Lifestyle and vascular risk effects on MRI-based biomarkers of Alzheimer's disease: a cross-sectional study of middle-aged adults from the broader New York City area.

OBJECTIVE: To investigate the effects of lifestyle and vascular-related risk factors for Alzheimer's disease (AD) on in vivo MRI-based brain atrophy in asymptomatic young to middle-aged adults. DESIGN: Cross-sectional, observational. SETTING: Broader New York City area. Two research centres affiliated with the Alzheimer's disease Core Center at New York University School of Medicine. PARTICIPANTS: We studied 116 cognitively normal healthy research participants aged 30-60 years, who completed a three-dimensional T1-weighted volumetric MRI and had lifestyle (diet, physical activity and intellectual enrichment), vascular risk (overweight, hypertension, insulin resistance, elevated cholesterol and homocysteine) and cognition (memory, executive function, language) data. Estimates of cortical thickness for entorhinal (EC), posterior cingulate, orbitofrontal, inferior and middle temporal cortex were obtained by use of automated segmentation tools. We applied confirmatory factor analysis and structural equation modelling to evaluate the associations between lifestyle, vascular risk, brain and cognition. RESULTS: Adherence to a Mediterranean-style diet (MeDi) and insulin sensitivity were both positively associated with MRI-based cortical thickness (diet: ßs≥0.26, insulin sensitivity ßs≥0.58, P≤0.008). After accounting for vascular risk, EC in turn explained variance in memory (P≤0.001). None of the other lifestyle and vascular risk variables were associated with brain thickness. In addition, the path associations between intellectual enrichment and better cognition were significant (ßs≥0.25 P≤0.001), as were those between overweight and lower cognition (ßs≥-0.22, P≤0.01). CONCLUSIONS: In cognitively normal middle-aged adults, MeDi and insulin sensitivity explained cortical thickness in key brain regions for AD, and EC thickness predicted memory performance in turn. Intellectual activity and overweight were associated with cognitive performance through different pathways. Our findings support further investigation of lifestyle and vascular risk factor modification against brain ageing and AD. More studies with larger samples are needed to replicate these research findings in more diverse, community-based settings.

Correction: Perimenopause and emergence of an Alzheimer's bioenergetic phenotype in brain and periphery.

[This corrects the article DOI: 10.1371/journal.pone.0185926.].

Perimenopause and emergence of an Alzheimer's bioenergetic phenotype in brain and periphery.

After advanced age, female sex is the major risk factor for Alzheimer's disease (AD). The biological mechanisms underlying the increased AD risk in women remain largely undetermined. Preclinical studies identified the perimenopause to menopause transition, a neuroendocrine transition state unique to the female, as a sex-specific risk factor for AD. In animals, estrogenic regulation of cerebral glucose metabolism (CMRglc) falters during perimenopause. This is evident in glucose hypometabolism and decline in mitochondrial efficiency which is sustained thereafter. This study bridges basic to clinical science to characterize brain bioenergetics in a cohort of forty-three, 40-60 year-old clinically and cognitively normal women at different endocrine transition stages including premenopause (controls, CNT, n = 15), perimenopause (PERI, n = 14) and postmenopause (MENO, n = 14). All participants received clinical, laboratory and neuropsychological examinations, 18F-fluoro-deoxyglucose (FDG)-Positron Emission Tomography (PET) FDG-PET scans to estimate CMRglc, and platelet mitochondrial cytochrome oxidase (COX) activity measures. Statistical parametric mapping and multiple regression models were used to examine clinical, CMRglc and COX data across groups. As expected, the MENO group was older than PERI and controls. Groups were otherwise comparable for clinical measures and distribution of APOE4 genotype. Both MENO and PERI groups exhibited reduced CMRglc in AD-vulnerable regions which was correlated with decline in mitochondrial COX activity compared to CNT (p's<0.001). A gradient in biomarker abnormalities was most pronounced in MENO, intermediate in PERI, and lowest in CNT (p<0.001). Biomarkers correlated with immediate and delayed memory scores (Pearson's 0.26≤r≤0.32, p≤0.05). These findings validate earlier preclinical findings and indicate emergence of bioenergetic deficits in perimenopausal and postmenopausal women, suggesting that the optimal window of opportunity for therapeutic intervention in women is early in the endocrine aging process.

