The 100 most-cited articles in Alzheimer s & Dementia, 2022

This article describes the public health impact of Alzheimer's disease (AD), including incidence and prevalence, mortality and morbidity, use and costs of care, and the overall impact on family caregivers, the dementia workforce and society. The Special Report discusses consumers' and primary care physicians' perspectives on awareness, diagnosis and treatment of mild cognitive impairment (MCI), including MCI due to Alzheimer's disease. An estimated 6.5 million Americans age 65 and older are living with Alzheimer's dementia today. This number could grow to 13.8 million by 2060 barring the development of medical breakthroughs to prevent, slow or cure AD. Official death certificates recorded 121,499 deaths from AD in 2019, the latest year for which data are available. Alzheimer's disease was officially listed as the sixth-leading cause of death in the United States in 2019 and the seventh-leading cause of death in 2020 and 2021, when COVID-19 entered the ranks of the top ten causes of death. Alzheimer's remains the fifth-leading cause of death among Americans age 65 and older. Between…

INTRODUCTION: Global estimates on numbers of persons in early stages of Alzheimer's disease (AD), including prodromal and preclinical, are lacking, yet are needed to inform policy decisions on preventive measures and planning for future therapies targeting AD pathology. METHODS: We synthesized the literature on prevalence across the AD continuum and derived a model estimating the number of persons, stratified by 5-year age groups, sex, and disease stage (AD dementia, prodromal AD, and preclinical AD). RESULTS: The global number of persons with AD dementia, prodromal AD, and preclinical AD were estimated at 32, 69, and 315 million, respectively. Together they constituted 416 million across the AD continuum, or 22% of all persons aged 50 and above. DISCUSSION: Considering predementia stages, the number of persons with AD is much larger than conveyed in available literature. Our estimates are uncertain, especially for predementia stages in low- and middle-income regions where biomarker studies are missing.

Blood-based markers (BBMs) have recently shown promise to revolutionize the diagnostic and prognostic work-up of Alzheimer's disease (AD), as well as to improve the design of interventional trials. Here we discuss in detail further research needed to be performed before widespread use of BBMs. We already now recommend use of BBMs as (pre-)screeners to identify individuals likely to have AD pathological changes for inclusion in trials evaluating disease-modifying therapies, provided the AD status is confirmed with positron emission tomography (PET) or cerebrospinal fluid (CSF) testing. We also encourage studying longitudinal BBM changes in ongoing as well as future interventional trials. However, BBMs should not yet be used as primary endpoints in pivotal trials. Further, we recommend to cautiously start using BBMs in specialized memory clinics as part of the diagnostic work-up of patients with cognitive symptoms and the results should be confirmed whenever possible with CSF or PET. Additional data are needed before use of BBMs as stand-alone diagnostic AD markers, or before…

To promote new thinking of the pathogenesis of Alzheimer's disease (AD), we examine the central role of mitochondrial dysfunction in AD. Pathologically, AD is characterized by progressive neuronal loss and biochemical abnormalities including mitochondrial dysfunction. Conventional thinking has dictated that AD is driven by amyloid beta pathology, per the Amyloid Cascade Hypothesis. However, the underlying mechanism of how amyloid beta leads to cognitive decline remains unclear. A model correctly identifying the pathogenesis of AD is critical and needed for the development of effective therapeutics. Mitochondrial dysfunction is closely linked to the core pathological feature of AD: neuronal dysfunction. Targeting mitochondria and associated proteins may hold promise for new strategies for the development of disease-modifying therapies. According to the Mitochondrial Cascade Hypothesis, mitochondrial dysfunction drives the pathogenesis of AD, as baseline mitochondrial function and mitochondrial change rates influence the progression of cognitive decline. HIGHLIGHTS: The Amyloid…

INTRODUCTION: We conducted a systematic review and meta-analysis of the cognitive effects of coronavirus disease 2019 (COVID-19) in adults with no prior history of cognitive impairment. METHODS: Searches in Medline/Web of Science/Embase from January 1, 2020, to December 13, 2021, were performed following Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. A meta-analysis of the Montreal Cognitive Assessment (MoCA) total score comparing recovered COVID-19 and healthy controls was performed. RESULTS: Oof 6202 articles, 27 studies with 2049 individuals were included (mean age = 56.05 years, evaluation time ranged from the acute phase to 7 months post-infection). Impairment in executive functions, attention, and memory were found in post-COVID-19 patients. The meta-analysis was performed with a subgroup of 290 individuals and showed a difference in MoCA score between post-COVID-19 patients versus controls (mean difference = -0.94, 95% confidence interval [CI] -1.59, -0.29; P = .0049). DISCUSSION: Patients recovered from COVID-19 have lower general…

INTRODUCTION: Plasma amyloid beta (Aβ)1-42/Aβ1-40 ratio, phosphorylated-tau181 (p-tau181), glial fibrillary acidic protein (GFAP), and neurofilament light (NfL) are putative blood biomarkers for Alzheimer's disease (AD). However, head-to-head cross-sectional and longitudinal comparisons of the aforementioned biomarkers across the AD continuum are lacking. METHODS: Plasma Aβ1-42, Aβ1-40, p-tau181, GFAP, and NfL were measured utilizing the Single Molecule Array (Simoa) platform and compared cross-sectionally across the AD continuum, wherein Aβ-PET (positron emission tomography)-negative cognitively unimpaired (CU Aβ-, n = 81) and mild cognitive impairment (MCI Aβ-, n = 26) participants were compared with Aβ-PET-positive participants across the AD continuum (CU Aβ+, n = 39; MCI Aβ+, n = 33; AD Aβ+, n = 46) from the Australian Imaging, Biomarker & Lifestyle Flagship Study of Ageing (AIBL) cohort. Longitudinal plasma biomarker changes were also assessed in MCI (n = 27) and AD (n = 29) participants compared with CU (n = 120) participants. In addition, associations between baseline plasma…

INTRODUCTION: The Alzheimer's disease (AD) continuum begins with a long asymptomatic or preclinical stage, during which amyloid beta (Aβ) is accumulating for more than a decade prior to widespread cortical tauopathy, neurodegeneration, and manifestation of clinical symptoms. The AHEAD 3-45 Study (BAN2401-G000-303) is testing whether intervention with lecanemab (BAN2401), a humanized immunoglobulin 1 (IgG1) monoclonal antibody that preferentially targets soluble aggregated Aβ, initiated during this asymptomatic stage can slow biomarker changes and/or cognitive decline. The AHEAD 3-45 Study is conducted as a Public-Private Partnership of the Alzheimer's Clinical Trial Consortium (ACTC), funded by the National Institute on Aging, National Institutes of Health (NIH), and Eisai Inc. METHODS: The AHEAD 3-45 Study was launched on July 14, 2020, and consists of two sister trials (A3 and A45) in cognitively unimpaired (CU) individuals ages 55 to 80 with specific dosing regimens tailored to baseline brain amyloid levels on screening positron emission tomography (PET) scans: intermediate…

INTRODUCTION: Direct comparisons of the main blood phosphorylated tau immunoassays in memory clinic populations are needed to understand possible differences. METHODS: In the BIODEGMAR study, 197 participants presenting with cognitive complaints were classified into an Alzheimer's disease (AD) or a non-AD cerebrospinal fluid (CSF) profile group, according to their amyloid beta 42/ phosphorylated tau (Aβ42/p-tau) ratio. We performed a head-to-head comparison of nine plasma and nine CSF tau immunoassays and determined their accuracy to discriminate abnormal CSF Aβ42/p-tau ratio. RESULTS: All studied plasma tau biomarkers were significantly higher in the AD CSF profile group compared to the non-AD CSF profile group and significantly discriminated abnormal CSF Aβ42/p-tau ratio. For plasma p-tau biomarkers, the higher discrimination accuracy was shown by Janssen p-tau217 (r = 0.76; area under the curve [AUC] = 0.96), ADx p-tau181 (r = 0.73; AUC = 0.94), and Lilly p-tau217 (r = 0.73; AUC = 0.94). DISCUSSION: Several plasma p-tau biomarkers can be used in a specialized memory clinic as a…

INTRODUCTION: Plasma biomarkers will likely revolutionize the diagnostic work-up of Alzheimer's disease (AD) globally. Before widespread use, we need to determine if confounding factors affect the levels of these biomarkers, and their clinical utility. METHODS: Participants with plasma and CSF biomarkers, creatinine, body mass index (BMI), and medical history data were included (BioFINDER-1: n = 748, BioFINDER-2: n = 421). We measured beta-amyloid (Aβ42, Aβ40), phosphorylated tau (p-tau217, p-tau181), neurofilament light (NfL), and glial fibrillary acidic protein (GFAP). RESULTS: In both cohorts, creatinine and BMI were the main factors associated with NfL, GFAP, and to a lesser extent with p-tau. However, adjustment for BMI and creatinine had only minor effects in models predicting either the corresponding levels in CSF or subsequent development of dementia. DISCUSSION: Creatinine and BMI are related to certain plasma biomarkers levels, but they do not have clinically relevant confounding effects for the vast majority of individuals. HIGHLIGHTS: Creatinine and body mass index (BMI)…

OBJECTIVE: Evaluating the efficacy of 3,6'-dithioPomalidomide in 5xFAD Alzheimer's disease (AD) mice to test the hypothesis that neuroinflammation is directly involved in the development of synaptic/neuronal loss and cognitive decline. BACKGROUND: Amyloid-β (Aβ) or tau-focused clinical trials have proved unsuccessful in mitigating AD-associated cognitive impairment. Identification of new drug targets is needed. Neuroinflammation is a therapeutic target in neurodegenerative disorders, and TNF-α a pivotal neuroinflammatory driver. NEW HYPOTHESIS: AD-associated chronic neuroinflammation directly drives progressive synaptic/neuronal loss and cognitive decline. Pharmacologically mitigating microglial/astrocyte activation without altering Aβ generation will define the role of neuroinflammation in AD progression. MAJOR CHALLENGES: Difficulty of TNF-α-lowering compounds reaching brain, and identification of a therapeutic-time window to preserve the beneficial role of neuroinflammatory processes. LINKAGE TO OTHER MAJOR THEORIES: Microglia/astroglia are heavily implicated in maintenance of…

Sex or gender differences in the risk of Alzheimer's disease and related dementias (ADRD) differ by world region, suggesting that there are potentially modifiable risk factors for intervention. However, few epidemiological or clinical ADRD studies examine sex differences; even fewer evaluate gender in the context of ADRD risk. The goals of this perspective are to: (1) provide definitions of gender, biologic sex, and sexual orientation. and the limitations of examining these as binary variables; (2) provide an overview of what is known with regard to sex and gender differences in the risk, prevention, and diagnosis of ADRD; and (3) discuss these sex and gender differences from a global, worldwide perspective. Identifying drivers of sex and gender differences in ADRD throughout the world is a first step in developing interventions unique to each geographical and sociocultural area to reduce these inequities and to ultimately reduce global ADRD risk. HIGHLIGHTS: The burden of dementia is unevenly distributed geographically and by sex and gender. Scientific advances in genetics and…

Abstract Introduction The mechanisms that lead to cognitive impairment associated with COVID‐19 are not well understood. Methods Brain lysates from control and COVID‐19 patients were analyzed for oxidative stress and inflammatory signaling pathway markers, and measurements of Alzheimer’s disease (AD)‐linked signaling biochemistry. Post‐translational modifications of the ryanodine receptor/calcium (Ca2+) release channels (RyR) on the endoplasmic reticuli (ER), known to be linked to AD, were also measured by co‐immunoprecipitation/immunoblotting of the brain lysates. Results We provide evidence linking SARS‐CoV‐2 infection to activation of TGF‐β signaling and oxidative overload. The neuropathological pathways causing tau hyperphosphorylation typically associated with AD were also shown to be activated in COVID‐19 patients. RyR2 in COVID‐19 brains demonstrated a “leaky” phenotype, which can promote cognitive and behavioral defects. Discussion COVID‐19 neuropathology includes AD‐like features and leaky RyR2 channels could be a therapeutic target for amelioration of some cognitive…

INTRODUCTION: For 30 years synapse loss has been referred to as the major pathological correlate of cognitive impairment in Alzheimer's disease (AD). However, this statement is based on remarkably few patients studied by autopsy or biopsy. With the recent advent of synaptic vesicle glycoprotein 2A (SV2A) positron emission tomography (PET) imaging, we have begun to evaluate the consequences of synaptic alterations in vivo. METHODS: C]UCB-J PET and neuropsychological test performance in 45 participants with early AD. RESULTS: Global synaptic density showed a significant positive association with global cognition and performance on five individual cognitive domains in participants with early AD. Synaptic density was a stronger predictor of cognitive performance than gray matter volume. CONCLUSION: These results confirm neuropathologic studies demonstrating a significant association between synaptic density and cognitive performance, and suggest that this correlation extends to the early stages of AD.

