Low HDL Cholesterol is Associated with Lower Gray Matter Volume in Cognitively Healthy Adults

Dyslipidemia is common in adults and contributes to high rates of cardiovascular disease and may be linked to subsequent neurodegenerative and neurovascular diseases. This study examined whether lower brain volumes and cognition associated with dyslipidemia could be observed in cognitively healthy adults, and whether apolipoprotein E (APOE) genotype or family history of Alzheimer's disease (FHAD) alters this effect. T1-weighted magnetic resonance imaging was used to examine regional brain gray matter (GM) and white matter (WM) in 183 individuals (58.4 ± 8.0 years) using voxel-based morphometry. A non-parametric multiple linear regression model was used to assess the effect of high-density lipoprotein (HDL) and non-HDL cholesterol, APOE, and FHAD on regional GM and WM volume. A post hoc analysis was used to assess whether any significant correlations found within the volumetric analysis had an effect on cognition. HDL was positively correlated with GM volume in the bilateral temporal poles, middle temporal gyri, temporo-occipital gyri, and left superior temporal gyrus and parahippocampal region. This effect was independent of APOE and FHAD. A significant association between HDL and the Brief Visuospatial Memory Test was found. Additionally, GM volume within the right middle temporal gyrus, the region most affected by HDL, was significantly associated with the Controlled Oral Word Association Test and the Center for Epidemiological Studies Depression Scale. These findings suggest that adults with decreased levels of HDL cholesterol may be experiencing cognitive changes and GM reductions in regions associated with neurodegenerative disease and therefore, may be at greater risk for future cognitive decline

Clinical criteria for limbic-predominant age-related TDP-43 encephalopathy

Limbic predominant age-related TDP-43 encephalopathy neuropathologic change (LATE-NC) is highly prevalent in late life and a common co-pathology with Alzheimer\u27s disease neuropathologic change (ADNC). LATE-NC is a slowly progressive, amnestic clinical syndrome. Alternatively, when present with ADNC, LATE-NC is associated with a more rapid course. With the emergence of anti-amyloid therapeutics, discrimination of LATE-NC from ADNC is critical and will lead to greater clinical recognition of amnestic patients without ADNC. Furthermore, co-pathology with LATE-NC may influence outcomes of these therapeutics. Thus there is a need to identify patients during life with likely LATE-NC. We propose criteria for clinical diagnosis of LATE as an initial framework for further validation. In the context of progressive memory loss and substantial hippocampal atrophy, criteria are laid out for probable (amyloid negative) or possible LATE (amyloid biomarkers are unavailable or when amyloid is present, but hippocampal neurodegeneration is out of proportion to expected pure ADNC). HIGHLIGHTS: Limbic-predominant age-related TDP-43 encephalopathy (LATE) is a highly prevalent driver of neuropathologic memory loss in late life. LATE neuropathologic change (LATE-NC) is a common co-pathology with Alzheimer\u27s disease neuropathologic change (ADNC) and may influence outcomes with emerging disease-modifying medicines. We provide initial clinical criteria for diagnosing LATE during life either when LATE-NC is the likely primary driver of symptoms or when observed in conjunction with AD. Definitions of possible and probable LATE are provided

NSAIDs May Protect Against Age-Related Brain Atrophy

The use of non-steroidal anti-inflammatory drugs (NSAIDs) in humans is associated with brain differences including decreased number of activated microglia. In animals, NSAIDs are associated with reduced microglia, decreased amyloid burden, and neuronal preservation. Several studies suggest NSAIDs protect brain regions affected in the earliest stages of AD, including hippocampal and parahippocampal regions. In this cross-sectional study, we examined the protective effect of NSAID use on gray matter volume in a group of middle-aged and older NSAID users (n = 25) compared to non-user controls (n = 50). All participants underwent neuropsychological testing and T1-weighted magnetic resonance imaging. Non-user controls showed smaller volume in portions of the left hippocampus compared to NSAID users. Age-related loss of volume differed between groups, with controls showing greater medial temporal lobe volume loss with age compared to NSAID users. These results should be considered preliminary, but support previous reports that NSAIDs may modulate age-related loss of brain volume

Elevated CSF angiopoietin-2 correlates with blood-brain barrier leakiness and markers of neuronal injury in early Alzheimer's disease

