received research support from Biogen Pharmaceuticals, has consulting agreements with Wave Neuroscience and Ionis Pharmaceuticals, and receives research support from NIH. Author disclosures are available in the supporting information.

Figures

**FIGURE 1**
Multivariate regression interaction models (baseline LS7 x carrier status) examining associations between baseline LS7 and cognitive and brain health outcomes in FTLD variant carriers compared to healthy non‐carrier controls. FTLD, frontotemporal lobar degeneration; LS7, Life's Simple 7; WMHs, white matter hyperintensities.

**FIGURE 2**
Linear mixed effects interaction models (baseline LS7 x time x carrier status) examining associations between baseline LS7 and cognitive trajectories in FTLD variant carriers compared to healthy non‐carrier controls. FTLD, frontotemporal lobar degeneration; LS7, Life's Simple 7; SD, standard deviation.

**FIGURE 3**
Linear mixed effects interaction models (baseline LS7 x time x carrier status) examining associations between baseline LS7 and neuroimaging trajectories in FTLD variant carriers compared to healthy non‐carrier controls. FTLD, frontotemporal lobar degeneration; LS7, Life's Simple 7; SD, standard deviation; WMH, white matter hyperintensity.

See this image and copyright information in PMC

References

1. Livingston G, Huntley J, Sommerlad A, et al. The Lancet Commissions Dementia prevention, intervention, and care: 2020 report of the Lancet Commission. Lancet. 2020;396:413‐459. - PMC - PubMed
1. Brain J, Greene L, Tang EYH, et al. Cardiovascular disease, associated risk factors, and risk of dementia: an umbrella review of meta‐analyses. Front Epidemiol. 2023;3:1095236. - PMC - PubMed
1. Song R, Pan KY, Xu H, et al. Association of cardiovascular risk burden with risk of dementia and brain pathologies: a population‐based cohort study. Alzheimers Dement. 2021;17:1914‐1922. https://onlinelibrary.wiley.com/doi/full/10.1002/alz.12343 - DOI - PMC - PubMed
1. Sheibani N, Wong KH, Turan TN, et al. White matter hyperintensity and cardiovascular disease outcomes in the SPRINT MIND trial. J Stroke Cerebrovasc Dis. 2021;30:105764. https://pmc/articles/PMC8107132/ - PMC - PubMed
1. Williamson JD, Pajewski NM, Auchus AP, et al. Effect of intensive vs standard blood pressure control on probable dementia: a randomized clinical trial. JAMA. 2019;321:553‐561. https://jamanetwork.com/journals/jama/fullarticle/2723256 - PMC - PubMed

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Better cardiovascular health is associated with slowed clinical progression in autosomal dominant frontotemporal lobar degeneration variant carriers

Affiliations

Better cardiovascular health is associated with slowed clinical progression in autosomal dominant frontotemporal lobar degeneration variant carriers

Authors

Affiliations

Abstract

Conflict of interest statement

Figures

References

MeSH terms

Grants and funding

LinkOut - more resources

Full Text Sources

Molecular Biology Databases