Review
Xinyi Wang*, Li Chen*, Weijian Li, Zhi He, Haiying Jiang *These authors contributed equally to this work.
Association of dipeptidyl peptidase-4 with Alzheimer’s disease: A new therapeutic prospect
Abstract: Alzheimer’s disease (AD) is the most common disease associated with cognitive dysfunction, which is closely associated with type 2 diabetes mellitus (T2DM) in clinical manifestations, pathological changes and prevention. Inhibition of dipeptidyl peptidase 4 (DPP-4) can lower blood glucose levels by stimulating insulin secretion. Besides, it can affect cognitive function through the neuroprotective effect of DPP-4 substrates, such as glucose-dependent insulin peptide and glucagon-like peptide-1, the proteolytic effect on amyloid-β and the protective effect on neuronal structure. This review discusses the relationship between cognitive impairment in T2DM and in AD, summarizes the effect of DPP-4 inhibitor (DPP-4i) on improving cognitive impairment in these two diseases based on the current studies. Given the lack of clinical randomized trials that evaluate the effect of DPP-4i on AD, this review is expected to provide preclinical evidence for DPP-4i as a potential therapy for the treatment and prevention of AD.
Systematic Review
Xichao Ma, Yu Wang, Xinxin Chen, Shijie Zhu, Yang Lin, Shaxin Liu, Yonghong Yang
Effects of home-based interventions on cognitive performance in patients with dementia: A systematic review and meta-analysis
Abstract: Background: With increasing age, dementia is a common disease in the elderly population，especially Alzheimer's disease. Owing to the nature of the disease, the function of patients deteriorates, which places a heavy burden on the country and family. Home-based training programs have been shown to improve cognitive function in patients with dementia. Objective: To examine the effects and methods of home-based interventions on the cognitive performance of patients with dementia. Methods: This systematic review and meta-analysis was conducted on the basis of the PRISMA statement. This protocol was registered in advance at PROSPERO (CRD42021277269). Six English electronic databases, including PubMed, EMBASE, the Cochrane Library, Web of Science, SCOPUS, and OTseeker, were searched and updated to January 31, 2024. Two researchers independently completed the literature retrieval and data extraction. RevMan 5.3 software was used to analyze the data. The standardized mean difference and the 95% confidence interval were used for statistical analysis. Subgroup analyses were performed by assessment tools, intervention duration and intervention methods. Results: Twenty randomized controlled trials with 3543 participants were included in the qualitative synthesis, and 17 studies were included in the meta-analysis. Compared with the control intervention, the home-based intervention significantly improved cognitive performance (SMD=0.45; 95% CI=[0.17, 0.74]; p=0.002). Conclusions: Moderate to high evidence shows that home-based interventions significantly improve the cognitive performance of patients with dementia, especially their comprehensive cognitive function.
Short Communication
Jeffrey N Weiss
Dynamic light scattering of the eye in the diagnosis of Alzheimer’s disease
Abstract: The early detection of Alzheimer’s disease, before symptoms have appeared, is integral to the development of effective treatments. Dynamic light scattering spectroscopy measures the Brownian movement of proteins at the molecular level. This technique may facilitate early Alzheimer’s disease diagnosis and the discovery of pharmaceuticals that may prevent symptom development.
Commentary
Andrea M Weinstein, Marissa A Gogniat, Meryl A Butters
The importance of cognitive correlates of plasma amyloid-β 42/40
Abstract: This commentary focuses on the clinical utility of plasma amyloid-β (Aβ) 42/40 to detect semantic intrusion errors in amnestic mild cognitive impairment, as investigated Curiel Cid et al. in a recent issue of the Journal of Alzheimer’s Disease. This commentary highlights the importance of testing the sensitivity of plasma Aβ42/40 to clinical symptoms in the quest to develop a comprehensive definition of AD that incorporates both biological precursors and clinical consequences.
Commentary
Rudolph J Castellani
Biomarker-only diagnosis of Alzheimer’s disease: Not ready for prime time
Abstract: The Alzheimer’s Association Workgroup research criteria for diagnosis and staging of Alzheimer’s disease hypothesize diagnostic meaning in the absence of clinical symptoms. If operationalized, this would trivialize neuropsychological assessment but would also expand the pool of candidates for anti-amyloid therapies. A recent survey of the reactions of clinical neuropsychologists to these criteria suggested that the purpose lacked clarity, among other concerns. Given the current landscape in Alzheimer’s disease therapeutics, with substantial toxicity and unclear benefit, as well as the poorly understood relationships between biomarkers and clinical signs at the individual level, the roll out of biomarker-only disease seems premature.
Editorial
Yohko Maki, Takayoshi Ubuka, Yoichi Yamane
The importance of non-pharmacological interventions to improve cognitive reserve prior to the administration of a drug against the causative agent of Alzheimer’s disease
Abstract: Lecanemab, an antibody drug targeting amyloid-β, has been approved to treat Alzheimer's disease (AD) in the United States and Japan recently. However, there are several concerns about Lecanemab, such as its minimum biological effects, possible side effects, and its economic burden. On the other hand, non-pharmacological approach without major side effects has a potential to alleviate the symptoms of AD by improving cognitive reserve, which is individual’s resilience to AD pathology. It is important to compare the benefits and risks of pharmacological and non-pharmacological approaches, especially in the oldest old with AD, to give priority to the safe and cost-effective approach.
