Arterial hypertension and ß-amyloid accumulation have spatially overlapping effects on posterior white matter hyperintensity volume: a cross-sectional study.

BACKGROUND: White matter hyperintensities (WMH) in subjects across the Alzheimer's disease (AD) spectrum with minimal vascular pathology suggests that amyloid pathology-not just arterial hypertension-impacts WMH, which in turn adversely influences cognition. Here we seek to determine the effect of both hypertension and Aß positivity on WMH, and their impact on cognition. METHODS: We analysed data from subjects with a low vascular profile and normal cognition (NC), subjective cognitive decline (SCD), and amnestic mild cognitive impairment (MCI) enrolled in the ongoing observational multicentre DZNE Longitudinal Cognitive Impairment and Dementia Study (n = 375, median age 70.0 [IQR 66.0, 74.4] years; 178 female; NC/SCD/MCI 127/162/86). All subjects underwent a rich neuropsychological assessment. We focused on baseline memory and executive function-derived from multiple neuropsychological tests using confirmatory factor analysis-, baseline preclinical Alzheimer's cognitive composite 5 (PACC5) scores, and changes in PACC5 scores over the course of three years (ΔPACC5). RESULTS: Subjects with hypertension or Aß positivity presented the largest WMH volumes (pFDR < 0.05), with spatial overlap in the frontal (hypertension: 0.42 ± 0.17; Aß: 0.46 ± 0.18), occipital (hypertension: 0.50 ± 0.16; Aß: 0.50 ± 0.16), parietal lobes (hypertension: 0.57 ± 0.18; Aß: 0.56 ± 0.20), corona radiata (hypertension: 0.45 ± 0.17; Aß: 0.40 ± 0.13), optic radiation (hypertension: 0.39 ± 0.18; Aß: 0.74 ± 0.19), and splenium of the corpus callosum (hypertension: 0.36 ± 0.12; Aß: 0.28 ± 0.12). Elevated global and regional WMH volumes coincided with worse cognitive performance at baseline and over 3 years (pFDR < 0.05). Aß positivity was negatively associated with cognitive performance (direct effect-memory: - 0.33 ± 0.08, pFDR < 0.001; executive: - 0.21 ± 0.08, pFDR < 0.001; PACC5: - 0.29 ± 0.09, pFDR = 0.006; ΔPACC5: - 0.34 ± 0.04, pFDR < 0.05). Splenial WMH mediated the relationship between hypertension and cognitive performance (indirect-only effect-memory: - 0.05 ± 0.02, pFDR = 0.029; executive: - 0.04 ± 0.02, pFDR = 0.067; PACC5: - 0.05 ± 0.02, pFDR = 0.030; ΔPACC5: - 0.09 ± 0.03, pFDR = 0.043) and WMH in the optic radiation partially mediated that between Aß positivity and memory (indirect effect-memory: - 0.05 ± 0.02, pFDR = 0.029). CONCLUSIONS: Posterior white matter is susceptible to hypertension and Aß accumulation. Posterior WMH mediate the association between these pathologies and cognitive dysfunction, making them a promising target to tackle the downstream damage related to the potentially interacting and potentiating effects of the two pathologies. TRIAL REGISTRATION: German Clinical Trials Register (DRKS00007966, 04/05/2015).

Serum IL-6, sAXL, and YKL-40 as systemic correlates of reduced brain structure and function in Alzheimer's disease: results from the DELCODE study.