Sex differences in Alzheimer risk: Brain imaging of endocrine vs chronologic aging.

OBJECTIVE: This observational multimodality brain imaging study investigates emergence of endophenotypes of late-onset Alzheimer disease (AD) risk during endocrine transition states in a cohort of clinically and cognitively normal women and age-matched men. METHODS: Forty-two 40- to 60-year-old cognitively normal women (15 asymptomatic perimenopausal by age [CNT], 13 perimenopausal [PERI], and 14 postmenopausal [MENO]) and 18 age- and education-matched men were examined. All patients had volumetric MRI, 18F-fluoro-2-deoxyglucose (FDG)-PET (glucose metabolism), and Pittsburgh compound B-PET scans (ß-amyloid [Aß] deposition, a hallmark of AD pathology). RESULTS: As expected, the MENO group was older than the PERI and CNT groups. Otherwise, groups were comparable on clinical and neuropsychological measures and APOE4 distribution. Compared to CNT women and to men, and controlling for age, PERI and MENO groups exhibited increased indicators of AD endophenotype, including hypometabolism, increased Aß deposition, and reduced gray and white matter volumes in AD-vulnerable regions (p < 0.001). AD biomarker abnormalities were greatest in MENO, intermediate in PERI, and lowest in CNT women (p < 0.001). Aß deposition was exacerbated in APOE4-positive MENO women relative to the other groups (p < 0.001). CONCLUSIONS: Multimodality brain imaging indicates sex differences in development of the AD endophenotype, suggesting that the preclinical AD phase is early in the female aging process and coincides with the endocrine transition of perimenopause. These data indicate that the optimal window of opportunity for therapeutic intervention in women is early in the endocrine aging process.

Effects of vascular risk factors, statins, and antihypertensive drugs on PiB deposition in cognitively normal subjects.

INTRODUCTION: Hypertension, hypercholesterolemia, and obesity increase the risk of dementia. Although their detection is commonly followed by an introduction of treatment, little is known about how medications frequently used to treat vascular risk affect amyloid deposition. METHODS: A cross-sectional study of 156 subjects who underwent positron emission tomography with PiB. Using linear regression, we tested whether blood pressure, cholesterol, overweight/obese status, angiotensin receptor blockers (ARBs), beta-blockers, diuretics, angiotensin converting enzyme inhibitors, and statins predicted amyloid deposition. RESULTS: The use of ARBs (ß = -.15, P = .044) and diuretics (ß = -.20, P = .006) predicted less amyloid accumulation; older age (ß = .29, P < .001) and statins (ß = .23, P = .004) were related to greater amyloid deposition. Overweight and/or obese women had more cortical amyloid than their peers. DISCUSSION: Prospective studies should confirm effects of drugs and increased body weight on amyloid accumulation and establish whether they translate into measurable clinical outcomes. Women may be more susceptible to harmful effects of obesity.

Let Food Be Thy Medicine: Diet, Nutrition, and Biomarkers' Risk of Alzheimer's Disease.

Epidemiological evidence linking diet-one of the most important modifiable lifestyle factors-and risk of Alzheimer's disease (AD)-the most common cause of dementia-is rapidly increasing. However, the biological mechanisms underlying the relationship between dietary nutrients, brain aging, and risk of AD are largely unexplored. Recent studies using brain imaging and biological markers of AD have begun to clarify how diet and nutrition modulate risk of AD in cognitively normal individuals, especially those at increased genetic risk. Such knowledge is critical prior to implementing dietary recommendations for prevention and treatment of disease.

Reduced retention of Pittsburgh compound B in white matter lesions.

