Kelsey Sewell

Background
Accumulating evidence indicates exercise may delay or prevent the onset of Alzheimer’s disease (AD). To our knowledge, no study has investigated the longitudinal impact of exercise on AD-related biomarkers in individuals with Autosomal dominant Alzheimer’s disease (ADAD) mutations who are destined to develop AD. This study examined longitudinal associations between self-reported exercise levels and AD-related biomarkers in a cohort of ADAD mutation carriers and investigated whether observed associations depended upon disease stage.

Method
This prospective cohort study included participants from the Dominantly Inherited Alzheimer’s Network (DIAN). Participants were n = 308 ADAD mutation carriers aged 39.7 ± 10.8 years (56.5% female) with data available for self-reported exercise participation and either brain imaging (hippocampal volume, total volume, gray matter volume, white matter hyperintensities, brain Aβ), or biomarkers quantified from cerebrospinal fluid (Aβ40, Aβ42, p-tau, t-tau, p-tau/Aβ42, and Aβ42/40). Associations between exercise and AD biomarkers (i.e., from brain imaging and CSF) were examined using linear mixed models.

Result
Greater weekly baseline exercise was associated with slower accumulation of brain Aβ at preclinical disease stages (β = -0.16, 95% CI -0.23 – -0.08), and slower decline of right and left hippocampal volume (β = 0.06, 95% CI 0.03–0.08; β = 0.06, 95% CI 0.02–0.09, respectively), total cortical volume (β = 0.03, 95% CI 0.01–0.05), total subcortical gray matter volume (β = 0.03, 95% CI 0.01–0.05), and total gray matter volume (β = 0.03, 95% CI 0.01–0.05), effects which became significant approximately 5 years before predicted cognitive symptom onset.

Conclusion
These findings demonstrate that exercise is associated with more favourable profiles of AD-related biomarkers in those with ADAD mutations. The causal direction of this research is difficult to ascertain, thus future study designs investigating the therapeutic potential of exercise in both ADAD and late-onset AD should be considered before clinical recommendation of exercise is implemented.

PURPOSE: Exercise may delay or prevent the onset of Alzheimer’s disease (AD). To our knowledge, no study has investigated the longitudinal impact of exercise on AD-related biomarkers in individuals with Autosomal dominant Alzheimer’s disease (ADAD) mutations who are destined to develop AD. This study examined longitudinal associations between self-reported exercise levels and AD-related biomarkers in a cohort of ADAD mutation carriers and investigated whether observed associations depended upon disease stage.

METHODS: This prospective cohort study included participants from the Dominantly Inherited Alzheimer’s Network (DIAN). Participants were n = 308 ADAD mutation carriers aged 39.7 ± 10.8 years (56.5% female) with data available for self-reported exercise participation and either brain imaging (hippocampal volume, total volume, gray matter volume, white matter hyperintensities, brain Aβ), or biomarkers quantified from cerebrospinal fluid (Aβ40, Aβ42, p-tau, t-tau, p-tau/Aβ42, and Aβ42/40). Participants reported their average time partaking in various leisure-time exercise activities (e.g., walking, running, cycling etc.) over the past 12-months to yield a measure of exercise minutes per week. Associations between exercise and AD biomarkers (i.e., from brain imaging and CSF) were examined using linear mixed models.

RESULTS: Greater weekly baseline exercise was associated with slower accumulation of brain Aβ at preclinical disease stages (β = -0.16, 95% CI -0.23 - -0.08), and slower decline of right and left hippocampal volume (β = 0.06, 95% CI 0.03-0.08; β = 0.06, 95% CI 0.02-0.09, respectively), total cortical volume (β = 0.03, 95% CI 0.01-0.05), total subcortical gray matter volume (β = 0.03, 95% CI 0.01-0.05), and total gray matter volume (β = 0.03, 95% CI 0.01-0.05), effects which became significant approximately 5 years before predicted cognitive symptom onset.