Breakdown of the neurovascular unit is associated with blood-brain barrier (BBB) leakiness contributing to cognitive decline and disease pathology in the early stages of Alzheimer's disease (AD). Vascular stability depends on angiopoietin-1 (ANGPT-1) signalling, antagonised by angiopoietin-2 (ANGPT-2) expressed upon endothelial injury. We examined the relationship between CSF ANGPT-2 and CSF markers of BBB leakiness and core AD biomarkers across three independent cohorts: (i) 31 AD patients and 33 healthy controls grouped according to their biomarker profile (i.e., AD cases t-tau > 400 pg/mL, p-tau > 60 pg/mL and Aβ42 < 550 pg/mL); (ii) 121 participants in the Wisconsin Registry for Alzheimer's Prevention or Wisconsin Alzheimer's Disease Research study (84 participants cognitively unimpaired (CU) enriched for a parental history of AD, 20 participants with mild cognitive impairment (MCI), and 17 with AD); (iii) a neurologically normal cohort aged 23-78 years with paired CSF and serum samples. CSF ANGPT-2, sPDGFRβ, albumin and fibrinogen levels were measured by sandwich ELISA. In cohort (i), CSF ANGPT-2 was elevated in AD and correlated with CSF t-tau and p-tau181 but not Aβ42. ANGPT-2 also correlated positively with CSF sPDGFRβ and fibrinogen - markers of pericyte injury and BBB leakiness. In cohort (ii), CSF ANGPT-2 was highest in MCI and correlated with CSF albumin in the CU and MCI cohorts but not in AD. CSF ANGPT-2 also correlated with CSF t-tau and p-tau and with markers of neuronal injury (neurogranin and α-synuclein) and neuroinflammation (GFAP and YKL-40). In cohort (iii), CSF ANGPT-2 correlated strongly with the CSF/serum albumin ratio. Serum ANGPT-2 showed non-significant positive associations with CSF ANGPT-2 and the CSF/serum albumin ratio. Together, these data indicate that CSF and possibly serum ANGPT-2 is associated with BBB leakiness in early AD and is closely related to tau pathology and neuronal injury. The utility of serum ANGPT-2 as a biomarker of BBB damage in AD requires further study

Associations between diffusion MRI microstructure and cerebrospinal fluid markers of Alzheimer's disease pathology and neurodegeneration along the Alzheimer's disease continuum

INTRODUCTION: White matter (WM) degeneration is a critical component of early Alzheimer's disease (AD) pathophysiology. Diffusion-weighted imaging (DWI) models, including diffusion tensor imaging (DTI), neurite orientation dispersion and density imaging (NODDI), and mean apparent propagator MRI (MAP-MRI), have the potential to identify early neurodegenerative WM changes associated with AD. METHODS: We imaged 213 (198 cognitively unimpaired) aging adults with DWI and used tract-based spatial statistics to compare 15 DWI metrics of WM microstructure to 9 cerebrospinal fluid (CSF) markers of AD pathology and neurodegeneration treated as continuous variables. RESULTS: We found widespread WM injury in AD, as indexed by robust associations between DWI metrics and CSF biomarkers. MAP-MRI had more spatially diffuse relationships with Aβ42/40 and pTau, compared with NODDI and DTI. DISCUSSION: Our results suggest that WM degeneration may be more pervasive in AD than is commonly appreciated and that innovative DWI models such as MAP-MRI may provide clinically viable biomarkers of AD-related neurodegeneration in the earliest stages of AD progression

Associations Between Performance on an Abbreviated CogState Battery, Other Measures of Cognitive Function, and Biomarkers in People at Risk for Alzheimer\u27s Disease

It is not known whether computerized cognitive assessments, like the CogState battery, are sensitive to preclinical cognitive changes or pathology in people at risk for Alzheimer\u27s disease(AD). In 469 late middle-aged participants from the Wisconsin Registry for Alzheimer\u27s Prevention(mean age 63.8±7 years at testing; 67% female; 39% APOE4+), we examined relationships between a CogState abbreviated battery(CAB) of seven tests and demographic characteristics, traditional paper-based neuropsychological tests as well as a composite cognitive impairment index, cognitive impairment status(determined by consensus review), and biomarkers for amyloid and tau(CSF phosphorylated-tau/Aβ42 and global PET-PiB burden) and neural injury(CSF neurofilament light protein). CSF and PET-PiB were collected in n = 71 and n = 91 participants, respectively, approximately four years prior to CAB testing. For comparison, we examined three traditional tests of delayed memory in parallel. Similar to studies in older samples, the CAB was less influenced by demographic factors than traditional tests. CAB tests were generally correlated with most paper-based cognitive tests examined and mapped onto the same cognitive domains. Greater composite cognitive impairment index was associated with worse performance on all CAB tests. Cognitively impaired participants performed significantly worse compared to normal controls on all but one CAB test. Poorer One Card Learning test performance was associated with higher levels of CSF phosphorylated-tau/Aβ42. These results support the use of the CogState battery as measures of early cognitive impairment in studies of people at risk for AD