Minos Kritikos#, Juin-Wan Zhou#, Chuan Huang, Sam Gandy, Alison C Pellecchia, Stephanie Santiago-Michels, Melissa A Carr, Shabab Islam, Yuan Yang, Megan K Horton, Roberto G Lucchini, Ana M Franceschi, Lev Bangiyev, Paul Vaska, Sean AP Clouston, Benjamin J Luft (Handling Associate Editor: Lilian Calderón-Garcidueñas) #These authors contributed equally to this work.
Exposure duration and cerebral amyloidosis in the olfactory cortex of World Trade Center responders: A positron emission tomography and magnetic resonance imaging study
Abstract: Background: Amyloid-β proteins, a hallmark of Alzheimer’s disease, are believed to play an adaptive role in the cerebral immune response. Objective: Noting that cognitive dysfunction, hippocampal inflammation, and hippocampal atrophy are associated with World Trade Center (WTC) exposure duration, we examined whether WTC exposure duration would be associated with cerebral amyloidosis in olfactory regions in WTC responders. Methods: WTC responders (aged 44-65 years) who varied in exposure duration but did not use personalized protective equipment were assessed using positron-emission tomography with [18F]-Florbetaben. The outcome was the cortical [18F]-Florbetaben burden, measured using regional standardized uptake value ratios (SUVRs) in 34 Desikan-Killiany regions of interest. Spearman’s ρ and generalized linear models were used to estimate correlations between WTC exposure duration and cortical [18F]-Florbetaben SUVR. Cognitive and behavioral symptoms were measured. Magnetic resonance imaging was used to measure cortical thickness and diffusivity. Results: The mean age of imaged responders was 56 years old. WTC exposure duration was associated with olfactory [18F]-Florbetaben SUVR (Spearman’s ρ=0.43, p=0.011), which was in turn associated with elevated [18F]-Florbetaben SUVR in ventral regions (ρ=0.41, p=0.016). Cortical [18F]-Florbetaben in ventral regions was associated with reduced response speed (ρ=-0.72, p<0.001), and was co-located with cortical diffusivity across regions in the parietal and frontal lobes, and with reduced cortical thickness in the isthmus cingulate (ρ=-0.53, p=0.001). Conclusions: Low-grade amyloidosis focused on the olfactory and frontal lobes was associated with WTC exposure duration. Future work should examine whether low-grade amyloidosis is correlated with the location or distribution of neurofibrillary tangles in WTC responders.
Isabel J Sible, Daniel A Nation
Comparison of visit-to-visit blood pressure variability and time in target range in predicting risk for cognitive outcomes in the SPRINT trial
Abstract: Background: Blood pressure (BP) variability (BPV) and time in target range (TTR) are emerging vascular risk factors for dementia, independent of traditionally targeted mean BP. Objective: Determine whether BPV or TTR is most strongly associated with cognitive risk. Methods: In this post hoc analysis of the SPRINT trial, 8034 participants underwent repeated BP measurement and cognitive testing at baseline and follow-up. Visit-to-visit BPV was calculated as average real variability. TTR was the percent of time in desired treatment arm target range (standard: 120-140 mmHg systolic BP; intensive: 110-130 mmHg systolic BP). Adjudicated clinical outcomes were no cognitive impairment, mild cognitive impairment (MCI), and probable dementia. We investigated a direct comparison of BPV and TTR in predicting cognitive risk, stratified by BP treatment group. Results: Elevated BPV was associated with increased risk for MCI (adjusted HR: 1.21 [95% CI 1.10, 1.33], p < 0.001) and MCI/dementia (HR: 1.17 [95% CI 1.07, 1.27], p < 0.001) in the standard group, and dementia (HR: 1.17 [95% CI 1.01, 1.36], p = 0.039) in the intensive group. Higher TTR was related to lower dementia risk (HR: 0.72 [95% CI 0.60, 0.86], p < 0.001) in the intensive group only. Conclusions: Visit-to-visit BPV outperformed TTR in predicting risk for MCI and MCI/dementia. TTR was more strongly associated with dementia risk under intensive treatment. Findings were independent of mean BP in a cohort with rigorously controlled BP and suggest newer aspects of BP control may be harnessed to further reduce cognitive risk.
