Search

Blood-based biomarkers continue to be explored for disease detection, monitoring of progression, and therapeutic outcomes as the diagnostic determination of Alzheimer's Disease in Down Syndrome (DS-AD) remains challenging in clinical settings. This perspective highlights the current status of this effort. Overall, amyloid (A), tau (T), and neurodegeneration (AT[N]) blood-based biomarkers have been shown to increase with disease pathology for individuals with DS. Phosphorylated tau biomarkers (p-tau217, p-tau181) have been consistently shown to track disease progression for DS-AD and are likely good candidates for use in clinical settings. Biomarkers of inflammation (glial fibrillary acidic protein) also show promise; however, additional work is needed. Findings from stability work of blood-based biomarkers conducted among non-DS also support the potential longitudinal utility of biomarkers such as neurofilament light chain and p-tau181 in DS. Gaps in our knowledge are highlighted, and a potential role for sex differences in biomarker outcomes is noted, along with recommendations for determining the appropriate context of use when translating biomarkers into clinical applications. HIGHLIGHTS: An overview of blood-based biomarkers for Alzheimer's disease (AD) was provided for consideration of their utility among individuals with Down syndrome when looking toward potential clinical applications. Longitudinal stability of many blood biomarkers and improvement in detection sensitivity make blood such as plasma a viable source for exploring AD pathology. Variability in reviewed findings regarding the application of blood biomarkers highlights the importance of understanding and defining the appropriate context of use, particularly when translating them into clinical practice., (© 2024 The Author(s). Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Anti-amyloid treatments for early symptomatic Alzheimer disease have recently become clinically available in some countries, which has greatly increased the need for biomarker confirmation of amyloid pathology. Blood biomarker (BBM) tests for amyloid pathology are more acceptable, accessible and scalable than amyloid PET or cerebrospinal fluid (CSF) tests, but have highly variable levels of performance. The Global CEO Initiative on Alzheimer's Disease convened a BBM Workgroup to consider the minimum acceptable performance of BBM tests for clinical use. Amyloid PET status was identified as the reference standard. For use as a triaging test before subsequent confirmatory tests such as amyloid PET or CSF tests, the BBM Workgroup recommends that a BBM test has a sensitivity of ≥90% with a specificity of ≥85% in primary care and ≥75-85% in secondary care depending on the availability of follow-up testing. For use as a confirmatory test without follow-up tests, a BBM test should have performance equivalent to that of CSF tests - a sensitivity and specificity of ~90%. Importantly, the predictive values of all biomarker tests vary according to the pre-test probability of amyloid pathology and must be interpreted in the complete clinical context. Use of BBM tests that meet these performance standards could enable more people to receive an accurate and timely Alzheimer disease diagnosis and potentially benefit from new treatments., (© 2024. Springer Nature Limited.)

Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

In January 2023, the Global Brain Health Institute (GBHI) at UCSF hosted an online salon to discuss the relationship between fairness and brain health equity. We aimed to address two primary questions: first, how is fairness perceived by the public, and how does it manifest in societal constructs like equity and justice? Second, what are the neurobiological foundations of fairness, and how do they impact brain health? Drawing from interdisciplinary fields such as philosophy, psychology, and neuroscience, the salon served as a platform for participants to share diverse perspectives on fairness. Fairness is a multifaceted concept encompassing equity, justice, empathy, opportunity, non-discrimination, and the Golden Rule, but by delving into its evolutionary origins, we can verify its deep-rooted presence in both human and animal behaviors. Real-world experiments, such as Frans de Waal's capuchin monkey study, have proven enlightening, elucidating many mechanisms that have shaped our neurobiological responses to fairness. Contemporary cognitive neuroscience research further emphasizes the role of neuroanatomical areas and neurotransmitters in encoding fairness-related processes. We also discussed the critical interconnection between fairness and healthcare equity, particularly its implications for brain health. These values are instrumental in promoting social justice and improving health outcomes. In our polarized social landscape, there are rising concerns about a potential decrease in fairness and prosocial behaviors due to isolated social bubbles. We stress the urgency for interventions that enhance perspective-taking, reasoning, and empathy. Overall, fairness is vital to fostering an equitable society and its subsequent influence on brain health outcomes., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Avelino-Silva, Trujillo and Udeh-Momoh.)

