Alzheimer's disease cortical morphological phenotypes are associated with TOMM40'523-APOE haplotypes.

Both the APOE ε4 and TOMM40 rs10524523 ("523") genes have been associated with risk for Alzheimer's disease (AD) and neuroimaging biomarkers of AD. No studies have investigated the relationship of TOMM40'523-APOE ε4 on the structural complexity of the brain in AD individuals. We quantified brain morphology and multiple cortical attributes in individuals with mild cognitive impairment (MCI) and AD, then tested whether APOE ε4 or TOMM40 poly-T genotypes were related to AD morphological biomarkers in cognitively unimpaired (CU) and MCI/AD individuals. We identified several AD-specific phenotypes in brain morphology and found that TOMM40 poly-T short alleles are associated with early, AD-specific brain morphological differences in healthy aging. We observed decreased cortical thickness, sulcal depth, and fractal dimension in CU individuals with the poly-T short alleles. Moreover, in MCI/AD participants, the APOE ε4 (TOMM40 L) individuals had a higher rate of gene-related morphological markers indicative of AD. Our data suggest that TOMM40'523 is associated with early brain structure variations in the precuneus, temporal, and limbic cortices.

Increased Functional Connectivity of the Precuneus in Individuals with a Family History of Alzheimer's Disease.

BACKGROUND: First-degree relatives of individuals with late-onset Alzheimer's disease (AD) have increased risk for AD, with children of affected parents at an especially high risk. OBJECTIVE: We aimed to investigate default mode network connectivity, medial temporal cortex volume, and cognition in cognitively healthy (CH) individuals with (FH+) and without (FH-) a family history of AD, alongside amnestic mild cognitive impairment (aMCI) and AD individuals, to determine the context and directionality of dysfunction in at-risk individuals. Our primary hypothesis was that there would be a linear decline (CH FH- > CH FH+ > aMCI > AD) within the risk groups on all measures of AD risk. METHODS: We used MRI and fMRI to study cognitively healthy individuals (n = 28) with and without AD family history (FH+ and FH-, respectively), those with aMCI (n = 31) and early-stage AD (n = 25). We tested connectivity within the default mode network, as well as measures of volume and thickness within the medial temporal cortex and selected seed regions. RESULTS: As expected, we identified decreased medial temporal cortex volumes in the aMCI and AD groups compared to cognitively healthy groups. We also observed patterns of connectivity across risk groups that suggest a nonlinear relationship of change, such that the FH+ group showed increased connectivity compared to the FH- and AD groups (CH FH+ > CH FH- > aMCI > AD). This pattern emerged primarily in connectivity between the precuneus and frontal regions. CONCLUSION: These results add to a growing literature that suggests compensatory brain function in otherwise cognitively healthy individuals with a family history of AD.

Sex Differences in Resilience and Resistance to Brain Pathology and Dysfunction Moderated by Cerebrovascular Response to Exercise and Genetic Risk for Alzheimer's Disease.

Sex as a biological variable appears to contribute to the multifactorial etiology of Alzheimer's disease. We tested sex-based interactions between cerebrovascular function and APOE4 genotype on resistance and resilience to brain pathology and cognitive executive dysfunction in cognitively-normal older adults. Female APOE4 carriers had higher amyloid-ß deposition yet achieved similar cognitive performance to males and female noncarriers. Further, female APOE4 carriers with robust cerebrovascular responses to exercise possessed lower amyloid-ß. These results suggest a unique cognitive resilience and identify cerebrovascular function as a key mechanism for resistance to age-related brain pathology in females with high genetic vulnerability to Alzheimer's disease.

Dementia risk and dynamic response to exercise: A non-randomized clinical trial.

