HAI Book 2025 - Flipbook - Page 428
Palmgren, Kailee
108
Physical frailty as a risk factor for increased tau accumulation and
cognitive decline in cognitively unimpaired older adults
Kailee Palmgren1, Paola Matos1, Dylan Kirn1,2, Talia Robinson1,2, Eva Pintucci1, Michael
Properzi1,4, Aaron Schultz1,3,4, Rebecca Amariglio1,2,3, Dorene Rentz1,2,3, Keith Johnson1,2,3, Reisa
Sperling1,2,3, Jasmeer Chhatwal1,2,3, Wai-Ying Wendy Yau1,2,3
1
Department of Neurology, Massachusetts General Hospital, Boston, MA, US
Department of Neurology, Brigham and Women’s Hospital, Boston, MA, US
3
Harvard Medical School, Boston, MA, US
4
Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital,
Charlestown, MA, US
2
Background: Frailty is an age-related syndrome of reduced physiological reserve and increased vulnerability to
adverse health outcomes. Physical frailty is a risk factor for dementia, including Alzheimer's disease (AD).
However, its impact on the accumulation of amyloid and tau pathology, especially during the preclinical period, is
unclear, limiting development of prevention/intervention strategies.
Method: We examined older adults from the Harvard Aging Brain Study who were cognitively unimpaired at
baseline with longitudinal cognition (N=327), amyloid (Pittsburgh Compound-B; N=269), and tau (Flortaucipir;
N=193) PET (Table 1). Physical frailty was measured using the cumulative deficit model with a 30-item frailty index
(FI; higher indicate greater frailty) (Table 2). Sensitivity analyses were performed using a modified 4-criteria Fried
frailty phenotype (shrinking, slowness, exhaustion, inactivity). Using linear mixed effects models, we examined
the impact of baseline frailty on longitudinal amyloid burden and the interactive associations between frailty and
baseline amyloid on longitudinal inferior temporal cortex (ITC) tau and cognitive decline (Preclinical Alzheimer
Cognitive Composite-5).
Result: Adjusting for age and sex, there were no significant associations between FI and baseline amyloid, tau, or
cognition (p>0.15). FI was not associated with longitudinal amyloid burden (p=0.42; Figure 1A). By contrast, higher
FI and elevated baseline amyloid were synergistically associated with faster ITC tau accumulation (t=2.64, p=0.01),
with no additional main effect of FI on longitudinal tau (p=0.50). There was a concordant interaction of higher FI
and amyloid on faster cognitive decline (t=-2.11, p=0.04), along with a modest main effect of higher FI on faster
decline independent of amyloid (t =-2.49, p = 0.01). Sensitivity analyses using modified Fried frailty phenotype
yielded similar results (Figure 1B).
Conclusion: Our findings suggest that targeting physical frailty in cognitively unimpaired older adults may help
slow amyloid-related tau accumulation and cognitive decline, as well as have a modest benefit on non-amyloidrelated cognitive aging.
HAI2025 - 428