CONCLUSIONS: These findings demonstrate that exercise is associated with more favourable profiles of AD-related biomarkers in those with ADAD mutations. The causal direction of this research is difficult to ascertain, thus future study designs investigating the therapeutic potential of exercise in both ADAD and late-onset AD should be considered before clinical recommendation of exercise is implemented.

Data collection and sharing for this project was supported by The Dominantly Inherited Alzheimer Network (DIAN, U19AG032438) funded by the National Institute on Aging (NIA), the Alzheimer's Association (SG-20-690363-DIAN, AARFD-21-851415), the German Center for Neurodegenerative Diseases (DZNE).

Background
Observational studies consistently demonstrate that physical activity is associated with enhanced cognitive function and reduced risk for dementia. However, there remains significant heterogeneity in study findings regarding the effect of exercise interventions on cognitive function. Individual variation in sleep behaviours are hypothesized to be a source of this variability in the effectiveness of exercise to influence cognition, however this has not yet been investigated. Thus, the current study aimed to 1) investigate the influence of a 6-month exercise intervention on sleep pre- and post-intervention and 2) investigate whether baseline sleep measures moderate exercise-induced cognitive changes.

Method
We utilised data from the Intense Physical Activity and Cognition (IPAC) study (n = 89), a 6-month moderate intensity and high intensity exercise intervention, in cognitively normal community-dwelling older adults aged 60-80 years (68.76 ± 5.32). Exercise was supervised and completed on a stationary exercise bicycle, and cognitive function was measured using a comprehensive neuropsychological battery administered pre- and post-intervention. Sleep was measured using the Pittsburgh sleep quality index (PSQI) to yield measures of sleep duration, efficiency, and sleep latency.

Result
There was no effect of the exercise intervention on any sleep outcomes from pre- to post-intervention. There was a significant moderating effect of baseline sleep efficiency on both episodic memory and global cognition within the moderate intensity exercise group (β = -0.024, SE = 0.008, p = .004; β = -0.011, SE = 0.005, p = .036), such that those with poorer sleep efficiency at baseline showed greater exercise-induced cognitive improvements.

Conclusion
These results indicate that those with poorer sleep may have the greatest exercise-induced cognitive benefits and that baseline sleep behaviours may be an important source of heterogeneity in previous exercise interventions targeting cognitive outcomes.

Background
There is increasing evidence of a bidirectional relationship between suboptimal sleep and brain Aβ‐amyloid (Aβ) accumulation. Suboptimal sleep is suggested to both result from and contribute to the accumulation of brain Aβ. This study tested whether aspects of self‐reported sleep quality predict the longitudinal accumulation of brain Aβ.

Method
Linear mixed effect model analyses were conducted on 192 cognitively normal older adults (M = 73.8 years, SD = 5.8, 51.6% female). These individuals, drawn from the Australian Imaging, Biomarkers and Lifestyle (AIBL) Study of Ageing, had self‐reported sleep characteristics assessed at baseline and positron emission tomography‐determined brain Aβ burden measured over a minimum of three AIBL timepoints (range 33.3‐73.9 months). Analyses included random slopes and intercepts, interaction for apolipoprotein E (APOE) ε4 allele status and time, adjusting for sex and baseline age.

Result
Sleep duration of <5 hours and sleep efficiency of <65% both significantly forecast the longitudinal trajectory of Aβ accumulation in the whole cohort (sleep duration <5 hrs β = 4.70 ± 1.58, p = 0.003; sleep efficiency <65% β = 2.94 ± 0.91, p = 0.001) and in APOE ε4 non‐carriers (sleep duration <5 hrs β = 4.70 ± 1.53, p = 0.003; sleep efficiency <65% β = 2.90 ± 0.87, p = 0.001) but not in APOE ε4 carriers.

Conclusion
These findings indicate a role for self‐reported suboptimal sleep efficiency and duration in the accumulation of Alzheimer's disease neuropathology in cognitively normal individuals. Individuals with suboptimal sleep may benefit from an intervention to improve these sleep parameters to lessen future Alzheimer's risk. Our findings also suggest the potential utility of self‐report screening for sleep efficiency and duration as a predictor of risk of Aβ accumulation.