Interactive Effects of Physical Activity and APOE-ε4 On White Matter Tract Diffusivity in Healthy Elders

Older adult apolipoprotein-E epsilon 4 (APOE-ε4) allele carriers vary considerably in the expression of clinical symptoms of Alzheimer\u27s disease (AD), suggesting that lifestyle or other factors may offer protection from AD-related neurodegeneration. We recently reported that physically active APOE-ε4 allele carriers exhibit a stable cognitive trajectory and protection from hippocampal atrophy over 18 months compared to sedentary ε4 allele carriers. The aim of this study was to examine the interactions between genetic risk for AD and physical activity (PA) on white matter (WM) tract integrity, using diffusion tensor imaging (DTI) MRI, in this cohort of healthy older adults (ages of 65 to 89). Four groups were compared based on the presence or absence of an APOE-ε4 allele (High Risk; Low Risk) and self-reported frequency and intensity of leisure time physical activity (PA) (High PA; Low PA). As predicted, greater levels of PA were associated with greater fractional anisotropy (FA) and lower radial diffusivity in healthy older adults who did not possess the APOE-ε4 allele. However, the effects of PA were reversed in older adults who were at increased genetic risk for AD, resulting in significant interactions between PA and genetic risk in several WM tracts. In the High Risk-Low PA participants, who had exhibited episodic memory decline over the previous 18-months, radial diffusivity was lower and fractional anisotropy was higher, compared to the High Risk-High PA participants. In WM tracts that subserve learning and memory processes, radial diffusivity (DR) was negatively correlated with episodic memory performance in physically inactive APOE-ε4 carriers, whereas DR was positively correlated with episodic memory performance in physically active APOE-ε4 carriers and the two Low Risk groups. The common model of demyelination-induced increase in radial diffusivity cannot directly explain these results. Rather, we hypothesize that PA may protect APOE-ε4 allele carriers from selective neurodegeneration of individual fiber populations at locations of crossing fibers within projection and association WM fiber tracts

The effect of physical activity on white matter integrity in aging and prodromal to mild Alzheimer’s disease with vascular comorbidity

Data availability statement; The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.Supplementary material: The Supplementary material for this article can be found online at: https://www.frontiersin.org/articles/10.3389/fnagi.2023.1096798/full#supplementary-materialCopyright © 2023 Konwar, Manca, De Marco, Soininen and Venneri. Background: Physical activity is a modifiable lifestyle factor that has been previously associated with reduced vascular burden and reduced risk of dementia. Objectives: This study tested whether physical activity (i.e., being inactive vs. active) contributed to preservation of white matter microstructure in healthy aging controls and patients in prodromal to mild Alzheimer’s disease with low/high vascular burden. Materials: A total of 213 participants were recruited from memory clinics. They were classified as being either physically active (n = 113) or inactive (n = 100) based on the Cardiovascular Risk Factors, Aging and Dementia (CAIDE) questionnaire. Diffusion-weighted images were acquired for all participants and pre-processed based on a standard protocol. Methods: A factorial design using voxel-wise tract-based spatial statistics (TBSS) was adopted, with 5,000 permutations and threshold-free cluster enhancement (TFCE), to identify significant clusters for fractional anisotropy (FA), axial diffusivity (AxD), mean diffusivity (MD), and radial diffusivity (RD). Results: Clusters of higher FA and lower AxD, MD, and RD values were found for physically active compared with inactive participants that were widespread covering mainly association and projection tracts but also some commissural tracts. A three-way Group × Physical Activity × Vascular Burden interaction effect was found for FA mostly in a variety of projection tracts with a right predominance, and some commissural and association tracts. Post hoc analyses revealed higher FA in patients with high vascular burden who were physically active compared with those patients with high vascular burden who were inactive mainly in projection and association/limbic tracts with a right predominance. Additionally, higher FA was observed in physically active patients with high vascular burden as compared with physically inactive controls with high vascular burden, mainly in bilateral projection fibers and cerebellar regions. Conclusion: Voxel-wise TBSS analysis revealed better preservation of white matter microstructure that was prominent in the high-risk group such as the patients with high vascular burden, specifically those who were physically active. The beneficial effects of physical activity on white matter microstructure were not observed in the controls.This study was supported by the European Union Seventh Framework Programme (FP7/2007e2013) (grant agreement no. 601055, VPH-DARE@IT) to AV and HS

The effects of physical function and genetics on cognition and blood biomarkers in individuals at-risk for Alzheimer’s disease and related dementias

Alzheimer’s disease and related dementia (ADRD) rates are expected to triple by the year 2050. Early detection and specific mitigation efforts are warranted to blunt the alarming rate. Physical function (PF) declines with age, but higher physical function is associated with better cognitive functioning in middle-to- older age individuals. Moreover, greater physical activity (PA) is associated with better global cognition; however, Apoliporotein e4 carriers may not gain the same benefits with exercise. Additionally, plasma phosphorylated tau 217 (p-tau217) has been identified as a novel diagnostic ADRD biomarker which needs further research to examine associations with risk factors. Therefore, the aims of this investigation were (1) Understand if higher physical function clusters produce better cognitive outcomes and blood biomarker profiles compared to lower functioning clusters among at-risk individuals, (2) Evaluate the ApoE gene’s mitigating effect on physical activity and blood biomarkers, (3) Examine the associations between risk factors and p-tau217. Participants (n=216;73.1% female; 45-75years) enrolled in the study and completed a DXA scan, venous blood draw, RBANS, handgrip, sit-to-stand power with tendo, dual-task (4-meter and 10-meter), 6-minute walk distance test, nine behavioral risk surveys, and 6 digital cognitive tests. A hierarchal cluster analysis was utilized to identify PF cluster for participants, a one-way ANCOVA was used to assess differences in cognition among clusters. A 2x2 factorial ANCOVA to examine interactions between PA and genetics. A multiple linear regression was used to evaluate risk factors (independent variables) on p-tau217 (dependent variable). Cluster 1 (C1; n =29) was characterized with the highest strength, power, faster dual-task walking time, and higher aerobic capacity, Cluster 3 (C3; n =113) had the lowest values among PF variables, Cluster 2 (C3; n = 74) was in-between C1 and C3. C1 had significantly higher global cognitive, visuospatial scores, digital executive functioning and associative learning compared to C2 (p \u3c 0.05). C3 and C1 had significantly higher values on line orientation task and figure recall than C2 (p \u3c 0.05). Moreover, physically active ApoE carriers had lower body mass index scores compared to physically inactive carriers where the opposite was seen among non-carriers (p \u3c 0.05). Lastly, the regression model accounted for 84% of the variance for p-tau217 (p = .01), SF-12 accounted for 9% of that model as the only significant predictor (p \u3c 0.05). The results from this current study demonstrate that individuals with higher physical functioning output among clustered variables have higher global cognitive scores than individuals with lower physical functioning output, lower BMI scores were found among physically active ApoE carriers, and quality of life may be directly linked to ptau217. Examining physical functioning variables together may be a valuable tool when assessing cognitive decline among at-risk individuals. However, larger sample sizes and longitudinal data is needed to substantiate these claims