Liver-Specific Polygenic Risk Score Is Associated with Alzheimer's Disease Diagnosis

BACKGROUND: Our understanding of the pathophysiology underlying Alzheimer's disease (AD) has benefited from genomic analyses, including those that leverage polygenic risk score (PRS) models of disease. The use of functional annotation has been able to improve the power of genomic models. OBJECTIVE: We sought to leverage genomic functional annotations to build tissue-specific AD PRS models and study their relationship with AD and its biomarkers. METHODS: We built 13 tissue-specific AD PRS and studied the scores' relationships with AD diagnosis, cerebrospinal fluid (CSF) amyloid, CSF tau, and other CSF biomarkers in two longitudinal cohort studies of AD. RESULTS: The AD PRS model that was most predictive of AD diagnosis (even without APOE) was the liver AD PRS: n = 1,115; odds ratio = 2.15 (1.67-2.78), p = 3.62×10-9. The liver AD PRS was also statistically significantly associated with cerebrospinal fluid biomarker evidence of amyloid-β (Aβ 42:Aβ 40 ratio, p = 3.53×10-6) and the phosphorylated tau:amyloid-β ratio (p = 1.45×10-5). CONCLUSION: These findings provide further evidence of the role of the liver-functional genome in AD and the benefits of incorporating functional annotation into genomic research

Effect of Pathway-Specific Polygenic Risk Scores for Alzheimer's Disease (AD) on Rate of Change in Cognitive Function and AD-Related Biomarkers Among Asymptomatic Individuals

BACKGROUND: Genetic scores for late-onset Alzheimer's disease (LOAD) have been associated with preclinical cognitive decline and biomarker variations. Compared with an overall polygenic risk score (PRS), a pathway-specific PRS (p-PRS) may be more appropriate in predicting a specific biomarker or cognitive component underlying LOAD pathology earlier in the lifespan. OBJECTIVE: In this study, we leveraged longitudinal data from the Wisconsin Registry for Alzheimer's Prevention and explored changing patterns in cognition and biomarkers at various age points along six biological pathways. METHODS: PRS and p-PRSs with and without APOE were constructed separately based on the significant SNPs associated with LOAD in a recent genome-wide association study meta-analysis and compared to APOE alone. We used a linear mixed-effects model to assess the association between PRS/p-PRSs and cognitive trajectories among 1,175 individuals. We also applied the model to the outcomes of cerebrospinal fluid biomarkers in a subset. Replication analyses were performed in an independent sample. RESULTS: We found p-PRSs and the overall PRS can predict preclinical changes in cognition and biomarkers. The effects of PRS/p-PRSs on rate of change in cognition, amyloid-β, and tau outcomes are dependent on age and appear earlier in the lifespan when APOE is included in these risk scores compared to when APOE is excluded. CONCLUSION: In addition to APOE, the p-PRSs can predict age-dependent changes in amyloid-β, tau, and cognition. Once validated, they could be used to identify individuals with an elevated genetic risk of accumulating amyloid-β and tau, long before the onset of clinical symptoms

Crosswalk study on blood collection-tube types for Alzheimer's disease biomarkers

Introduction: Blood-based Alzheimer's disease (AD) biomarkers show promise, but pre-analytical protocol differences may pose problems. We examined seven AD blood biomarkers (amyloid beta [ A β ] 42 , A β 40 , phosphorylated tau [ p - ta u 181 , total tau [t-tau], neurofilament light chain [NfL], A β 42 40 , and p - ta u 181 A β 42 ) in three collection tube types (ethylenediaminetetraacetic acid [EDTA] plasma, heparin plasma, serum). Methods: Plasma and serum were obtained from cerebrospinal fluid or amyloid positron emission tomography-positive and -negative participants (N = 38) in the Wisconsin Registry for Alzheimer's Prevention. We modeled AD biomarker values observed in EDTA plasma versus heparin plasma and serum, and assessed correspondence with brain amyloidosis. Results: Results suggested bias due to tube type, but crosswalks are possible for some analytes, with excellent model fit for NfL ( R 2 = 0.94), adequate for amyloid ( R 2 = 0.40-0.69), and weaker for t-tau ( R 2 = 0.04-0.42) and p - ta u 181 ( R 2 = 0.22-0.29). Brain amyloidosis differentiated several measures, especially EDTA plasma pTa u 181 A β 42 ( d = 1.29). Discussion: AD biomarker concentrations vary by tube type. However, correlations for some biomarkers support harmonization across types, suggesting cautious optimism for use in banked blood