Yu, Fang

Abstract Falls are a public health concern for older adults, particularly those with cognitive impairments, like mild cognitive impairment (MCI) and Alzheimer’s disease (AD) dementia. Executive function (EF) is linked to falls in older adults, but little is known about the relationship between individual EF assessments and falls in individuals with varying cognitive statuses. Using cross-sectional secondary data analyses with binary logistic regression, we examined the associations between EF assessments (Trail Making Test (ΔTMT), Digit Span (DS), Stroop test, Clock Drawing Test, and phonemic/semantic fluency tests) and falls (fall history and subsequent falls) in 466 participants (aged 66-103) with either intact cognition, MCI, or AD dementia. Surprisingly, a significant interaction effect emerged with AD dementia and EF assessments (ΔTMT, DS, and semantic fluency), revealing that individuals with AD dementia with worse EF had a lower probability of prior fall history. These findings were influenced by a low percentage of reported falls in people with severe AD dementia. Further stratified analysis of the interaction effects showed that DS and semantic fluency were significantly associated with fall history in people without AD dementia. While some EF assessments were individually associated with falls, interpretations should be made cautiously, especially considering the appropriateness of the assessments for specific populations. The counterintuitive result may stem from factors specific to severe AD dementia. In conclusion, this study uncovers complex interactions between cognitive status, EF assessments, and fall history, and the potential for further investigation to enhance our understanding of falls in individuals with severe AD dementia.

AbstractBackgroundPhysical activity is associated with reduced risk for Alzheimer’s disease (AD). Aerobic exercise produced modest‐to‐moderate cognitive gains in older adults with mild cognitive impairment or AD dementia. In animal models, aerobic exercise modifies AD’s AT(N) biomarkers of Amyloid‐beta (Aβ), hyperphosphorylated Tau, and Neurodegeneration. However, most observational studies didn’t find significant associations between physical activity and AT(N) biomarkers. Few exercise trials included biomarkers, partially attributable to the prohibitive cost and invasiveness of cerebrospinal fluid or PET biomarkers and reported mixed effects on central AT(N) biomarkers. Plasma Aβ42/40 ratio, phosphorylated tau 181 (p‐tau181), and total tau (t‐tau) demonstrate robust correlations with central amyloid and tau levels and offer an opportunity for inclusion in exercise trials.MethodThis pilot study examined the preliminary effects of 6‐month aerobic exercise on plasma Aβ42/40 ratio, p‐tau181, and t‐tau in older adults with mild‐to‐moderate AD dementia. Twenty‐six participants were eligible, and all consented to enroll (8 in stretching, 18 in cycling). Plasma Aβ42/40 ratio, p‐tau181, and t‐tau were measured using Simoa™ assays at baseline, 3, and 6 months. Data were analyzed using Cohen’s d, multilevel model, and intention‐to‐treat.ResultThe sample averaged 77.58±6.99 years old, 15.44±3.00 years of education, 65% male, and 96.2% carrying an APOE e4 allele. The 6‐month within‐group trajectories of changes in outcomes trended differently but were not statistically significant. Aβ42/40 ratio (mean ± standard deviation) increased by 0.001±0.012, p‐tau181 increased by 0.609±1.417 pg/ml, and t‐tau decreased by 0.020±0.279 ng/ml in the stretching group, while Aβ42/40 ratio decreased by 0.001±0.010, p‐tau181 increased by 0.101±1.579 pg/ml, and t‐tau decreased by 0.075±0.215 pg/ml in the cycling group. Between‐group differences were not significant. Effect sizes for 6‐month within‐group changes were small except for p‐tau181 in stretching (d = 0.43 [‐.65, 1.45]) and t‐tau in cycling (‐0.35 [‐0.87, 0.17]). Most 6‐month between‐group effect sizes were also small except for p‐tau181 (d = .40 [‐.70, 1.51]) and t‐tau (d = .53 [‐.40, 1.46]), a trend favoring cycling.ConclusionBlood biomarkers are highly feasible and tolerable. Exercise modalities may affect AD plasma biomarkers differently. Aerobic exercise may reduce p‐tau181 levels and stretching exercise may improve Aβ42/40 ratio, which need to be validated in future trials.