PURPOSE: One of the interesting features of the amyloid tracer Pittsburgh compound B (PiB) is that it generates a signal in the white matter (WM) in both healthy subjects and cognitively impaired individuals. This characteristic gave rise to the possibility that PiB could be used to trace WM pathology. In a group of cognitively healthy elderly we examined PiB retention in normal-appearing WM (NAWM) and WM lesions (WML), one of the most common brain pathologies in aging. METHODS: We segmented WML and NAWM on fluid attenuation inversion recovery (FLAIR) images of 73 subjects (age 61.9 ± 10.0, 71 % women). PiB PET images were corrected for partial volume effects and coregistered to FLAIR images and WM masks. WML and NAWM PiB signals were then extracted. RESULTS: PiB retention in WML was lower than in NAWM (p < 0.001, 14.6 % reduction). This was true both for periventricular WML (p < 0.001, 17.8 % reduction) and deep WML (p = 0.001, 7.5 % reduction). CONCLUSION: PiB binding in WM is influenced by the presence of WML, which lower the signal. Our findings add to the growing evidence that PiB can depict WM pathology and should prompt further investigations into PiB binding targets in WM.

Periodontal disease associates with higher brain amyloid load in normal elderly.

The accumulation of amyloid-ß (Aß) plaques is a central feature of Alzheimer's disease (AD). First reported in animal models, it remains uncertain if peripheral inflammatory and/or infectious conditions in humans can promote Aß brain accumulation. Periodontal disease, a common chronic infection, has been previously reported to be associated with AD. Thirty-eight cognitively normal, healthy, and community-residing elderly (mean age, 61 and 68% female) were examined in an Alzheimer's Disease Research Center and a University-Based Dental School. Linear regression models (adjusted for age, apolipoprotein E, and smoking) were used to test the hypothesis that periodontal disease assessed by clinical attachment loss was associated with brain Aß load using (11)C-Pittsburgh compound B (PIB) positron emission tomography imaging. After adjusting for confounders, clinical attachment loss (≥3 mm), representing a history of periodontal inflammatory/infectious burden, was associated with increased PIB uptake in Aß vulnerable brain regions (p = 0.002). We show for the first time in humans an association between periodontal disease and brain Aß load. These data are consistent with the previous animal studies showing that peripheral inflammation/infections are sufficient to produce brain Aß accumulations.

FDG and Amyloid PET in Cognitively Normal Individuals at Risk for Late-Onset Alzheimer's Disease.

Having a parent affected by late-onset Alzheimer's disease (AD) is a major risk factor for cognitively normal (NL) individuals. This study explores the potential of PET with 18F-FDG and the amyloid- ß (Aß) tracer 11C-Pittsburgh Compound B (PiB) for detection of individual risk in NL adults with AD-parents. METHODS: FDG- and PiB-PET was performed in 119 young to late-middle aged NL individuals including 80 NL with positive family history of AD (FH+) and 39 NL with negative family history of any dementia (FH-). The FH+ group included 50 subjects with maternal (FHm) and 30 with paternal family history (FHp). Individual FDG and PiB scans were Z scored on a voxel-wise basis relative to modality-specific reference databases using automated procedures and rated as positive or negative (+/-) for AD-typical abnormalities using predefined criteria. To determine the effect of age, the cohort was separated into younger (49 ± 9 y) and older (68 ± 5 y) groups relative to the median age (60 y). RESULTS: Among individuals of age >60 y, as compared to controls, NL FH+ showed a higher frequency of FDG+ scans vs. FH- (53% vs. 6% p < 0.003), and a trend for PiB+ scans (27% vs. 11%; p = 0.19). This effect was observed for both FHm and FHp groups. Among individuals of age ≤60 y, NL FHm showed a higher frequency of FDG+ scans (29%) compared to FH- (5%, p = 0.04) and a trend compared to FHp (11%) (p = 0.07), while the distribution of PiB+ scans was not different between groups. In both age cohorts, FDG+ scans were more frequent than PiB+ scans among NL FH+, especially FHm (p < 0.03). FDG-PET was a significant predictor of FH+ status. Classification according to PiB status was significantly less successful. CONCLUSIONS: Automated analysis of FDG- and PiB-PET demonstrates higher rates of abnormalities in at-risk FH+ vs FH- subjects, indicating potentially ongoing early AD-pathology in this population. The frequency of metabolic abnormalities was higher than that of Aß pathology in the younger cohort, suggesting that neuronal dysfunction may precede major aggregated Aß burden in young NL FH+. Longitudinal follow-up is required to determine if the observed abnormalities predict future AD.

