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Following regulatory approval of anti‐amyloid beta (Aβ) therapies, a better characterization of patients receiving these treatments is needed to guide clinical management and inclusion in future trials. This Alzheimer's Association‐convened workgroup proposes a terminology, treatment‐related amyloid clearance (TRAC), to reflect alterations in disease pathophysiology based on biomarker evidence for clearance of Aβ deposits. TRAC designates biomarker‐defined pharmacodynamic changes, rather than direct neuropathological evidence, and applies to individuals with (1) pretreatment biomarker confirmation of cerebral Aβ deposition, (2) treatment with an Aβ‐targeting therapy, and (3) a follow‐up biomarker test indicative of partial or full clearance of Aβ deposits. The workgroup currently recommends defining TRAC using amyloid‐positron emission tomography (PET) and emphasizes the role of quantitative measurements for defining the degree of clearance. This framework is expected to be adapted over time in response to rapidly evolving biomarker and clinical advances and with the accumulation of real‐world data on patients receiving anti‐Aβ therapies. Highlights TRAC identifies patients with biomarker evidence for clearance of amyloid deposits. TRAC is currently defined using amyloid‐PET. Full TRAC means that PET levels dropped below predetermined positivity threshold. Partial TRAC means that PET levels dropped significantly but remain above threshold. This framework is meant to guide future research on patients receiving treatment.

INTRODUCTION Studies suggest distinct differences in the development, presentation, progression, and response to treatment of Alzheimer's disease (AD) between females and males. We investigated sex differences in cognition, neuroimaging, and fluid biomarkers in dominantly inherited AD (DIAD). METHODS Three hundred twenty‐five mutation carriers (55% female) and one hundred eighty‐six non‐carriers (58% female) of the Dominantly Inherited Alzheimer Network Observational Study were analyzed. Linear mixed models and Spearman's correlation explored cross‐sectional sex differences in cognition, cerebrospinal fluid (CSF) biomarkers, Pittsburgh compound B positron emission tomography (11C‐PiB PET) and structural magnetic resonance imaging (MRI). RESULTS Female carriers performed better than males on delayed recall and processing speed despite similar hippocampal volumes. As the disease progressed, symptomatic females revealed higher increases in MRI markers of neurodegeneration and memory impairment. PiB PET and established CSF AD markers revealed no sex differences. DISCUSSION Our findings suggest an initial cognitive reserve in female carriers followed by a pronounced increase in neurodegeneration coupled with worse performance on delayed recall at later stages of DIAD.

Polymorphisms in TMEM106B, a gene on chromosome 7p21.3 involved in lysosomal trafficking, correlates to worse neuropathological, and clinical outcomes in frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS) with TDP‐43 inclusions. In a small cohort of C9orf72 expansion carriers, we previously found an atypical, neuroglial tauopathy in cases harboring a TMEM106B rs1990622 A/A genotype. To test whether TMEM106B genotype affects the risk of developing atypical tauopathy under a recessive genotype model (presence versus absence of two major alleles: A/A vs. A/G and G/G). We characterized the atypical tauopathy neuropathologically and determined its frequency by TMEM106B rs1990622 genotypes in 90 postmortem cases with a primary diagnosis of FTLD/ALS‐TDP [mean age at death 65.5 years (±8.1), 40% female]. We investigated the effect of this new atypical tauopathy on demographics and clinical and neuropsychological metrics. We also genotyped TMEM106B in an independent series with phenotypically similar cases. Sixteen cases (16/90, 17.7 %) showed the temporal‐predominant neuro‐astroglial tauopathy, and 93.7% of them carried an A/A genotype (vs. ~35% in a population cohort). The odds ratio of FTLD/ALS‐TDP individuals with the A/A genotype showing neuro‐astroglial tauopathy was 13.9. Individuals with this tauopathy were older at onset (p = 0.01). The validation cohort had a similarly high proportion of rs1990622 A/A genotype. TDP‐43 and tau changes co‐occur in a subset of neurons. Our data add to the growing body of evidence that TMEM106B polymorphisms may modulate neurodegeneration. A distinctive medial temporal predominant, 4‐repeat, neuro‐astroglial tauopathy strongly correlates to TMEM106B A/A genotype in FTLD/ALS‐TDP cases. noFTLD‐TDP cases with a TMEM106b A/A genotype have a much‐increased odds to show a distinct temporal‐predominant neuro‐astroglial tauopahty.

