Preclinical changes that precede the onset of symptoms and eventual diagnosis of Alzheimer's disease (AD) are a target for potential preventive interventions. A large body of evidence suggests that ...inflammation is closely associated with AD pathogenesis and may be a promising target pathway for such interventions. However, little is known about the association between systemic inflammation and preclinical AD pathophysiology. We first examined whether the acute-phase protein, alpha-2 macroglobulin (A2M), a major component of the innate immune system, was associated with cerebrospinal fluid (CSF) markers of neuronal injury in preclinical AD and risk of incident AD in the predictors of cognitive decline among normal individuals (BIOCARD) cohort. We find that A2M concentration in blood is significantly associated with CSF concentrations of the neuronal injury markers, tau and phosphorylated tau, and that higher baseline serum A2M concentration is associated with an almost threefold greater risk of progression to clinical symptoms of AD in men. These findings were replicated in the Alzheimer's Disease Neuroimaging (ADNI) study. Then, utilizing a systems level approach combining large multi-tissue gene expression datasets with mass spectrometry-based proteomic analyses of brain tissue, we identified an A2M gene network that includes regulator of calcineurin (RCAN1), an inhibitor of calcineurin, a well-characterized tau phosphatase. A2M gene and protein expression in the brain were significantly associated with gene and protein expression levels of calcineurin. Collectively these novel findings suggest that A2M is associated with preclinical AD, reflects early neuronal injury in the disease course and may be responsive to tau phosphorylation in the brain through the RCAN1-calcineurin pathway.
Objectives
To examine the effect of late-life body mass index (BMI) and rapid weight loss on incident mild cognitive impairment (MCI) and Alzheimer’s disease (AD).
Design
Prospective longitudinal ...cohort study.
Setting
National Alzheimer’s Coordinating Center (NACC) Uniform Data Set, including 34 past and current National Institute on Aging-funded AD Centers across the United States.
Participants
6940 older adults (n=5061 normal cognition NC; n=1879 MCI).
Measurements
BMI (kg/m
2
) and modified Framingham Stroke Risk Profile (FSRP) score (sex, age, systolic blood pressure, anti-hypertension medication, diabetes mellitus, cigarette smoking, prevalent cardiovascular disease, atrial fibrillation) were assessed at baseline. Cognition and weight were assessed annually.
Results
Multivariable binary logistic regression, adjusting for age, sex, race, education, length of follow-up, and modified FSRP related late-life BMI to risk of diagnostic conversion from NC to MCI or AD and from MCI to AD. Secondary analyses related late-life BMI to diagnostic conversion in the presence of rapid weight loss (>5% decrease in 12 months) and apolipoprotein E (APOE) ε4. During a mean 3.8-year follow-up period, 12% of NC participants converted to MCI or AD and 49% of MCI participants converted to AD. Higher baseline BMI was associated with a reduced probability of diagnostic conversion, such that for each one-unit increase in baseline BMI there was a reduction in diagnostic conversion for both NC (OR=0.977, 95%CI 0.958-0.996, p=0.015) and MCI participants (OR=0.962, 95%CI 0.942-0.983, p<0.001). The protective effect of higher baseline BMI did not persist in the setting of rapid weight loss but did persist when adjusting for APOE ε4.
Conclusions
Higher late-life BMI is associated with a lower risk of incident MCI and AD but is not protective in the presence of rapid weight loss.
Autopsy measures of Alzheimer's disease neuropathology have been leveraged as endophenotypes in previous genome-wide association studies (GWAS). However, despite evidence of sex differences in ...Alzheimer's disease risk, sex-stratified models have not been incorporated into previous GWAS analyses. We looked for sex-specific genetic associations with Alzheimer's disease endophenotypes from six brain bank data repositories. The pooled dataset included 2701 males and 3275 females, the majority of whom were diagnosed with Alzheimer's disease at autopsy (70%). Sex-stratified GWAS were performed within each dataset and then meta-analysed. Loci that reached genome-wide significance (P < 5 × 10-8) in stratified models were further assessed for sex interactions. Additional analyses were performed in independent datasets leveraging cognitive, neuroimaging and CSF endophenotypes, along with age-at-onset data. Outside of the APOE region, one locus on chromosome 7 (rs34331204) showed a sex-specific association with neurofibrillary tangles among males (P = 2.5 × 10-8) but not females (P = 0.85, sex-interaction P = 2.9 × 10-4). In follow-up analyses, rs34331204 was also associated with hippocampal volume, executive function, and age-at-onset only among males. These results implicate a novel locus that confers male-specific protection from tau pathology and highlight the value of assessing genetic associations in a sex-specific manner.
To test the hypothesis that increased aortic stiffening is associated with greater CSF evidence of core Alzheimer disease pathology (β-amyloid Aβ, phosphorylated tau p-tau), neurodegeneration (total ...tau t-tau), synaptic dysfunction (neurogranin), neuroaxonal injury (neurofilament light NFL), and neuroinflammation (YKL-40, soluble triggering receptor expressed on myeloid cells 2 sTREM2), we analyzed pulse wave velocity (PWV) data and CSF data among older adults.
