JOINT CONTRIBUTION OF MARKERS OF NEURODEGENERATION AND HYPERCHOLESTEROLEMIA TO DEMENTIA RISK

Background The examination of markers of neurodegeneration (glial fibrillary acidic protein; GFAP, neurofilament light chain; NfL, phosphorylated tau181; p-tau181) among individuals with high comorbidity of neurodegenerative and cerebrovascular disease and their interplay with vascular risk factors, particularly high cholesterol levels, might contribute to explaining the link between body and brain. The aim of this study was to assess whether the association of GFAP, NfL, and p-tau181 with dementia risk varies depending on levels of total cholesterol (TC) and APOE ε4 genotype. Methods Nested case-control study embedded within a population-based cohort and including 768 older adults (261 dementia cases and 508 randomly selected controls) followed for up to 17 years with regard to clinical diagnosis of various age-related diseases. GFAP, NfL, and p-tau181 were measured in baseline blood samples using the Single-Molecule Array (Simoa) Technology (Quanterix, USA) and categorized into high (quartile 4) versus low (quartiles 1-3). Logistic regression analyses and spline regression models for dose-response analyses were used. ROC curves by cholesterol levels were also calculated. Results The risk of a dementia diagnosis was significantly increased between participants with high vs. low levels of GFAP and NfL and the risk substantially varied by TC levels. For GFAP and NfL the ORs of a dementia diagnosis were 5.10 (2.45-10.60) and 2.96 (1.43-6.14) in participants with high and 2.44 (1.47-4.07) and 1.15 (0.69-1.92) in those with low TC. APOE ε4 genotype further modified the strength of the associations with different patterns, depending on specific marker and type of dementia. No significant association was seen with p-tau181. Conclusions These results suggest that in the general population blood GFAP and NfL are better predictors of dementia than p-tau181 and that their associations with dementia risk are highly amplified by hypercholesterolemia, also depending on APOE ε4 genotype.

Neighborhood greenspace exposure as a protective factor in dementia risk among U.S. adults 75 years or older: a cohort study

Background Research suggests that greenspace may confer neurocognitive benefits. This study examines whether residential greenspace is associated with risk of dementia among older adults. Methods Greenspace exposure was computed for 3047 participants aged 75 years and older enrolled in the Gingko Evaluation of Memory Study (GEMS) across four U.S. sites that prospectively evaluated dementia and its subtypes, Alzheimer’s disease (AD), vascular dementia (VaD), and mixed pathologies, using neuropsychiatric evaluations between 2000 and 2008. After geocoding participant residences at baseline, three greenspace metrics—Normalized Difference Vegetative Index, percent park overlap within a 2-km radius, and linear distance to nearest park—were combined to create a composite residential greenspace measure categorized into tertiles. Cox proportional hazards models estimated the associations between baseline greenspace and risk of incident all-cause dementia, AD, and Mixed/VaD. Results Compared to low residential greenspace, high residential greenspace was associated with a reduced risk of dementia (HR = 0.76 95% CI: 0.59,0.98) in models adjusted for multiple covariates. After additional adjustment for behavioral characteristics, Apolipoprotein E ɛ4 status, and other covariates, the association was slightly attenuated (HR = 0.82; 95% CI:0.63,1.06). Those exposed to medium levels of greenspace also had 28% lower risk (HR = 0.72; CI: 0.55, 0.95) of dementia compared to those with low greenspace in adjusted models. Subtype associations between high residential greenspace and AD were not statistically significant. Greenspace was not found to be significantly associated with mixed/vascular pathologies. Conclusions This study showed evidence for an association between residential greenspace and all-cause dementia among older adults. Future research with larger sample size, precise characterization of different dementia subtypes, and assessment of residential greenspace earlier in life may help clarify the role between exposure to greenspace and dementia risk.

Severe Hypoglycemia Increases Dementia Risk and Related Mortality: A Nationwide, Population-Based Cohort Study

Context There are few studies focused on the relationship between hypoglycemia and new-onset dementia in patients with type 2 diabetes and no study regarding mortality of dementia after hypoglycemia. Objective We investigated the effect of severe hypoglycemia on dementia subtypes and its relation to overall mortality in patients with type 2 diabetes. Methods We evaluated incident dementia, including Alzheimer disease and vascular dementia, among health checkup participants aged 40 years or older in the National Health Insurance System in Korea from January 2009 to December 2015. Episodes of severe hypoglycemia were examined for 3 years before the date of the health checkup. Results Among 2 032 689 participants (1 172 271 men, 860 418 women), 14 443 (0.7%) experienced severe hypoglycemia, during a mean follow-up period of 6.9 ± 1.7 years. Individuals in the severe hypoglycemia group were more likely to be diagnosed with dementia compared to individuals without severe hypoglycemia (23.3% vs 7.3%; P < .001) and the overall incidence of Alzheimer disease was higher than vascular dementia. Dementia risk rose with increasing number of severe hypoglycemic episodes (1 episode [hazard ratio (HR) = 1.54; 95% CI, 1.48-1.60], 2 or more episodes [HR = 1.80; 95% CI, 1.66-1.94]). Overall mortality was higher in participants with dementia, but without severe hypoglycemia (HR = 2.03; 95% CI, 1.96-2.10) and severe hypoglycemia, but without dementia (HR = 4.24; 95% CI, 4.29-4.40), and risk of death was highest in those with both severe hypoglycemia and dementia (HR = 5.08; 95% CI, 4.83-5.35). Conclusion Severe hypoglycemia is associated with dementia, especially Alzheimer disease and mortality; together, they have an additive effect on overall mortality.