BACKGROUND: Neuroinflammation constitutes a pathological hallmark of Alzheimer's disease (AD). Still, it remains unresolved if peripheral inflammatory markers can be utilized for research purposes similar to blood-based beta-amyloid and neurodegeneration measures. We investigated experimental inflammation markers in serum and analyzed interrelations towards AD pathology features in a cohort with a focus on at-risk stages of AD. METHODS: Data of 74 healthy controls (HC), 99 subjective cognitive decline (SCD), 75 mild cognitive impairment (MCI), 23 AD relatives, and 38 AD subjects were obtained from the DELCODE cohort. A panel of 20 serum biomarkers was determined using immunoassays. Analyses were adjusted for age, sex, APOE status, and body mass index and included correlations between serum and CSF marker levels and AD biomarker levels. Group-wise comparisons were based on screening diagnosis and routine AD biomarker-based schematics. Structural imaging data were combined into composite scores representing Braak stage regions and related to serum biomarker levels. The Preclinical Alzheimer's Cognitive Composite (PACC5) score was used to test for associations between the biomarkers and cognitive performance. RESULTS: Each experimental marker displayed an individual profile of interrelations to AD biomarkers, imaging, or cognition features. Serum-soluble AXL (sAXL), IL-6, and YKL-40 showed the most striking associations. Soluble AXL was significantly elevated in AD subjects with pathological CSF beta-amyloid/tau profile and negatively related to structural imaging and cognitive function. Serum IL-6 was negatively correlated to structural measures of Braak regions, without associations to corresponding IL-6 CSF levels or other AD features. Serum YKL-40 correlated most consistently to CSF AD biomarker profiles and showed the strongest negative relations to structure, but none to cognitive outcomes. CONCLUSIONS: Serum sAXL, IL-6, and YKL-40 relate to different AD features, including the degree of neuropathology and cognitive functioning. This may suggest that peripheral blood signatures correspond to specific stages of the disease. As serum markers did not reflect the corresponding CSF protein levels, our data highlight the need to interpret serum inflammatory markers depending on the respective protein's specific biology and cellular origin. These marker-specific differences will have to be considered to further define and interpret blood-based inflammatory profiles for AD research.

New insights into the genetic etiology of Alzheimer's disease and related dementias.

Characterization of the genetic landscape of Alzheimer's disease (AD) and related dementias (ADD) provides a unique opportunity for a better understanding of the associated pathophysiological processes. We performed a two-stage genome-wide association study totaling 111,326 clinically diagnosed/'proxy' AD cases and 677,663 controls. We found 75 risk loci, of which 42 were new at the time of analysis. Pathway enrichment analyses confirmed the involvement of amyloid/tau pathways and highlighted microglia implication. Gene prioritization in the new loci identified 31 genes that were suggestive of new genetically associated processes, including the tumor necrosis factor alpha pathway through the linear ubiquitin chain assembly complex. We also built a new genetic risk score associated with the risk of future AD/dementia or progression from mild cognitive impairment to AD/dementia. The improvement in prediction led to a 1.6- to 1.9-fold increase in AD risk from the lowest to the highest decile, in addition to effects of age and the APOE ε4 allele.

Associations and correlates of general versus specific successful ageing components.

The heterogeneity in the operationalisation of successful ageing (SA) hinders a straightforward examination of SA associations and correlates, and in turn, the identification of potentially modifiable predictors of SA. It is unclear which SA associations and correlates influence all facets of the SA construct, and whether psychosocial reserve models developed in neuropathological ageing research can also be linked to SA. It was therefore the aim of this study to disentangle the effect of various previously identified SA associations and correlates on (1) a general SA factor, which represents the shared underpinnings of three SA facets, and (2) more confined, specific factors, using bifactor modelling. The associations and correlates of three recently validated SA operationalisations were compared in 2478 participants from the German AgeCoDe study, aged 75 years and above. Based on participants' main occupation, cognitive reserve (CR) and motivational reserve (MR) models were built. Younger age, male gender, more education, higher socio-economic status, being married or widowed, as well as more physical exercise and cognitive activities in old age were found to correlate positively with the general SA factor, indicating a simultaneous effect on all aspects of SA. Smoking and ApoE-ε4 were related only to the physiological facet of SA. CR models were significantly related to the general SA factor. Among all SA associations and correlates, proxy indicators of lifelong cognitive activity and physical exercise showed the strongest effects on SA. Future intervention studies should assess the influence of the preservation of active lifestyle across the life span on SA.

Sex-Specific Associations Between Depressive Symptoms and Risk for Subsequent Dementia.