Participants free of stroke and dementia from the Vanderbilt Memory and Aging Project, an observational community-based study, underwent cardiac magnetic resonance to assess aortic PWV (meters per second) and lumbar puncture to obtain CSF. Linear regressions related aortic PWV to CSF Aβ, p-tau, t-tau, neurogranin, NFL, YKL-40, and sTREM2 concentrations after adjustment for age, race/ethnicity, education, apolipoprotein (APOE) ε4 status, Framingham Stroke Risk Profile, and cognitive diagnosis. Models were repeated testing PWV interactions with age, diagnosis,
ε4, and hypertension on each biomarker.
One hundred forty-six participants were examined (age 72 ± 6 years). Aortic PWV interacted with age on p-tau (β = 0.31,
= 0.04), t-tau, (β = 2.67,
= 0.05), neurogranin (β = 0.94,
= 0.04), and sTREM2 (β = 20.4,
= 0.05). Among participants >73 years of age, higher aortic PWV related to higher p-tau (β = 2.4,
= 0.03), t-tau (β = 19.3,
= 0.05), neurogranin (β = 8.4,
= 0.01), and YKL-40 concentrations (β = 7,880,
= 0.005). Aortic PWV had modest interactions with diagnosis on neurogranin (β = -10.76,
= 0.03) and hypertension status on YKL-40 (β = 18,020,
< 0.001).
Among our oldest participants, ≥74 years of age, greater aortic stiffening is associated with in vivo biomarker evidence of neuroinflammation, tau phosphorylation, synaptic dysfunction, and neurodegeneration, but not amyloidosis. Central arterial stiffening may lead to cumulative cerebral microcirculatory damage and reduced blood flow delivery to tissue, resulting in neuroinflammation and neurodegeneration in more advanced age.
•We describe a novel association between blood VEGF expression levels and memory.•We describe a novel association between blood VEGF protein levels and AD pathology biomarkers.•Expression and ...proteins levels of VEGF in blood are potential biomarkers of AD.
The vascular endothelial growth factor (VEGF) family of genes has been implicated in the clinical development of Alzheimer's Disease (AD). A previous study identified associations between gene expression of VEGF family members in the prefrontal cortex and cognitive performance and AD pathology. This study explored if those associations were also observed in the blood. Consistent with previous observations in brain tissue, higher blood gene expression of placental growth factor (PGF) was associated with a faster rate of memory decline (p=0.04). Higher protein abundance of FMS-related receptor tyrosine kinase 4 (FLT4) in blood was associated with biomarker levels indicative of lower amyloid and tau pathology, opposite the direction observed in brain. Also, higher gene expression of VEGFB in blood was associated with better baseline memory (p=0.008). Notably, we observed that higher gene expression of VEGFB in blood was associated with lower expression of VEGFB in the brain (r=-0.19, p=0.02). Together, these results suggest that the VEGFB, FLT4, and PGF alterations in the AD brain may be detectable in the blood compartment.
A series of 1,3,5-triazine-based estrogen receptor (ER) modulators that are modestly selective for the ERβ subtype are reported. Compound 1, which displayed modest potency and selectivity for ERβ vs ...ERα, was identified via high-throughput screening utilizing an ERβ SPA-based binding assay. Subsequent analogue preparation resulted in the identification of compounds such as 21 and 43 that display 25- to 30-fold selectivity for ERβ with potencies in the 10−30 nM range. These compounds profile as full antagonists at ERβ and weak partial agonists at ERα in a cell-based reporter gene assay. In addition, the X-ray crystal structure of compound 15 complexed with the ligand binding domain of ERβ has been solved and was utilized in the design of more conformationally restrained analogues such as 31 in an attempt to increase selectivity for the ERβ subtype.
•RDT within several white matter tracts is associated with SCD.•RDT contributes unique variance to SCD beyond that of CSF Aβ42.•Our findings suggest that RDT is a sensitive marker of SCD.