INTRODUCTION: There is a great need for fully automated plasma assays that can measure amyloid beta (Aβ) pathology and predict future Alzheimer's disease (AD) dementia. METHODS: Two cohorts (n = 920) were examined: Panel A+ (n = 32 cognitively unimpaired [CU], n = 106 mild cognitive impairment [MCI], and n = 89 AD) and BioFINDER-1 (n = 461 CU, n = 232 MCI). Plasma Aβ42/Aβ40, phosphorylated tau (p-tau)181, two p-tau217 variants, ApoE4 protein, neurofilament light, and GFAP were measured using Elecsys prototype immunoassays. RESULTS: The best biomarker for discriminating Aβ-positive versus Aβ-negative participants was Aβ42/Aβ40 (are under the curve [AUC] 0.83-0.87). Combining Aβ42/Aβ40, p-tau181, and ApoE4 improved the AUCs significantly (0.90 to 0.93; P< 0.01). Adding additional biomarkers had marginal effects (ΔAUC ≤0.01). In BioFINDER, p-tau181, p-tau217, and ApoE4 predicted AD dementia within 6 years in CU (AUC 0.88) and p-tau181, p-tau217, and Aβ42/Aβ40 in MCI (AUC 0.87). DISCUSSION: The high accuracies for Aβ pathology and future AD dementia using fully automated instruments are…

Chitinase-3-like protein 1 (CHI3L1/YKL-40) has long been known as a biomarker for early detection of neuroinflammation and disease diagnosis of Alzheimer's disease (AD). In the brain, CHI3L1 is primarily provided by astrocytes and heralds the reactive, neurotoxic state triggered by inflammation and other stress signals. However, how CHI3L1 acts in neuroinflammation or how it contributes to AD and relevant neurodegenerative conditions remains unknown. In peripheral tissues, our group and others have uncovered that CHI3L1 is a master regulator for a wide range of injury and repair events, including the innate immunity pathway that resembles the neuroinflammation process governed by microglia and astrocytes. Based on assessment of current knowledge regarding CHI3L1 biology, we hypothesize that CHI3L1 functions as a signaling molecule mediating distinct neuroinflammatory responses in brain cells and misfunctions to precipitate neurodegeneration. We also recommend future research directions to validate such assertions for better understanding of disease mechanisms.

INTRODUCTION: Neurological complications among hospitalized COVID-19 patients may be associated with elevated neurodegenerative biomarkers. METHODS: Among hospitalized COVID-19 patients without a history of dementia (N = 251), we compared serum total tau (t-tau), phosphorylated tau-181 (p-tau181), glial fibrillary acidic protein (GFAP), neurofilament light chain (NfL), ubiquitin carboxy-terminal hydrolase L1 (UCHL1), and amyloid beta (Aβ40,42) between patients with or without encephalopathy, in-hospital death versus survival, and discharge home versus other dispositions. COVID-19 patient biomarker levels were also compared to non-COVID cognitively normal, mild cognitive impairment (MCI), and Alzheimer's disease (AD) dementia controls (N = 161). RESULTS: Admission t-tau, p-tau181, GFAP, and NfL were significantly elevated in patients with encephalopathy and in those who died in-hospital, while t-tau, GFAP, and NfL were significantly lower in those discharged home. These markers correlated with severity of COVID illness. NfL, GFAP, and UCHL1 were higher in COVID patients than in…

INTRODUCTION: Cardiometabolic diseases (CMDs) have been individually associated with adverse cognitive outcomes, but their combined effect has not been investigated. METHODS: A total of 2577 dementia-free participants 60 years of age or older were followed for 12 years to observe changes in cognitive function and to detect incident cognitive impairment, no dementia (CIND) and dementia. CMDs (including type 2 diabetes, heart disease, and stroke) were assessed at baseline through medical records and clinical examinations. Cardiometabolic multimorbidity was defined as the presence of two or more CMDs. Data were analyzed using multi-adjusted linear mixed-effects models, Cox regression, and Laplace regression. RESULTS: CMD multimorbidity was associated with cognitive decline, CIND (hazard ratio [HR] 1.73; 95% confidence interval CI 1.23 to 2.44), and its progression to dementia (HR 1.86; 95% CI 1.17 to 2.97). CMD multimorbidity accelerated the onset of CIND by 2.3 years and dementia by 1.8 years. CONCLUSIONS: CMD multimorbidity accelerates cognitive decline and increases the risk of both…

BACKGROUND: Epidemiological studies of mild cognitive impairment (MCI) and subtypes of MCI have rarely focused on rural residents in China. METHODS: This population-based study included 5068 participants (age ≥60 years) who were living in rural communities. We defined MCI, amnestic MCI (aMCI), and non-amnestic MCI (naMCI) following the Petersen's criteria that integrated neuropsychological assessments with in-person clinical evaluations. RESULTS: The overall prevalence of MCI, aMCI, and naMCI was 26.48%, 22.30%, and 4.18%, respectively. The prevalence of MCI increased with age. The adjusted odds ratio (OR) of MCI was 0.71 (95% confidence interval [CI] 0.61 to 0.82) for primary school (vs. illiteracy), 0.30 (0.24 to 0.39) for middle school or above, 1.35 (1.09 to 1.67) for being farmers, 0.65 (0.54 to 0.78) for alcohol consumption, 1.43 (1.20 to 1.70) for stroke history, and 1.14 (0.95 to 1.36) for any apolipoprotein E (APOE) ε4 allele (vs ε3/ε3). CONCLUSIONS: MCI affects over one-fourth of rural older adults in China. Overall MCI was associated with demographic factors, non-alcohol…

INTRODUCTION: The Alzheimer's Disease Neuroimaging Initiative (ADNI) aims to validate biomarkers for Alzheimer's disease (AD) clinical trials. To improve generalizability, ADNI4 aims to enroll 50-60% of its new participants from underrepresented populations (URPs) using new biofluid and digital technologies. ADNI4 has received funding from the National Institute on Aging beginning September 2022. METHODS: ADNI4 will recruit URPs using community-engaged approaches. An online portal will screen 20,000 participants, 4000 of whom (50-60% URPs) will be tested for plasma biomarkers and APOE. From this, 500 new participants will undergo in-clinic assessment joining 500 ADNI3 rollover participants. Remaining participants (∼3500) will undergo longitudinal plasma and digital cognitive testing. ADNI4 will add MRI sequences and new PET tracers. Project 1 will optimize biomarkers in AD clinical trials. RESULTS AND DISCUSSION: ADNI4 will improve generalizability of results, use remote digital and blood screening, and continue providing longitudinal clinical, biomarker, and autopsy data to…

INTRODUCTION: Daytime napping is frequently seen in older adults. The longitudinal relationship between daytime napping and cognitive aging is unknown. METHODS: Using data from 1401 participants of the Rush Memory and Aging Project, we examined the longitudinal change of daytime napping inferred objectively by actigraphy, and the association with incident Alzheimer's dementia during up to 14-year follow-up. RESULTS: Older adults tended to nap longer and more frequently with aging, while the progression of Alzheimer's dementia accelerates this change by more than doubling the annual increases in nap duration/frequency. Longer and more frequent daytime naps were associated with higher risk of Alzheimer's dementia. Interestingly, more excessive (longer or more frequent) daytime napping was correlated with worse cognition a year later, and conversely, worse cognition was correlated with more excessive naps a year later. DISCUSSION: Excessive daytime napping and Alzheimer's dementia may possess a bidirectional relationship or share common pathophysiological mechanisms.

Clinical trials for Alzheimer's disease (AD) are slower to enroll study participants, take longer to complete, and are more expensive than trials in most other therapeutic areas. The recruitment and retention of a large number of qualified, diverse volunteers to participate in clinical research studies remain among the key barriers to the successful completion of AD clinical trials. An advisory panel of experts from academia, patient-advocacy organizations, philanthropy, non-profit, government, and industry convened in 2020 to assess the critical challenges facing recruitment in Alzheimer's clinical trials and develop a set of recommendations to overcome them. This paper briefly reviews existing challenges in AD clinical research and discusses the feasibility and implications of the panel's recommendations for actionable and inclusive solutions to accelerate the development of novel therapies for AD.

Abstract Introduction Despite the clinical implementation, there remain significant gaps in our knowledge regarding the impact of race/ethnicity or common medical comorbidity on plasma Alzheimer's disease (AD) biomarkers. Methods Plasma biomarkers of amyloid beta (Aβ)40, Aβ42, total tau, and neurofilament light chain (NfL) were measured across cognitively normal Mexican Americans (n = 445) and non‐Hispanic Whites (n = 520). Results Dyslipidemia was associated with elevated Aβ40 (P = .01) and Aβ42 (P = .001) while hypertension was associated with elevated Aβ40 (P = .003), Aβ42 (P < .001), and total tau (P = .002) levels. Diabetes was associated with higher Aβ40 (P < .001), Aβ42 (P < .001), total tau (P < .001), and NfL (P < .001) levels. Chronic kidney disease (CKD) was associated with elevations in Aβ40 (P < .001), Aβ42 (P < .001), total tau (P < .001), and NfL (P < .001) levels. Mexican Americans had significantly lower Aβ40 (P < .001) and higher total tau (P = .005) levels. Discussion Plasma AD biomarkers vary significantly in association with common medical comorbidities as well…

Dementia with Lewy bodies (DLB) is clinically defined by the presence of visual hallucinations, fluctuations, rapid eye movement (REM) sleep behavioral disorder, and parkinsonism. Neuropathologically, it is characterized by the presence of Lewy pathology. However, neuropathological studies have demonstrated the high prevalence of coexistent Alzheimer's disease, TAR DNA-binding protein 43 (TDP-43), and cerebrovascular pathologic cases. Due to their high prevalence and clinical impact on DLB individuals, clinical trials should account for these co-pathologies in their design and selection and the interpretation of biomarkers values and outcomes. Here we discuss the frequency of the different co-pathologies in DLB and their cross-sectional and longitudinal clinical impact. We then evaluate the utility and possible applications of disease-specific and disease-nonspecific biomarkers and how co-pathologies can impact these biomarkers. We propose a framework for integrating multi-modal biomarker fingerprints and step-wise selection and assessment of DLB individuals for clinical trials,…

INTRODUCTION: It is uncertain whether subjective cognitive decline (SCD) in individuals who seek medical help serves the identification of the initial symptomatic stage 2 of the Alzheimer's disease (AD) continuum. METHODS: Cross-sectional and longitudinal data from the multicenter, memory clinic-based DELCODE study. RESULTS: The SCD group showed slightly worse cognition as well as more subtle functional and behavioral symptoms than the control group (CO). SCD-A+ cases (39.3% of all SCD) showed greater hippocampal atrophy, lower cognitive and functional performance, and more behavioral symptoms than CO-A+. Amyloid concentration in the CSF had a greater effect on longitudinal cognitive decline in SCD than in the CO group. DISCUSSION: Our data suggests that SCD serves the identification of stage 2 of the AD continuum and that stage 2, operationalized as SCD-A+, is associated with subtle, but extended impact of AD pathology in terms of neurodegeneration, symptoms and clinical progression.

