%0 Journal Article %J J Alzheimers Dis %D 2022 %T Associations Between Brainstem Volume and Alzheimer's Disease Pathology in Middle-Aged Individuals of the Framingham Heart Study. %A Jacobs, Heidi I L %A O'Donnell, Adrienne %A Satizabal, Claudia L %A Lois, Cristina %A Kojis, Daniel %A Hanseeuw, Bernard J %A Thibault, Emma %A Sanchez, Justin S %A Buckley, Rachel F %A Yang, Qiong %A DeCarli, Charles %A Killiany, Ron %A Sargurupremraj, Muralidharan %A Sperling, Reisa A %A Johnson, Keith A %A Beiser, Alexa S %A Seshadri, Sudha %X

The brainstem is among the first regions to accumulate Alzheimer's disease (AD)-related hyperphosphorylated tau pathology during aging. We aimed to examine associations between brainstem volume and neocortical amyloid-β or tau pathology in 271 middle-aged clinically normal individuals of the Framingham Heart Study who underwent MRI and PET imaging. Lower volume of the medulla, pons, or midbrain was associated with greater neocortical amyloid burden. No associations were detected between brainstem volumes and tau deposition. Our results support the hypothesis that lower brainstem volumes are associated with initial AD-related processes and may signal preclinical AD pathology.

%B J Alzheimers Dis %V 86 %P 1603-1609 %8 2022 Apr 19 %G eng %N 4 %R 10.3233/JAD-215372 %0 Journal Article %J J Alzheimers Dis %D 2022 %T Associations of Pulmonary Function with MRI Brain Volumes: A Coordinated Multi-Study Analysis. %A Frenzel, Stefan %A Bis, Josh C %A Gudmundsson, Elias F %A O'Donnell, Adrienne %A Simino, Jeannette %A Yaqub, Amber %A Bartz, Traci M %A Brusselle, Guy G O %A Bülow, Robin %A DeCarli, Charles S %A Ewert, Ralf %A Gharib, Sina A %A Ghosh, Saptaparni %A Gireud-Goss, Monica %A Gottesman, Rebecca F %A Ikram, M Arfan %A Knopman, David S %A Launer, Lenore J %A London, Stephanie J %A Longstreth, W T %A Lopez, Oscar L %A Melo van Lent, Debora %A O'Connor, George %A Satizabal, Claudia L %A Shrestha, Srishti %A Sigurdsson, Sigurdur %A Stubbe, Beate %A Talluri, Rajesh %A Vasan, Ramachandran S %A Vernooij, Meike W %A Völzke, Henry %A Wiggins, Kerri L %A Yu, Bing %A Beiser, Alexa S %A Gudnason, Vilmundur %A Mosley, Thomas %A Psaty, Bruce M %A Wolters, Frank J %A Grabe, Hans J %A Seshadri, Sudha %X

BACKGROUND: Previous studies suggest poor pulmonary function is associated with increased burden of cerebral white matter hyperintensities and brain atrophy among elderly individuals, but the results are inconsistent.

OBJECTIVE: To study the cross-sectional associations of pulmonary function with structural brain variables.

METHODS: Data from six large community-based samples (N = 11,091) were analyzed. Spirometric measurements were standardized with respect to age, sex, height, and ethnicity using reference equations of the Global Lung Function Initiative. Associations of forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC), and their ratio FEV1/FVC with brain volume, gray matter volume, hippocampal volume, and volume of white matter hyperintensities were investigated using multivariable linear regressions for each study separately and then combined using random-effect meta-analyses.

RESULTS: FEV1 and FVC were positively associated with brain volume, gray matter volume, and hippocampal volume, and negatively associated with white matter hyperintensities volume after multiple testing correction, with little heterogeneity present between the studies. For instance, an increase of FVC by one unit was associated with 3.5 ml higher brain volume (95% CI: [2.2, 4.9]). In contrast, results for FEV1/FVC were more heterogeneous across studies, with significant positive associations with brain volume, gray matter volume, and hippocampal volume, but not white matter hyperintensities volume. Associations of brain variables with both FEV1 and FVC were consistently stronger than with FEV1/FVC, specifically with brain volume and white matter hyperintensities volume.

CONCLUSION: In cross-sectional analyses, worse pulmonary function is associated with smaller brain volumes and higher white matter hyperintensities burden.

