Table 1. Insulin-related changes in AD... | Rockefeller University Press

Table 1.

Insulin-related changes in AD

Parameter	AD ↑ ↓	Study	Details
Blood insulin	↑	Bucht et al., 1983; Fujisawa et al., 1991; Stolk et al., 1997; Craft et al., 1998; Ma et al., 2016	-Fasting or after glucose tolerance test -In women only (1 study) -Only in non-APOE4 and moderate/severe AD (1 study) -Meta-analysis of 11 studies: 5 report overall ↑, 1 ↑ in women, 1 ↑ with advanced stage (Ma et al., 2016)
CSF insulin	↑	Fujisawa et al., 1991	-Also found small increase with vascular dementia
	↓	Craft et al., 1998; Gil-Bea et al., 2010	-Only in non-APOE4 and moderate/severe AD -No relationship to APOE or AD severity
	No change	Molina et al., 2002	-No relationship with AD severity or cognition
Brain insulin	No change	Frölich et al., 1998	-Comparing controls >65 y/o and AD patients
Brain insulin	↓	Frölich et al., 1998; Rivera et al., 2005; Steen et al., 2005	-Comparing controls <65 y/o and AD patients -mRNA: in hippocampus and hypothalamus -mRNA: progressive reduction with Braak stage
Brain IR (total)	↓	Frölich et al., 1998; Rivera et al., 2005; Steen et al., 2005	-Comparing controls <65 y/o and AD patients -mRNA and protein -mRNA: progressive reduction with Braak stage
	↑	Frölich et al., 1998	-Comparing controls >65 y/o and AD patients
	No change	Moloney et al., 2010; Liu et al., 2011; Ho et al., 2012; Talbot et al., 2012	-Potential changes in cellular distribution -Also no change in p-IR -Only reduced in patients with T2D and AD
Brain p-IR and activity	↓	Frölich et al., 1998; Rivera et al., 2005; Steen et al., 2005	-In hippocampus -Reduced insulin binding -TK activity reduced compared to all controls
Brain IRS1 (total)	↓	Steen et al., 2005; Moloney et al., 2010	-mRNA in 3 regions -Also reductions in IRS2
Brain IRS1 (total)	No change	Liu et al., 2011; Talbot et al., 2012	-Also no change in IRS2 -Only reduced in patients with T2D and AD
Brain p(Ser)-IRS1	↑	Moloney et al., 2010 ,Talbot et al., 2012 ,Bomfim et al., 2012 ,Yarchoan et al., 2014	-Regardless of APOE status and reduced ex vivo insulin stimulation -Highest in AD, but also elevated in some tauopathies
Brain AKT (total)	↓	Griffin et al., 2005; Liu et al., 2011	-Reduced in AD and in patients with T2D and AD
Brain AKT (total)	No change	Steen et al., 2005; Talbot et al., 2012
Brain p-AKT	↑	Pei et al., 2003; Griffin et al., 2005; Talbot et al., 2012; Yarchoan et al., 2014	-Associated with tangles
	↓	Steen et al., 2005	-In hippocampus
	No change	Liu et al., 2011	-Only reduced in patients with T2D and AD
Brain GSK3 (total)	↓	Ho et al., 2012	-With advanced AD
Brain GSK3 (total)	No change	Steen et al., 2005; Liu et al., 2011; Talbot et al., 2012	-Only reduced in patients with T2D or T2D and AD
Brain p(Ser)-GSK3	↓	Steen et al., 2005 ,Griffin et al., 2005	-In hippocampus
Brain p(Ser)-GSK3	No change	Liu et al., 2011	-Only reduced in patients with T2D or T2D and AD
Brain p-GSK3	↑	Pei et al., 2003	-Associated with tangles
Brain p-JNK	↑	Bomfim et al., 2012; Talbot et al., 2012
Other IR signaling molecules	↓	Griffin et al., 2005; Liu et al., 2011; Talbot et al., 2012	-PDK1, p-PDK1 and p-PI3K -PIP3, PKC, p-mTOR, p-ERK2 -PTEN