INTRODUCTION: Blood biomarkers for Alzheimer's disease (AD) are the future of AD risk assessment. The aim of this study was to determine the association between plasma-measured phosphorylated tau (p-tau181), glial fibrillary acidic protein (GFAP), and neurofilament light (NfL) levels and risk of clinical AD incidence with consideration to the impact of cardiovascular health. METHODS: Within a community-based cohort, biomarker levels were measured at baseline using single molecule array technology in 768 participants (aged 50-75) followed over 17 years. Associations among biomarkers and AD, vascular dementia, and mixed dementia incidence were assessed. RESULTS: GFAP was associated with clinical AD incidence even more than a decade before diagnosis (9-17 years), while p-tau181 and NfL were associated with more intermediate AD risk (within 9 years). Significant interaction was detected between cardiovascular health and p-tau181/NfL. DISCUSSION: GFAP may be an early AD biomarker increasing before p-tau181 and NfL and the effect modifying role of cardiovascular health should be…

Abstract Introduction In this longitudinal study, we aimed to examine if slowing gait speed preceded cognitive decline and correlated with brain amyloidosis. Methods The sample (n = 287) was derived from the Gothenburg H70 Birth Cohort Studies, with follow‐ups between 2000 and 2015. Gait speed was measured by indoor walk, and cognition using the Clinical Dementia Rating (CDR) score. All participants had CDR = 0 at baseline. Some participants had data on cerebrospinal fluid (CSF) amyloid beta (Aβ) 1‐42 concentrations at the 2009 examination. Results Gait speed for participants who worsened in CDR score during follow‐up was slower at most examinations. Baseline gait speed could significantly predict CDR change from baseline to follow‐up. Subjects with pathological CSF Aβ 1‐ 42 concentrations at the 2009 visit had lost more gait speed compared to previous examinations. Discussion Our results indicate that gait speed decline precedes cognitive decline, is linked to Alzheimer's pathology, and might be used for early detection of increased risk for dementia development.

The Alzheimer's Association hosted the second Latinos & Alzheimer's Symposium in May 2021. Due to the COVID-19 pandemic, the meeting was held online over 2 days, with virtual presentations, discussions, mentoring sessions, and posters. The Latino population in the United States is projected to have the steepest increase in Alzheimer's disease (AD) in the next 40 years, compared to other ethnic groups. Latinos have increased risk for AD and other dementias, limited access to quality care, and are severely underrepresented in AD and dementia research and clinical trials. The symposium highlighted developments in AD research with Latino populations, including advances in AD biomarkers, and novel cognitive assessments for Spanish-speaking populations, as well as the need to effectively recruit and retain Latinos in clinical research, and how best to deliver health-care services and to aid caregivers of Latinos living with AD.

INTRODUCTION: Twelve risk factors (RFs) account for 40% of dementia cases worldwide. However, most data for population attributable fractions (PAFs) are from high-income countries (HIC). We estimated how much these RFs account for dementia cases in Brazil, stratifying estimates by race and socioeconomic level. METHODS: We calculated the prevalence and communalities of 12 RFs using 9412 Brazilian Longitudinal Study of Aging participants, then stratified according to self-reported race and country macro-regions. RESULTS: The overall weighted PAF was 48.2%. Less education had the largest PAF (7.7%), followed by hypertension (7.6%), and hearing loss (6.8%). PAF was 49.0% and 54.0% in the richest and poorest regions, respectively. PAFs were similar among White and Black individuals (47.8% and 47.2%, respectively) but the importance of the main RF varied by race. DISCUSSION: Brazil's potential for dementia prevention is higher than in HIC. Education, hypertension, and hearing loss should be priority targets.

BACKGROUND: An ample literature documents the growing prevalence of dementia and associated costs. Less attention has been paid to decreased dementia incidence in some countries. METHODS: We analyzed trends in age-standardized dementia, stroke, and ischemic heart disease (the triple threat) incidence rates and population attributable fraction of death and disability attributable to 12 risk factors in 204 countries and territories and 51 regions using Global Burden of Disease 2019 data. RESULTS: During 1990 to 2019, dementia incidence declined in 71 countries; 18 showed statistically significant declines, ranging from -12.1% (95% uncertainty intervals -16.9 to -6.8) to -2.4% (-4.6 to -0.5). During 2010 to 2019, 16 countries showed non-significant declines. Globally, the burden of the triple threat attributable to air pollution, dietary risks, non-optimal temperature, lead exposure, and tobacco use decreased from 1990 to 2019. CONCLUSION: The declining incidence of dementia in some countries, despite growing prevalence, is encouraging and urges further investigation.

INTRODUCTION: Alzheimer's disease (AD) is accompanied by metabolic alterations both in the periphery and the central nervous system. However, so far, a global view of AD-associated metabolic changes in the brain has been missing. METHODS: We metabolically profiled 500 samples from the dorsolateral prefrontal cortex. Metabolite levels were correlated with eight clinical parameters, covering both late-life cognitive performance and AD neuropathology measures. RESULTS: We observed widespread metabolic dysregulation associated with AD, spanning 298 metabolites from various AD-relevant pathways. These included alterations to bioenergetics, cholesterol metabolism, neuroinflammation, and metabolic consequences of neurotransmitter ratio imbalances. Our findings further suggest impaired osmoregulation as a potential pathomechanism in AD. Finally, inspecting the interplay of proteinopathies provided evidence that metabolic associations were largely driven by tau pathology rather than amyloid beta pathology. DISCUSSION: This work provides a comprehensive reference map of metabolic brain…

INTRODUCTION: Dementia in its various forms represents one of the most frightening emergencies for the aging population. Cognitive decline-including Alzheimer's disease (AD) dementia-does not develop in few days; disease mechanisms act progressively for several years before clinical evidence. METHODS: A preclinical stage, characterized by measurable cognitive impairment, but not overt dementia, is represented by mild cognitive impairment (MCI), which progresses to-or, more accurately, is already in a prodromal form of-AD in about half cases; people with MCI are therefore considered the population at risk for AD deserving special attention for validating screening methods. RESULTS: Graph analysis tools, combined with machine learning methods, represent an interesting probe to identify the distinctive features of physiological/pathological brain aging focusing on functional connectivity networks evaluated on electroencephalographic data and neuropsychological/imaging/genetic/metabolic/cerebrospinal fluid/blood biomarkers. DISCUSSION: On clinical data, this innovative approach for…

Abstract Introduction Further evidence is needed to support the use of plasma amyloid β (Aβ) biomarkers as Alzheimer's disease prescreening tools. This study evaluated the clinical performance and robustness of plasma Aβ 42 /Aβ 40 for amyloid positivity prescreening. Methods Data were collected from 333 BioFINDER and 121 Alzheimer's Disease Neuroimaging Initiative study participants. Risk and predictive values versus percentile of plasma Aβ 42 /Aβ 40 evaluated the actionability of plasma Aβ 42 /Aβ 40 , and simulations modeled the impact of potential uncertainties and biases. Amyloid PET was the brain amyloidosis reference standard. Results Elecsys plasma Aβ 42 /Aβ 40 could potentially rule out amyloid pathology in populations with low‐to‐moderate amyloid positivity prevalence. However, simulations showed small measurement or pre‐analytical errors in Aβ 42 and/or Aβ 40 cause misclassifications, impacting sensitivity or specificity. The minor fold change between amyloid PET positive and negative cases explains the biomarkers low robustness. Discussion Implementing plasma Aβ 42 /Aβ 40…

INTRODUCTION: Dietary supplements are touted for cognitive protection, but supporting evidence is mixed. COSMOS-Mind tested whether daily administration of cocoa extract (containing 500 mg/day flavanols) versus placebo and a commercial multivitamin-mineral (MVM) versus placebo improved cognition in older women and men. METHODS: COSMOS-Mind, a large randomized two-by-two factorial 3-year trial, assessed cognition by telephone at baseline and annually. The primary outcome was a global cognition composite formed from mean standardized (z) scores (relative to baseline) from individual tests, including the Telephone Interview of Cognitive Status, Word List and Story Recall, Oral Trail-Making, Verbal Fluency, Number Span, and Digit Ordering. Using intention-to-treat, the primary endpoint was change in this composite with 3 years of cocoa extract use. The pre-specified secondary endpoint was change in the composite with 3 years of MVM supplementation. Treatment effects were also examined for executive function and memory composite scores, and in pre-specified subgroups at higher risk for…

Abstract Introduction To test the utility of the “A/T/N” system in the Chinese population, we study core Alzheimer's disease (AD) biomarkers in a newly established Chinese cohort. Methods A total of 411 participants were selected, including 96 cognitively normal individuals, 94 patients with mild cognitive impairment (MCI) patients, 173 patients with AD, and 48 patients with non‐AD dementia. Fluid biomarkers were measured with single molecule array. Amyloid beta (Aβ) deposition was determined by 18F‐Flobetapir positron emission tomography (PET), and brain atrophy was quantified using magnetic resonance imaging (MRI). Results Aβ42/Aβ40 was decreased, whereas levels of phosphorylated tau (p‐tau) were increased in cerebrospinal fluid (CSF) and plasma from patients with AD. CSF Aβ42/Aβ40, CSF p‐tau, and plasma p‐tau showed a high concordance in discriminating between AD and non‐AD dementia or elderly controls. A combination of plasma p‐tau, apolipoprotein E (APOE) genotype, and MRI measures accurately predicted amyloid PET status. Discussion These results revealed a universal…

INTRODUCTION: The effect of random error on the performance of blood-based biomarkers for Alzheimer's disease (AD) must be determined before clinical implementation. METHODS: We measured test-retest variability of plasma amyloid beta (Aβ)42/Aβ40, neurofilament light (NfL), glial fibrillary acidic protein (GFAP), and phosphorylated tau (p-tau)217 and simulated effects of this variability on biomarker performance when predicting either cerebrospinal fluid (CSF) Aβ status or conversion to AD dementia in 399 non-demented participants with cognitive symptoms. RESULTS: Clinical performance was highest when combining all biomarkers. Among single-biomarkers, p-tau217 performed best. Test-retest variability ranged from 4.1% (Aβ42/Aβ40) to 25% (GFAP). This variability reduced the performance of the biomarkers (≈ΔAUC [area under the curve] -1% to -4%) with the least effects on models with p-tau217. The percent of individuals with unstable predicted outcomes was lowest for the multi-biomarker combination (14%). DISCUSSION: Clinical prediction models combining plasma biomarkers-particularly…

INTRODUCTION: Grip strength and walking pace have been linked to cognitive dysfunction. Their relationships, however, demand further clarification as the evidence is derived primarily from less-comprehensive investigations. METHODS: A total of 340212 UK Biobank participants without dementia and cardiovascular diseases at baseline were analyzed. Cox proportional hazard models assessed the longitudinal associations. RESULTS: Over a mean follow-up of 8.51 ± 2.68 years, 2424 incident dementia cases were documented. A 5 kg increment of absolute grip strength was associated with lower risks of all-cause dementia (hazard ratio [HR] 0.857), Alzheimer's disease (HR 0.874), and vascular dementia (HR 0.788). The patterns of associations remained similar when grip strength was expressed in relative terms and quintiles. A slow walking pace demonstrated consistent associations with increased risks of all dementia types. DISCUSSION: Our findings provide amplified evidence and suggest that muscle fitness, reflected by objective grip strength measures and self-reported walking pace, may be…

INTRODUCTION: Mild behavioral impairment (MBI) is characterized by later-life emergence of neuropsychiatric symptoms. Investigating its relationship with progression to Alzheimer's disease (AD) would provide insight on its importance as a predictor of AD. METHODS: Cognitively normal participants (N = 11,372) from the National Alzheimer's Coordinating Center were stratified by MBI status, using the Neuropsychiatric Inventory-Questionnaire. We investigated whether MBI and its domains were predictors of progression to clinically-diagnosed AD. MBI as a predictor of progression to neuropathology-confirmed AD was also investigated in those with neuropathological data. RESULTS: Six percent (N = 671) of participants progressed to AD. MBI (N = 2765) was a significant predictor of progression to clinically-diagnosed (hazard ratio [HR] = 1.75) and neuropathology-confirmed AD (HR = 1.59). MBI domains were also associated with clinically-diagnosed AD, with psychosis having the greatest effect (HR = 6.49). DISCUSSION: These findings support the biological underpinnings of MBI, emphasizing the…