BACKGROUND: Physical exercise may support brain health and cognition over the course of typical aging. The goal of this nonrandomized clinical trial was to examine the effect of an acute bout of aerobic exercise on brain blood flow and blood neurotrophic factors associated with exercise response and brain function in older adults with and without possession of the Apolipoprotein epsilon 4 (APOE4) allele, a genetic risk factor for developing Alzheimer's. We hypothesized that older adult APOE4 carriers would have lower cerebral blood flow regulation and would demonstrate blunted neurotrophic response to exercise compared to noncarriers. METHODS: Sixty-two older adults (73±5 years old, 41 female [67%]) consented to this prospectively enrolling clinical trial, utilizing a single arm, single visit, experimental design, with post-hoc assessment of difference in outcomes based on APOE4 carriership. All participants completed a single 15-minute bout of moderate-intensity aerobic exercise. The primary outcome measure was change in cortical gray matter cerebral blood flow in cortical gray matter measured by magnetic resonance imaging (MRI) arterial spin labeling (ASL), defined as the total perfusion (area under the curve, AUC) following exercise. Secondary outcomes were changes in blood neurotrophin concentrations of insulin-like growth factor-1 (IGF-1), vascular endothelial growth factor (VEGF), and brain derived neurotrophic factor (BDNF). RESULTS: Genotyping failed in one individual (n = 23 APOE4 carriers and n = 38 APOE4 non-carriers) and two participants could not complete primary outcome testing. Cerebral blood flow AUC increased immediately following exercise, regardless of APOE4 carrier status. In an exploratory regional analyses, we found that cerebral blood flow increased in hippocampal brain regions, while showing no change in cerebellum across both groups. Among high inter-individual variability, there were no significant changes in any of the 3 neurotrophic factors for either group immediately following exercise. CONCLUSIONS: Our findings show that both APOE4 carriers and non-carriers show similar effects of exercise-induced increases in cerebral blood flow and neurotrophic response to acute aerobic exercise. Our results provide further evidence that acute exercise-induced increases in cerebral blood flow may be regional specific, and that exercise-induced neurotrophin release may show a differential effect in the aging cardiovascular system. Results from this study provide an initial characterization of the acute brain blood flow and neurotrophin responses to a bout of exercise in older adults with and without this known risk allele for cardiovascular disease and Alzheimer's disease. TRIAL REGISTRATION: Dementia Risk and Dynamic Response to Exercise (DYNAMIC); Identifier: NCT04009629.

Cerebrovascular response to exercise interacts with individual genotype and amyloid-beta deposition to influence response inhibition with aging.

The etiology of cognitive dysfunction associated with Alzheimer's disease (AD) and dementia is multifactorial. Yet, mechanistic interactions among key neurobiological factors linked to AD pathology are unclear. This study tested the effect of interactions between cerebrovascular function, individual genotype, and structural brain pathology on response inhibition performance, an early and sensitive indicator of cognitive executive dysfunction with aging. We quantified cerebrovascular response (CVR) to moderate-intensity aerobic exercise using transcranial doppler ultrasound and global amyloid-beta (Aß) deposition using positron emission tomography in a group of cognitively normal older adults genotyped as APOE4 carriers and noncarriers. We quantified response inhibition during a cognitive Stroop test. Individuals with blunted CVR possessed greater Aß deposition. There was CVR-by-carrier status-by-Aß interaction on response inhibition. Blunted CVR was associated with impaired response inhibition specifically in APOE4 carriers. Despite having greater Aß deposition, APOE4 carriers with higher CVR demonstrated better response inhibition. Cerebrovascular interactions with individual genotype and structural brain pathology may provide a physiologically-informed target for precision-medicine approaches for early treatment and prevention of cognitive dysfunction with aging.

Relationship of fasting glucose and longitudinal Alzheimer's disease imaging markers.