Megan Witbracht, Yiren Xu, Olivia B Morgan, Christian R Salazar, Dan Hoang, Amy Kind, Daniel L Gillen, Joshua D Grill (Handling Associate Editor: Shana Stites)
Research Attitudes Questionnaire scores and retention in a recruitment registry
Abstract: Background: Recruitment registries are maximally effective when registrants are retained to the point of referral. The Research Attitudes Questionnaire (RAQ) has previously been shown to predict research participation behaviors, including Alzheimer’s disease clinical trial completion. Objective: To test the hypothesis that RAQ score is associated with retention behaviors in a local recruitment registry. Methods: Using data from the UC Irvine Consent-to-Contact Registry, a recruitment registry that enrolls adults 18 years and older, we used logistic regression to quantify the association of RAQ score and the odds of first-year non-renewal. Covariates included demographic variables, comorbidities, and recruitment source. In longitudinal analyses, we used discrete proportional hazards and Cox proportional hazards models to quantify the relationship between RAQ score and time to non-renewal and time to active withdrawal, respectively. Results: Among n=4,663 participants, we estimated that a 5-point higher baseline RAQ score was associated with a 15% lower odds of first-year non-renewal, after adjustment for potential confounding factors (OR: 0.85, 95% CI: (0.79, 0.92), p < 0.001). Older age and higher education were also associated with lower odds of non-renewal while Asian race, Hispanic ethnicity, and certain recruitment sources (e.g., doctor or friend referral) were associated with higher odds of non-renewal. Higher baseline RAQ and higher annually updated RAQ were both significantly associated with lower odds of non-renewal longitudinally. Age, education, and some recruitment sources, but not RAQ, were associated with active withdrawal. Conclusions: Opportunities exist to identify predictors of registry retention behaviors and possible targets for intervention to improve related outcomes.
Thomas Benke and George Karagiannis
Memory anosognosia in early Alzheimer’s disease: A memory clinic study
Abstract: Background: Unawareness or anosognosia of memory impairment is a common phenomenon in patients with Alzheimer’s disease (AD). Different findings have been reported regarding its presentation, assessment procedure, and cognitive correlates. Objective: To assess memory awareness of early AD patients predictively (before memory testing) and online (immediately after performing a memory test). Methods: All participants were outpatients of a memory clinic. AD patients were compared with participants having mild cognitive impairment (MCI) and a group with normal cognitive aging (NC). We used a performance-based assessment procedure to measure self-perceived memory abilities. An anosognosia ratio was calculated by matching self-estimates with objective memory scores derived from the Consortium to Establish a Registry for Alzheimer’s disease Neuropsychological battery. Results: Memory anosognosia in terms of self-overestimation was found in almost half of the AD sample, only rarely in MCI, and was not present in NC. Most AD patients had both, a low prediction and also a deficient online accuracy of self-estimation. Memory overestimators were older, less educated, and had significantly poorer neuropsychological scores. A stepwise linear regression analysis showed that memory anosognosia was predicted by age, everyday functional abilities and neuropsychological variables, including executive and mnestic abilities. Conclusions: Poor cognitive and memory functions combined with memory anosognosia are a hallmark of early AD. Further, mnemonic anosognosia as assessed by performance based measures separates AD patients already in the early disease stage from subjects with MCI or normal controls. Our findings highlight the importance of assessing memory self-appraisal in subjects attending a memory clinic, in addition to clinical and cognitive variables.
Werner J Geldenhuys#, Gina N Wilson#, Katrina Hernandez, Kailee Monaghan, Kaitlynn Smith, Dominick S Cicala, Terri J Poling, James C Walton, Peng Cheng Han, Jason D Huber (Handling Associate Editor: Pamela Maher) #These authors contributed equally to this work.
Loss of the mitochondrial protein mitoNEET in mice is associated with cognitive impairments and increased neuroinflammation
Abstract: Background: Mitochondrial dysfunction is implicated in several neurodegenerative diseases associated with memory and cognitive deficits, including Alzheimer’s disease. Changes in bioenergetic function results in reactive oxygen species, oxidative damage and consequently neuroinflammation, which contributes to neuronal cell loss. Objective: In this study, we evaluated the impact of the loss of the redox active [2Fe-2S] mitochondrial-associated protein mitoNEET (CISD1) on neuroinflammation and cognition using an age-appropriate preclinical model. While associations between neuroinflammation and poor cognitive impacts have been shown in recent work, little has been done to assess whether loss of mitoNEET is associated with changes in neuroinflammatory markers or negative cognitive-behavioral outcomes. Methods: Using 9-11-month-old mitoNEET knockout (CISD1-/-) and wild-type mice, we conducted a battery of cognitive tests to assess the impact of mitoNEET loss on performance. We then histologically evaluated the effect of absence of mitoNEET on markers of neuroinflammation in the aged brain. Results: We found loss of mitoNEET in mice was associated with a significant reduction in willingness to explore within an open field and impaired short-term spatial working memory in the Y-maze. We also found a significant reduction in novel object recognition memory that was gene-dependent and accompanied by reduced c-fos expression in hippocampus and cortical regions. Conclusions: Our findings indicate that mitoNEET loss is significantly associated with impairments in cognitive-behavioral and neuroinflammatory outcomes; specifically, learning and memory, anxiety-like behaviors, neuroinflammation, and neural activation. This is the first study to demonstrate cognitive-associated behavioral deficits with neuroinflammation in the mitoNEET knockout mouse model.