The World Health Organization (WHO) has reframed health and healthcare for older people around achieving the goal of healthy ageing. The recent WHO Integrated Care for Older People (ICOPE) guidelines focus on maintaining intrinsic capacity, i.e., addressing declines in neuromusculoskeletal, vitality, sensory, cognitive, psychological, and continence domains, aiming to prevent or delay the onset of dependence. The target group with 1 or more declines in intrinsic capacity (DICs) is broad, and implementation may be challenging in less-resourced settings. We aimed to inform planning by assessing intrinsic capacity prevalence, by characterising the target group, and by validating the general approach-testing hypotheses that DIC was consistently associated with higher risks of incident dependence and death. We conducted population-based cohort studies (baseline, 2003-2007) in urban sites in Cuba, Dominican Republic, Puerto Rico, and Venezuela, and rural and urban sites in Peru, Mexico, India, and China. Door-knocking identified eligible participants, aged 65 years and over and normally resident in each geographically defined catchment area. Sociodemographic, behaviour and lifestyle, health, and healthcare utilisation and cost questionnaires, and physical assessments were administered to all participants, with incident dependence and mortality ascertained 3 to 5 years later (2008-2010). In 12 sites in 8 countries, 17,031 participants were surveyed at baseline. Overall mean age was 74.2 years, range of means by site 71.3-76.3 years; 62.4% were female, range 53.4%-67.3%. At baseline, only 30% retained full capacity across all domains. The proportion retaining capacity fell sharply with increasing age, and declines affecting multiple domains were more common. Poverty, morbidity (particularly dementia, depression, and stroke), and disability were concentrated among those with DIC, although only 10% were frail, and a further 9% had needs for care. Hypertension and lifestyle risk factors for chronic disease, and healthcare utilisation and costs, were more evenly distributed in the population. In total, 15,901 participants were included in the mortality cohort (2,602 deaths/53,911 person-years of follow-up), and 12,939 participants in the dependence cohort (1,896 incident cases/38,320 person-years). One or more DICs strongly and independently predicted incident dependence (pooled adjusted subhazard ratio 1.91, 95% CI 1.69-2.17) and death (pooled adjusted hazard ratio 1.66, 95% CI 1.49-1.85). Relative risks were higher for those who were frail, but were also substantially elevated for the much larger sub-groups yet to become frail. Mortality was mainly concentrated in the frail and dependent sub-groups. The main limitations were potential for DIC exposure misclassification and attrition bias. In this study we observed a high prevalence of DICs, particularly in older age groups. Those affected had substantially increased risks of dependence and death. Most needs for care arose in those with DIC yet to become frail. Our findings provide some support for the strategy of optimising intrinsic capacity in pursuit of healthy ageing. Implementation at scale requires community-based screening and assessment, and a stepped-care intervention approach, with redefined roles for community healthcare workers and efforts to engage, train, and support them in these tasks. ICOPE might be usefully integrated into community programmes for detecting and case managing chronic diseases including hypertension and diabetes.