Frontotemporal dementia (FTD) covers a spectrum of neurodegenerative disorders with different phenotypes, genetic backgrounds, and pathological states. Its clinicopathological diversity challenges the diagnostic process and the execution of clinical trials, calling for specific diagnostic biomarkers of pathologic FTD types. There is also a need for biomarkers that facilitate disease staging, quantification of severity, monitoring in clinics and observational studies, and for evaluation of target engagement and treatment response in clinical trials. This review discusses current FTD biofluid-based biomarker knowledge taking into account the differing applications. The limitations, knowledge gaps, and challenges for the development and implementation of such markers are also examined. Strategies to overcome these hurdles are proposed, including the technologies available, patient cohorts, and collaborative research initiatives. Access to robust and reliable biomarkers that define the exact underlying pathophysiological FTD process will meet the needs for specific diagnosis, disease quantitation, clinical monitoring, and treatment development., (© 2022 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Background: Practice effects (PE), after repeated cognitive measurements, may mask cognitive decline and represent a challenge in clinical and research settings. However, an attenuated practice effect may indicate the presence of brain pathologies. This study aimed to evaluate practice effects on the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) scale, and their associations with brain amyloid status and other factors in a cohort of cognitively unimpaired older adults enrolled in the CHARIOT-PRO SubStudy., Materials and Methods: 502 cognitively unimpaired participants aged 60-85 years were assessed with RBANS in both screening and baseline clinic visits using alternate versions (median time gap of 3.5 months). We tested PE based on differences between test and retest scores in total scale and domain-specific indices. Multiple linear regressions were used to examine factors influencing PE, after adjusting for age, sex, education level, APOE -ε4 carriage and initial RBANS score. The latter and PE were also evaluated as predictors for amyloid positivity status based on defined thresholds, using logistic regression., Results: Participants' total scale, immediate memory and delayed memory indices were significantly higher in the second test than in the initial test (Cohen's d z = 0.48, 0.70 and 0.35, P < 0.001). On the immediate memory index, the PE was significantly lower in the amyloid positive group than the amyloid negative group ( P = 0.022). Older participants (≥70 years), women, non- APOE -ε4 carriers, and those with worse initial RBANS test performance had larger PE. No associations were found between brain MRI parameters and PE. In addition, attenuated practice effects in immediate or delayed memory index were independent predictors for amyloid positivity ( P < 0.05)., Conclusion: Significant practice effects on RBANS total scale and memory indices were identified in cognitively unimpaired older adults. The association with amyloid status suggests that practice effects are not simply a source of measurement error but may be informative with regard to underlying neuropathology., Competing Interests: SB and GN were employed by Janssen Research and Development LLC. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The authors declare that this study received funding from Janssen Research & Development, USA. This is a collaborative study with the sponsor’s clinicians and scientists., (Copyright © 2022 Zheng, Udeh-Momoh, Watermeyer, de Jager Loots, Ford, Robb, Giannakopoulou, Ahmadi-Abhari, Baker, Novak, Price and Middleton.)

Alzheimer's disease (AD) includes a long asymptomatic stage, which precedes the formal diagnosis of dementia. AD biomarker models provide a framework for precision medicine approaches during this stage. However, such approaches have ignored the possible influence of sex on cognition and brain health, despite female sex noted as a major risk factor. Since AD-related changes may emerge in midlife, intervention efforts are being redirected around this period. Midlife coincides with several endocrinological changes, such as the menopausal transition experienced by women. In this narrative review, we discuss evidence for sex-differences in AD neuropathological burden and outline key endocrinological mechanisms for both sexes, focussing on hormonal events throughout the lifespan that may influence female susceptibility to AD neuropathology and dementia onset. We further consider common non-modifiable (genetic) and modifiable (lifestyle and health) risk factors, highlighting possible sex-dependent differential effects for the AD disease course. Finally, we evaluate the studies selected for this review demonstrating sex-differences in cognitive, pathological and health factors, summarising the state of sex differences in AD risk factors. We further provide recommendations for targeted research on female-specific risk factors, to inform personalised strategies for AD-prevention and the promotion of female brain health., (Copyright © 2021. Published by Elsevier B.V.)