BACKGROUND: Glial fibrillary acidic protein (GFAP) is a promising candidate blood-based biomarker for Alzheimer's disease (AD) diagnosis and prognostication. The timing of its disease-associated changes, its clinical correlates, and biofluid-type dependency will influence its clinical utility. METHODS: We evaluated plasma, serum, and cerebrospinal fluid (CSF) GFAP in families with autosomal dominant AD (ADAD), leveraging the predictable age at symptom onset to determine changes by stage of disease. RESULTS: Plasma GFAP elevations appear a decade before expected symptom onset, after amyloid beta (Aβ) accumulation and prior to neurodegeneration and cognitive decline. Plasma GFAP distinguished Aβ-positive from Aβ-negative ADAD participants and showed a stronger relationship with Aβ load in asymptomatic than symptomatic ADAD. Higher plasma GFAP was associated with the degree and rate of neurodegeneration and cognitive impairment. Serum GFAP showed similar relationships, but these were less pronounced for CSF GFAP. CONCLUSION: Our findings support a role for plasma GFAP as a clinical…

INTRODUCTION: Blood-based biomarkers for Alzheimer's disease (AD) are urgently needed. Here, four plasma biomarkers were measured at baseline in a community-based cohort followed over 17 years, and the association with clinical AD risk was determined. METHODS: Amyloid beta (Aβ) misfolding status as a structure-based biomarker as well as phosphorylated tau 181 (P-tau181), glial fibrillary acidic protein (GFAP), and neurofilament light (NfL) concentration levels were determined at baseline in heparin plasma from 68 participants who were diagnosed with AD and 240 controls without dementia diagnosis throughout follow-up. RESULTS: Aβ misfolding exhibited high disease prediction accuracy of AD diagnosis within 17 years. Among the concentration markers, GFAP showed the best performance, followed by NfL and P-tau181. The combination of Aβ misfolding and GFAP increased the accuracy. DISCUSSION: Aβ misfolding and GFAP showed a strong ability to predict clinical AD risk and may be important early AD risk markers. Aβ misfolding illustrated its potential as a prescreening tool for AD risk…

INTRODUCTION: Reliable data on the incidence rates for young-onset dementia (YOD) are lacking, but are necessary for research on disease etiology and to raise awareness among health care professionals. METHODS: We performed a systematic review and meta-analysis on population-based studies on the incidence of YOD, published between January 1, 1990 and February 1, 2022, according to Meta-analyses of Observational Studies in Epidemiology (MOOSE) guidelines. Data were analyzed using random-effects meta-analyses. Results were age-standardized, and heterogeneity was assessed by subgroup analyses and meta-regression. RESULTS: Sixty-one articles were included. Global age-standardized incidence rates increased from 0.17/100,000 in age 30 to 34 years, to 5.14/100,000 in age 60 to 64 years, giving a global total age-standardized incidence rate of 11 per 100,000 in age 30 to 64. This corresponds to 370,000 new YOD cases annually worldwide. Heterogeneity was high and meta-regression showed geographic location significantly influenced this heterogeneity. DISCUSSION: This meta-analysis shows the…

INTRODUCTION: Recent evidence has shown that the marker of reactive astrogliosis, glial fibrillary acidic protein (GFAP), has a stronger relationship with cerebral amyloid beta (Aβ) pathology in blood than in cerebrospinal fluid (CSF). This study investigates if pre-analytical treatment of blood and CSF contribute to these unexpected findings. METHODS: Paired CSF and serum samples from 49 individuals (Aβ-negative = 28; Aβ-positive = 21) underwent a series of seven freeze-thaw cycles (FTCs). All samples were analyzed for GFAP and neurofilament light (NfL) using single molecule array technology including a fresh unfrozen sample from each patient. RESULTS: FTC significantly affected CSF GFAP concentration (-188.12 pg/ml per FTC) but not serum GFAP. In the same samples, NfL remained stable. Serum GFAP had a higher discrimination of Aβ burden than CSF GFAP, irrespective of FTC, which also included unfrozen samples. DISCUSSION: This study demonstrates large stability differences of GFAP in CSF and serum. However, this disparity does not seem to fully explain the stronger association of…

A crucial aspect of any clinical trial is using the right outcome measure to assess treatment efficacy. Compared to the rapidly evolved understanding and measurement of pathophysiology in preclinical and early symptomatic stages of Alzheimer's disease (AD), relatively less progress has been made in the evolution of clinical outcome assessments (COAs) for those stages. The current paper aims to provide a benchmark for the design and evaluation of COAs for use in early AD trials. We discuss lessons learned on capturing cognitive changes in predementia stages of AD, including challenges when validating novel COAs for those early stages and necessary evidence for their implementation in clinical trials. Moving forward, we propose a multi-step framework to advance the use of more effective COAs to assess clinically meaningful changes in early AD, which will hopefully contribute to the much-needed consensus around more appropriate outcome measures to assess clinical efficacy of putative treatments. HIGHLIGHTS: We discuss lessons learned on capturing cognitive changes in predementia stages…

INTRODUCTION: Objective and accessible markers for Alzheimer's disease (AD) and other dementias are critically needed. METHODS: We identified NMDAR2A, a protein related to synaptic function, as a novel marker of central nervous system (CNS)-derived plasma extracellular vesicles (EVs) and developed a flow cytometry-based technology for detecting such plasma EVs readily. The assay was initially tested in our local cross-sectional study to distinguish AD patients from healthy controls (HCs) or from Parkinson's disease (PD) patients, followed by a validation study using an independent cohort collected from multiple medical centers (the Alzheimer's Disease Neuroimaging Initiative). Cerebrospinal fluid AD molecular signature was used to confirm diagnoses of all AD participants. RESULTS: Likely CNS-derived EVs in plasma were significantly reduced in AD compared to HCs in both cohorts. Integrative models including CNS-derived EV markers and AD markers present on EVs reached area under the curve of 0.915 in discovery cohort and 0.810 in validation cohort. DISCUSSION: This study demonstrated…

INTRODUCTION: The primary aim of this paper is to improve the clinical interpretation of white matter hyperintensities (WMHs) and provide an overarching summary of methodological approaches, allowing researchers to design future studies targeting current knowledge gaps. METHODS: A meta-analysis and systematic review was performed investigating associations between baseline WMHs and longitudinal cognitive outcomes in cognitively normal populations, and populations with mild cognitive impairment (MCI), Alzheimer's disease (AD), and stroke. RESULTS: Baseline WMHs increase the risk of cognitive impairment and dementia across diagnostic categories and most consistently in MCI and post-stroke populations. Apolipoprotein E (APOE) genotype and domain-specific cognitive changes relating to strategic anatomical locations, such as frontal WMH and executive decline, represent important considerations. Meta-analysis reliability was assessed using multiple methods of estimation, and results suggest that heterogeneity in study design and reporting remains a significant barrier. DISCUSSION:…

INTRODUCTION: It remains unknown whether the global small vessel disease (SVD) burden predicts post-stroke outcomes. METHODS: In a prospective multicenter study of 666 ischemic and hemorrhagic stroke patients, we quantified magnetic resonance imaging (MRI)-based SVD markers (lacunes, white matter hyperintensities, microbleeds, perivascular spaces) and explored associations with 6- and 12-month cognitive (battery of 15 neuropsychological tests) and functional (modified Rankin scale) outcomes. RESULTS: A global SVD score (range 0-4) was associated with cognitive impairment; worse performance in executive function, attention, language, and visuospatial ability; and worse functional outcome across a 12-month follow-up. Although the global SVD score did not improve prediction, individual SVD markers, assessed across their severity range, improved the calibration, discrimination, and reclassification of predictive models including demographic, clinical, and other imaging factors. DISCUSSION: SVD presence and severity are associated with worse cognitive and functional outcomes 12 months…

INTRODUCTION: Automated computational assessment of neuropsychological tests would enable widespread, cost-effective screening for dementia. METHODS: A novel natural language processing approach is developed and validated to identify different stages of dementia based on automated transcription of digital voice recordings of subjects' neuropsychological tests conducted by the Framingham Heart Study (n = 1084). Transcribed sentences from the test were encoded into quantitative data and several models were trained and tested using these data and the participants' demographic characteristics. RESULTS: Average area under the curve (AUC) on the held-out test data reached 92.6%, 88.0%, and 74.4% for differentiating Normal cognition from Dementia, Normal or Mild Cognitive Impairment (MCI) from Dementia, and Normal from MCI, respectively. DISCUSSION: The proposed approach offers a fully automated identification of MCI and dementia based on a recorded neuropsychological test, providing an opportunity to develop a remote screening tool that could be adapted easily to any language.

Abstract Introduction The inositol polyphosphate‐5‐phosphatase D ( INPP5D ) gene encodes a dual‐specificity phosphatase that can dephosphorylate both phospholipids and phosphoproteins. Single nucleotide polymorphisms in INPP5D impact risk for developing late onset sporadic Alzheimer's disease (LOAD). Methods To assess the consequences of inducible Inpp5d knockdown in microglia of APP KM670/671NL /PSEN1 Δexon9 (PSAPP) mice, we injected 3‐month‐old Inpp5d fl/fl /Cx3cr1 CreER/+ and PSAPP/Inpp5d fl/fl /Cx3cr1 CreER/+ mice with either tamoxifen (TAM) or corn oil (CO) to induce recombination. Results At age 6 months, we found that the percent area of 6E10 + deposits and plaque‐associated microglia in Inpp5d knockdown mice were increased compared to controls. Spatial transcriptomics identified a plaque‐specific expression profile that was extensively altered by Inpp5d knockdown. Discussion These results demonstrate that conditional Inpp5d downregulation in the PSAPP mouse increases plaque burden and recruitment of microglia to plaques. Spatial transcriptomics highlighted an extended gene…

Olfactory impairment is a potential marker for prodromal dementia, but the underlying mechanisms are poorly understood. This population-based study included 4214 dementia-free participants (age ≥65 years). Olfaction was assessed using the 16-item Sniffin' Sticks identification test. In the subsamples, we measured plasma amyloid beta (Aβ)40, Aβ42, total tau, and neurofilament light chain (NfL; n = 1054); and quantified hippocampal, entorhinal cortex, and white matter hyperintensity (WMH) volumes, and Alzheimer's disease (AD)-signature cortical thickness (n = 917). Data were analyzed with logistic and linear regression models. In the total sample, mild cognitive impairment (MCI) was diagnosed in 1102 persons (26.2%; amnestic MCI, n = 931; non-amnestic MCI, n = 171). Olfactory impairment was significantly associated with increased likelihoods of MCI, amnestic MCI, and non-amnestic MCI. In the subsamples, anosmia was significantly associated with higher plasma total tau and NfL concentrations, smaller hippocampal and entorhinal cortex volumes, and greater WMH volume, and marginally with…

INTRODUCTION: Limbic age-related TDP-43 encephalopathy neuropathologic change (LATE-NC) is common in advanced age and can underlie a clinical presentation mimicking Alzheimer's disease (AD). We studied whether an autopsy-derived fluorodeoxyglucose positron emission tomography (FDG-PET) signature of LATE-NC provides clinical utility for differential diagnosis of amnestic dementia patients. METHODS: Ante mortem FDG-PET patterns from autopsy-confirmed LATE-NC (N = 7) and AD (N = 23) patients were used to stratify an independent cohort of clinically diagnosed AD dementia patients (N = 242) based on individual FDG-PET profiles. RESULTS: Autopsy-confirmed LATE-NC and AD groups showed markedly distinct temporo-limbic and temporo-parietal FDG-PET patterns, respectively. Clinically diagnosed AD dementia patients showing a LATE-NC-like FDG-PET pattern (N = 25, 10%) were significantly older, showed less abnormal AD biomarker levels, lower APOE ε4, and higher TMEM106B risk allele load. Clinically, they exhibited a more memory-predominant profile and a generally slower disease course.…