%B J Alzheimers Dis %V 90 %P 1073-1083 %8 2022 Nov 22 %G eng %N 3 %R 10.3233/JAD-220667 %0 Journal Article %J J Alzheimers Dis %D 2022 %T Insulin-Like Growth Factor, Inflammation, and MRI Markers of Alzheimer's Disease in Predominantly Middle-Aged Adults. %A Wittfeld, Katharina %A Raman, Mekala R %A Conner, Sarah C %A Aslam, Asra %A Teumer, Alexander %A Nauck, Matthias %A Hosten, Norbert %A Habes, Mohamad %A DeCarli, Charles %A Vasan, Ramachandran S %A Beiser, Alexa S %A Himali, Jayandra J %A Seshadri, Sudha %A Grabe, Hans J %A Satizabal, Claudia L %X

BACKGROUND: Insulin-like growth factor 1 (IGF-1) signaling has been implicated in Alzheimer's disease pathogenesis, and further evidence suggests inflammation can be a moderator of this association. However, most research to date has been conducted on older adults.

OBJECTIVE: To investigate the association of serum IGF-1 and IGF binding protein 3 (IGFBP-3) concentrations with MRI markers of Alzheimer's disease in predominantly middle-aged adults, and further assess moderation by chronic inflammation.

METHODS: We included participants from the Framingham Heart Study (n = 1,852, mean age 46±8, 46% men) and the Study of Health in Pomerania (n = 674, mean age 50±13, 42% men) with available serum IGF-1, IFGBP-3, as well as brain MRI. IGF-1 and IFGBP-3 were related to MRI outcomes (i.e., total brain, cortical gray matter, white matter, white matter hyperintensities (WMH), and hippocampal volumes) using multivariable regression models adjusting for potential confounders. Subgroup analyses by C-reactive protein (CRP) concentrations were also performed. Cohort-specific summary statistics were meta-analyzed using random-effects models and corrected for multiple comparisons.

RESULTS: Meta-analysis results revealed that higher IGF-1 concentrations were associated with lower WMH (estimate [β] [95% CI], -0.05 [-0.09, -0.02], p = 0.006) and larger hippocampal volumes (0.07 [0.02, 0.12], p = 0.01), independent of vascular risk factors. These associations occurred predominantly in individuals with CRP concentrations < 75th percentile. We did not observe associations between IGFBP-3 and MRI outcomes.

CONCLUSION: Our findings suggest that IGF-1-related signaling may be implicated in brain health as early as midlife.

%B J Alzheimers Dis %V 88 %P 311-32 %8 2022 Jun 28 %G eng %N 1 %R 10.3233/JAD-220356 %0 Journal Article %J J Alzheimers Dis %D 2022 %T Non-Alcoholic Fatty Liver Disease, Liver Fibrosis, and Regional Amyloid-β and Tau Pathology in Middle-Aged Adults: The Framingham Study. %A Weinstein, Galit %A O'Donnell, Adrienne %A Davis-Plourde, Kendra %A Zelber-Sagi, Shira %A Ghosh, Saptaparni %A DeCarli, Charles S %A Thibault, Emma G %A Sperling, Reisa A %A Johnson, Keith A %A Beiser, Alexa S %A Seshadri, Sudha %X

BACKGROUND: Liver steatosis and fibrosis are emerging as risk factors for multiple extrahepatic health conditions; however, their relationship with Alzheimer's disease pathology is unclear.

OBJECTIVE: To examine whether non-alcoholic fatty liver disease (NAFLD) and FIB-4, a non-invasive index of advanced fibrosis, are associated with brain amyloid-β (Aβ) and tau pathology.

METHODS: The study sample included Framingham Study participants from the Offspring and Third generation cohorts who attended exams 9 (2011-2014) and 2 (2008-2011), respectively. Participants underwent 11C-Pittsburgh Compound-B amyloid and 18F-Flortaucipir tau positron emission tomography (PET) imaging and abdomen computed tomography, or had information on all components of the FIB-4 index. Linear regression models were used to assess the relationship of NAFLD and FIB-4 with regional tau and Aβ, adjusting for potential confounders and multiple comparisons.

RESULTS: Of the subsample with NAFLD information (N = 169; mean age 52±9 y; 57% males), 57 (34%) had NAFLD. Of the subsample with information on liver fibrosis (N = 177; mean age 50±10 y; 51% males), 34 (19%) had advanced fibrosis (FIB-4 >  1.3). Prevalent NAFLD was not associated with Aβ or tau PET. However, FIB-4 index was significantly associated with increased rhinal tau (β= 1.03±0.33, p = 0.002). Among individuals with prevalent NAFLD, FIB-4 was related to inferior temporal, parahippocampal gyrus, entorhinal and rhinal tau (β= 2.01±0.47, p <  0.001; β= 1.60±0.53, p = 0.007, and β= 1.59±0.47, p = 0.003 and β= 1.60±0.42, p = 0.001, respectively) and to Aβ deposition overall and in the inferior temporal and parahippocampal regions (β= 1.93±0.47, p <  0.001; β= 1.59±0.38, p <  0.001, and β= 1.52±0.54, p = 0.008, respectively).