With disease-modifying treatments for Alzheimer's disease (AD) still elusive, the search for alternative intervention strategies has intensified. Growing evidence suggests that dysfunction in hypothalamic-pituitaryadrenal-axis (HPAA) activity may contribute to the development of AD pathology. The HPAA, may therefore offer a novel target for therapeutic action. This review summarises and critically evaluates animal and human studies investigating the effects of pharmacological and non-pharmacological intervention on HPAA modulation alongside cognitive performance. The interventions discussed include glucocorticoid receptor antagonists and 11β-hydroxysteroid dehydrogenase inhibitors as well as lifestyle treatments such as physical activity, diet, sleep and contemplative practices. Pharmacological HPAA modulators improve pathology and cognitive deficit in animal AD models, but human pharmacological trials are yet to provide definitive support for such benefits. Lifestyle interventions may offer promising strategies for HPAA modification and cognitive health, but several methodological caveats across these studies were identified. Directions for future research in AD studies are proposed., (Crown Copyright © 2020. Published by Elsevier Inc. All rights reserved.)

Background: Morning cortisol levels have been reported to be elevated among patients with Alzheimer's disease (AD); yet no meta-analysis has been conducted to confirm the existence and magnitude of this association. It also remains unclear whether hypercortisolism is a risk factor for AD., Methods: PubMed, EMBASE, and PsycINFO were systematically searched for eligible studies. Cross-sectional data were pooled using random-effects meta-analyses; the differences in morning cortisol levels between patients and cognitively normal controls were quantified. Longitudinal studies were qualitatively synthesised due to methodological heterogeneity., Results: 17,245 participants from 57 cross-sectional studies and 19 prospective cohort studies were included. Compared with cognitively normal controls, AD patients had moderately increased morning cortisol in blood (g = 0.422, P < 0.001; I 2 = 48.5 %), saliva (g = 0.540, P < 0.001; I 2 = 13.6 %), and cerebrospinal fluids (g = 0.565, P = 0.003; I 2 = 75.3 %). A moderate elevation of morning cortisol was also detected in cerebrospinal fluids from patients with mild cognitive impairment (MCI) versus controls (g = 0.309, P = 0.001; I 2 = 0.0 %). Cohort studies suggested that higher morning cortisol may accelerate cognitive decline in MCI or mild AD patients, but the results in cognitively healthy adults were inconsistent., Conclusions: Morning cortisol was confirmed to be moderately elevated in AD patients and may have diagnostic and prognostic values for AD., (Crown Copyright © 2020. Published by Elsevier B.V. All rights reserved.)

Alzheimer's disease (AD) is the most common form of dementia, impacting global cognitive performance, including episodic memory. Semantic clustering is a learning strategy involving grouping words of similar meaning and can improve episodic memory performance, e.g., list learning. As the APOE ε4 allele is the most validated genetic risk factor for AD, we predicted that its presence would be associated with poorer list learning performance, and we hypothesized that semantic clustering moderates or mediates this association. The sample comprised 699 healthy older adults participating in the CHARIOT PRO Main Study, 169 of whom were APOE ε4 carriers. Participants' ability to form groups of related stimuli (assessed via a categorization task, CAT), and their use of semantic clustering during list learning, were investigated using the Neuropsychological Assessment Battery (NAB). CAT scores predicted the use of semantic clustering in, and performance on, the list learning task. CAT scores were not significantly lower in APOE ε4 carriers, suggesting that the ability to categorize was preserved. However, APOE ε4 carriers made less use of semantic clustering in list learning. Semantic clustering use partially mediated the relationship between CAT scores and list learning performance, and, in women only, moderated the impact of APOE ε4 on list learning performance. The results suggest that better categorization ability is associated with greater use of mnemonic strategies and better performance on memory tasks regardless of genetic risk, but that APOE ε4 carriers make less use of such strategies. Furthermore, female APOE ε4 carriers may benefit more than their non-carriers from using semantic clustering to aid list learning. Thus, semantic clustering may be a contributing factor of their "cognitive reserve", compensating for potential deficits in episodic memory.