Nutrient intake and brain biomarkers of Alzheimer's disease in at-risk cognitively normal individuals: a cross-sectional neuroimaging pilot study.

OBJECTIVE: There is increasing evidence to suggest that diet, one of the most important modifiable environmental factors, may play a role in preventing or delaying cognitive decline and Alzheimer's disease (AD). This study examines the relationship between dietary nutrients and brain biomarkers of AD in cognitively normal individuals (NL) with and without AD risk factors. DESIGN: As part of an ongoing brain imaging study, participants received clinical and laboratory examinations, a neurocognitive test battery, positron emission tomography (PET) with (11)C-Pittsburgh Compound-B (PiB; a measure of amyloid-ß (Aß) load) and (18)F-fluorodeoxyglucose (FDG; a proxy of neuronal activity), and completed semiquantitative food frequency questionnaires. SETTING: Research centre affiliated with the Alzheimer's disease Core Center at New York University School of Medicine. PARTICIPANTS: 49 NL individuals (age 25-72 years, 69% women) with dietary information, (11)C-PiB and (18)F-FDG PET scans were examined. RESULTS: Controlling for age and total caloric intake, higher intake of vitamin B12, vitamin D and ω-3 polyunsaturated fatty acid (PUFA) was associated with lower Aß load in AD regions on PiB-PET, while higher intake of ß-carotene and folate was associated with higher glucose metabolism on FDG-PET. ß-carotene and folate were associated with reduced glucose metabolism for women, apolipoprotein E epsilon 4 (APOE4) carriers and participants with positive AD family history, but not for their risk-free counterparts. The associations of vitamin B12, vitamin D and ω-3 PUFA with PiB retention were independent of gender, APOE and family history. The identified nutrient combination was associated with higher intake of vegetables, fruit, whole grains, fish and legumes, and lower intake of high-fat dairies, meat and sweets. CONCLUSIONS: Our data provide a potential pathophysiological mechanism for epidemiological findings showing that dietary interventions may play a role in the prevention of AD. Longitudinal studies are needed to determine whether there is a direct link between nutrient intake, brain biomarkers and risk of AD.

A conceptual framework for research on subjective cognitive decline in preclinical Alzheimer's disease.

There is increasing evidence that subjective cognitive decline (SCD) in individuals with unimpaired performance on cognitive tests may represent the first symptomatic manifestation of Alzheimer's disease (AD). The research on SCD in early AD, however, is limited by the absence of common standards. The working group of the Subjective Cognitive Decline Initiative (SCD-I) addressed this deficiency by reaching consensus on terminology and on a conceptual framework for research on SCD in AD. In this publication, research criteria for SCD in pre-mild cognitive impairment (MCI) are presented. In addition, a list of core features proposed for reporting in SCD studies is provided, which will enable comparability of research across different settings. Finally, a set of features is presented, which in accordance with current knowledge, increases the likelihood of the presence of preclinical AD in individuals with SCD. This list is referred to as SCD plus.

Brain imaging of cognitively normal individuals with 2 parents affected by late-onset AD.