Abstract Alzheimer’s disease (AD) biomarkers have become increasingly more reliable in predicting AD pathology. While phosphorylated tau fluid biomarkers have been studied for over 20 years, there is a lack of deep characterization of these sites in the postmortem brain. Neurofibrillary tangle-bearing neurons, one of the major neuropathologic hallmarks of AD, undergo morphologic changes that mature along a continuum as hyperphosphorylated tau aggregates. To facilitate interpretation of phosphorylated tau sites as an early fluid biomarker, our goal was to characterize which neurofibrillary tangle maturity levels (pretangle, intermediary 1, mature tangle, intermediary 2, and ghost tangle) they recognize. We queried the Florida Autopsied Multi-Ethnic (FLAME) cohort for cases from Braak stages I-VI. We excluded non-AD pathologies and tauopathies. A total of 24 cases, 2 males and 2 females for each Braak stage, were selected. We performed immunohistochemistry on the posterior hippocampus using antibodies directed towards phospho (p) threonine (T) 181, pT205, pT217, and pT231. Slides were…

HYPOTHESIS: We hypothesized that Lomecel-B, an allogeneic medicinal signaling cell (MSC) therapeutic candidate for Alzheimer's disease (AD), is safe and potentially disease-modifying via pleiotropic mechanisms of action. KEY PREDICTIONS: We prospectively tested the predictions that Lomecel-B administration to mild AD patients is safe (primary endpoint) and would provide multiple exploratory indications of potential efficacy in clinical and biomarker domains (prespecified secondary/exploratory endpoints). STRATEGY AND KEY RESULTS: Mild AD patient received a single infusion of low- or high-dose Lomecel-B, or placebo, in a double-blind, randomized, phase I trial. The primary safety endpoint was met. Fluid-based and imaging biomarkers indicated significant improvement in the Lomecel-B arms versus placebo. The low-dose Lomecel-B arm showed significant improvements versus placebo on neurocognitive and other assessments. INTERPRETATION: Our results support the safety of Lomecel-B for AD, suggest clinical potential, and provide mechanistic insights. This early-stage study provides important…

INTRODUCTION: We investigated the association of the area deprivation index (ADI) with cognitive decline, mild cognitive impairment (MCI), and dementia in older adults (≥50 years old). ADI is a neighborhood socioeconomic disadvantage measure assessed at the census block group level. METHODS: The study included 4699 participants, initially without dementia, with available ADI values for 2015 and at least one study visit in 2008 through 2018. Using logistic regression and Cox proportional hazards models with age as the time scale, we assessed the odds for MCI and the risk for dementia, respectively. RESULTS: In cognitively unimpaired (CU) adults at baseline, the risk for progression to dementia increased for every decile increase in the ADI state ranking (hazard ratio = 1.06, 95% confidence interval (1.01-1.11), P = .01). Higher ADI values were associated with subtly faster cognitive decline. DISCUSSION: In older CU adults, higher baseline neighborhood socioeconomic deprivation levels were associated with progression to dementia and slightly faster cognitive decline. HIGHLIGHTS: The…

INTRODUCTION: This study assessed the associations of multimorbidity burden and its developmental trajectory with later-life dementia. METHODS: Among 5923 Health and Retirement Study participants, major chronic conditions including hypertension, diabetes mellitus, cancer, lung diseases, heart disease, stroke, psychological disorders, and arthritis were self- or proxy-reported in 1994-2008. Dementia diagnosis was self- or proxy-reported in 2008-2018. We used Cox regression to assess the associations of multimorbidity with incident dementia. RESULTS: During follow-up (median = 8 years), 701 participants developed dementia. Each additional chronic condition in 2008 was related to 15% (confidence interval: 9% to 22%) higher hazard of dementia. Multimorbidity trajectories in 1994-2008 were classified as "rapid growth", "steady growth", "slow growth", and "no new condition" by the group-based trajectory modelling methods. Compared to "no new condition", the "rapid growth" trajectory was related to 32% (3% to 69%) higher dementia risk. CONCLUSIONS: Both multimorbidity burden and its…

INTRODUCTION: Impact of white matter hyperintensities (WMH) on cognition likely depends on lesion location, but a comprehensive map of strategic locations is lacking. We aimed to identify these locations in a large multicenter study. METHODS: Individual patient data (n = 3525) from 11 memory clinic cohorts were harmonized. We determined the association of WMH location with attention and executive functioning, information processing speed, language, and verbal memory performance using voxel-based and region of interest tract-based analyses. RESULTS: WMH in the left and right anterior thalamic radiation, forceps major, and left inferior fronto-occipital fasciculus were significantly related to domain-specific impairment, independent of total WMH volume and atrophy. A strategic WMH score based on these tracts inversely correlated with performance in all domains. DISCUSSION: The data show that the impact of WMH on cognition is location-dependent, primarily involving four strategic white matter tracts. Evaluation of WMH location may support diagnosing vascular cognitive impairment.…

INTRODUCTION: The association of testosterone concentrations with dementia risk remains uncertain. We examined associations of serum testosterone and sex hormone-binding globulin (SHBG) with incidence of dementia and Alzheimer's disease. METHODS: Serum total testosterone and SHBG were measured by immunoassay. The incidence of dementia and Alzheimer's disease (AD) was recorded. Cox proportional hazards regression was adjusted for age and other variables. RESULTS: In 159,411 community-dwelling men (median age 61, followed for 7 years), 826 developed dementia, including 288 from AD. Lower total testosterone was associated with a higher incidence of dementia (overall trend: P = .001, lowest vs highest quintile: hazard ratio [HR] = 1.43, 95% confidence interval [CI] = 1.13-1.81), and AD (P = .017, HR = 1.80, CI = 1.21-2.66). Lower SHBG was associated with a lower incidence of dementia (P < .001, HR = 0.66, CI = 0.51-0.85) and AD (P = .012, HR = 0.53, CI = 0.34-0.84). DISCUSSION: Lower total testosterone and higher SHBG are independently associated with incident dementia and AD in older…

INTRODUCTION: The aim of this study was to estimate the potential cost-effectiveness of the Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability (FINGER) program. METHODS: A life-time Markov model with societal perspective, simulating a cohort of people at risk of dementia reflecting usual care and the FINGER program. RESULTS: Costs were 1,653,275 and 1,635,346 SEK and quality-adjusted life years (QALYs) were 8.636 and 8.679 for usual care and the FINGER program, respectively, resulting in savings of 16,928 SEK (2023 US$) and 0.043 QALY gains per person, supporting extended dominance for the FINGER program. A total of 1623 dementia cases were avoided with 0.17 fewer person-years living with dementia. The sensitivity analysis confirmed the conclusions in most scenarios. DISCUSSION: The model provides support that programs like FINGER have the potential to be cost-effective in preventing dementia. Results at the individual level are rather modest, but the societal benefits can be substantial because of the large potential target population.

INTRODUCTION: It is unknown whether vascular and metabolic diseases assessed in early adulthood are associated with Alzheimer's disease (AD) later in life. METHODS: Association of AD with lipid fractions, glucose, blood pressure, body mass index (BMI), and smoking obtained prospectively from 4932 Framingham Heart Study (FHS) participants across nine quadrennial examinations was evaluated using Cox proportional hazard and Kaplan-Meier models. Age-, sex-, and education-adjusted models were tested for each factor measured at each exam and within three adult age groups (early = 35-50, middle = 51-60, and late = 61-70). RESULTS: A 15 mg/dL increase in high density lipoprotein (HDL) cholesterol was associated with decreased AD risk during early (15.4%, P = 0.041) and middle (17.9%, P = 0.014) adulthood. A 15 mg/dL increase in glucose measured during middle adulthood was associated with 14.5% increased AD risk (P = 0.00029). These findings remained significant after adjusting for treatment. DISCUSSION: Our findings suggest that careful management of cholesterol and glucose beginning in…

The pathophysiology underlying cognitive decline is multifactorial, with increasing literature suggesting a role for cerebrovascular health. Cerebral blood flow (CBF) is an important element of cerebrovascular health, which raises questions regarding the relation between CBF and cognitive decline. Cross-sectional studies demonstrate lower CBF in patients with cognitive decline compared to healthy age-matched peers. Remarkably, longitudinal studies do not support a link between CBF reductions and cognitive decline. These studies, however, are often limited by small sample sizes and may therefore be underpowered to detect small effect sizes. Therefore, through a systematic review and meta-analysis of longitudinal studies, we examined whether longitudinal changes in global CBF are related to cognitive decline in subjects with Alzheimer's disease, and qualitatively described findings on regional CBF. Considering the growing impact of dementia and the lack of treatment options, it is important to understand the role of CBF as a prognostic biomarker and/or treatment target in dementia.

In Alzheimer's disease (AD), the distribution of the amyloid precursor protein (APP) and its fragments other than amyloid beta, has not been fully characterized. Here, we investigate the distribution of APP and its fragments in human AD brain samples and in mouse models of AD in reference to its proteases, synaptic proteins, and histopathological features characteristic of the AD brain, by combining an extensive set of histological and analytical tools. We report that the prominent somatic distribution of APP observed in control patients remarkably vanishes in human AD patients to the benefit of dense accumulations of extra-somatic APP, which surround dense-core amyloid plaques enriched in APP-Nter. These features are accentuated in patients with familial forms of the disease. Importantly, APP accumulations are enriched in phosphorylated tau and presynaptic proteins whereas they are depleted of post-synaptic proteins suggesting that the extra-somatic accumulations of APP are of presynaptic origin. Ultrastructural analyses unveil that APP concentrates in autophagosomes and in…

This review summarizes recent evidence on how mid-life hypertension, hyperhomocysteinemia (HHcy) and blood pressure variability, as well as late-life hypotension, exacerbate Alzheimer's disease (AD) and dementia risk. Intriguingly, HHcy also increases the risk for hypertension, revealing the importance of understanding the relationship between comorbid cardiovascular risk factors. Hypertension-induced dementia presents more evidently in women, highlighting the relevance of sex differences in the impact of cardiovascular risk. We summarize each major antihypertensive drug class's effects on cognitive impairment and AD pathology, revealing how carbonic anhydrase inhibitors, diuretics modulating cerebral blood flow, have recently gained preclinical evidence as promising treatment against AD. We also report novel vascular biomarkers for AD and dementia risk, highlighting those associated with hypertension and HHcy. Importantly, we propose that future studies should consider hypertension and HHcy as potential contributors to cognitive impairment, and that uncovering the underlying…

Abstract Introduction We investigated the incidence of diagnosed dementia and whether age at diagnosis and survival afterward differs among the United Kingdom's three largest ethnic groups. Methods We used primary care electronic health records, linked Hospital Episode Statistics and mortality data for adults aged ≥65 years. We compared recorded dementia incidence 1997–2018, age at diagnosis, survival time and age at death after diagnosis in White, South Asian, and Black people. Results Dementia incidence was higher in Black people (incidence rate ratios [IRR] 1.22, 95% CI 1.15–1.30). South Asian and Black people with dementia had a younger age of death than White participants (mean difference for South Asian participants ‐2.97 years, (95% CI ‐3.41 to ‐2.53); and Black participants ‐2.66 years, (95% CI ‐3.08 to ‐2.24). Discussion South Asian and Black peoples’ younger age of diagnosis and death means targeted prevention and care strategies for these groups should be prioritized and tailored to facilitate take‐up.