The COVID-19 pandemic is imposing a profound negative impact on the health and wellbeing of societies and individuals, worldwide. One concern is the effect of social isolation as a result of social distancing on the mental health of vulnerable populations, including older people. Within six weeks of lockdown, we initiated the CHARIOT COVID-19 Rapid Response Study, a bespoke survey of cognitively healthy older people living in London, to investigate the impact of COVID-19 and associated social isolation on mental and physical wellbeing. The sample was drawn from CHARIOT, a register of people over 50 who have consented to be contacted for aging related research. A total of 7,127 men and women (mean age=70.7 [SD=7.4]) participated in the baseline survey, May-July 2020. Participants were asked about changes to the 14 components of the Hospital Anxiety Depression scale (HADS) after lockdown was introduced in the UK, on 23 rd March. A total of 12.8% of participants reported feeling worse on the depression components of HADS (7.8% men and 17.3% women) and 12.3% reported feeling worse on the anxiety components (7.8% men and 16.5% women). Fewer participants reported feeling improved (1.5% for depression and 4.9% for anxiety). Women, younger participants, those single/widowed/divorced, reporting poor sleep, feelings of loneliness and who reported living alone were more likely to indicate feeling worse on both the depression and/or anxiety components of the HADS. There was a significant negative association between subjective loneliness and worsened components of both depression (OR 17.24, 95% CI 13.20, 22.50) and anxiety (OR 10.85, 95% CI 8.39, 14.03). Results may inform targeted interventions and help guide policy recommendations in reducing the effects of social isolation related to the pandemic, and beyond, on the mental health of older people., (Copyright © 2020 Robb, de Jager, Ahmadi-Abhari, Giannakopoulou, Udeh-Momoh, McKeand, Price, Car, Majeed, Ward and Middleton.)