CONCLUSION: This study suggests a possible association between liver fibrosis and early Alzheimer's disease pathology, independently of cardio-metabolic risk factors.

%B J Alzheimers Dis %V 86 %P 1371-1383 %8 2022 Apr 05 %G eng %N 3 %R 10.3233/JAD-215409 %0 Journal Article %J J Alzheimers Dis %D 2021 %T Accelerometer-Measured, Habitual Physical Activity and Circulating Brain-Derived Neurotrophic Factor: A Cross-Sectional Study. %A Spartano, Nicole L %A Himali, Jayandra J %A Trinquart, Ludovic %A Yang, Qiong %A Weinstein, Galit %A Satizabal, Claudia L %A Dukes, Kimberly A %A Beiser, Alexa S %A Murabito, Joanne M %A Vasan, Ramachandran S %A Seshadri, Sudha %X

BACKGROUND: One of the mechanisms suggested to link physical activity (PA) to favorable brain health is through stimulation of neural growth factors such as brain-derived neurotrophic factor (BDNF). Acute bouts of PA stimulate circulating BDNF levels.

OBJECTIVE: In this investigation, we assessed whether habitual, accelerometer-measured PA levels were related to circulating BDNF levels in a middle-aged cohort.

METHODS: In the Framingham Heart Study Third Generation cohort, 1,769 participants provided reliable accelerometry data and were not missing BDNF measurement and platelet counts. In a cross-sectional analysis, using multivariable regression, we related PA measures to serum BDNF levels, adjusting for age, sex, smoking status, platelet count, depression status, and accelerometer wear time.

RESULTS: Our study participants (mean age 47±9 years, 50.8% women) spent an average of 22.3 mins/day moderate-to-vigorous (MV)PA. Most PA variables (steps, MVPA, light activity, and sedentary time) were not related to BDNF levels (p > 0.05). We observed a non-linear trend, where 15-50 mins/week vigorous activity was associated with lower BDNF compared to those with 0 min vigorous activity (β= -0.049±0.024, p = 0.05), but with no significant associations at lower or higher vigorous activity levels. In smokers, MVPA was also associated with lower BDNF levels (β= -0.216±0.079, p = 0.01).

CONCLUSION: Our study reveals that circulating BDNF is not chronically elevated in individuals with higher levels of habitual PA in middle-aged adults from the community and may even be chronically suppressed with higher PA in subgroups, including current smokers. These results do not contradict previous studies demonstrating that circulating BDNF rises acutely after PA.

%B J Alzheimers Dis %V 85 %P 805-814 %8 2022 Jan 18 %G eng %N 2 %R 10.3233/JAD-215109 %0 Journal Article %J J Alzheimers Dis %D 2021 %T Association of Midlife Depressive Symptoms with Regional Amyloid-β and Tau in the Framingham Heart Study. %A Gonzales, Mitzi M %A Samra, Jasmeet %A O'Donnell, Adrienne %A Mackin, R Scott %A Salinas, Joel %A Jacob, Mini %A Satizabal, Claudia L %A Aparicio, Hugo J %A Thibault, Emma G %A Sanchez, Justin S %A Finney, Rebecca %A Rubinstein, Zoe B %A Mayblyum, Danielle V %A Killiany, Ron J %A Decarli, Charlie S %A Johnson, Keith A %A Beiser, Alexa S %A Seshadri, Sudha %X

BACKGROUND: Depressive symptoms predict increased risk for dementia decades before the emergence of cognitive symptoms. Studies in older adults provide preliminary evidence for an association between depressive symptoms and amyloid-β (Aβ) and tau accumulation. It is unknown if similar alterations are observed in midlife when preventive strategies may be most effective.

OBJECTIVE: The study aim was to evaluate the association between depressive symptoms and cerebral Aβ and tau in a predominately middle-aged cohort with examination of the apolipoprotein (APOE) ɛ4 allele as a moderator.