INTRODUCTION: Fasting glucose increases with age and is linked to modifiable Alzheimer's disease risk factors such as cardiovascular disease and Type 2 diabetes (T2D). METHODS: We leveraged available biospecimens and neuroimaging measures collected during the Alzheimer's Prevention Through Exercise (APEx) trial (n = 105) to examine the longitudinal relationship between change in blood glucose metabolism and change in regional cerebral amyloid deposition and gray and white matter (WM) neurodegeneration in older adults over 1 year of follow-up. RESULTS: Individuals with improving fasting glucose (n = 61) exhibited less atrophy and regional amyloid accumulation compared to those whose fasting glucose worsened over 1 year (n = 44). Specifically, while individuals with increasing fasting glucose did not yet show cognitive decline, they did have regional atrophy in the hippocampus and inferior parietal cortex, and increased amyloid accumulation in the precuneus cortex. Signs of early dementia pathology occurred in the absence of significant group differences in insulin or body composition, and was not modified by apolipoprotein E ε4 carrier status. DISCUSSION: Dysregulation of glucose in late life may signal preclinical brain change prior to clinically relevant cognitive decline. Additional work is needed to determine whether treatments specifically targeting fasting glucose levels may impact change in brain structure or cerebral amyloid in older adults.

Association between the Estimated Glomerular Filtration Rate and Brain Atrophy in Older Adults.

End-stage kidney disease has been associated with cognitive impairment and brain atrophy. It remains unclear if mild to moderate kidney dysfunction is associated with brain atrophy, especially in older adults. We used cross-sectional data from the Alzheimer's Disease Neuroimaging Initiative (ADNI), an NIH-funded multicenter longitudinal cohort study, to better understand the association between estimated glomerular filtration rate (eGFR) and brain volumes. We included all ADNI participants with both baseline serum creatinine values and MRI brain volume assessments. We used multiple linear regression modeling to assess cross-sectional associations between eGFR and whole-brain gray matter, hippocampus, entorhinal, fusiform, and middle temporal brain volumes. Participants (n = 1,596) were 74 ± 7 years old with a mean eGFR of 69.4 ± 14.8 mL/min/1.73 m2; 53% had mild cognitive impairment, and 19% had dementia. Unadjusted analysis showed an association between lower eGFR and smaller brain volumes. After adjusting for age, sex, and education, there was no association between eGFR brain volumes (p > 0.05 for all). These results remained consistent after subgroup analysis by age stratification and baseline cognitive status. Age was a confounding variable in the unadjusted association between the eGFR and brain volumes. Thus, a mild to moderately reduced eGFR was not associated with brain atrophy in ADNI participants.

High Glycemic Diet Is Related to Brain Amyloid Accumulation Over One Year in Preclinical Alzheimer's Disease.

Objective: To test the hypothesis that high glycemic diet is related to 1-year change in brain amyloid based on our prior cross-sectional evidence that high glycemic diet is associated with brain amyloid. Methods: This longitudinal, observational study assessed the relationship between reported habitual consumption of a high glycemic diet (HGDiet) pattern and 1-year brain amyloid change measured by Florbetapir F18 PET scans in 102 cognitively normal older adults with elevated or sub-threshold amyloid status that participated in a 1-year randomized, controlled exercise trial at the University of Kansas Medical Center in Kansas City. Results: Among all participants (n = 102), higher daily intake of the HGDiet pattern (ß = 0.06, p = 0.04), sugar (ß = 0.07, p = 0.01), and total carbohydrate (ß = 0.06, p = 0.04) were related to more precuneal amyloid accumulation. These relationships in the precuneus were accentuated in participants with elevated amyloid at enrollment (n = 70) where higher intake of the HGDiet pattern, sugar, and carbohydrate were related to more precuneal amyloid accumulation (ß = 0.11, p = 0.01 for all measures). In individuals with elevated amyloid, higher intake of the HGDiet pattern was also related to more amyloid accumulation in the lateral temporal lobe (ß = 0.09, p < 0.05) and posterior cingulate gyrus (ß = 0.09, p < 0.05) and higher sugar and carbohydrate intake were also related to more amyloid accumulation in the posterior cingulate gyrus (ß = 0.10, p < 0.05 for both measures). Conclusion: This longitudinal observational analysis suggests that a high glycemic diet relates to higher brain amyloid accumulation over 1 year in regions of the temporoparietal cortex in cognitively normal adults, particularly in those with elevated amyloid status. Further studies are required to assess whether there is causal link between a high glycemic diet and brain amyloid. Clinical Trial Registration: ClinicalTrials.gov, Identifier (NCT02000583).

