Reduced Mitochondria Cytochrome Oxidase Activity in Adult Children of Mothers with Alzheimer's Disease

Abstract

Biomarker studies demonstrate inheritance of glucose hypometabolism and increased amyloid-β deposition in adult offspring of mothers, but not fathers, affected by late-onset Alzheimer's disease (LOAD). The underlying genetic mechanisms are unknown. We investigated whether cognitively normal (NL) individuals with a maternal history of LOAD (MH) have reduced platelet mitochondrial cytochrome oxidase activity (COX, electron transport chain complex IV) compared to those with paternal (PH) or negative family history (NH). Thirty-six consecutive NL individuals (age 55 15 y, range 27–71 y, 56% female, CDR = 0, MMSE ≥28, 28% APOE-4 carriers), including 12 NH, 12 PH, and 12 MH, received ± a blood draw to measure platelet mitochondrial COX activity. Citrate synthase activity (CS) was measured as a reference. Groups were comparable for clinical and neuropsychological measures. We found that after correcting for CS, COX activity was reduced by 29% in MH compared to NH, and by 30% in MH compared to PH (p ≤ 0.006). Results remained significant controlling for age, gender, education, and APOE. No differences were found between PH and NH. COX measures discriminated MH from the other groups with accuracy ≥75%, and relative risk ≥3 (p ≤ 0.005). Among NL with LOAD-parents, only those with MH showed reduced COX activity in platelet mitochondria compared to PH and NH. The association between maternal history of LOAD and systemic COX reductions suggests transmission via mitochondrial DNA, which is exclusively maternally inherited in humans.

The Alzheimer’s Disease Mitochondrial Cascade Hypothesis: A Current Overview

“…Another endophenotype study measured platelet mitochondria COX activity in middle-aged, cognitively normal individuals with an AD mother, father, or cognitively intact parents. COX activity was lowest in those with an AD mother [95], a finding consistent with the possibility that mtDNA inheritance influences COX and by extension AD risk.…”

The Alzheimer’s Disease Mitochondrial Cascade Hypothesis: A Current Overview

“…Another endophenotype study measured platelet mitochondria COX activity in middle-aged, cognitively normal individuals with an AD mother, father, or cognitively intact parents. COX activity was lowest in those with an AD mother [95], a finding consistent with the possibility that mtDNA inheritance influences COX and by extension AD risk.…”

Mitochondria and Cell Bioenergetics: Increasingly Recognized Components and a Possible Etiologic Cause of Alzheimer's Disease

“…On memory tests, APOE4 carriers with AD mothers do not perform as well as APOE4 carriers with AD fathers (69). Platelet mitochondria COX activity is lower in those with AD mothers than it is in those with AD fathers (185). Cybrid, endophenotype, and positive mtDNA-AD association studies are consistent with epidemiology data that suggest an AD maternal inheritance bias does exist (10,77,79,183).…”

New Targets for Diagnosis and Treatment Against Alzheimer’s Disease: The Mitochondrial Approach

“…Platelets presented intracellular calcium deregulation [152,153], an increase in oxidative damage [152,153], a decrease in CoxIV and ATP synthase activities [154][155][156][157][158], and as we previously mentioned, a reduced mitochondrial potential in the cybrid condition [140]. Interestingly, in a study with cognitively normal individuals with maternal history of late onset of AD was found a reduced activity of platelet CoxIV compared to those with paternal or negative family history [159]. These findings suggest not only a possible mitochondrial peripheral biomarker but also an exclusively maternally inherited marker in humans [159].…”

The Alzheimer’s Disease Mitochondrial Cascade Hypothesis: A Current Overview

“…Another endophenotype study measured platelet mitochondria COX activity in middle-aged, cognitively normal individuals with an AD mother, father, or cognitively intact parents. COX activity was lowest in those with an AD mother [95], a finding consistent with the possibility that mtDNA inheritance influences COX and by extension AD risk.…”

Mitochondria and Cell Bioenergetics: Increasingly Recognized Components and a Possible Etiologic Cause of Alzheimer's Disease

“…On memory tests, APOE4 carriers with AD mothers do not perform as well as APOE4 carriers with AD fathers (69). Platelet mitochondria COX activity is lower in those with AD mothers than it is in those with AD fathers (185). Cybrid, endophenotype, and positive mtDNA-AD association studies are consistent with epidemiology data that suggest an AD maternal inheritance bias does exist (10,77,79,183).…”

New Targets for Diagnosis and Treatment Against Alzheimer’s Disease: The Mitochondrial Approach

“…Platelets presented intracellular calcium deregulation [152,153], an increase in oxidative damage [152,153], a decrease in CoxIV and ATP synthase activities [154][155][156][157][158], and as we previously mentioned, a reduced mitochondrial potential in the cybrid condition [140]. Interestingly, in a study with cognitively normal individuals with maternal history of late onset of AD was found a reduced activity of platelet CoxIV compared to those with paternal or negative family history [159]. These findings suggest not only a possible mitochondrial peripheral biomarker but also an exclusively maternally inherited marker in humans [159].…”

The Alzheimer’s Disease Mitochondrial Cascade Hypothesis: A Current Overview

“…Another endophenotype study measured platelet mitochondria COX activity in middle-aged, cognitively normal individuals with an AD mother, father, or cognitively intact parents. COX activity was lowest in those with an AD mother [95], a finding consistent with the possibility that mtDNA inheritance influences COX and by extension AD risk.…”

Mitochondria and Cell Bioenergetics: Increasingly Recognized Components and a Possible Etiologic Cause of Alzheimer's Disease

“…On memory tests, APOE4 carriers with AD mothers do not perform as well as APOE4 carriers with AD fathers (69). Platelet mitochondria COX activity is lower in those with AD mothers than it is in those with AD fathers (185). Cybrid, endophenotype, and positive mtDNA-AD association studies are consistent with epidemiology data that suggest an AD maternal inheritance bias does exist (10,77,79,183).…”

New Targets for Diagnosis and Treatment Against Alzheimer’s Disease: The Mitochondrial Approach

“…Platelets presented intracellular calcium deregulation [152,153], an increase in oxidative damage [152,153], a decrease in CoxIV and ATP synthase activities [154][155][156][157][158], and as we previously mentioned, a reduced mitochondrial potential in the cybrid condition [140]. Interestingly, in a study with cognitively normal individuals with maternal history of late onset of AD was found a reduced activity of platelet CoxIV compared to those with paternal or negative family history [159]. These findings suggest not only a possible mitochondrial peripheral biomarker but also an exclusively maternally inherited marker in humans [159].…”