Yen Ying Lim, Andrea Mills, Maya Norfolk, Emily Rosenich, Paul Maruff
Factors influencing rates of unsupervised assessment of short-term learning in cognitively unimpaired adults
Abstract: Background: In older adults with preclinical Alzheimer’s disease (AD), learning curves derived from validated psychological learning paradigms are reduced to an extent greater than impairment, or decline, on neuropsychological memory tests. Objective: This study aimed to examine how age, sex, education, mood, and general dementia risk, which also increases risk for preclinical AD, could influence learning curves. Methods: 1050 adults enrolled in the BetterBrains trial completed 10 blocks of ORCA-LLT learning trials over 5 days. Learning curves were derived from improvement in accuracy over trials. Participants also completed questionnaires of demography and mood, and the CAIDE risk score was computed for each participant. Results: Most participants (67%) completed ≥6 blocks of ORCA-LLT. Older age (d=0.75), lower education (d=0.50), and higher dementia risk (d=0.36) were associated significantly with slower learning rates. Conclusions: In older adults, learning curves are influenced subtly by age, education, and dementia risk but not by sex or mood.
Iman Jahani, Ali Jahani, Mehdi Delrobaei, Ali Khadem, Bradley J MacIntosh ( Handling Associate Editor: Ralph Buchert)
Classifying cognitive impairment based on FDG-PET and combined T1-MRI and rs-fMRI: An ADNI study
Abstract: Background: Mild cognitive impairment (MCI) refers to a memory impairment among non-demented adults. It is a condition that increases the risk of dementia, notably due to Alzheimer's disease (AD). MCI is heterogeneous and there is a need for novel diagnostic approaches. Fluorodeoxyglucose positron emission tomography (FDG-PET) imaging provides robust AD biomarker characteristics, while anatomical and functional magnetic resonance imaging (MRI) offer complementary information. Objective: Classify MCI and cognitively normal (CN) adults using FDG-PET images; predict individuals with MCI that convert to AD dementia; determine if MRI can achieve comparable performance to FDG-PET classification. Methods: Four ADNI cohorts were created. Cohort 1: 805 participants (MCI n=455; CN n=350) that underwent FDG-PET. FDG-PET images were inputs to a one-channel 3-dimensional (3D) DenseNet deep learning model. Cohort 2: 348 participants (MCI n=174; CN n=174) with MRI and functional MRI. Cohort 3: overlapping cases from cohorts 1 and 2 (MCI n=70; CN n=70). Cohort 4: 336 participants (MCI-converters n=168; MCI-stable n=168) with FDG-PET from cohort 1. The one/two-channel models’ inputs were T1-weighted MRI and/or amplitude of low-frequency fluctuations images, with classification metrics evaluated through 10-fold cross-validation. Results: The FDG-PET model achieved 88.02%±3.82 accuracy for MCI versus CN classification, with 88.70%±4.70 sensitivity and 87.14%±5.03 specificity. Neither MRI model outperformed the FDG-PET model, as the highest MRI-based accuracy was 76.86%±1.95. The FDG-PET model achieved 63.23%±4.68 accuracy in classifying MCI-converters versus MCI-stable. Conclusions: FDG-PET images produced the highest accuracy in classifying MCI versus CN. While MRI-based approaches were inferior to FDG-PET, multi-contrast MRI still offers value for neurodegeneration classification.
Nancy E Ruiz-Uribe, Paul Manser, Brandon Butcher, Yihao Li, Mira Blendstrup, Suzanne Baker, Sandra Sanabria Bohorquez, Edmond Teng
Cross-sectional and prognostic associations of baseline [18F]GTP1 tau PET signal and white matter lesion volumes for cognitive and functional decline in prodromal-to-mild Alzheimer’s disease
Abstract: Background: In Alzheimer’s disease (AD), tau and white matter lesion pathology are associated with clinical severity and subsequent decline, but their relative relationships with clinical assessments remain uncertain. Objective: To examine cross-sectional and prognostic associations between baseline [18F]GTP1 tau positron emission tomography (PET) standardized uptake value ratio (SUVRs) and T1 white matter hypointensity (WMHypo) volumes with clinical indices. Methods: We analyzed participants with biomarker-confirmed prodromal (n=127) or mild (n=233) AD with baseline [18F]GTP1 tau PET and MRI and longitudinal Clinical Dementia Rating-Sum of Boxes (CDR-SB), 13-item version of the Alzheimer’s Disease Assessment Scale-Cognitive Subscale (ADAS-Cog13), Repeatable Battery for the Assessment of Neuropsychological Status (RBANS), Mini-Mental Status Examination (MMSE), and Alzheimer’s Disease Cooperative Study-Activities of Daily Living (ADCS-ADL) data. Results: Higher baseline [18F]GTP1 SUVRs were independently associated with poorer baseline performance and faster rates of subsequent decline on all five clinical outcome measures. Higher baseline WMHypo volumes were independently associated with poorer baseline performance on the CDR-SB, ADAS-Cog13, RBANS, and MMSE and faster rates of subsequent decline on the CDR-SB and ADCS-ADL. Conclusions: The independent associations of tau and white matter lesion pathology with clinical decline in AD suggest future prognostic models should include both imaging modalities.