BACKGROUND: An association between depression and an increased risk for subsequent dementia is well-established. Sexspecific associations are understudied yet. OBJECTIVE: We aimed to investigate sex-specific associations between depressive symptoms and dementia risk. METHODS: Longitudinal analyses were conducted in a pooled data set (n = 4,255, mean age = 80 years) of two prospective cohort studies (LEILA 75+, AgeCoDe). Depressive symptoms were harmonized by dichotomized scores of two different depression screening scales using established cutoffs. Transition to dementia was used as outcome in Cox proportional hazards models. RESULTS: Depressive symptoms at baseline were associated with an increased risk for subsequent dementia, and this association was more pronounced in males (interaction of depressive symptoms × sex: HR = 1.64, 95% CI: 1.02-2.64, p = 0.042) in a model adjusted for study, age, and education. After additional adjustment for subjective and objective cognition, depressive symptoms and their interaction with sex (HR = 1.38, 95% CI: 0.85-2.23, p = 0.188) were no longer significantly associated with the risk for subsequent dementia. Sex-stratified analyses showed stronger and significant associations between depressive symptoms and subsequent dementia in men (e.g., HR= 2.10, 95% CI: 1.36-3.23, p = 0.001, compared to HR= 1.28, 95% CI: 1.04-1.58, p = 0.020, in women). CONCLUSIONS: Overall, we provide evidence for a stronger association between depression and dementia in men compared to women. Depressive symptoms should be diagnosed, monitored, and treated, not only due to depression, but also with respect to the risk for subsequent dementia, especially in elderly men.

Lifestyle Aspects As A Predictor Of Pain Among Oldest-Old Primary Care Patients - A Longitudinal Cohort Study.

PURPOSE: Dealing with the high prevalence of pain among the oldest-old (+75) is becoming a major health issue. Therefore, the aim of the study was to uncover health-related lifestyle behaviors (HLB) and age-related comorbidities which may predict, influence and prevent pain in old age. PATIENTS AND METHODS: In this longitudinal cohort study, data were obtained initially from 3.327 individuals aged 75+ from over 138 general practitioners (GP) during structured clinical interviews in 2003. Nine follow-ups (FU) were assessed until 2017. Available data from 736 individuals scoring in FU3 and FU7 were included in this analysis. Data were assembled in an ambulatory setting at participant's homes. Associations were tested using a linear regression model (model 1) and ordered logistic regression model (model 2). RESULTS: Statistical analyses revealed increased likelihood to experience pain for participants with comorbidities such as peripheral arterial disease (PAD) (coef. 13.51, P>t = 0.00) or chronic back pain (CBP) (coef. 6.64, P>t = 0.003) or higher body mass index (BMI) (coef. 0.57, P>t = 0.015) and, female gender (coef. 6.00, SE 3.0, t = 2.02, P>t = 0.044). Participants with medium education and former smokers showed significantly lower pain rating (coef. -5.05, P>t = 0.026; coef. -5.27, P>t = 0.026). Suffering from chronic back pain (OR = 2.03), osteoarthritis (OR = 1.49) or depressive symptoms (OR = 1.10) raised the odds to experience impairments in daily living due to pain. Physical activity showed no significant results. CONCLUSION: Chronic conditions such as PAD, or CBP, female gender and higher BMI may increase the risk of experiencing more pain while successful smoking cessation can lower pain ratings at old age. Early and consistent support through GPs should be given to older patients in order to prevent pain at old age.

Prevalence of pain and its associated factors among the oldest-olds in different care settings - results of the AgeQualiDe study.

BACKGROUND: The prevalence of pain is very common in the oldest age group. Managing pain successfully is a key topic in primary care, especially within the ageing population. Different care settings might have an impact on the prevalence of pain and everyday life. METHODS: Participants from the German longitudinal cohort study on Needs, Health Service Use, Costs and Health-related Quality of Life in a large Sample of Oldest-old Primary Care Patients (85+) (AgeQualiDe) were asked to rate their severity of pain as well as the impairment with daily activities. Besides gender, age, education, BMI and use of analgesics we focused on the current housing situation and on cognitive state. Associations of the dependent measures were tested using four ordinal logistic regression models. Model 1 and 4 consisted of the overall sample, model 2 and 3 were divided according to no cognitive impairment (NCI) and mild cognitive impairment (MCI). RESULTS: Results show a decline in pain at very old age but nonetheless a high prevalence among the 85+ year olds. Sixty-three per cent of the participants report mild to severe pain and 69% of the participants mild to extreme impairment due to pain with daily activities. Use of analgesics, depression and living at home with care support are significantly associated with higher and male gender with lower pain ratings. CONCLUSIONS: Sufficient pain management among the oldest age group is inevitable. Outpatient care settings are at risk of overlooking pain. Therefore focus should be set on pain management in these settings.