Hypertension is an important risk factor for Alzheimer's disease (AD) and all-cause dementia. The mechanisms underlying this association are unclear. Hypertension may be associated with AD neuropathological changes (ADNC), but reports are sparse and inconsistent. This systematic review included 15 autopsy studies (n = 5879) from observational cohorts. Studies were highly heterogeneous regarding populations, follow-up duration, hypertension operationalization, neuropathological methods, and statistical analyses. Hypertension seems associated with higher plaque and tangle burden, but results are inconsistent. Four studies (n = 3993/5879; 68%), reported clear associations between hypertension and ADNC. Another four suggested that antihypertensive medication may protect against ADNC. Larger studies with longer follow-up reported the strongest relationships. Our findings suggest a positive association between hypertension and ADNC, but effects may be modest, and possibly attenuate with higher hypertension age and antihypertensive medication use. Investigating interactions among plaques,…

We propose the hypothesis that small high-density lipoprotein (HDL) particles reduce the risk of Alzheimer's disease (AD) by virtue of their capacity to exchange lipids, affecting neuronal membrane composition and vascular and synaptic functions. Concentrations of small HDLs in cerebrospinal fluid (CSF) and plasma were measured in 180 individuals ≥60 years of age using ion mobility methodology. Small HDL concentrations in CSF were positively associated with performance in three domains of cognitive function independent of apolipoprotein E (APOE) ε4 status, age, sex, and years of education. Moreover, there was a significant correlation between levels of small HDLs in CSF and plasma. Further studies will be aimed at determining whether specific components of small HDL exchange across the blood, brain, and CSF barriers, and developing approaches to exploit small HDLs for therapeutic purposes.

With population growth and aging, the number of people with dementia and related disorders will grow substantially in the years ahead, bringing with it significant societal, health-care, and economic challenges. Here, we analyze dementia policies of seven major countries in Asia/Pacific, Europe, and North America to identify opportunities for early actions to mitigate disease burden. We find that most countries are addressing this need by including a specific focus on early action in their national dementia strategies (five of seven countries), implementing public health initiatives for risk reduction, prevention, and early detection and diagnosis (six of seven countries); supporting enabling research for early detection and risk reduction (six of seven countries); and enacting a system for early, regular brain health screening (one of seven). We discuss risks and opportunities for integrating early action policies and conducting additional systematic research to understand the potential benefits and impacts of these policies.

INTRODUCTION: Synaptic degeneration is a key part of the pathophysiology of neurodegenerative diseases, and biomarkers reflecting the pathological alterations are greatly needed. METHOD: Seventeen synaptic proteins were quantified in a pathology-confirmed cerebrospinal fluid cohort of patients with Alzheimer's disease (AD; n = 63), frontotemporal lobar degeneration (FTLD; n = 53), and Lewy body spectrum of disorders (LBD; n = 21), as well as healthy controls (HC; n = 48). RESULTS: Comparisons revealed four distinct patterns: markers decreased across all neurodegenerative conditions compared to HC (the neuronal pentraxins), markers increased across all neurodegenerative conditions (14-3-3 zeta/delta), markers selectively increased in AD compared to other neurodegenerative conditions (neurogranin and beta-synuclein), and markers selectively decreased in LBD and FTLD compared to HC and AD (AP2B1 and syntaxin-1B). DISCUSSION: Several of the synaptic proteins may serve as biomarkers for synaptic dysfunction in AD, LBD, and FTLD. Additionally, differential patterns of synaptic protein…

Abstract Introduction Education, and less frequently occupation, has been associated with lower dementia risk in studies from high‐income countries. We aimed to investigate the association of cognitive impairment with education and occupation in a low‐middle‐income country sample. Methods In this cross‐sectional study, cognitive function was assessed by the Clinical Dementia Rating sum of boxes (CDR‐SOB). We investigated the association of occupation complexity and education with CDR‐SOB using adjusted linear regression models for age, sex, and neuropathological lesions. Results In 1023 participants, 77% had < 5 years of education, and 56% unskilled occupations. Compared to the group without education, those with formal education had lower CDR‐SOB (1–4 years: = ‐0.99, 95% confidence interval [CI] = –1.85; –0.14, P = .02; ≥5 years: = –1.42, 95% CI = –2.47; –0.38, P = .008). Occupation complexity and demands were unrelated to cognition. Discussion Education, but not occupation, was related to better cognitive abilities independent of the presence of neuropathological insults.

Abstract Introduction Biomarkers for the prediction of cognitive decline in patients with amnestic mild cognitive impairment (MCI) and amnestic mild dementia are needed for both clinical practice and clinical trials. Methods We evaluated the ability of tau‐PET (positron emission tomography), cortical atrophy on magnetic resonance imaging (MRI), baseline cognition, apolipoprotein E gene (APOE) status, plasma and cerebrospinal fluid (CSF) levels of phosphorylated tau‐217, neurofilament light (NfL), and amyloid beta (Aβ)42/40 ratio (individually and in combination) to predict cognitive decline over 2 years in BioFINDER‐2 and Alzheimer's Disease Neuroimaging Initiative (ADNI). Results Baseline tau‐PET and a composite baseline cognitive score were the strongest independent predictors of cognitive decline. Cortical thickness and NfL provided some additional information. Using a predictive algorithm to enrich patient selection in a theoretical clinical trial led to a significantly lower required sample size. Discussion Models including baseline tau‐PET and cognition consistently provided…

Abstract A new model of Alzheimer's disease (AD) is presented: Alzheimer's disease as an autoimmune disease (AD 2 ). In response to pathogen‐/damage‐associated molecular pattern‐stimulating events (e.g., infection, trauma, ischemia, pollution), amyloid beta (Aβ) is released as an early responder cytokine triggering an innate immunity cascade in which Aβ exhibits immunomodulatory/antimicrobial duality. However, Aβ’s antimicrobial properties result in a misdirected attack upon “self” neurons, arising from the electrophysiological similarities between neurons and bacteria in terms of transmembrane potential gradients and anionic charges on outer membrane macromolecules. The subsequent breakdown products of necrotic neurons elicit further release of Aβ leading to a chronic, self‐perpetuating cycle. In AD 2 , amino acid (trp, arg) metabolism is a central control player in modulating AD autoimmunity. AD 2 includes Aβ as an important molecular player, but rejects the “amyloid hypothesis,” recognizing Aβ as a physiologically oligomerizing cytokine and part of a larger immunopathic…

The past few years have seen an explosion in sensitive and specific assays for cerebrospinal fluid (CSF) and blood biomarkers for Alzheimer's disease (AD) and related disorders, as well as some novel assays based on pathological seed-induced protein misfolding in patient samples. Here, I review this exciting field that promises to transform dementia diagnostics and disease monitoring. I discuss data on biomarkers for amyloid beta (Aβ) and tau pathology, neurodegeneration, and glial activation, mention the most promising biomarkers for α-synuclein and TDP-43 pathology, and highlight the need for further research into common co-pathologies. Finally, I consider practical aspects of blood-based biomarker-supported AD diagnostics and emphasize the importance of biomarker interpretation in a full clinical context.

INTRODUCTION: Few resources address steps clinicians can take to help patients reduce their risk of dementia, despite growing recognition that brain health can be optimized and that risk reduction for cognitive decline can be accomplished by lifestyle modifications. METHODS: To address this gap, UsAgainstAlzheimer's convened a risk reduction workgroup (RRWG) to review existing evidence and develop recommendations for primary care clinicians discussing cognitive decline and risk reduction with their patients. RESULTS: The RRWG produced 11 consensus-based recommendations and implementation strategies across six topics: neurovascular risk management, physical activity, sleep, nutrition, social isolation, and cognitive stimulation. DISCUSSION: These recommendations are a first step for clinicians to address brain health with patients and potentially help them prevent cognitive decline. To ensure there is routine care for brain health, proper incentives and policies must be instituted and more education for consumers should be provided.

INTRODUCTION: This report details the approach taken to providing a dataset allowing for analyses on the performance of recently developed assays of amyloid beta (Aβ) peptides in plasma and the extent to which they improve the prediction of amyloid positivity. METHODS: Alzheimer's Disease Neuroimaging Initiative plasma samples with corresponding amyloid positron emission tomography (PET) data were run on six plasma Aβ assays. Statistical tests were performed to determine whether the plasma Aβ measures significantly improved the area under the receiver operating characteristic curve for predicting amyloid PET status compared to age and apolipoprotein E (APOE) genotype. RESULTS: The age and APOE genotype model predicted amyloid status with an area under the curve (AUC) of 0.75. Three assays improved AUCs to 0.81, 0.81, and 0.84 (P < .05, uncorrected for multiple comparisons). DISCUSSION: Measurement of Aβ in plasma contributes to addressing the amyloid component of the ATN (amyloid/tau/neurodegeneration) framework and could be a first step before or in place of a PET or cerebrospinal…

INTRODUCTION: How care-related time and emotional health over the day differ for those assisting older adults with and without dementia is unclear. METHODS: Using 2134 time diaries from the National Study of Caregiving, we compared emotional health and care time for caregivers of older adults with and without dementia. RESULTS: Caregivers to older adults with dementia experienced worse (higher scores) on a composite measure of negative emotional health (4.2 vs 3.3; P < .05) and provided more physical/medical care (33.7 vs 16.2 minutes; P < .05) and less transportation assistance (12.6 vs 24.8 minutes; P < .05) than other caregivers. In models, providing physical/medical care was associated with worse emotional health (β = 0.15; P < .01) and socializing with the care recipient was associated with worse emotional health when the recipient had dementia (β = 0.28; P < .01). DISCUSSION: Findings highlight the opportunity for targeted interventions to address the emotional consequences of different types of care time in the context of dementia.

BACKGROUND: Recent data support beta-synuclein as a blood biomarker to study synaptic degeneration in Alzheimer's disease (AD). METHODS: We provide a detailed comparison of serum beta-synuclein immunoprecipitation - mass spectrometry (IP-MS) with the established blood markers phosphorylated tau 181 (p-tau181) (Simoa) and neurofilament light (NfL) (Ella) in the German FTLD consortium cohort (n = 374) and its relation to brain atrophy (magnetic resonance imaging) and cognitive scores. RESULTS: Serum beta-synuclein was increased in AD but not in frontotemporal lobar degeneration (FTLD) syndromes. Beta-synuclein correlated with atrophy in temporal brain structures and was associated with cognitive impairment. Serum p-tau181 showed the most specific changes in AD but the lowest correlation with structural alterations. NfL was elevated in all diseases and correlated with frontal and temporal brain atrophy. DISCUSSION: Serum beta-synuclein changes differ from those of NfL and p-tau181 and are strongly related to AD, most likely reflecting temporal synaptic degeneration. Beta-synuclein can…

INTRODUCTION: Inositol polyphosphate-5-phosphatase (INPP5D) is a microglia-enriched lipid phosphatase in the central nervous system. A non-coding variant (rs35349669) in INPP5D increases the risk for Alzheimer's disease (AD), and elevated INPP5D expression is associated with increased plaque deposition. INPP5D negatively regulates signaling via several microglial cell surface receptors, including triggering receptor expressed on myeloid cells 2 (TREM2); however, the impact of INPP5D inhibition on AD pathology remains unclear. METHODS: We used the 5xFAD mouse model of amyloidosis to assess how Inpp5d haplodeficiency regulates amyloid pathogenesis. RESULTS: Inpp5d haplodeficiency perturbs the microglial intracellular signaling pathways regulating the immune response, including phagocytosis and clearing of amyloid beta (Aβ). It is important to note that Inpp5d haploinsufficiency leads to the preservation of cognitive function. Spatial transcriptomic analysis revealed that pathways altered by Inpp5d haploinsufficiency are related to synaptic regulation and immune cell activation.…

INTRODUCTION: This increasing body of literature indicates that menopause hormonal replacement therapy (MHT) may substantially mitigate the risk of developing late-life cognitive decline due to progressive Alzheimer's disease (AD) pathophysiology. For the first time, we investigated the question whether MHT impacts AD biomarker-informed pathophysiological dynamics in de-novo diagnosed menopausal women. METHODS: We analyzed baseline and longitudinal differences between MHT-taking and -not women in terms of concentrations of core pathophysiological AD plasma biomarkers, validated in symptomatic and cognitively healthy individuals, including biomarkers of (1) the amyloid-β (Aβ) pathway, (2) tau pathophysiology, (3) neuronal loss, and (4) axonal damage and neurodegeneration. RESULTS: We report a prominent and significant treatment response at the Aβ pathway biomarker level. Women at genetic risk for AD (APOE e4 allele carriers) have particularly shown favorable results from treatment. DISCUSSION: To our knowledge, we present first prospective clinical evidence on effects of MHT on AD…

Abstract Introduction Growing evidence implicates air pollution as a risk factor for dementia, but prior work is limited by challenges in diagnostic accuracy and assessing exposures in the decades prior to disease development. We evaluated the impact of long‐term fine particulate matter (PM2.5) exposures on incident dementia (all‐cause, Alzheimer's disease [AD], and vascular dementia [VaD]) in older adults. Methods A panel of neurologists adjudicated dementia cases based on extensive neuropsychological testing and magnetic resonance imaging. We applied validated fine‐scale air pollutant models to reconstructed residential histories to assess exposures. Results An interquartile range increase in 20‐year PM2.5 was associated with a 20% higher risk of dementia (95% confidence interval [CI]: 5%, 37%) and an increased risk of mixed VaD/AD but not AD alone. Discussion Our findings suggest that air pollutant exposures over decades contribute to dementia and that effects of current exposures may be experienced years into the future.