Lingfeng Xu, Kewei Chen, Kimberly D Mueller, Julie Liss, Visar Berisha
Articulatory precision from connected speech as a marker of cognitive decline in Alzheimer’s disease risk-enriched cohorts
Abstract: Background: Mild cognitive impairment (MCI) has been recognized as a possible precursor to Alzheimer’s disease (AD). Recent research focusing on connected speech has uncovered various features strongly correlated with MCI due to AD and related dementias. Despite these advancements, the impact of early cognitive decline on articulatory precision has not been thoroughly investigated. Objective: This study introduced the phoneme log-likelihood ratio (PLLR) to assess the articulatory precision of speakers across different cognitive status levels and compared its effectiveness to existing well-studied acoustic features. Methods: The study utilized speech recordings from a picture description task, which included data from 324 cognitively unimpaired participants with low amyloid-β burden (CU, Aβ(-)), 47 cognitively unimpaired participants with high amyloid-β burden (CU, Aβ(+)), 69 participants with MCI, and 20 participants with dementia. Nine acoustic features were extracted from the speech recordings, covering three categories: speech fluency, speech pace, and articulatory precision. Welch’s t-test and Hedge’s g were adopted to assess their discriminative ability. Results: A reduction in speech fluency and pace was observed among participants in the MCI and dementia groups. The PLLR shows large effect sizes in distinguishing between cognitively unimpaired participants with low Aβ burden and those diagnosed with MCI or dementia. Additionally, the test-retest reliability experiment indicated moderate repeatability of the features under study. Conclusions: The study reveals PLLR as a sensitive indicator capable of detecting subtle articulatory variations across groups, while also providing further support for the association between reduced articulatory precision and early cognitive decline.
Pei Zhang, Yan Liu, Xin Jin, Zhaoliang Hu, Jucui Yang, Haotian Lu, Taijun Hang, Min Song (Handling Associate Editor: Xianwen Li)
Alzheimer’s disease-like pathology induced by Porphyromonas gingivalis in middle-aged mice is mediated by NLRP3 inflammasome via the microbiota-gut-brain axis
Abstract: Background: Porphyromonas gingivalis (P. gingivalis) has been found to enter the brain and induce inflammation, contributing to Alzheimer’s disease (AD). P. gingivalis is also closely linked to gut dysbiosis. However, does P. gingivalis induce AD-like pathology through the microbiota-gut-brain axis? There is limited literature on this topic. Objective: To determine the precise causal link among P. gingivalis, intestinal inflammation, and AD-related pathology. Methods: 12- to 13-month-old female C57BL/6J mice were subjected to ligature placement and oral administration of P. gingivalis over a 24-week period. Then, cognitive performance was evaluated with behavioral tests, while AD neuropathological changes, neuroinflammation, and intestinal inflammation were assessed through qPCR, immunofluorescence, and western blot, and gut microbiota was analyzed by 16S rRNA. Results: Mice exposed to P. gingivalis showed impaired behavior in Open field test, Novel object recognition, and Y-maze tests. The bacterium infiltrated their brains, increasing Aβ42, AβPP, and Aβ fragments, promoting tau phosphorylation and microglial activation, and reducing levels of ZO-1, PSD95, SYP, and NeuN proteins. Inflammatory factors like NLRP3, caspase-1, IL-1β, IL-6, and TNF-α were elevated in both brains and intestine, while ZO-1 and occludin levels decreased in intestine. P. gingivalis also altered gut microbial compositions. Conclusions: P. gingivalis induced gut dysbiosis and activated the NLRP3 inflammasome in the intestine and brains of mice. This led to impairment of both the intestinal and brain-blood barriers, triggering neuroinflammation and promoting the progression of AD. These findings highlight the critical role of NLRP3 inflammasome activation in the microbiota-gut-brain axis in the AD-like pathology induced by P. gingivalis.
Deborah A Levine, Jeremy B Sussman, Rodney A Hayward, Andrzej T Gałecki, Rachael T Whitney, Emily M Briceño, Alden L Gross, Bruno J Giordani, Mitchell SV Elkind, Rebecca F Gottesman, Darrell J Gaskin, Stephen Sidney, Kristine Yaffe, James F Burke
The potential impact of optimal blood pressure treatment intensity to reduce disparities in dementia between black and white individuals
Abstract: Background: Black adults have higher dementia risk than White adults. Whether tighter population-level blood pressure (BP) control reduces this disparity is unknown. Objective: Estimate the impact of optimal BP treatment intensity on racial disparities in dementia. Methods: A microsimulation study of US adults ≥18 across a life-time policy-planning horizon. BP treatment strategies were the Systolic Blood Pressure Intervention Trial (SPRINT) protocol, the Eighth Joint National Committee (JNC-8) recommendations, and usual care (non-intervention control). Outcomes were all-cause dementia, atherosclerotic cardiovascular disease (ASCVD), stroke, myocardial infarction, non-ASCVD death, global cognitive performance, and optimal brain health (being free of dementia, cognitive impairment, or stroke). Population-level and individual-level effects stratified by race were estimated. Results: Optimal population-level implementation of a SPRINT-based BP treatment strategy, compared to usual care, would increase average annual dementia incidence in White, but not Black, adults (1% versus 0%), due to hypertensive individuals’ greater survival, and reduce annual ASCVD events more in Black than White adults (13% versus 5%). Under a SPRINT-based strategy, individuals with hypertension gained more years lived without dementia, ASCVD, myocardial infarction, or stroke and more years lived in optimal brain health. A SPRINT-based strategy did not attenuate individual-level race disparities in outcomes, except stroke. Due to longer life expectancy, a SPRINT-based strategy did not substantially reduce lifetime dementia risk in either group. The JNC-8-based strategy had similar but smaller effects as the SPRINT-based strategy. Conclusions: Our results suggest that tighter population-level BP control would not reduce population-level disparities in dementia between US Black and White adults.