OBJECTIVES: This brain imaging study examines whether cognitively normal (NL) individuals with 2 parents affected by late-onset Alzheimer disease (LOAD) show evidence of more extensive Alzheimer disease pathology compared with those who have a single parent affected by LOAD. METHODS: Fifty-two NL individuals received MRI, (11)C-Pittsburgh compound B (PiB)-PET, and (18)F-fluoro-2-deoxyglucose (FDG)-PET. These included 4 demographically balanced groups (n = 13/group, aged 32-72 years, 60% female, 30% APOE ε4 carriers) of NL individuals with maternal (FHm), paternal (FHp), and maternal and paternal (FHmp) family history of LOAD, and with negative family history (FH-). Statistical parametric mapping, voxel-based morphometry, and z-score mapping were used to compare MRI gray matter volumes (GMVs), partial volume-corrected PiB retention, and FDG metabolism across FH groups and vs FH-. RESULTS: NL FHmp showed more severe abnormalities in all 3 biomarkers vs the other groups regarding the number of regions affected and magnitude of impairment. PiB retention and hypometabolism were most pronounced in FHmp, intermediate in FHm, and lowest in FHp and FH-. GMV reductions were highest in FHmp and intermediate in FHm and FHp vs FH-. In all FH+ groups, amyloid-ß deposition exceeded GMV loss and hypometabolism exceeded GMV loss (p < 0.001), while amyloid-ß deposition exceeded hypometabolism in FHmp and FHp but not in FHm. CONCLUSIONS: These biomarker findings show a "LOAD parent-dose effect" in NL individuals several years, if not decades, before possible clinical symptoms.

Blood pressure decrease correlates with tau pathology and memory decline in hypertensive elderly.

In hypertension (HTN), cerebral blood flow regulation limits are changed, and the threshold for blood pressure (BP) at which perfusion is safely maintained is higher. This shift may increase the brain's vulnerability to lower BP in subjects with vascular disease. We investigated whether longitudinal reduction in mean arterial pressure (MAP) was related to changes in cerebrospinal fluid (CSF) biomarkers of Alzheimer's disease in a group of cognitively healthy elderly with and without HTN. The relationships among MAP, memory decline, and hippocampal atrophy were also examined. Seventy-seven subjects (age 63.4 ± 9.4, range 44-86 years; education 16.9 ± 2.1, range 10-22 years; 60% women) were assessed twice, 2 ± 0.5 years apart. At both time points, all subjects underwent full medical and neuropsychological evaluations, lumbar punctures, and magnetic resonance imaging examinations. Twenty-five subjects had HTN. Hyper- and normotensive subjects did not differ in their CSF biomarkers, hippocampal volumes (HipVs), or memory scores at baseline. In the entire study group, the increase in tau phosphorylated at threonine 181 (p-tau(181)) was associated with a decline in verbal episodic memory (ß = -0.30, p = 0.01) and HipV reduction (ß = -0.27, p = 0.02). However, longitudinal decrease in MAP was related to memory decline (ß = 0.50, p = 0.01) and an increase in p-tau(181) (ß = -0.50, p = 0.01) only in subjects with HTN. Our findings suggest that the hypertensive group may be sensitive to BP reductions.

Physical Activity, Mediterranean Diet and Biomarkers-Assessed Risk of Alzheimer's: A Multi-Modality Brain Imaging Study.

Increased physical activity and higher adherence to a Mediterranean-type diet (MeDi) have been independently associated with reduced risk of Alzheimer's disease (AD). Their association has not been investigated with the use of biomarkers. This study examines whether, among cognitively normal (NL) individuals, those who are less physically active and show lower MeDi adherence have brain biomarker abnormalities consistent with AD. METHODS: Forty-five NL individuals (age 54 ± 11, 71% women) with complete leisure time physical activity (LTA), dietary information, and cross-sectional 3D T1-weigthed MRI, 11C-Pittsburgh Compound B (PiB) and 18F-fluorodeoxyglucose (FDG) Positron Emission Tomography (PET) scans were examined. Voxel-wise multivariate partial least square (PLS) regression was used to examine the effects of LTA, MeDi and their interaction on brain biomarkers. Age, gender, ethnicity, education, caloric intake, BMI, family history of AD, Apolipoprotein E (APOE) genotype, presence of hypertension and insulin resistance were examined as confounds. Subjects were dichotomized into more and less physically active (LTA+ vs. LTA-; n = 21 vs. 24), and into higher vs. lower MeDi adherence groups (n = 18 vs. 27) using published scoring methods. Spatial patterns of brain biomarkers that represented the optimal association between the images and the groups were generated for all modalities using voxel-wise multivariate Partial Least Squares (PLS) regression. RESULTS: Groups were comparable for clinical and neuropsychological measures. Independent effects of LTA and MeDi factors were observed in AD-vulnerable brain regions for all modalities (p < 0.001). Increased AD-burden (in particular higher Aß load and lower glucose metabolism) were observed in LTA- compared to LTA+ subjects, and in MeDi- as compared to MeDi+ subjects. A gradient effect was observed for all modalities so that LTA-/MeDi- subjects had the highest and LTA+/MeDi+ subjects had the lowest AD-burden (p < 0.001), although the LTA × MeDi interaction was significant only for FDG measures (p < 0.03). Adjusting for covariates did not attenuate these relationships. CONCLUSION: Lower physical activity and MeDi adherence were associated with increased brain AD-burden among NL individuals, indicating that lifestyle factors may modulate AD risk. Studies with larger samples and longitudinal evaluations are needed to determine the predictive power of the observed associations.

