Functional segregation loss over time is moderated by APOE genotype in healthy elderly

Abstract

We investigated the influence of the apolipoprotein E-ɛ4 allele (APOE-ɛ4) on longitudinal age-related changes in brain functional connectivity (FC) and cognition, in view of mixed cross-sectional findings. One hundred and twenty-two healthy older adults (aged 58-79; 25 APOE-ɛ4 carriers) underwent task-free fMRI scans at baseline. Seventy-eight (16 carriers) had at least one follow-up (every 2 years). Changes in intra- and internetwork FCs among the default mode (DMN), executive control (ECN), and salience (SN) networks, as well as cognition, were quantified using linear mixed models. Cross-sectionally, APOE-ɛ4 carriers had lower functional connectivity between the ECN and SN than noncarriers. Carriers also showed a stronger age-dependent decrease in visuospatial memory performance. Longitudinally, carriers had steeper increase in inter-ECN-DMN FC, indicating loss of functional segregation. The longitudinal change in processing speed performance was not moderated by APOE-ɛ4 genotype, but the brain-cognition association was. In younger elderly, faster loss of segregation was correlated with greater decline in processing speed regardless of genotype. In older elderly, such relation remained for noncarriers but reversed for carriers. APOE-ɛ4 may alter aging by accelerating the change in segregation between high-level cognitive systems. Its modulation on the longitudinal brain-cognition relationship was age-dependent.

Impact of APOE ε4 Carrier Status on Associations Between Subthreshold, Positive Amyloid-β Deposition, Brain Function, and Cognitive Performance in Cognitively Normal Older Adults: A Prospective Study

“…The function of the CEN has been demonstrated to be supported by that of the DMN in maintaining a normal cognition (Turner and Spreng, 2015 ). In this respect, the present results support previous observational studies that have shown a positive association between the cognitive function and the inter-network FC of DMN-CEN in the cognitively normal APOE ε4 carrier of similar age to the present study (Ng et al, 2018 ).…”

Impact of APOE ε4 Carrier Status on Associations Between Subthreshold, Positive Amyloid-β Deposition, Brain Function, and Cognitive Performance in Cognitively Normal Older Adults: A Prospective Study

“…The function of the CEN has been demonstrated to be supported by that of the DMN in maintaining a normal cognition (Turner and Spreng, 2015 ). In this respect, the present results support previous observational studies that have shown a positive association between the cognitive function and the inter-network FC of DMN-CEN in the cognitively normal APOE ε4 carrier of similar age to the present study (Ng et al, 2018 ).…”

Genetic risk of late-onset Alzheimer’s disease is associated with longitudinal loss of functional brain network segregation in middle-aged cognitively healthy individuals: The PREVENT-Dementia Study

“…Previous studies addressing this research question have yielded inconsistent findings regarding which networks are susceptible to segregation loss across the adult lifespan (Ballard et al, 2022;Cassady et al, 2019;Chan et al, 2014), possibly due to differences in statistical power associated with different sample sizes, correction methods for multiple comparisons to control for false positive rates, and measures of network segregation (Varangis et al, 2019). Despite these differences in study design, the present study, together with previous studies (Ballard et al, 2022;Chan et al, 2014;Chong et al, 2019;Grady et al, 2016;Malagurski et al, 2020;Ng et al, 2018), provides further evidence for age-related declines in functional segregation of high-order networks, supporting their vulnerability during healthy ageing.…”

“…To the best of our knowledge, this is the first study to show a prominent decline in functional segregation of the DMN with ageing in cognitively healthy individuals at risk for late-onset AD in midlife. A greater loss of network segregation with ageing, particularly in high-order networks (i.e., DMN, FPN and SN), was previously shown in cognitively unimpaired older APOE ε4 carriers compared to non-carriers (Ng et al, 2018). Furthermore, accelerated age-related decline in network segregation was predictive of dementia severity (Chan et al, 2021).…”

Source connectivity patterns in the default mode network differ between elderly golf-novices and non-golfers

“…www.nature.com/scientificreports/ However, the potential effects of learning to play golf on source connectivity patterns of the DMN remain to be established, preferably in a randomized controlled design with an appropriate sample size. Golf is one of several lifestyle-related factors influencing cognitive performance and functional network characteristics, including cardiovascular fitness 28,50 , leisure time activities like chess or playing an instrument 32 , genetic predisposition [51][52][53] as well as diet 54,55 , which may have influenced our findings. The non-golfing control group did not receive additional treatment to account for the influence of other factors related to the intervention that may also had an effect on results, such as an increased social interaction.…”

Impact of APOE ε4 Carrier Status on Associations Between Subthreshold, Positive Amyloid-β Deposition, Brain Function, and Cognitive Performance in Cognitively Normal Older Adults: A Prospective Study