Akihiro Koreki, Shoko Nozaki, Ryo Shikimoto, Shoichiro Tsugane, Masaru Mimura, Norie Sawada
A longitudinal cohort study demonstrating the beneficial effect of moderate consumption of green tea and coffee on the prevention of dementia: The JPHC Saku Mental Health Study
Abstract: Background: While the preventive effects of green tea and coffee on cognitive decline have been demonstrated, their long-term effects on cognition remain unclear. Objective: This study aims to investigate the effect of green tea and coffee consumption in middle age on the prevention of dementia. Methods: This population-based cohort study included 1155 participants (aged 44-66 in 1995). Participants’ consumption of green tea and coffee was assessed using questionnaires in 1995 and 2000. Their cognitive levels were neuropsychologically evaluated in 2014-2015. Logistic regression analyses were conducted with significant cognitive decline (defined as multi-domain cognitive decline and more severe conditions) as the dependent variable. Stratified analyses were also conducted by sex and age. Results: Individuals who consumed 2-3 cups of green tea daily had a significantly reduced risk of cognitive decline (OR = 0.56, 95%CI: 0.35-0.91) after adjusting potential confounders. However, this effect was not significant with consumption of 4 or more cups. This protective effect was particularly observed in males (OR = 0.38, 95%CI: 0.19-0.76). A significant risk reduction was also observed in individuals consuming one or more cups of coffee daily (OR = 0.54, 95%CI: 0.34-0.84) in the older subjects (median age [53 years old] and older in 1995) in the same fully adjusted model, but not in the entire sample. Conclusions: Our findings suggest that moderate green tea consumption in midlife may have a beneficial effect on preventing dementia, particularly in males. The effects of coffee consumption may be more advantageous for older individuals.
Mercè Boada, Anuja Neve, Bibha Das, Jakub Wojtowicz, Zhiyue Huang, Szofia Bullain, Michelle Watkin, Dominik Lott, Tobias Bittner, Paul Delmar, Gregory Klein, Carsten Hofmann, Geoffrey A Kerchner, Janice Smith, Monika Baudler, Paulo Fontoura, Rachelle S Doody
Long-term safety of gantenerumab in participants with Alzheimer’s disease: A phase III, open-label extension study (SCarlet RoAD)
Abstract: Background: Gantenerumab is a fully human anti-amyloid-β (Aβ) immunoglobulin G1 monoclonal antibody for subcutaneous (SC) administration. The efficacy and safety of low-dose (105 mg or 225 mg) gantenerumab were investigated in SCarlet RoAD (SR; NCT01224106), a Phase III, double-blind (DB), placebo-controlled study in participants with prodromal Alzheimer’s disease. Following a pre-planned futility analysis, SR was converted into an open-label extension (OLE) study. Objective: To assess the long-term safety and tolerability of SC gantenerumab at doses of up to 1200 mg every 4 weeks (Q4W) in OLE participants who previously received placebo or gantenerumab in the DB part of SR. Methods: Participants of the DB part of SR, who met the eligibility criteria for the OLE, were offered the opportunity to receive gantenerumab up-titrated to 1200 mg Q4W according to prespecified titration regimens. Safety and tolerability were assessed using magnetic resonance imaging (MRI), physical and neurologic examinations, and adverse event monitoring. Results: Overall, 154 participants were rolled over from the DB part of SR and received at least one dose of gantenerumab in the SR OLE. The median duration of treatment was 2.9 years (152.9 weeks). Forty-seven (30.5%) participants had an amyloid-related imaging abnormalities – edema (ARIA-E) MRI finding, and 51 (33.1%) had an ARIA – hemorrhage MRI finding. Most ARIA-E findings were asymptomatic and manageable by MRI monitoring and dose intervention. There were no unexpected safety findings. Conclusions: SC gantenerumab at doses of up to 1200 mg Q4W was well tolerated with no unexpected safety findings in participants with prodromal Alzheimer’s disease.
Dennis M Hedderich, Roland Opfer, Julia Krüger, Lothar Spies, Igor Yakushev, Ralph Buchert
Clinical validation of artificial intelligence-based single-subject morphometry without normative reference database
Abstract: Background: Single-subject voxel-based morphometry (VBM) is a powerful technique for reader-independent detection of brain atrophy in structural magnetic resonance imaging (MRI) to support the (differential) diagnosis and staging of neurodegenerative diseases in individual patients. However, VBM is sensitive to the MRI scanner platform and details of the acquisition sequence. To mitigate this limitation, we recently proposed and technically validated a convolutional neural network (CNN)-based VBM which does not rely on a normative reference database. Objective: Clinical validation of CNN-based VBM. Methods: CNN-based VBM was compared with conventional VBM based on a mixed-scanner normative database in 227 consecutive patients (66.0±9.6 years, 53.3% female) with suspected dementing neurodegenerative disease. VBM maps were interpreted visually by two experienced readers, first with respect to the presence of any neurodegenerative disease, then for the differentiation between Alzheimer’s disease (AD)-typical and non-AD atrophy patterns. A Likert 6-score was used for both tasks. Simultaneously acquired positron emission tomography (PET) with 18F-fluorodeoxyglucose (FDG) served as reference standard. Results: Repeated-measures ANOVA revealed a significant impact of the VBM method on the visual detection of any neurodegenerative disease (p<0.001). Balanced accuracy/sensitivity/specificity were 80.4/86.3/74.5% for CNN-based VBM versus 75.7/79.5/71.8% for conventional VBM. Differentiation between AD and non-AD typical atrophy patterns did not differ between both VBM methods (p=0.871). Conclusions: CNN-based VBM provides clinically useful accuracy for the detection of neurodegeneration-suspect atrophy with higher sensitivity than conventional VBM with a mixed-scanner normative reference database and without compromising specificity.
