Effect of APOE ε4 Status on Intrinsic Network Connectivity in Cognitively Normal Elderly Subjects

Abstract

ObjectiveTo examine default mode and salience network functional connectivity as a function of APOE ε4 status in a group of cognitively normal age-, sex-, and education-matched older adults.DesignCase-control study.SubjectsFifty-six cognitively normal APOE ε4 carriers and 56 age-, sex- and education-matched cognitively normal APOE ε4 noncarriers.Main Outcome MeasureAlterations in in-phase default mode and salience network connectivity in APOE ε4 carriers compared with APOE ε4 noncarriers ranging from 63 to 91 years of age.ResultsA posterior cingulate seed revealed decreased in-phase connectivity in regions of the posterior default mode network that included the left inferior parietal lobe, left middle temporal gyrus, and bilateral anterior temporal lobes in the ε4 carriers relative to APOE ε4 noncarriers. An anterior cingulate seed showed greater in-phase connectivity in the salience network including the cingulate gyrus, medial prefrontal cortex, bilateral insular cortex, striatum, and thalamus in APOE ε4 carriers vs noncarriers. There were no groupwise differences in brain anatomy.ConclusionsThe observation of functional alterations in default mode and salience network connectivity in the absence of structural changes between APOE ε4 carriers and noncarriers suggests that alterations in connectivity may have the potential to serve as an early biomarker.

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

“…Unexpectedly, despite previous cross‐sectional findings on the differences in intranetwork FC between APOE ‐ɛ4 groups (Machulda et al, ; Wu et al, ), we did not find APOE ‐ɛ4‐related intranetwork FC changes over time (nor cross‐sectionally). Age‐related decrease in intranetwork FC, a sign of compromised specialized processing, is also a common phenomenon in aging (Damoiseaux, ).…”

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

“…Unexpectedly, despite previous cross‐sectional findings on the differences in intranetwork FC between APOE ‐ɛ4 groups (Machulda et al, ; Wu et al, ), we did not find APOE ‐ɛ4‐related intranetwork FC changes over time (nor cross‐sectionally). Age‐related decrease in intranetwork FC, a sign of compromised specialized processing, is also a common phenomenon in aging (Damoiseaux, ).…”

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

“…Additionally, the SN has been documented to display distinctive FC activation from normal aging to AD progression (He et al, 2014 ). Contrary to the current findings, the APOE ε4 carrier in the preclinical phase has demonstrated increased FC related to the insula, which is attributed to the reduction of the inhibitory control of the DMN (Machulda et al, 2011 ). However, in the present study, there were no significant differences in the intra-network FC of the DMN and the inter-network FC between the DMN and SN depending on the APOE ε4 carrier status in the CN Aβ+ group.…”

Cascading network failure across the Alzheimer’s disease spectrum

“…5 ), suggesting that the posterior DMN decline related to ageing and the initiation of Alzheimer’s disease-related network failure may be a more proximate event than amyloid accumulation currently measurable in vivo . These results are consistent with our previous finding ( Machulda et al ., 2011 ) of an APOE ε4 -related decline in posterior DMN connectivity in cognitively normal elderly and also that this occurs in APOE ε4 allele carriers who are documented to be amyloid-negative, as previously reported by others ( Sheline et al ., 2010 ). In addition, the brain regions within the posterior DMN largely overlap with the areas of the brain that have a unique vulnerability to reductions in glucose metabolism as a function of both age and APOE ε4 allele carriage, which are also independent of amyloid status ( Jagust and Landau, 2012 ; Knopman et al ., 2014 ).…”

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

“…Unexpectedly, despite previous cross‐sectional findings on the differences in intranetwork FC between APOE ‐ɛ4 groups (Machulda et al, ; Wu et al, ), we did not find APOE ‐ɛ4‐related intranetwork FC changes over time (nor cross‐sectionally). Age‐related decrease in intranetwork FC, a sign of compromised specialized processing, is also a common phenomenon in aging (Damoiseaux, ).…”

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

“…Additionally, the SN has been documented to display distinctive FC activation from normal aging to AD progression (He et al, 2014 ). Contrary to the current findings, the APOE ε4 carrier in the preclinical phase has demonstrated increased FC related to the insula, which is attributed to the reduction of the inhibitory control of the DMN (Machulda et al, 2011 ). However, in the present study, there were no significant differences in the intra-network FC of the DMN and the inter-network FC between the DMN and SN depending on the APOE ε4 carrier status in the CN Aβ+ group.…”

Cascading network failure across the Alzheimer’s disease spectrum

“…5 ), suggesting that the posterior DMN decline related to ageing and the initiation of Alzheimer’s disease-related network failure may be a more proximate event than amyloid accumulation currently measurable in vivo . These results are consistent with our previous finding ( Machulda et al ., 2011 ) of an APOE ε4 -related decline in posterior DMN connectivity in cognitively normal elderly and also that this occurs in APOE ε4 allele carriers who are documented to be amyloid-negative, as previously reported by others ( Sheline et al ., 2010 ). In addition, the brain regions within the posterior DMN largely overlap with the areas of the brain that have a unique vulnerability to reductions in glucose metabolism as a function of both age and APOE ε4 allele carriage, which are also independent of amyloid status ( Jagust and Landau, 2012 ; Knopman et al ., 2014 ).…”

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

“…Unexpectedly, despite previous cross‐sectional findings on the differences in intranetwork FC between APOE ‐ɛ4 groups (Machulda et al, ; Wu et al, ), we did not find APOE ‐ɛ4‐related intranetwork FC changes over time (nor cross‐sectionally). Age‐related decrease in intranetwork FC, a sign of compromised specialized processing, is also a common phenomenon in aging (Damoiseaux, ).…”

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

“…Additionally, the SN has been documented to display distinctive FC activation from normal aging to AD progression (He et al, 2014 ). Contrary to the current findings, the APOE ε4 carrier in the preclinical phase has demonstrated increased FC related to the insula, which is attributed to the reduction of the inhibitory control of the DMN (Machulda et al, 2011 ). However, in the present study, there were no significant differences in the intra-network FC of the DMN and the inter-network FC between the DMN and SN depending on the APOE ε4 carrier status in the CN Aβ+ group.…”

Cascading network failure across the Alzheimer’s disease spectrum

“…5 ), suggesting that the posterior DMN decline related to ageing and the initiation of Alzheimer’s disease-related network failure may be a more proximate event than amyloid accumulation currently measurable in vivo . These results are consistent with our previous finding ( Machulda et al ., 2011 ) of an APOE ε4 -related decline in posterior DMN connectivity in cognitively normal elderly and also that this occurs in APOE ε4 allele carriers who are documented to be amyloid-negative, as previously reported by others ( Sheline et al ., 2010 ). In addition, the brain regions within the posterior DMN largely overlap with the areas of the brain that have a unique vulnerability to reductions in glucose metabolism as a function of both age and APOE ε4 allele carriage, which are also independent of amyloid status ( Jagust and Landau, 2012 ; Knopman et al ., 2014 ).…”