“…The function of the CEN has been demonstrated to be supported by that of the DMN in maintaining a normal cognition (Turner and Spreng, 2015 ). In this respect, the present results support previous observational studies that have shown a positive association between the cognitive function and the inter-network FC of DMN-CEN in the cognitively normal APOE ε4 carrier of similar age to the present study (Ng et al, 2018 ).…”

Genetic risk of late-onset Alzheimer’s disease is associated with longitudinal loss of functional brain network segregation in middle-aged cognitively healthy individuals: The PREVENT-Dementia Study

“…Previous studies addressing this research question have yielded inconsistent findings regarding which networks are susceptible to segregation loss across the adult lifespan (Ballard et al, 2022;Cassady et al, 2019;Chan et al, 2014), possibly due to differences in statistical power associated with different sample sizes, correction methods for multiple comparisons to control for false positive rates, and measures of network segregation (Varangis et al, 2019). Despite these differences in study design, the present study, together with previous studies (Ballard et al, 2022;Chan et al, 2014;Chong et al, 2019;Grady et al, 2016;Malagurski et al, 2020;Ng et al, 2018), provides further evidence for age-related declines in functional segregation of high-order networks, supporting their vulnerability during healthy ageing.…”

“…To the best of our knowledge, this is the first study to show a prominent decline in functional segregation of the DMN with ageing in cognitively healthy individuals at risk for late-onset AD in midlife. A greater loss of network segregation with ageing, particularly in high-order networks (i.e., DMN, FPN and SN), was previously shown in cognitively unimpaired older APOE ε4 carriers compared to non-carriers (Ng et al, 2018). Furthermore, accelerated age-related decline in network segregation was predictive of dementia severity (Chan et al, 2021).…”

Source connectivity patterns in the default mode network differ between elderly golf-novices and non-golfers

“…www.nature.com/scientificreports/ However, the potential effects of learning to play golf on source connectivity patterns of the DMN remain to be established, preferably in a randomized controlled design with an appropriate sample size. Golf is one of several lifestyle-related factors influencing cognitive performance and functional network characteristics, including cardiovascular fitness 28,50 , leisure time activities like chess or playing an instrument 32 , genetic predisposition [51][52][53] as well as diet 54,55 , which may have influenced our findings. The non-golfing control group did not receive additional treatment to account for the influence of other factors related to the intervention that may also had an effect on results, such as an increased social interaction.…”

Impact of APOE ε4 Carrier Status on Associations Between Subthreshold, Positive Amyloid-β Deposition, Brain Function, and Cognitive Performance in Cognitively Normal Older Adults: A Prospective Study

“…The function of the CEN has been demonstrated to be supported by that of the DMN in maintaining a normal cognition (Turner and Spreng, 2015 ). In this respect, the present results support previous observational studies that have shown a positive association between the cognitive function and the inter-network FC of DMN-CEN in the cognitively normal APOE ε4 carrier of similar age to the present study (Ng et al, 2018 ).…”

Genetic risk of late-onset Alzheimer’s disease is associated with longitudinal loss of functional brain network segregation in middle-aged cognitively healthy individuals: The PREVENT-Dementia Study

“…Previous studies addressing this research question have yielded inconsistent findings regarding which networks are susceptible to segregation loss across the adult lifespan (Ballard et al, 2022;Cassady et al, 2019;Chan et al, 2014), possibly due to differences in statistical power associated with different sample sizes, correction methods for multiple comparisons to control for false positive rates, and measures of network segregation (Varangis et al, 2019). Despite these differences in study design, the present study, together with previous studies (Ballard et al, 2022;Chan et al, 2014;Chong et al, 2019;Grady et al, 2016;Malagurski et al, 2020;Ng et al, 2018), provides further evidence for age-related declines in functional segregation of high-order networks, supporting their vulnerability during healthy ageing.…”

“…To the best of our knowledge, this is the first study to show a prominent decline in functional segregation of the DMN with ageing in cognitively healthy individuals at risk for late-onset AD in midlife. A greater loss of network segregation with ageing, particularly in high-order networks (i.e., DMN, FPN and SN), was previously shown in cognitively unimpaired older APOE ε4 carriers compared to non-carriers (Ng et al, 2018). Furthermore, accelerated age-related decline in network segregation was predictive of dementia severity (Chan et al, 2021).…”

Source connectivity patterns in the default mode network differ between elderly golf-novices and non-golfers

“…www.nature.com/scientificreports/ However, the potential effects of learning to play golf on source connectivity patterns of the DMN remain to be established, preferably in a randomized controlled design with an appropriate sample size. Golf is one of several lifestyle-related factors influencing cognitive performance and functional network characteristics, including cardiovascular fitness 28,50 , leisure time activities like chess or playing an instrument 32 , genetic predisposition [51][52][53] as well as diet 54,55 , which may have influenced our findings. The non-golfing control group did not receive additional treatment to account for the influence of other factors related to the intervention that may also had an effect on results, such as an increased social interaction.…”