Amyloid and metabolic positron emission tomography imaging of cognitively normal adults with Alzheimer's parents.

This study examines the relationship between fibrillar beta-amyloid (Aß) deposition and reduced glucose metabolism, a proxy for neuronal dysfunction, in cognitively normal (NL) individuals with a parent affected by late-onset Alzheimer's disease (AD). Forty-seven 40-80-year-old NL received positron emission tomography (PET) with (11)C-Pittsburgh compound B (PiB) and 18F-fluoro-2-deoxy-d-glucose (FDG). These included 19 NL with a maternal history (MH), 12 NL with a paternal history (PH), and 16 NL with negative family history of AD (NH). Automated regions of interest, statistical parametric mapping, voxel-wise intermodality correlations, and logistic regressions were used to examine cerebral-to-cerebellar PiB and FDG standardized uptake value ratios across groups. The MH group showed higher PiB retention and lower metabolism in AD regions compared with NH and PH, which were negatively correlated in posterior cingulate, frontal, and parieto-temporal regions (Pearson r ≤ -0.57, p ≤ 0.05). No correlations were observed in NH and PH. The combination of Aß deposition and metabolism yielded accuracy ≥ 69% for MH vs. NH and ≥ 71% for MH vs. PH, with relative risk = 1.9-5.1 (p values < 0.005). NL individuals with AD-affected mothers show co-occurring Aß increases and hypometabolism in AD-vulnerable regions, suggesting an increased risk for AD.

Alzheimer's disease markers, hypertension, and gray matter damage in normal elderly.

It is not well known whether Alzheimer's disease (AD) cerebrospinal fluid (CSF) biomarkers are associated with brain damage in cognitively normal elderly. The combined influence of CSF biomarkers and hypertension (HTN) on the gray matter (GM) is also not well described. One hundred fifteen cognitively healthy subjects (mean age 62.6 ± 9.5%, 62% women) received clinical assessment, a high resolution magnetic resonance imaging (MRI), and a lumbar puncture. The CSF levels of total tau (t-tau), hyperphosphorylated tau (p-tau(231)), amyloid beta (Aß42/Aß40), p-tau(231)/Aß42, and t-tau/Aß42 were dichotomized as "high" and "low" based on accepted cut off values. Statistical parametric mapping was used to examine MRI scans for regional GM density, studied as a function of the CSF markers, HTN, and combination of both. Global and medial temporal lobe (MTL) GM was also assessed. Voxel based morphometry revealed that higher t-tau was associated with lower GM density in the precunei. Subjects with higher p-tau(231) and p-tau(231)/Aß42 had less GM in temporal lobes. Low Aß42/Aß40 was related to less GM in the thalami, caudate, and midbrain. Subjects with hypertension showed more GM atrophy in the cerebellum, occipital, and frontal regions. Simultaneous presence of elevated CSF AD biomarkers and HTN was associated with more GM atrophy than either marker individually, but no interaction effects were identified. In conclusion, in normal elderly CSF tau markers were associated predominantly with lower GM estimates in structures typically affected early in the AD process. In this presymptomatic stage when no cognitive impairment is present, AD biomarkers and HTN have additive effects on gray matter damage.

Maternal age affects brain metabolism in adult children of mothers affected by Alzheimer's disease.