Subjective ...cognitive decline (SCD) is a perceived cognitive change prior to objective cognitive deficits, and although it is associated with Alzheimer’s disease (AD) pathology, it likely results from multiple underlying pathologies. We investigated the association of white matter microstructure to SCD as a sensitive and early marker of cognitive decline and quantified the contribution of white matter microstructure separate from amyloidosis. Vanderbilt Memory & Aging Project participants with diffusion MRI data and a 45-item measure of SCD were included n = 236, 137 cognitively unimpaired (CU), 99 with mild cognitive impairment (MCI), 73 ± 7 years, 37% female. A subset of participants (64 CU, 40 MCI) underwent a fasting lumbar puncture for quantification of cerebrospinal fluid (CSF) amyloid-β(CSF Aβ42), total tau (CSF t-tau), and phosphorylated tau (CSF p-tau). Diffusion MRI data was post-processed using the free-water (FW) elimination technique, which allowed quantification of extracellular (FW) and intracellular compartment (fractional anisotropy, mean diffusivity, axial diffusivity, and radial diffusivity) microstructure. Microstructural values were quantified within 11 cognitive-related white matter tracts, including medial temporal lobe, frontal transcallosal, and fronto-parietal tracts using a region of interest approach. General linear modeling related each tract to SCD scores adjusting for age, sex, race/ethnicity, education, Framingham Stroke Risk Profile scores, APOE ε4 carrier status, diagnosis, Geriatric Depression Scale scores, hippocampal volume, and total white matter volume. Competitive models were analyzed to determine if white matter microstructural values have a unique role in SCD scores separate from CSF Aβ42. FW-corrected radial diffusivity (RDT) was related to SCD scores in 8 tracts: cingulum bundle, inferior longitudinal fasciculus, as well as inferior frontal gyrus (IFG) pars opercularis, IFG orbitalis, IFG pars triangularis, tapetum, medial frontal gyrus, and middle frontal gyrus transcallosal tracts. While CSF Aβ42 was related to SCD scores in our cohort (Radj2 = 39.03%; β = −0.231; p = 0.020), competitive models revealed that fornix and IFG pars triangularis transcallosal tract RDT contributed unique variance to SCD scores beyond CSF Aβ42 (Radj2 = 44.35% and Radj2 = 43.09%, respectively), with several other tract measures demonstrating nominal significance. All tracts which demonstrated nominal significance (in addition to covariates) were input into a backwards stepwise regression analysis. ILF RDT, fornix RDT, and UF FW were best associated with SCD scores (Radj2 = 46.69%; p = 6.37 × 10-12). Ultimately, we found that medial temporal lobe and frontal transcallosal tract microstructure is an important driver of SCD scores independent of early amyloid deposition. Our results highlight the potential importance of abnormal white matter diffusivity as an early contributor to cognitive decline. These results also highlight the value of incorporating multiple biomarkers to help disentangle the mechanistic heterogeneity of SCD as an early stage of cognitive decline.
Vascular health factors frequently co-occur with Alzheimer's disease (AD). A better understanding of how systemic vascular and cerebrovascular health intersects with clinical and pathological AD may ...inform prevention and treatment opportunities.
To establish the Vanderbilt Memory & Aging Project, a case-control longitudinal study investigating vascular health and brain aging, and describe baseline methodology and participant characteristics.
From September 2012 to November 2014, 335 participants age 60- 92 were enrolled, including 168 individuals with mild cognitive impairment (MCI, 73±8 years, 41% female) and 167 age-, sex-, and race-matched cognitively normal controls (NC, 72±7 years, 41% female). At baseline, participants completed a physical and frailty examination, fasting blood draw, neuropsychological assessment, echocardiogram, cardiac MRI, and brain MRI. A subset underwent 24-hour ambulatory blood pressure monitoring and lumbar puncture for cerebrospinal fluid (CSF) collection.
As designed, participant groups were comparable for age (p = 0.31), sex (p = 0.95), and race (p = 0.65). MCI participants had greater Framingham Stroke Risk Profile scores (p = 0.008), systolic blood pressure values (p = 0.008), and history of left ventricular hypertrophy (p = 0.04) than NC participants. As expected, MCI participants performed worse on all neuropsychological measures (p-values < 0.001), were more likely to be APOEɛ4 carriers (p = 0.02), and had enhanced CSF biomarkers, including lower Aβ42 (p = 0.02), higher total tau (p = 0.004), and higher p-tau (p = 0.02) compared to NC participants.
Diverse sources of baseline and longitudinal data will provide rich opportunities to investigate pathways linking vascular and cerebrovascular health, clinical and pathological AD, and neurodegeneration contributing to novel strategies to delay or prevent cognitive decline.
Introduction
Patterns of atrophy can distinguish normal cognition from Alzheimer's disease (AD), but neuropathological drivers of this pattern are unknown. This study examined associations between ...cerebrospinal fluid biomarkers of AD pathology, synaptic dysfunction, and neuroaxonal injury with two AD imaging signatures.
Methods
Signatures were calculated using published guidelines. Linear regressions related each biomarker to both signatures, adjusting for demographic factors. Bootstrapped analyses tested if associations were stronger with one signature versus the other.
Results
Increased phosphorylated tau (p‐tau), total tau, and neurofilament light (P‐values <.045) related to smaller signatures (indicating greater atrophy). Diagnosis and sex modified associations between p‐tau and neurogranin (P‐values<.05) and signatures, such that associations were stronger among participants with mild cognitive impairment and female participants. The strength of associations did not differ between signatures.
Discussion
Increased evidence of neurodegeneration, axonopathy, and tau phosphorylation relate to greater AD‐related atrophy. Tau phosphorylation and synaptic dysfunction may be more prominent in AD‐affected regions in females.
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