Rationale and methods to characterize the acute exercise response in aging and Alzheimer's Disease: the AEROBIC pilot study.

There is evidence that exercise benefits the brain, but the mechanisms for this benefit are unclear. The chronic benefits of exercise are likely a product of discreet, acute responses in exercise-related blood biomarkers and brain metabolism. This acute exercise response has not been compared in aging and Alzheimer's Disease (AD). It is known that acute exercise elicits a powerful peripheral response in young individuals, and exercise-related biomarkers such as glucose and lactate readily penetrate the brain. How this changes with aging and neurodegenerative disease is less clear. It is critical to characterize and understand the acute effects of exercise, including different exercise intensities, in terms of the peripheral metabolic response and relationship with brain metabolism. This will help determine potential mechanisms for brain benefits of exercise and better inform the design of future clinical trials. The primary goal of the AEROBIC study is to characterize the acute exercise response of brain glucose metabolism and exercise-related blood biomarkers. We will measure how cerebral metabolism is affected by an acute bout of moderate and higher intensity exercise and characterize the extent to which this differs between cognitively healthy older adults and individuals with AD. Related to this primary goal, we will quantify the peripheral biomarker response to moderate and higher intensity exercise and how this relates to brain metabolic change in both groups.

Aerobic exercise improves hippocampal blood flow for hypertensive Apolipoprotein E4 carriers.

Cerebrovascular dysfunction likely contributes causally to Alzheimer's disease (AD). The strongest genetic risk factor for late-onset AD, Apolipoprotein E4 (APOE4), may act synergistically with vascular risk to cause dementia. Therefore, interventions that improve vascular health, such as exercise, may be particularly beneficial for APOE4 carriers. We assigned cognitively normal adults (65-87 years) to an aerobic exercise intervention or education only. Arterial spin labeling MRI measured hippocampal blood flow (HBF) before and after the 52-week intervention. We selected participants with hypertension at enrollment (n = 44). For APOE4 carriers, change in HBF (ΔHBF) was significantly (p = 0.006) higher for participants in the exercise intervention (4.09 mL/100g/min) than the control group (-2.08 mL/100g/min). There was no difference in ΔHBF between the control (-0.32 mL/100g/min) and exercise (-0.54 mL/100g/min) groups for non-carriers (p = 0.918). Additionally, a multiple regression showed an interaction between change in systolic blood pressure (ΔSBP) and APOE4 carrier status on ΔHBF (p = 0.035), with reductions in SBP increasing HBF for APOE4 carriers only. Aerobic exercise improved HBF for hypertensive APOE4 carriers only. Additionally, only APOE4 carriers exhibited an inverse relationship between ΔSBP and ΔHBF. This suggests exercise interventions, particularly those that lower SBP, may be beneficial for individuals at highest genetic risk of AD.ClinicalTrials.gov Identifier: NCT02000583.

Effect of aerobic exercise on amyloid accumulation in preclinical Alzheimer's: A 1-year randomized controlled trial.

BACKGROUND: Our goal was to investigate the role of physical exercise to protect brain health as we age, including the potential to mitigate Alzheimer's-related pathology. We assessed the effect of 52 weeks of a supervised aerobic exercise program on amyloid accumulation, cognitive performance, and brain volume in cognitively normal older adults with elevated and sub-threshold levels of cerebral amyloid as measured by amyloid PET imaging. METHODS AND FINDINGS: This 52-week randomized controlled trial compared the effects of 150 minutes per week of aerobic exercise vs. education control intervention. A total of 117 underactive older adults (mean age 72.9 [7.7]) without evidence of cognitive impairment, with elevated (n = 79) or subthreshold (n = 38) levels of cerebral amyloid were randomized, and 110 participants completed the study. Exercise was conducted with supervision and monitoring by trained exercise specialists. We conducted 18F-AV45 PET imaging of cerebral amyloid and anatomical MRI for whole brain and hippocampal volume at baseline and Week 52 follow-up to index brain health. Neuropsychological tests were conducted at baseline, Week 26, and Week 52 to assess executive function, verbal memory, and visuospatial cognitive domains. Cardiorespiratory fitness testing was performed at baseline and Week 52 to assess response to exercise. The aerobic exercise group significantly improved cardiorespiratory fitness (11% vs. 1% in the control group) but there were no differences in change measures of amyloid, brain volume, or cognitive performance compared to control. CONCLUSIONS: Aerobic exercise was not associated with reduced amyloid accumulation in cognitively normal older adults with cerebral amyloid. In spite of strong systemic cardiorespiratory effects of the intervention, the observed lack of cognitive or brain structure benefits suggests brain benefits of exercise reported in other studies are likely to be related to non-amyloid effects. TRIAL REGISTRATION: NCT02000583; ClinicalTrials.gov.