METHODS: Participants included 201 adults (mean age 53±8 years) who underwent 11C-Pittsburgh Compound B amyloid and 18F-Flortaucipir tau positron emission tomography (PET) imaging. Depressive symptoms were evaluated with the Center for Epidemiological Studies Depression Scale (CES-D) at the time of PET imaging, as well as eight years prior. Associations between depressive symptoms at both timepoints, as well as depression (CES-D≥16), with regional Aβ and tau PET retention were evaluated with linear regression adjusting for age and sex. Interactions with the APOE ɛ4 allele were explored.

RESULTS: Depressive symptoms and depression were not associated with PET outcomes in the overall sample. However, among APOE ɛ4 allele carriers, there was a significant cross-sectional association between depressive symptoms and increased tau PET uptake in the entorhinal cortex (β= 0.446, SE = 0.155, p = 0.006) and amygdala (β= 0.350, SE = 0.133, p = 0.012).

CONCLUSION: Although longitudinal studies are necessary, the results suggest that APOE ɛ4 carriers with depressive symptoms may present with higher susceptibility to early tau accumulation in regions integral to affective regulation and memory consolidation.

%B J Alzheimers Dis %V 82 %P 249-260 %8 2021 Jun 29 %G eng %N 1 %R 10.3233/JAD-210232 %0 Journal Article %J J Alzheimers Dis %D 2021 %T Plasma EFEMP1 Is Associated with Brain Aging and Dementia: The Framingham Heart Study. %A McGrath, Emer R %A Himali, Jayandra J %A Levy, Daniel %A Yang, Qiong %A DeCarli, Charles S %A Courchesne, Paul %A Satizabal, Claudia L %A Finney, Rebecca %A Vasan, Ramachandran S %A Beiser, Alexa S %A Seshadri, Sudha %X

BACKGROUND: Epidermal growth factor containing fibulin extracellular matrix protein-1 (EFEMP1) has been associated with increased white matter hyperintensities (WMH) burden and disorders of premature aging and may have a shared pathophysiological role in the development of WMH and dementia.

OBJECTIVE: To determine the association between plasma EFEMP1 levels and MRI markers of vascular brain injury and incident all-cause and Alzheimer's disease (AD) dementia.

METHODS: We measured plasma EFEMP1 levels in 1597 [53% women, mean age 68.7 (SD 5.7) years] dementia-free Framingham Offspring cohort participants between 1998-2001 and subsequently followed them for incident dementia. Secondary outcomes included stroke, structural MRI brain measures and neurocognitive test performance.

RESULTS: During a median 11.8 [Q1, Q3 : 7.1, 13.3] year follow-up, 131 participants developed dementia. The highest quintile of plasma EFEMP1, compared to the bottom four quintiles, was associated with an increased risk of time to incident all-cause dementia (HR 1.77, 95% CI 1.18-2.64) and AD dementia (HR 1.76, 95% CI 1.11-2.81) but not with markers of vascular brain injury (WMH, covert brain infarcts or stroke). Higher circulating EFEMP1 concentrations were also cross-sectionally associated with lower total brain (β±SE, -0.28±0.11, p = 0.01) and hippocampal volumes (-0.006±0.003, p = 0.04) and impaired abstract reasoning (Similarities test, -0.18±0.08, p = 0.018 per standard deviation increment in EFEMP1).

CONCLUSION: Elevated circulating EFEMP1 is associated with an increased risk of all-cause and AD dementia, smaller hippocampal and total brain volumes, and poorer cognitive performance. EFEMP1 may play an important biological role in the development of AD dementia. Further studies to validate these findings are warranted.

%B J Alzheimers Dis %V 85 %P 1657-1666 %8 2022 Feb 15 %G eng %N 4 %R 10.3233/JAD-215053 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Genetic Interaction with Plasma Lipids on Alzheimer's Disease in the Framingham Heart Study. %A Peloso, Gina M %A Beiser, Alexa S %A DeStefano, Anita L %A Seshadri, Sudha %X