Mild behavioral impairment: measurement and clinical correlates of a novel marker of preclinical Alzheimer’s disease

Background Late-life onset neuropsychiatric symptoms are established risk factors for dementia. The mild behavioral impairment (MBI) diagnostic framework was designed to standardize assessment to determine dementia risk better. In this Mini Review, we summarize the emerging clinical and biomarker evidence, which suggests that for some, MBI is a marker of preclinical Alzheimer’s disease. Main MBI is generally more common in those with greater cognitive impairment. In community and clinical samples, frequency is around 10–15%. Mounting evidence in cognitively normal samples links MBI symptoms with known AD biomarkers for amyloid, tau, and neurodegeneration, as well as AD risk genes. Clinical studies have found detectable differences in cognition associated with MBI in cognitively unimpaired people. Conclusion The emerging evidence from biomarker and clinical studies suggests MBI can be an early manifestation of underlying neurodegenerative disease. Future research must now further validate MBI to improve identification of those at the very earliest stages of disease.

Dementia Risk Scores and Their Role in the Implementation of Risk Reduction Guidelines

Dementia prevention is a global health priority. In 2019, the World Health Organisation published its first evidence-based guidelines on dementia risk reduction. We are now at the stage where we need effective tools and resources to assess dementia risk and implement these guidelines into policy and practice. In this paper we review dementia risk scores as a means to facilitate this process. Specifically, we (a) discuss the rationale for dementia risk assessment, (b) outline some conceptual and methodological issues to consider when reviewing risk scores, (c) evaluate some dementia risk scores that are currently in use, and (d) provide some comments about future directions. A dementia risk score is a weighted composite of risk factors that reflects the likelihood of an individual developing dementia. In general, dementia risks scores have a wide range of implementations and benefits including providing early identification of individuals at high risk, improving risk perception for patients and physicians, and helping health professionals recommend targeted interventions to improve lifestyle habits to decrease dementia risk. A number of risk scores for dementia have been published, and some are widely used in research and clinical trials e.g., CAIDE, ANU-ADRI, and LIBRA. However, there are some methodological concerns and limitations associated with the use of these risk scores and more research is needed to increase their effectiveness and applicability. Overall, we conclude that, while further refinement of risk scores is underway, there is adequate evidence to use these assessments to implement guidelines on dementia risk reduction.

Association of improved air quality with lower dementia risk in older women

Late-life ambient air pollution is a risk factor for brain aging, but it remains unknown if improved air quality (AQ) lowers dementia risk. We studied a geographically diverse cohort of older women dementia free at baseline in 2008 to 2012 (n = 2,239, aged 74 to 92). Incident dementia was centrally adjudicated annually. Yearly mean concentrations of fine particulate matter (PM2.5) and nitrogen dioxide (NO2) were estimated using regionalized national universal kriging models and averaged over the 3-y period before baseline (recent exposure) and 10 y earlier (remote exposure). Reduction from remote to recent exposures was used as the indicator of improved AQ. Cox proportional hazard ratios (HRs) for dementia risk associated with AQ measures were estimated, adjusting for sociodemographic, lifestyle, and clinical characteristics. We identified 398 dementia cases during follow up (median = 6.1 y). PM2.5 and NO2 reduced significantly over the 10 y before baseline. Larger AQ improvement was associated with reduced dementia risks (HRPM2.5 0.80 per 1.78 μg/m3, 95% CI 0.71–0.91; HRNO2 0.80 per 3.91 parts per billion, 95% CI 0.71–0.90), equivalent to the lower risk observed in women 2.4 y younger at baseline. Higher PM2.5 at baseline was associated with higher dementia risk (HRPM2.5 1.16 per 2.90 μg/m3, 95% CI 0.98–1.38), but the lower dementia risk associated with improved AQ remained after further adjusting for recent exposure. The observed associations did not substantially differ by age, education, geographic region, Apolipoprotein E e4 genotypes, or cardiovascular risk factors. Long-term AQ improvement in late life was associated with lower dementia risk in older women.

Digital phenotyping and the (data) shadow of Alzheimer's disease

In this paper, we examine the practice and promises of digital phenotyping. We build on work on the ‘data self’ to focus on a medical domain in which the value and nature of knowledge and relations with data have been played out with particular persistence, that of Alzheimer's disease research. Drawing on research with researchers and developers, we consider the intersection of hopes and concerns related to both digital tools and Alzheimer's disease using the metaphor of the ‘data shadow’. We suggest that as a tool for engaging with the nature of the data self, the shadow is usefully able to capture both the dynamic and distorted nature of data representations, and the unease and concern associated with encounters between individuals or groups and data about them. We then consider what the data shadow ‘is’ in relation to ageing data subjects, and the nature of the representation of the individual's cognitive state and dementia risk that is produced by digital tools. Second, we consider what the data shadow ‘does’, through researchers and practitioners’ discussions of digital phenotyping practices in the dementia field as alternately empowering, enabling and threatening.