Characterization of the Meal-Stimulated Incretin Response and Relationship With Structural Brain Outcomes in Aging and Alzheimer's Disease.

BACKGROUND: Individuals with Alzheimer's Disease (AD) are often characterized by systemic markers of insulin resistance; however, the broader effects of AD on other relevant metabolic hormones, such as incretins that affect insulin secretion and food intake, remains less clear. METHODS: Here, we leveraged a physiologically relevant meal tolerance test to assess diagnostic differences in these metabolic responses in cognitively healthy older adults (CH; n = 32) and AD (n = 23) participants. All individuals also underwent a comprehensive clinical examination, cognitive evaluation, and structural magnetic resonance imaging. RESULTS: The meal-stimulated response of glucose, insulin, and peptide tyrosine tyrosine (PYY) was significantly greater in individuals with AD as compared to CH. Voxel-based morphometry revealed negative relationships between brain volume and the meal-stimulated response of insulin, C-Peptide, and glucose-dependent insulinotropic polypeptide (GIP) in primarily parietal brain regions. CONCLUSION: Our findings are consistent with prior work that shows differences in metabolic regulation in AD and relationships with cognition and brain structure.

Long-chain polyunsaturated fatty acid supplementation in the first year of life affects brain function, structure, and metabolism at age nine years.

The present study sought to determine whether supplementation of long-chain polyunsaturated fatty acids (LCPUFA) during the first year of life influenced brain function, structure, and metabolism at 9 years of age. Newborns were randomly assigned to consume formula containing either no LCPUFA (control) or formula with 0.64% of total fatty acids as arachidonic acid (ARA; 20:4n6) and variable amounts of docosahexaenoic acid (DHA; 22:6n3) (0.32%, 0.64%, or 0.96% of total fatty acids) from birth to 12 months. At age 9 years (±0.6), 42 children enrolled in a follow-up multimodal magnetic resonance imaging (MRI) study including functional (fMRI, Flanker task), resting state (rsMRI), anatomic, and proton magnetic resonance spectroscopy (1 H MRS). fMRI analysis using the Flanker task found that trials requiring greater inhibition elicited greater brain activation in LCPUFA-supplemented children in anterior cingulate cortex (ACC) and parietal regions. rsMRI analysis showed that children in the 0.64% group exhibited greater connectivity between prefrontal and parietal regions compared to all other groups. In addition, voxel-based analysis (VBM) revealed that the 0.32% and 0.64% groups had greater white matter volume in ACC and parietal regions compared to controls and the 0.96% group. Finally, 1 H MRS data analysis identified that N-acetylaspartate (NAA) and myo-inositol (mI) were higher in LCPUFA groups compared to the control group. LCPUFA supplementation during infancy has lasting effects on brain structure, function, and neurochemical concentrations in regions associated with attention (parietal) and inhibition (ACC), as well as neurochemicals associated with neuronal integrity (NAA) and brain cell signaling (mI).

Aerobic exercise for Alzheimer's disease: A randomized controlled pilot trial.