Alzheimer disease (AD) prevention trials hold the promise to delay or prevent cognitive decline and dementia onset by intervening before significant neuronal damage occurs. In recent years, the first AD prevention trials have launched and are yielding important findings on the biology of targeting asymptomatic AD pathology. However, there are limitations that impact the design of these prevention trials, including the translation of animal models that recapitulate key stages and multiple pathological aspects of the human disease, missing target validation in asymptomatic disease, uncertain causality of the association of pathophysiologic changes with cognitive and clinical symptoms, and limited biomarker validation for novel targets. The field is accelerating advancements in key areas including the development of highly specific and quantitative biomarker measures for AD pathology, increasing our understanding of the course and relationship of amyloid and tau pathology in asymptomatic through symptomatic stages, and the development of powerful interventions that can slow or reverse AD amyloid pathology. We review the current status of prevention trials and propose key areas of needed research as a call to basic and translational scientists to accelerate AD prevention. Specifically, we review (1) sporadic and dominantly inherited primary and secondary AD prevention trials, (2) proposed targets, mechanisms, and drugs including the amyloid, tau, and inflammatory pathways and combination treatments, (3) the need for more appropriate prevention animal models and experiments, and (4) biomarkers and outcome measures needed to design human asymptomatic prevention trials. We conclude with actions needed to effectively move prevention targets and trials forward.

INTRODUCTION Leveraging the nonmonolithic structure of Latin America, which represents a large variability in social determinants of health (SDoH) and high levels of genetic admixture, we aim to evaluate the relative contributions of SDoH and genetic ancestry in predicting dementia prevalence in Latin American populations. METHODS Community‐dwelling participants aged 65 and older (N = 3808) from Cuba, Dominican Republic, Mexico, and Peru completed the 10/66 protocol assessments. Dementia was diagnosed using the cross‐culturally validated 10/66 algorithm. Multivariate linear regression models adjusted for SDoH were used in the main analysis. This study used cross‐sectional data from the 1066 population‐based study. RESULTS Individuals with higher proportions of Native American (>70%) and African American (>70%) ancestry were more likely to exhibit factors contributing to worse SDoH, such as lower educational levels (p < 0.001), lower socioeconomic status (p < 0.001), and higher frequency of vascular risk factors (p < 0.001). After adjusting for measures of SDoH, there was no association between ancestry proportion and dementia probability, and ancestry proportions no longer significantly accounted for the variance in cognitive performance (African predominant p = 0.31 [‐0.19, 0.59] and Native predominant p = 0.74 [‐0.24, 0.33]). DISCUSSION The findings suggest that social and environmental factors play a more crucial role than genetic ancestry in predicting dementia prevalence in Latin American populations. This underscores the need for public health strategies and policies that address these social determinants to effectively reduce dementia risk in these communities. Highlights Countries in Latin America express a large variability in social determinants of health and levels of admixture. After adjustment for downstream societal factors linked to SDoH, genetic ancestry shows no link to dementia. Population ancestry profiles alone do not influence cognitive performance. SDoH are key drivers of racial disparities in dementia and cognitive performance.

INTRODUCTION This study involved evaluating a tailored genetic counseling and testing (GCT) protocol for families at risk of autosomal dominant Alzheimer's disease (ADAD) in Latin America (LatAm), focusing on essential cultural and regional adaptations. METHODS We conducted a non‐randomized controlled trial among ADAD families in Colombia and Argentina. Participants were categorized based on their decision to learn their genetic status (GS), with further comparisons between mutation‐positive versus mutation‐negative participants who learned their status. Psychological impacts were measured using validated scales for anxiety and depression. RESULTS Of the 122 eligible participants, 97 completed the GCT protocol, and 87 opted to learn their GS. There were no clinically significant differences in psychological distress between those who learned their status and those who did not, nor between mutation‐positive and mutation‐negative individuals. DISCUSSION The GCT protocol effectively managed psychological impacts in ADAD families and was positively received, demonstrating the importance of culturally adapted GCT protocols. Highlights We examined the adaptation and efficacy of a GCT protocol in LatAm for families at risk of ADAD. The GCT protocol mitigated psychological distress among at‐risk ADAD families. The study confirms the protocol's cultural appropriateness and psychological safety. Future studies should explore the long‐term psychological and public health impacts of GCT and use of GCT for treatment options.