Cognitively normal (NL) individuals with a maternal history of late-onset Alzheimer's disease (MH) show reduced brain glucose metabolism on FDG-PET as compared to those with a paternal history (PH) and those with negative family history (NH) of Alzheimer's disease (AD). This FDG-PET study investigates whether metabolic deficits in NL MH are associated with advancing maternal age at birth. Ninety-six NL individuals with FDG-PET were examined, including 36 MH, 24 PH, and 36 NH. Regional-to-whole brain gray matter standardized FDG uptake value ratios were examined for associations with parental age across groups using automated regions-of-interest and statistical parametric mapping. Groups were comparable for clinical and neuropsychological measures. Brain metabolism in AD-vulnerable regions was lower in MH compared to NH and PH, and negatively correlated with maternal age at birth only in MH. There were no associations between paternal age and metabolism in any group. Evidence for a maternally inherited, maternal age-related mechanism provides further insight on risk factors and genetic transmission in late-onset AD.

Reduced mitochondria cytochrome oxidase activity in adult children of mothers with Alzheimer's disease.

Biomarker studies demonstrate inheritance of glucose hypometabolism and increased amyloid-ß 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.

Oxidative stress and amyloid-beta pathology in normal individuals with a maternal history of Alzheimer's.

BACKGROUND: Epidemiology and imaging studies showed that cognitively normal (NL) individuals with a maternal history (MH) of late-onset Alzheimer's disease (LOAD) might be at increased risk for Alzheimer's disease (AD) compared with NL with a paternal history (PH) and NL with a negative family history of LOAD (NH). With a panel of cerebrospinal fluid (CSF) markers, this study examined whether NL MH showed evidence for AD pathology compared with PH and NH. METHODS: Fifty-nine 40-80-year-old NL subjects were examined, including 23 MH and 14 PH whose parents had a clinician-certified diagnosis of LOAD and 22 NH. All subjects completed clinical neuropsychological examinations and a lumbar puncture to measure CSF levels of amyloid-beta (Aß(40), Aß(42), Aß(42/40)), total and hyperphosphorylated tau (T-Tau and P-Tau(231); markers of axonal degeneration and neurofibrillary tangles, respectively), and F2-isoprostanes (IsoP) (a marker of oxidative stress). RESULTS: Groups were comparable for demographic and neuropsychological measures. The MH subjects showed higher IsoP and reduced Aß(42/40) CSF levels compared with NH and with PH (p values ≤ .05), whereas no differences were found between NH and PH. No group differences were found for P-Tau(231) and T-Tau. The IsoP and Aß(42/40) levels were correlated only within the MH group (R² = .32, p = .005) and discriminated MH from the other subjects with 70% accuracy (relative risk = 3.7%, 95% confidence interval = 1.6-9.7, p < .001). Results remained significant controlling for age, gender, education, and apolipoprotein E genotype. CONCLUSIONS: Adult children of LOAD-affected mothers express a pathobiological phenotype characterized by Aß-associated oxidative stress consistent with AD, which might reflect increased risk for developing the disease.

Plasma BDNF is reduced among middle-aged and elderly women with impaired insulin function: evidence of a compensatory mechanism.

Brain-derived neurotrophic factor (BDNF) plays a regulatory role in neuronal differentiation and synaptic plasticity and has been linked to glucose regulation and cognition. Associations among plasma BDNF, cognition, and insulin function were explored. Forty-one participants with impaired insulin function (IIF), ranging from insulin resistance to type 2 diabetes mellitus (T2DM), were matched with 41 healthy controls on gender, age, education, and IQ. Participants received complete medical, neurological, psychiatric, and neuropsychological evaluations. IIF individuals had significantly lower plasma BDNF levels than controls, particularly females, and higher BDNF levels were associated with poorer explicit memory in IIF females, suggesting that higher levels within this group may reflect the body's efforts to respond to damage. After accounting for age, education, and HbA1c, BDNF significantly predicted 13.1-23.5% of the variance in explicit memory in IIF women. These findings suggest that BDNF elevations within diseased groups may not always be a marker of health.