INTRODUCTION: Plasma-measured tau phosphorylated at threonine 217 (p-tau217) is a potential non-invasive biomarker of Alzheimer's disease (AD). We investigated whether plasma p-tau217 predicts subsequent cognition and positron emission tomography (PET) markers of pathology in autosomal dominant AD. METHODS: We analyzed baseline levels of plasma p-tau217 and its associations with amyloid PET, tau PET, and word list delayed recall measured 7.61 years later in non-demented age- and education-matched presenilin-1 E280A carriers (n = 24) and non-carrier (n = 20) family members. RESULTS: Carriers had higher plasma p-tau217 levels than non-carriers. Baseline plasma p-tau217 was associated with subsequent amyloid and tau PET pathology levels and cognitive function. DISCUSSION: Our findings suggest that plasma p-tau217 predicts subsequent brain pathological burden and memory performance in presenilin-1 E280A carriers. These results provide support for plasma p-tau217 as a minimally invasive diagnostic and prognostic biomarker for AD, with potential utility in clinical practice and trials.…

Limited knowledge on dementia biomarkers in Latin American and Caribbean (LAC) countries remains a serious barrier. Here, we reported a survey to explore the ongoing work, needs, interests, potential barriers, and opportunities for future studies related to biomarkers. The results show that neuroimaging is the most used biomarker (73%), followed by genetic studies (40%), peripheral fluids biomarkers (31%), and cerebrospinal fluid biomarkers (29%). Regarding barriers in LAC, lack of funding appears to undermine the implementation of biomarkers in clinical or research settings, followed by insufficient infrastructure and training. The survey revealed that despite the above barriers, the region holds a great potential to advance dementia biomarkers research. Considering the unique contributions that LAC could make to this growing field, we highlight the urgent need to expand biomarker research. These insights allowed us to propose an action plan that addresses the recommendations for a biomarker framework recently proposed by regional experts.

INTRODUCTION: We evaluated the prevalence of dementia and mild cognitive impairment (MCI) in indigenous Tsimane and Moseten, who lead a subsistence lifestyle. METHODS: Participants from population-based samples ≥ 60 years of age (n = 623) were assessed using adapted versions of the Modified Mini-Mental State Examination, informant interview, longitudinal cognitive testing and brain computed tomography (CT) scans. RESULTS: Tsimane exhibited five cases of dementia (among n = 435; crude prevalence = 1.2%, 95% confidence interval [CI]: 0.4, 2.7); Moseten exhibited one case (among n = 169; crude prevalence = 0.6%, 95% CI: 0.0, 3.2), all age ≥ 80 years. Age-standardized MCI prevalence was 7.7% (95% CI: 5.2, 10.3) in Tsimane and 9.8% (95% CI: 4.9, 14.6) in Moseten. Cognitive impairment was associated with visuospatial impairments, parkinsonian symptoms, and vascular calcification in the basal ganglia. DISCUSSION: The prevalence of dementia in this cohort is among the lowest in the world. Widespread intracranial medial arterial calcifications suggest a previously unrecognized,…

INTRODUCTION: Epidemiological studies report an association between traumatic brain injury (TBI) and post-traumatic stress disorder (PTSD) and clinically diagnosed Alzheimer's disease (AD). We examined the association between TBI/PTSD and biomarker-defined AD. METHODS: We identified 289 non-demented veterans with TBI and/or PTSD and controls who underwent clinical evaluation, cerebrospinal fluid (CSF) collection, magnetic resonance imaging (MRI), amyloid beta (Aβ) and tau positron emission tomography, and apolipoprotein E testing. Participants were followed for up to 5.2 years. RESULTS: Exposure groups (TBI, PTSD, and TBI + PTSD) had higher prevalence of mild cognitive impairment (MCI: P < .0001) and worse Mini-Mental State Examination scores (PTSD: P = .008; TBI & PTSD: P = .009) than controls. There were no significant differences in other cognitive scores, MRI volumes, Aβ or tau accumulation, or in most longitudinal measures. DISCUSSION: TBI and/or PTSD were not associated with elevated AD biomarkers. The poorer cognitive status of exposed veterans may be due to other comorbid…

Abstract The P522R variant of PLCG2, expressed by microglia, is associated with reduced risk of Alzheimer's disease (AD). Yet, the impact of this protective mutation on microglial responses to AD pathology remains unknown. Chimeric AD and wild‐type mice were generated by transplanting PLCG2‐P522R or isogenic wild‐type human induced pluripotent stem cell microglia. At 7 months of age, single‐cell and bulk RNA sequencing, and histological analyses were performed. The PLCG2‐P522R variant induced a significant increase in microglial human leukocyte antigen (HLA) expression and the induction of antigen presentation, chemokine signaling, and T cell proliferation pathways. Examination of immune‐intact AD mice further demonstrated that the PLCG2‐P522R variant promotes the recruitment of CD8 + T cells to the brain. These data provide the first evidence that the PLCG2‐P522R variant increases the capacity of microglia to recruit T cells and present antigens, promoting a microglial transcriptional state that has recently been shown to be reduced in AD patient brains.

Abstract Introduction Increased plasma levels of C‐reactive protein (CRP) in midlife are associated with increased risk of Alzheimer's disease (AD), whereas in older age the opposite association is observed. Whether genetically determined CRP is associated with AD remains unclear. Methods A total of 111,242 White individuals from the Copenhagen General Population Study and the Copenhagen City Heart Study were included. Plasma levels of CRP and four regulatory genetic variants in the CRP gene were determined. Results For CRP percentile group 1 to 5 (lowest plasma CRP) versus the 50 to 75 group (reference), the hazard ratio for AD was 1.69 (95% confidence interval 1.29–2.16). Genetically low CRP was associated with increased risk of AD in individuals with body mass index ≤25 kg/m 2 ( P = 4 × 10 −6 ). Discussion Low plasma levels of CRP at baseline were associated with high risk of AD in individuals from the general population. These observational findings were supported by genetic studies.

INTRODUCTION: Physical activity (PA) is widely recommended for age-related brain health, yet its neurobiology is not well understood. Animal models indicate PA is synaptogenic. We examined the relationship between PA and synaptic integrity markers in older adults. METHODS: Four hundred four decedents from the Rush Memory and Aging Project completed annual actigraphy monitoring (Mean visits = 3.5±2.4) and post mortem evaluation. Brain tissue was analyzed for presynaptic proteins (synaptophysin, synaptotagmin-1, vesicle-associated membrane proteins, syntaxin, complexin-I, and complexin-II), and neuropathology. Models examined relationships between late-life PA (averaged across visits), and timing-specific PA (time to autopsy) with synaptic proteins. RESULTS: Greater late-life PA associated with higher presynaptic protein levels (0.14 < β < 0.20), except complexin-II (β = 0.08). Relationships were independent of pathology but timing specific; participants who completed actigraphy within 2 years of brain tissue measurements showed largest PA-to-synaptic protein associations (0.32 < β <…

INTRODUCTION: Variants in the tau gene (MAPT) region are associated with breast cancer in women and Alzheimer's disease (AD) among persons lacking apolipoprotein E ε4 (ε4-). METHODS: To identify novel genes associated with tau-related pathology, we conducted two genome-wide association studies (GWAS) for AD, one among 10,340 ε4- women in the Alzheimer's Disease Genetics Consortium (ADGC) and another in 31 members (22 women) of a consanguineous Hutterite kindred. RESULTS: ) datasets. Multi-omics analyses showed that the most significant and largest number of associations among the single nucleotide polymorphisms (SNPs), DNA-methylated CpGs, MGMT expression, and AD-related neuropathological traits were observed among women. Furthermore, promoter capture Hi-C analyses revealed long-range interactions of the MGMT promoter with MGMT SNPs and CpG sites. DISCUSSION: These findings suggest that epigenetically regulated MGMT expression is involved in AD pathogenesis, especially in women.

INTRODUCTION: Relying on magnetic resonance imaging (MRI) for quantification of positron emission tomography (PET) images may limit generalizability of the results. We evaluated several MRI-free approaches for amyloid beta (Aβ) and tau PET quantification relative to MRI-dependent quantification cross-sectionally and longitudinally. METHODS: We compared baseline MRI-free and MRI-dependent measurements of Aβ PET ([18F]florbetapir [FBP], N = 1290, [18F]florbetaben [FBB], N = 290) and tau PET ([18F]flortaucipir [FTP], N = 768) images with respect to continuous and dichotomous agreement, effect sizes of Aβ+ impaired versus Aβ- unimpaired groups, and longitudinal standardized uptake value ratio (SUVR) slopes in a subset of individuals. RESULTS: ≥0.95; ± agreement ≥92%) and for Alzheimer's disease-related effect sizes; agreement was slightly lower for entorhinal flortaucipir and longitudinal slopes. DISCUSSION: There is no consistent loss of baseline or longitudinal AD-related signal with MRI-free Aβ and tau PET image quantification.

INTRODUCTION: Cognitive training and physical exercise have shown positive effects on delaying progression of mild cognitive impairment (MCI) to dementia. METHODS: We explored the enhancing effect from Tai Chi when it was provided with cognitive training for MCI. In the first 12 months, the cognitive training group (CT) had cognitive training, and the mixed group (MixT) had additional Tai Chi training. In the second 12 months, training was only provided for a subgroup of MixT. RESULTS: In the first 12 months, MixT and CT groups were benefited from training. Compared to the CT group, MixT had additional positive effects with reference to baseline. In addition, Compared to short-time training, prolonged mixed training further delayed decline in global cognition and memory. Functional magnetic resonance imaging showed more increased regional activity in both CT and MixT. DISCUSSION: Tai Chi enhanced cognitive training effects in MCI. Moreover, Tai Chi and cognitive mixed training showed effects on delaying cognitive decline.

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…

OBJECTIVE: Evidence on simultaneous changes in body mass index (BMI) and cognitive decline, which better reflect the natural course of both health phenomena, is limited. METHODS: We capitalized on longitudinal data from 15,977 initially non-demented elderly from the Alzheimer's Disease Centers followed for 5 years on average. Changes in BMI were defined as (1) last minus first BMI, (2) mean of all follow-up BMIs minus first BMI, and (3) standard deviation of BMI change from baseline and all follow-up visits (representing variability). RESULTS: Participants with significant changes in BMI (increase or decrease of ≥5%), or who had greater variability in BMI, had faster cognitive decline. This pattern was consistent irrespective of normal (BMI < 25; N = 5747), overweight (25 ≤ BMI < 30; N = 6302), or obese (BMI ≥ 30; N = 3928) BMI at baseline. CONCLUSIONS: Stability in BMI predicts better cognitive trajectories suggesting clinical value in tracking BMI change, which is simple to measure, and may point to individuals whose cognition is declining.