BACKGROUND: There is increasing interest in the role of physical exercise as a therapeutic strategy for individuals with Alzheimer's disease (AD). We assessed the effect of 26 weeks (6 months) of a supervised aerobic exercise program on memory, executive function, functional ability and depression in early AD. METHODS AND FINDINGS: This study was a 26-week randomized controlled trial comparing the effects of 150 minutes per week of aerobic exercise vs. non-aerobic stretching and toning control intervention in individuals with early AD. A total of 76 well-characterized older adults with probable AD (mean age 72.9 [7.7]) were enrolled and 68 participants completed the study. Exercise was conducted with supervision and monitoring by trained exercise specialists. Neuropsychological tests and surveys were conducted at baseline,13, and 26 weeks to assess memory and executive function composite scores, functional ability (Disability Assessment for Dementia), and depressive symptoms (Cornell Scale for Depression in Dementia). Cardiorespiratory fitness testing and brain MRI was performed at baseline and 26 weeks. Aerobic exercise was associated with a modest gain in functional ability (Disability Assessment for Dementia) compared to individuals in the ST group (X2 = 8.2, p = 0.02). There was no clear effect of intervention on other primary outcome measures of Memory, Executive Function, or depressive symptoms. However, secondary analyses revealed that change in cardiorespiratory fitness was positively correlated with change in memory performance and bilateral hippocampal volume. CONCLUSIONS: Aerobic exercise in early AD is associated with benefits in functional ability. Exercise-related gains in cardiorespiratory fitness were associated with improved memory performance and reduced hippocampal atrophy, suggesting cardiorespiratory fitness gains may be important in driving brain benefits. TRIAL REGISTRATION: ClinicalTrials.gov NCT01128361.

Structural Brain Imaging in People With Low Back Pain.

STUDY DESIGN: Cross-sectional study. OBJECTIVE: The aim of this study was to determine whether low back pain (subacute and chronic) is related to differences in brain volume. SUMMARY OF BACKGROUND DATA: Inconsistent findings have been reported about the effect of chronic low back pain on brain volume, and the effect of subacute low back pain on brain volume has not been sufficiently investigated. METHODS: A total of 130 participants were included (23 subacute and 68 chronic low back pain; 39 healthy controls). The main outcome measure was whole and regional brain volume. Clinical outcome measures included pain duration, pain intensity, fear avoidance belief questionnaire, Oswestry Disability Index, and Beck's Depression Inventory. RESULTS: Decrease in brain volume in several regions was observed in chronic low back pain when compared with health subjects; however, after correcting for multiple comparisons, no significant differences were detected between any of the three groups in whole-brain volume. Regionally, we detected less gray matter volume in two voxels in the middle frontal gyrus in chronic low back pain participants compared with healthy controls. None of the clinical outcome measures were correlated with brain volume measurements. CONCLUSION: Low back pain (subacute or chronic) is not related to significant differences in brain volume after correction for multiple comparisons. The effect size was too small to detect possible subtle changes unless much larger sample sizes are examined, or it is possible that low back pain does not affect brain volume. LEVEL OF EVIDENCE: 5.

Voxel-based morphometry reveals brain gray matter volume changes in successful dieters.

OBJECTIVE: To compare regional brain volume predictors of percent weight loss (WL) in dieters with obesity (DwO) and in the same participants categorized as "successful" (≥7% WL) or "unsuccessful" dieters (<7% WL). METHODS: DwO (n = 72) and participants with healthy weight (n = 22) completed a structural MRI at baseline and 3 months. All DwO participants were enrolled in a 12-week program consisting of a reduced calorie diet, increased physical activity, and behavioral modification. SPM8-based voxel-based morphometry processing streams were used for measurements of regional gray (GMV) and white matter volume and longitudinal changes in volume. Correlations between WL and baseline brain volume and change in brain volume, as well as differences between groups, were then tested. RESULTS: %WL was positively correlated with baseline GMV in right parahippocampal and orbitofrontal gyri in DwO. Successful dieters showed greater GMV loss in the left precentral gyrus and the insula compared with unsuccessful dieters. A negative correlation was found between %WL and GMV change from baseline in the left prefrontal regions. CONCLUSIONS: Findings illustrate that WL is related to volumetric changes in brain areas previously linked to interoception and food motivation.