INTRODUCTION Estimating treatment effects as time savings in disease progression may be more easily interpretable than assessing the absolute difference or a percentage reduction. In this study, we investigate the statistical considerations of the existing method for estimating time savings and propose alternative complementary methods. METHODS We propose five alternative methods to estimate the time savings from different perspectives. These methods are applied to simulated clinical trial data that mimic or modify the Clinical Dementia Rating Sum of Boxes progression trajectories observed in the Clarity AD lecanemab trial. RESULTS Our study demonstrates that the proposed methods can generate more precise estimates by considering two crucial factors: (1) the absolute difference between treatment arms, and (2) the observed progression rate in the treatment arm. DISCUSSION Quantifying treatment effects as time savings in disease progression offers distinct advantages. To provide comprehensive estimations, it is important to use various methods. Highlights We explore the statistical considerations of the current method for estimating time savings. We proposed alternative methods that provide time savings estimations based on the observed absolute differences. By using various methods, a more comprehensive estimation of time savings can be achieved.

Background: Due to the high prevalence of Alzheimer's disease (AD) in middle and low-income countries, there is an urgent need for inexpensive and minimally invasive diagnostic tests to detect biomarkers in the earliest and asymptomatic stages of the disease. Blood-based biomarkers biomarkers are predicted to have the most impact for use as a screening tool and predict the onset of AD. Methods: Medline/Pubmed was searched to identify current relevant studies published from January 2016 to December 2020. We included all full-text articles examining blood-based biomarkers, or set of protein markers, to aid in the early diagnosis, prognosis, and characterization of AD. Results: Sixty-six articles met the inclusion criteria to be included in the systematic review. The majority of studies reported biomarkers in plasma and serum. Conventional biomarkers amyloid-beta and tau, and neuroinflammatory biomarkers were the most represented, with amyloid beta-42, amyloid beta-40, total tau, phosphorylated tau-181, brain-derived neurotrophic factor, and complement C3 proposed in three or more studies. Protein-based biomarker panels were reported to aid in AD diagnosis and prognosis. We found amyloid beta-42/amyloid beta-40 ratio combined with APOEε4 status to be most represented with high accuracy for predicting amyloid beta-positron emission tomography status. In addition, complement C3 combined with A1-Microglobulin and A2-Macroglobulin reported high accuracy in panels for discriminating between AD and healthy individuals. Conclusions: The assessment of Alzheimer's disease biomarkers in blood as a noninvasive and cost-effective alternative will potentially contribute to the early diagnosis and improvement of therapeutic interventions. Given the heterogeneous nature of AD, a combination of markers seems to perform better for the diagnosis and prognosis of the disease than individual biomarkers.

INTRODUCTION This study aimed to determine the associations between parkinsonism and Parkinson's disease (PD) with cognitive impairment and dementia in a multi‐country cohort in Latin America, using data from the 10/66 Dementia Research Group. METHODS This population‐based prospective cohort study was conducted in six Latin American countries, including 11,321 participants 65 years of age or older living in urban and rural areas. RESULTS At baseline, the prevalence of cognitive impairment in people with parkinsonism and PD was 33% and 26%, respectively. Parkinsonism (odds ratio [OR] 2.2 [95% confidence interval [CI] 1.9–2.6] and PD (OR 1.9 [95% CI 1.4–2.4]) were individually associated with baseline cognitive impairment and incident dementia. The pooled sub‐hazard ratios for dementia in fixed‐effect meta‐analysis were 1.5 (95% CI 1.2–1.9) for parkinsonism and 1.5 (95% CI 1.0–2.2) for PD. DISCUSSION Parkinsonism and PD were cross‐sectionally associated with cognitive impairment and prospectively associated with incident dementia. These findings underscore the importance of routine screening for cognitive impairment in individuals with parkinsonism and PD, to facilitate early detection and intervention strategies that mitigate adverse outcomes. Highlights The present study is one of the first longitudinal investigations into the association of parkinsonism and Parkinson's disease (PD) with cognitive impairment and dementia incidence in Latin America. Parkinsonism and PD showed strong cross‐sectional associations with cognitive impairment, with consistent estimates across countries, independent of demographic factors. Parkinsonism and PD were linked to a significantly higher incidence of dementia over a 4‐year follow‐up period. Findings emphasize the need for routine cognitive screening in Parkinsonism and PD.