Parameter	AD ↑ ↓	Study	Details
Blood insulin	↑	Bucht et al., 1983; Fujisawa et al., 1991; Stolk et al., 1997; Craft et al., 1998; Ma et al., 2016	-Fasting or after glucose tolerance test -In women only (1 study) -Only in non-APOE4 and moderate/severe AD (1 study) -Meta-analysis of 11 studies: 5 report overall ↑, 1 ↑ in women, 1 ↑ with advanced stage (Ma et al., 2016)
CSF insulin	↑	Fujisawa et al., 1991	-Also found small increase with vascular dementia
	↓	Craft et al., 1998; Gil-Bea et al., 2010	-Only in non-APOE4 and moderate/severe AD -No relationship to APOE or AD severity
	No change	Molina et al., 2002	-No relationship with AD severity or cognition
Brain insulin	No change	Frölich et al., 1998	-Comparing controls >65 y/o and AD patients
Brain insulin	↓	Frölich et al., 1998; Rivera et al., 2005; Steen et al., 2005	-Comparing controls <65 y/o and AD patients -mRNA: in hippocampus and hypothalamus -mRNA: progressive reduction with Braak stage
Brain IR (total)	↓	Frölich et al., 1998; Rivera et al., 2005; Steen et al., 2005	-Comparing controls <65 y/o and AD patients -mRNA and protein -mRNA: progressive reduction with Braak stage
	↑	Frölich et al., 1998	-Comparing controls >65 y/o and AD patients
	No change	Moloney et al., 2010; Liu et al., 2011; Ho et al., 2012; Talbot et al., 2012	-Potential changes in cellular distribution -Also no change in p-IR -Only reduced in patients with T2D and AD
Brain p-IR and activity	↓	Frölich et al., 1998; Rivera et al., 2005; Steen et al., 2005	-In hippocampus -Reduced insulin binding -TK activity reduced compared to all controls
Brain IRS1 (total)	↓	Steen et al., 2005; Moloney et al., 2010	-mRNA in 3 regions -Also reductions in IRS2
Brain IRS1 (total)	No change	Liu et al., 2011; Talbot et al., 2012	-Also no change in IRS2 -Only reduced in patients with T2D and AD
Brain p(Ser)-IRS1	↑	Moloney et al., 2010 Talbot et al., 2012 Bomfim et al., 2012 Yarchoan et al., 2014	-Regardless of APOE status and reduced ex vivo insulin stimulation -Highest in AD, but also elevated in some tauopathies
Brain AKT (total)	↓	Griffin et al., 2005; Liu et al., 2011	-Reduced in AD and in patients with T2D and AD
Brain AKT (total)	No change	Steen et al., 2005; Talbot et al., 2012
Brain p-AKT	↑	Pei et al., 2003; Griffin et al., 2005; Talbot et al., 2012; Yarchoan et al., 2014	-Associated with tangles
	↓	Steen et al., 2005	-In hippocampus
	No change	Liu et al., 2011	-Only reduced in patients with T2D and AD
Brain GSK3 (total)	↓	Ho et al., 2012	-With advanced AD
Brain GSK3 (total)	No change	Steen et al., 2005; Liu et al., 2011; Talbot et al., 2012	-Only reduced in patients with T2D or T2D and AD
Brain p(Ser)-GSK3	↓	Steen et al., 2005 Griffin et al., 2005	-In hippocampus
Brain p(Ser)-GSK3	No change	Liu et al., 2011	-Only reduced in patients with T2D or T2D and AD
Brain p-GSK3	↑	Pei et al., 2003	-Associated with tangles
Brain p-JNK	↑	Bomfim et al., 2012; Talbot et al., 2012
Other IR signaling molecules	↓	Griffin et al., 2005; Liu et al., 2011; Talbot et al., 2012	-PDK1, p-PDK1 and p-PI3K -PIP3, PKC, p-mTOR, p-ERK2 -PTEN

Reported alterations in ins and brain IS in AD are categorized by the specific component measured, whether there have been reports of an increase, decrease (up and down arrows), or no change in individuals with AD, the studies that report this specific alteration, and important details. For blood and CSF insulin, AD diagnosis was based on clinical criteria. For postmortem analysis of brain insulin and IS components, AD was confirmed by clinical diagnosis and histological analyses. All reported changes were at the protein level unless mRNA is specified in the details. Overall, data from this table supports a higher level of blood insulin in individuals with AD and some degree of brain insulin resistance.

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