Cognitive Function and White Matter Changes Associated with Renal Transplantation.

BACKGROUND: End-stage renal disease (ESRD) is a disease with an aging population and a high prevalence of cognitive impairment affecting quality of life, health care costs and mortality. Structural changes in the brain with decreased white matter integrity have been observed in ESRD. Understanding the changes in cognition and associated changes in brain structure after renal transplantation can help define the mechanisms underlying cognitive impairment in ESRD. METHODS: We conducted a prospective, observational cohort study in ESRD patients listed for renal transplantation and followed them post-transplantation. We assessed their cognitive function with a battery of neuropsychological tests and brain white matter integrity with diffusion tensor imaging (DTI) both before transplant and 3 months after transplant. RESULTS: Eleven patients, aged 56.5 ± 10.7 years, completed the study. Cognitive measures of memory and executive function improved after the transplant, specifically on tests of logical memory I (p = 0.004), logical memory II (p = 0.003) and digit symbol (p < 0.0001). DTI metrics also improved post the transplant with an increase in fractional anisotropy (p = 0.01) and decrease in mean diffusivity (p = 0.004). These changes were more prominent in tracts associated with memory and executive function. CONCLUSIONS: Cognitive function, particularly memory and executive function, improve post the transplant with concurrent improvements in white matter integrity in tracts associated with memory and executive function. These data suggest that abnormalities in cognition and brain structure seen in the ESRD population are at least partially reversible.

A combined measure of vascular risk for white matter lesions.

BACKGROUND: Though hypertension is a commonly studied risk factor for white matter lesions (WMLs), measures of blood pressure may fluctuate depending on external conditions resulting in measurement error. Indicators of arterial stiffening and reduced elasticity may be more sensitive indicators of risk for WMLs in aging; however the interdependent nature of vascular indicators creates statistical complications. OBJECTIVE: The purpose of the study was to determine whether a factor score comprised of multiple vascular indicators would be a stronger predictor of WMLs than traditional measures of blood pressure. METHODS: In a sample of well-characterized nondemented older adults, we used a factor analytic approach to account for variance common across multiple vascular measures while reducing measurement error. The result was a single factor score reflecting arterial stiffness and reduced elasticity. We used this factor score to predict white matter lesion volumes acquired via fluid attenuated inversion recovery (FLAIR) magnetic resonance imaging. RESULTS: The combined vascular factor score was a stronger predictor of deep WML (ß = 0.42, p < 0.001) and periventricular WML volumes (ß = 0.49, p < 0.001). After accounting for the vascular factor, systolic and diastolic blood pressure measurements were not significant predictors. CONCLUSIONS: This suggests that a combined measure of arterial elasticity and stiffening may be a stronger predictor of WMLs than systolic and diastolic blood pressure accounting for the multicollinearity associated with a variety of interrelated vascular measures.

Is Alzheimer's disease a systemic disease?

Although Alzheimer's disease (AD) is the most common neurodegenerative disease, the etiology of AD is not well understood. In some cases, genetic factors explain AD risk, but a high percentage of late-onset AD is unexplained. The fact that AD is associated with a number of physical and systemic manifestations suggests that AD is a multifactorial disease that affects both the CNS and periphery. Interestingly, a common feature of many systemic processes linked to AD is involvement in energy metabolism. The goals of this review are to 1) explore the evidence that peripheral processes contribute to AD risk, 2) explore ways that AD modulates whole-body changes, and 3) discuss the role of genetics, mitochondria, and vascular mechanisms as underlying factors that could mediate both central and peripheral manifestations of AD. Despite efforts to strictly define AD as a homogeneous CNS disease, there may be no single etiologic pathway leading to the syndrome of AD dementia. Rather, the neurodegenerative process may involve some degree of baseline genetic risk that is modified by external risk factors. Continued research into the diverse but related processes linked to AD risk is necessary for successful development of disease-modifying therapies.