AbstractBackgroundIn animal models of Alzheimer’s disease (AD), aerobic exercise favorably modified the accumulation, degradation, and removal of Aβ and tau. However, human mechanistic randomized controlled trials (RCTs) are limited with mixed findings on hippocampal volume and biofluid Aβ and tau. Hence, an objective of the FIT‐AD Trial was to examine the effects of 6‐month aerobic exercise on magnetic resonance imaging (MRI) biomarkers in community‐dwelling older adults with AD dementia.MethodThe FIT‐AD Trial was a pilot RCT that first qualified participants for the main exercise study eligibility and then for MRI. Participants were randomized to moderate intensity cycling or low intensity stretching for 20‐50 minutes, 3 times a week for six months on a 2:1 ratio with three age strata (66‐75, 76‐85, and 85+ years of age) and followed up for another six months. MRI biomarkers included hippocampal volume, temporal meta‐regions of interest cortical thickness, white matter hyperintensity (WMH) volume, and network failure quotient (NFQ) measured at baseline, six months, and 12 months.ResultSixty participants met MRI eligibility, but one was excluded when this participant’s baseline MRI failed quality control. Among the 59 remaining participants, 38 were randomized to cycling and 21 to stretching. The sample characteristics (n=59) were 77.3±6.3 years old with 15.6±2.9 years of education and 53% men. Both groups experienced significant declines in hippocampal volume (2.64% in cycling vs. 2.89% in stretching) and cortical thickness (0.94% vs. 1.54%) over six months and over 12 months (hippocampal volume: 4.47% vs. 3.84%; cortical thickness: 2.27% vs. 1.79%). These declines didn’t differ between groups. WMH volume increased significantly, but the cycling group increased >50% less than stretching (10.9% vs. 24.5% over six months [f=4.47, p=.04]; 12.1% vs. 27.6% over 12 months [f=5.88, p=.02]). NFQ didn’t change significantly over time nor differed between group.ConclusionAerobic exercise may reduce hippocampal volume and cortical thickness declines during the intervention period; however, its effects are likely to be small and dose‐dependent and reverse after the intervention stops. Aerobic exercise is effective on reducing WMH progression but has no effect on NFQ.

Background: Utilities of blood-based biomarkers in Alzheimer’s disease (AD) clinical trials remain unknown. Objective: To evaluate the ability of plasma neurofilament light chain (NfL) to predict future declines in cognition and activities of daily living (ADL) outcomes in 26 older adults with mild-to-moderate AD dementia from the FIT-AD Trial. Methods: Plasma NfL was measured at baseline and 3 and 6 months. Cognition and ADL were assessed using the AD Assessment Scale-Cognition (ADAS-Cog) and AD Uniform Dataset Instruments and Disability Assessment for Dementia (DAD), respectively, at baseline, 3, 6, 9, and 12 months. Linear mixed effects models were used to examine the associations between baseline or change in plasma NfL and changes in outcomes. Results: Higher baseline plasma NfL was associated with greater rate of decline in ADAS-Cog from baseline to 6 months (standardized estimate of 0.00462, p = 0.02853) and in ADL from baseline to 12 months (standardized estimate of –0.00284, p = 0.03338). Greater increase in plasma NfL in short term from baseline to 3 months was associated with greater rate of decline in memory and ADL from 3 to 6 months (standardized estimate of –0.04638 [0.003], p = 0.01635; standardized estimate of –0.03818, p = 0.0435) and greater rate of decline in ADL from 3 to 12 month (standardized estimate of –0.01492, p = 0.01082). Conclusion: This study demonstrated that plasma NfL might have the potential to predict cognitive and function decline up to 12 months. However, future studies with bigger sample sizes need to confirm the findings.