Shari David, Ana S Costa, Christian Hohenfeld, Sandro Romanzetti, Shahram Mirzazade, Jennifer Pahl, Luisa Haberl, Kai M Schneider, Axel Kilders, Thomas Eggermann, Christian Trautwein, Frank Hildebrand, Jörg B Schulz, Kathrin Reetz, Alexa Haeger
Modulating effects of fitness and physical activity on Alzheimer’s disease: Implications from a six-month randomized controlled sports intervention
Abstract: Background: Physical activity and fitness are major targets in Alzheimer’s disease (AD) preventive research. However, current research is heterogeneous and often disregards the relationship between these parameters and disease outcomes. Objective: To assess the effects of physical activity and fitness on AD within the context of a multicomponent sports intervention. Methods: 46 participants with early-stage AD (mean age 70±7 years, 18 women, mean Montreal Cognitive Assessment (MoCA) score 19±5) were included in a six-month randomized controlled trial (Dementia-MOVE), participating in either a multicomponent sports intervention or a control condition with a psychoeducational program. The modulating effect of fitness and physical activity changes on AD outcome parameters such as cognition, function and cerebral brain structure from 3T-MRI were examined using multiple linear regression analyses. Results: An increase in VO2max was associated with assignment to the intervention group (p=0.016), lower baseline fitness (p=0.001), and an increased rate of physical activity (p=0.046). Only in the intervention group, ΔVO2max had a beneficial modulating effect on the MoCA score (p=0.039), the executive functions (p=0.017) and regional brain volumes of the temporal lobe, e.g., the hippocampus (p=0.044). High daily step count was associated with preserved executive functions (p=0.001), and caregivers’ quality of life (p≤0.001) in the overall sample. Conclusions: Our results confirm that multicomponent exercise improves cardiorespiratory fitness in AD, which is associated with advantageous developments in cognitive performance and preservation of brain structure. These findings suggest that especially patients with comparably worse cognition and fitness benefit and should be encouraged for activity engagement.
Andrea M Weinstein, Fang Fang, Chung-Chou H Chang, Ann Cohen, Brian J Lopresti, Charles M Laymon, Neelesh K Nadkarni, Howard J Aizenstein, Victor L Villemagne, M Ilyas Kamboh, C Elizabeth Shaaban, Marissa A Gogniat, Minjie Wu, Thomas K Karikari, Mary Ganguli, Beth E Snitz
Multimodal neuroimaging biomarkers and subtle cognitive decline in a population-based cohort without dementia
Abstract: Background: The relationship between subtle cognitive decline and Alzheimer’s disease (AD) pathology as measured by biomarkers in settings outside of specialty memory clinics is not well characterized. Objective: To investigate how subtle longitudinal cognitive decline relates to neuroimaging biomarkers in individuals drawn from a population-based study in an economically depressed, small-town area in southwestern Pennsylvania, USA. Methods: A subset of participants without dementia (N=115, age 76.53 years ± 6.25) from the Monongahela Youghiogheny Healthy Aging Team (MYHAT) study completed neuroimaging including magnetic resonance imaging (MRI) measures of AD-signature region cortical thickness and white matter hyperintensities (WMH), Pittsburgh compound B (PiB)-positron emission tomography (PET) for amyloid-β (Aβ) deposition, and [18F]AV-1451-PET for tau deposition. Neuropsychological evaluations were completed at multiple timepoints up to 11 years prior to neuroimaging. Aβ positivity was determined using a regional approach. We used linear mixed models to examine neuroimaging biomarker associations with retrospective cognitive slopes in five domains and a global cognitive composite. Results: Among Aβ(+) participants (38%), there were associations between (i) tau Braak III/IV and language decline (p<0.05), (ii) cortical thickness and both memory decline (p<0.001) and global cognitive decline (p<0.01), and (iii) WMH and decline in executive function (p<0.05) and global cognition (p<0.05). Among Aβ(-) participants, there was an association between tau Braak III/IV and decline on tests of attention/psychomotor speed (p<0.05). Conclusions: These findings confirm an Aβ-dependent early AD biomarker pathway, and suggest a possible Aβ-independent, non-AD process underlying subtle cognitive decline in a population-based sample of older adults without dementia.