Objective: To determine whether hypothalamus-pituitary-adrenal axis (HPAA) dysfunction is prospectively associated with global cognitive impairment in later life., Methods: This cross-cohort study integrates 2 large longitudinal datasets, Whitehall II and the National Survey for Health and Development (NSHD), on data collected in the Whitehall II study between 2002-2004, 2007-2009, and 2012-2013; and for NSHD between 2006-2010 and in 2015. Serial salivary cortisol samples were collected multiple times within a 24-hour period at mean ages 61.2 and 65.9 years in Whitehall II and at age 60-64 years from NSHD participants. Cortisol profile is defined using cortisol awakening response and am:pm ratio. Cognitive function was measured using the Mini-Mental State Examination in Whitehall II and Addenbrooke's Cognitive Examination, third version, in NSHD, harmonized into a 30-point score. Models were adjusted for age, sex, diagnoses of hypertension and diabetes, body mass index (BMI), educational attainment, and interval between HPAA and cognitive assessments., Results: In fully adjusted models, increased am:pm cortisol ratio was prospectively associated with better later-life cognitive function years later (0.02 fewer errors per SD increase in am:pm cortisol ratio, p < 0.01) and verbal fluency (0.03 SD increase in verbal fluency per SD increase in am:pm ratio, p < 0.01). Increasing age, lower educational attainment, diagnosis of hypertension, diagnosis of diabetes, and increased BMI were associated with worse cognitive function and poorer verbal fluency. There were no associations between depression and later-life cognition or reverse associations between cognition and later-life cortisol profiles., Conclusions: Loss of diurnal HPAA variation is evident in individuals subsequently experiencing more cognitive impairment. It may serve as an early preclinical marker of cognitive decline., (Copyright © 2019 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Introduction: The role of TOMM40-APOE 19q13.3 region variants is well documented in Alzheimer's disease (AD) but remains contentious in dementia with Lewy bodies (DLB) and Parkinson's disease dementia (PDD)., Methods: We dissected genetic profiles within the TOMM40-APOE region in 451 individuals from four European brain banks, including DLB and PDD cases with/without neuropathological evidence of AD-related pathology and healthy controls., Results: TOMM 40 -L/ APOE -ε4 alleles were associated with DLB (OR TOMM40 - L  = 3.61; P value = 3.23 × 10 -9 ; OR APOE -ε4  = 3.75; P value = 4.90 × 10 -10 ) and earlier age at onset of DLB (HR TOMM40 -L  = 1.33, P value = .031; HR APOE -ε4  = 1.46, P value = .004), but not with PDD. The TOMM40 -L/ APOE -ε4 effect was most pronounced in DLB individuals with concomitant AD pathology (OR TOMM40 -L  = 4.40, P value = 1.15 × 10 -6 ; OR APOE - ε 4  = 5.65, P value = 2.97 × 10 -8 ) but was not significant in DLB without AD. Meta-analyses combining all APOE -ε4 data in DLB confirmed our findings (OR DLB  = 2.93, P value = 3.78 × 10 -99 ; OR DLB+AD  = 5.36, P value = 1.56 × 10 -47 )., Discussion: APOE -ε4/ TOMM 40 -L alleles increase susceptibility and risk of earlier DLB onset, an effect explained by concomitant AD-related pathology. These findings have important implications in future drug discovery and development efforts in DLB., (© 2019 The Authors.)

This study examined the feasibility of including myfood24, an online 24-hour dietary recall tool, in a cohort studies of older adults. Participants ( n = 319) were recruited during follow-up visits for the CHARIOT-Pro Sub-study, a prospective study of cognitively healthy adults aged 60-85 years at baseline. Email invitations were sent over three consecutive months, with weekly reminders. Multivariable regression models were applied to examine the number of recalls completed in relation to technology readiness (TR) scores and demographic characteristics. Ninety-four percent of people agreed to participate. Among participants, 67% completed at least one recall, and 48% completed two or more. Participants who completed multiple recalls reported higher self-confidence with technology and received a higher TR score than those who did not complete any recalls. A one-point higher TR score was associated with higher odds of completing three recalls compared to zero recalls (OR 1.70, 95% CI 0.96-3.01); this association was further attenuated after adjustment for demographic and other TR-related covariates (OR 1.35, 95% CI 0.63-2.88). This study demonstrates reasonable participation rates for a single myfood24 recall among older adults participating in a cohort study but suggests that further support may be required to obtain multiple recalls in this population.

Background: Little is known of possible associations between Alzheimer's disease (AD) biomarkers and instrumental activities of daily living (IADL) change over time., Objective: The present study seeks to identify relationships between baseline imaging and fluid biomarker profiles, and decline in IADL utilizing data collated from the Alzheimer's Disease Neuroimaging Initiative (ADNI) cohort., Methods: Generalized estimating equations analysis, adjusted for cognitive deterioration, was applied to a cohort of 509 individuals from all stages of ADNI, including 156 healthy controls, 189 early mild cognitive impairment (MCI) patients and 164 MCI patients., Results: A significant correlation was found between baseline biomarkers, specifically CSF Aβ and FDG PET, and IADL change over a 3-year period in individuals with MCI. Importantly, comparable correlations between presence of pathological biomarker levels and temporal decline in both functional and cognitive performance were also noted., Discussion: We show that distinct baseline biomarkers may predict latent changes in IADL. Our results necessitate a revision of the commonly held view upholding cognitive changes as the predominant endpoint measure associated with presence of abnormal baseline biomarkers.