Abstract Background Obesity has been associated with increased risk of dementia with several studies reporting a reverse causality, with weight loss preceding the onset of dementia. Methods Two thousand forty‐five non‐demented Framingham Offspring participants, aged 30 to 50 years, were included to determine effect of body mass index (BMI) decline patterns from mid‐ to late life over a 39‐year follow‐up. Group‐based trajectory models were used to create BMI trajectories. Results Decreasing BMI trends were associated with higher risk of developing dementia in late life. Decliners with first early mid‐life increasing and then later mid‐life declining patterns of BMI were at greater increased risk of dementia compared to non‐decliners (hazard ratio 3.84, 95% confidence interval 1.39–10.60). Conclusion While patterns of decline in BMI were associated with dementia, a subgroup with a pattern of initial increasing BMI followed by declining BMI, both occurring within mid‐life, appeared to be central to declining BMI–dementia association. Further validations are needed to provide robust…

INTRODUCTION: Clinical research focused on aging, Alzheimer's disease and related dementias (ADRD), and caregiving often does not recruit Asian Americans and Pacific Islanders (AAPIs). METHODS: With funding from the National Institute on Aging, we designed and launched the Collaborative Approach for AAPIs Research and Education (CARE), a research recruitment registry to increase AAPIs' participation in ADRD, aging, and caregiving research. We present the design of this novel recruitment program. RESULTS: CARE uses community-based participatory research methods that are culturally and linguistically appropriate. Since CARE's launch, it has enrolled >7000 AAPIs in a 1-year period. The majority enrolled in CARE via community organizations and reported never having participated in any kind of research before. CARE also engages researchers by establishing a recruitment referral request protocol. DISCUSSION: CARE provides a promising venue to foster meaningful inclusion of AAPIs who are under-represented in aging and dementia-related research.

INTRODUCTION: An analysis of the ethnocultural and socioeconomic composition of Alzheimer's Disease Neuroimaging Initiative (ADNI) participants is needed to assess the generalizability of ADNI data to diverse populations. METHODS: ADNI data collected between October 2004 and November 2020 were used to determine ethnocultural and educational composition of the sample and differences in the following metrics: screening, screen fails, enrollment, biomarkers. RESULTS: Of 3739 screened individuals, 11% identified as being from ethnoculturally underrepresented populations (e.g., Black, Latinx) and 16% had <12 years of education. Of 2286 enrolled participants, 11% identified as ethnoculturally underrepresented individuals and 15% had <12 years of education. This participation is considerably lower than US Census data for adults 60+ (ethnoculturally underrepresented populations: 25%; <12 years of education: 4%). Individuals with <12 years of education failed screening at a higher rate. DISCUSSION: Our findings suggest that ADNI results may not be entirely generalizable to ethnoculturally…

INTRODUCTION: The entorhinal cortex is among the earliest areas involved in Alzheimer's disease. Volume reduction and neural loss in this area have been widely reported. Human entorhinal cortex atrophy is, in part, due to neural loss, but microglial and/or astroglial involvement in the different layers remains unclear. Additionally, -omic approaches in the human entorhinal cortex are scarce. METHODS: Herein, stereological layer-specific and proteomic analyses were carried out in the human brain. RESULTS: Neurodegeneration, microglial reduction, and astrogliosis have been demonstrated, and proteomic data have revealed relationships with up- (S100A6, PPP1R1B, BAG3, and PRDX6) and downregulated (GSK3B, SYN1, DLG4, and RAB3A) proteins. Namely, clusters of these proteins were related to synaptic, neuroinflammatory, and oxidative stress processes. DISCUSSION: Differential layer involvement among neural and glial populations determined by proteinopathies and identified proteins related to neurodegeneration and astrogliosis could explain how the cortical circuitry facilitates pathological…

INTRODUCTION: We examined the association between cerebrospinal fluid (CSF)-derived biomarkers of Alzheimer's disease and neuropsychiatric symptoms (NPS) in older non-demented adults. METHODS: We included 784 persons (699 cognitively unimpaired, 85 with mild cognitive impairment) aged ≥ 50 years who underwent CSF amyloid beta (Aβ42), hyperphosphorylated tau 181 (p-tau), and total tau (t-tau) as well as NPS assessment using Beck Depression and Anxiety Inventories (BDI-II, BAI), and Neuropsychiatric Inventory Questionnaire (NPI-Q). RESULTS: Lower CSF Aβ42, and higher t-tau/Aβ42 and p-tau/Aβ42 ratios were associated with BDI-II and BAI total scores, clinical depression (BDI-II ≥ 13), and clinical anxiety (BAI ≥ 10), as well as NPI-Q-assessed anxiety, apathy, and nighttime behavior. DISCUSSION: CSF Aβ42, t-tau/Aβ42, and p-tau/Aβ42 ratios were associated with NPS in community-dwelling individuals free of dementia. If confirmed by a longitudinal cohort study, the findings have clinical relevance of taking into account the NPS status of individuals with abnormal CSF biomarkers.

INTRODUCTION: Updated estimates of the US Alzheimer's disease (AD) population, including under-represented populations, are needed to improve clinical trial diversity. METHODS: A step-wise approach calculating prevalent numbers from clinical syndrome to biomarker-positive mild cognitive impairment (MCI) due to AD and mild AD was developed, using age-and-race/ethnicity-stratified data where available. RESULTS: The estimated percentage of Americans aged ≥ 65 years with MCI due to AD was 9.2% of non-Hispanic Whites, 13.6% of non-Hispanic Blacks, 11.1% Hispanics, and 9.7% other race/ethnicities. The estimated percentage of Americans aged ≥ 65 years with mild dementia due to AD among non-Hispanic Whites was 3.7%, non-Hispanic Blacks 7.0%, Hispanics 5.3%, and 3.9% other race/ethnicities. Of these early-stage AD cases, few are likely diagnosed, ranging from 13% of prevalent non-Hispanic Black cases to 27% of non-Hispanic White cases. DISCUSSION: Under-representation in clinical trials may be improved by setting recruitment goals reflecting the diversity of the AD patient population and…

INTRODUCTION: Mapping the preclinical dementia phase is important for early detection and evaluation of interventions. We assessed the trajectories of cognitive decline in preclinical dementia over 12 years and investigated whether being a fast decliner across 6 years is associated with increased risk of dementia the following 6 years. METHODS: Rates of cognitive decline were determined using mixed-effects models for 1646 participants from the Swedish National Study on Aging and Care in Kungsholmen (SNAC-K) cohort. Cox regression was used to assess the future likelihood of dementia for fast decliners (declining ≥1.5 standard deviations [SDs] faster than the age-specific rates). RESULTS: Participants in a preclinical phase of dementia showed increased rates of decline in all cognitive tests compared to the no-dementia group, particularly closer (0-6 years) to diagnosis. Participants declining fast in three or more cognitive tests 12-6 years before diagnosis demonstrated a high risk of dementia 6 years later (hazard ratio [HR] 3.90, 95% confidence interval [CI] 2.28-6.69). DISCUSSION:…

INTRODUCTION: Clinical trials targeting tau in Alzheimer's disease (AD) need to recruit individuals at risk of tau accumulation. Here, we studied cerebrospinal fluid (CSF) biomarkers and plasma phosphorylated tau (p-tau)181 as predictors of tau accumulation on positron emission tomography (PET) to evaluate implications for trial designs. METHODS: We included older individuals who had serial tau-PET scans, baseline amyloid beta (Aβ)-PET, and baseline CSF biomarkers (n = 163) or plasma p-tau181 (n = 74). We studied fluid biomarker associations with tau accumulation and estimated trial sample sizes and screening failure reductions by implementing these markers into participant selection for trials. RESULTS: P-tau181 in CSF and plasma predicted tau accumulation (r > 0.36, P < .001), even in AD-continuum individuals with normal baseline tau-PET (A+T-; r > 0.37, P < .05). Recruitment based on CSF biomarkers yielded comparable sample sizes to Aβ-PET. Prescreening with plasma p-tau181 reduced up to ≈50% of screening failures. DISCUSSION: Clinical trials testing tau-targeting therapies may…

Disturbances in the brain's capacity to meet its energy demand increase the risk of synaptic loss, neurodegeneration, and cognitive decline. Nutritional and metabolic interventions that target metabolic pathways combined with diagnostics to identify deficits in cerebral bioenergetics may therefore offer novel therapeutic potential for Alzheimer's disease (AD) prevention and management. Many diet-derived natural bioactive components can govern cellular energy metabolism but their effects on brain aging are not clear. This review examines how nutritional metabolism can regulate brain bioenergetics and mitigate AD risk. We focus on leading mechanisms of cerebral bioenergetic breakdown in the aging brain at the cellular level, as well as the putative causes and consequences of disturbed bioenergetics, particularly at the blood-brain barrier with implications for nutrient brain delivery and nutritional interventions. Novel therapeutic nutrition approaches including diet patterns are provided, integrating studies of the gut microbiome, neuroimaging, and other biomarkers to guide future…

INTRODUCTION: Neuropsychiatric symptoms (NPS) are common in Lewy body disease (LBD), but their etiology is poorly understood. METHODS: In a population-based post mortem study neuropathological data was collected for Lewy body (LB) neuropathology, neurofibrillary tangles (NFT), amyloid beta burden, TDP-43, lacunar infarcts, cerebral amyloid angiopathy (CAA), and hyaline atherosclerosis. Post mortem interviews collected systematic information regarding NPS and cognitive status. A total of 1038 cases were included: no pathology (NP; n = 761), Alzheimer's disease (AD; n = 189), LBD (n = 60), and AD+LBD (n = 28). RESULTS: Hallucinations were associated with higher LB Braak stages, while higher NFT Braak staging was associated with depression, agitation, and greater number of symptoms in the Neuropsychiatric Inventory. Cases with dual AD+LBD pathology had the highest risk of hallucinations, agitation, apathy, and total symptoms but a multiplicative interaction between these pathologies was not significant. DISCUSSION: LB and AD pathology contribute differentially to NPS likely with an…

INTRODUCTION: Longitudinal multivariable analyses are needed to determine if the rate of olfactory decline during normal cognition predicts subsequent Alzheimer's disease (AD) diagnoses and brain dysmorphology. METHODS: Older adults (n = 515) were assessed annually for odor identification, cognitive function and dementia clinical diagnosis (max follow-up 18 years). Regional gray matter volumes (GMV) were quantified (3T MRI) in a cross-sectional subsample (n = 121). Regression models were adjusted for APOE-ε4 genotype, dementia risk factors and demographics. RESULTS: Faster olfactory decline during periods of normal cognition predicted higher incidence of subsequent MCI or dementia (OR 1.89, 95% CI: 1.26, 2.90, p < 0.01; comparable to carrying an APOE-ε4 allele) and smaller GMV in AD and olfactory regions (β = -0.11, 95% CI -0.21, -0.00). DISCUSSION: Rapid olfactory decline during normal cognition, using repeated olfactory measurement, predicted subsequent cognitive impairment, dementia, and smaller GMVs, highlighting its potential as a simple biomarker for early AD detection.…

INTRODUCTION: Identifying CSF-based biomarkers for the β-amyloidosis that initiates Alzheimer's disease (AD) could provide inexpensive and dynamic tests to distinguish AD from normal aging and predict future cognitive decline. METHODS: We developed immunoassays specifically detecting all C-terminal variants of secreted amyloid β-protein and identified a novel biomarker, the Aβ 37/42 ratio, that outperforms the canonical Aβ42/40 ratio as a means to evaluate the γ-secretase activity and brain Aβ accumulation. RESULTS: We show that Aβ 37/42 can distinguish physiological and pathological status in (1) presenilin-1 mutant vs wild-type cultured cells, (2) AD vs control brain tissue, and (3) AD versus cognitively normal (CN) subjects in CSF, where 37/42 (AUC 0.9622) outperformed 42/40 (AUC 0.8651) in distinguishing CN from AD. DISCUSSION: We conclude that the Aβ 37/42 ratio sensitively detects presenilin/γ-secretase dysfunction and better distinguishes CN from AD than Aβ42/40 in CSF. Measuring this novel ratio alongside promising phospho-tau analytes may provide highly discriminatory fluid…