Epidemiological and genetic studies have pointed to the role of cholesterol in Alzheimer's disease (AD). We explored the interaction of a genetic risk score (GRS) of AD risk alleles with mid-life plasma lipid levels (LDL-C, HDL-C, and triglycerides) on risk for AD in the Framingham Heart Study (FHS). Mid-life (between the ages of 40-60 years old) lipid levels were obtained from individuals in the FHS Original and Offspring cohorts (157 cases and 2,882 controls) with genetic data and AD status available. Cox proportional hazards regression was performed to test the interaction between mid-life lipid levels and an AD GRS, as well as the individual contributing SNPs, on risk of incident AD adjusting for age, sex, and cohort. We found a significant interaction between a GRS of AD loci and log triglyceride levels on risk of clinical AD (p = 0.006), but no interaction of the GRS with HDL-C (p = 0.458) or LDL-C (p = 0.366). We then tested the interaction between the individual SNPs contributing to the GRS and log triglycerides. We found two SNPs that had interactions with triglycerides on AD risk that reached a p-value < 0.05 (rs11218343 and APOEɛ4). The association between some AD SNPs and risk of AD may be modified by triglyceride levels. Furthermore, sequential testing of a GRS with a set of traits on disease followed by testing individual SNPs for interaction provides a framework for narrowing the associations that need to be tested for interaction analyses. Replication is needed to confirm these findings.

%B J Alzheimers Dis %V 66 %P 1275-1282 %8 2018 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/30412497?dopt=Abstract %R 10.3233/JAD-180751 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Association of Physical Function with Clinical and Subclinical Brain Disease: The Framingham Offspring Study. %A Camargo, Erica C %A Weinstein, Galit %A Beiser, Alexa S %A Tan, Zaldy S %A DeCarli, Charles %A Kelly-Hayes, Margaret %A Kase, Carlos %A Murabito, Joanne M %A Seshadri, Sudha %X

BACKGROUND: Handgrip strength and gait speed are simple measures of physical capability and have been associated with current and future health outcomes. However, studies on their associations with brain structure and function in middle-aged adults are lacking.

OBJECTIVE: To assess the relationship of fast-paced walking speed and handgrip strength with risk of dementia, Alzheimer's disease (AD), and stroke, as well as the cross-sectional associations with cognitive and brain magnetic resonance imaging (MRI) measures in a middle-aged community sample.

METHODS: Framingham Offspring (n = 2,176; mean age 62, 54% female) had physical function, brain MRI, and cognitive evaluations between 1999 and 2005 and were followed-up for incident dementia AD and stroke until 11 years later. We related walking speed and handgrip strength to incident dementia, AD, and stroke using Cox models, and to brain and cognitive measures using multivariable linear and logistic regression. Models were adjusted for age, sex, education, and vascular risk factors.

RESULTS: Slow walking and weak handgrip were associated with more than 2.5-fold increase in risk of AD. Weaker handgrip was associated with an increased risk of incident stroke (HR 1.74, 95% CI: 1.12-2.70/SDU, p = 0.01) in persons ≥65 years. Both measures were associated with lower total brain volume and poorer performance on tests of visual memory, language, executive function, and visuoperceptual function. Slower gait was also related to poorer verbal memory, and weaker handgrip to poorer abstraction.

CONCLUSION: Tests of walking speed and handgrip strength may serve as clinical markers of brain structure and function and may improve dementia risk prediction.

%B J Alzheimers Dis %V 53 %P 1597-608 %8 2016 Jul 14 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/27540965?dopt=Abstract %R 10.3233/JAD-160229 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Interaction Between Midlife Blood Glucose and APOE Genotype Predicts Later Alzheimer's Disease Pathology. %A Bangen, Katherine J %A Himali, Jayandra J %A Beiser, Alexa S %A Nation, Daniel A %A Libon, David J %A Fox, Caroline S %A Seshadri, Sudha %A Wolf, Philip A %A McKee, Ann C %A Au, Rhoda %A Delano-Wood, Lisa %X

Elevated blood glucose and the apolipoprotein (APOE) ɛ4 allele have both been associated with increased dementia risk; however, the neuropathological mechanisms underlying these associations remain unclear. We examined the impact of APOE genotype and midlife blood glucose on post-mortem vascular and Alzheimer's disease (AD) neuropathology. Ninety-four participants from the Framingham Heart Study without diagnosed diabetes underwent health examination at midlife and brain autopsy at death. Histopathological measures of vascular and AD neuropathology were obtained and analyzed. Results demonstrated that, among APOE ɛ4 carriers, elevated blood glucose was associated with more severe AD pathology. There was no such relationship with vascular pathology. In a relatively healthy sample with low vascular risk burden, midlife elevated blood glucose was associated with greater AD pathology among APOE ɛ4 carriers. A better understanding of interactive effects of APOE genotype and vascular risk on neuropathology has implications for identification of individuals at risk for decline and long-term preventive treatment.

%B J Alzheimers Dis %V 53 %P 1553-62 %8 2016 Jul 06 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/27392855?dopt=Abstract %R 10.3233/JAD-160163