Xiangjun Zhou, Zhe Wang, Yi Zhu, Shuang Feng, Haijian Wu, Dongliang Zhu, Zheyuan Wu, Qingjun Kao
Effect of serum uric acid to creatinine ratio on cognitive function decline in middle-aged adults: Longitudinal evidence from CHARLS
Abstract: Background: Serum uric acid (SUA) was a predictor of cognitive function. The association of SUA/serum creatinine ratio (Scr), which represents renal function-normalized SUA and cognitive function is unknown. Objective: This study investigated the association of the SUA/Scr with cognitive function and the potential mediation effect of inflammation in the above relationship. Methods: This study used 1–5 waves of data from the China Health and Retirement Longitudinal Study. 3302 participants aged 45–60 years at baseline were included. Among them, 1129 who attended subsequent 2–3 waves were further included for cumulative exposure calculation to the SUA/Scr ratio. The Cox models were used to evaluate the impact of baseline SUA/Scr ratio and its cumulative exposure on cognitive function decline. Results: During a median follow-up of 8.6 years, there were 1512 (45.8%) cognitive function declined. After adjustment, the highest quartile of the SUA/SCr ratio was associated with the highest risk of cognitive function decline (Hazard ratio, 1.175; 95% confidence interval, 1.015–1.360). Restricted cubic spline showed a linear association between the SUA/Scr ratio and the risk of cognitive function decline (pnon-linear= 0.514). There were a stronger association of cumulative SUA/Scr ratio and its exposure burden with cognitive function decline [the highest versus lowest quartile: 1.635 (1.006–2.656), the high versus low group: 1.729 (1.212–2.466), respectively]. No significant mediating effect through white blood cell count or C-reactive protein in SUA/Scr ratio-cognitive function decline was found. Conclusions: The SUA/Scr ratio was associated with a higher risk of cognitive decline, whereas the mechanism mediated by inflammation indicators was not found.
Andrew Aballa, Linda Khakali, Willie Njoroge, Lucy Kamau, Zul Merali, Edna Bosire
“They are perceived to be witches, and some are killed”: Community perceptions of elderly people living with dementia in Kilifi, Kenya
Abstract: Background: The risk of dementia, including the most common form, Alzheimer’s disease, is forecasted to increase in low- and middle-income countries due to longer lifespans and the rising prevalence of non-communicable diseases. However, little research has been conducted on the knowledge and perceptions about dementia in rural communities in Kenya. Objective: To explore the community’s knowledge, attitudes, and perceptions about dementia in Kilifi County, a resource constrained rural coastal area in Kenya. Methods: We conducted an ethnographic study comprising five focused group discussions (n=35, each with 7-8 people) and 25 key informant interviews with various stakeholders from Kilifi County. The interviews and discussions were recorded, transcribed verbatim and thematically analyzed. Results: There was a general lack of knowledge about dementia by community members. People suspected to have dementia were labeled using stigmatizing and derogatory words such as “neurologically deficient”, “crazy”, or “wendawazimu” [mad person]. Dementia was also associated with normal aging. Others associated neurodegenerative behaviors associated with dementia to witchcraft or curses. This led to individuals suspected to have dementia being isolated from the community, neglected, dispossessed assets, killed or denied medical care. Conclusions: Dementia is not well understood in Kilifi County, Kenya. People with dementia are stigmatized, neglected and socially excluded from community. Our results could be leveraged by the Kenyan government, the healthcare system, and communities to develop policies and strategies for protecting elderly people with dementia and improving their care, especially in rural areas.
Roham Hadidchi, Rachel Pakan, Tharun Alamuri, Noel Cercizi, Yousef Al-Ani, Stephen Wang, Sonya Henry, Tim Q Duong (Handling Associate Editor: Karel Kostev)
Long COVID-19 outcomes of patients with pre-existing dementia
Abstract: Background: Although COVID-19 has been linked to worse acute outcomes in patients with some neurodegenerative disorders, its long-term impact on dementia remains unclear. Objective: To investigate the outcomes of COVID-19 survivors with dementia. Methods: This retrospective study evaluated 9,806 patients with dementia in the Montefiore Health System (January 2016 to July 2023). Comparisons were made between dementia patients with and without a positive SARS-CoV-2 polymerase-chain-reaction test who had a follow up at least two weeks post-infection. Outcomes included all-cause mortality, major adverse cardiovascular events (MACE), new-onset dysphagia, dyspnea, fatigue, new-onset sleep disturbances, altered mental status, first-time fall, headache, new-onset depression, and new-onset anxiety. Adjusted hazard ratios (aHR) were computed adjusting for age, sex, race, ethnicity, and pre-existing comorbidities. Results: Dementia patients with COVID-19 were younger, more likely to be male, and had a higher prevalence of major pre-existing comorbidities compared to those without COVID-19. Patients who survived acute COVID-19 were more likely to die than non-COVID controls after adjusting for covariates (aHR=1.65 [1.43, 1.91]). COVID-19 was significantly associated with higher risk of MACE (aHR = 1.58 [1.41, 1.78]), new-onset dysphagia (aHR = 1.64 [1.42, 1.91]), dyspnea (aHR = 1.27 [1.12, 1.44]), fatigue (aHR = 1.42 [1.22, 1.65]), new-onset sleep disturbances (aHR = 1.36 [1.15, 1.60]), altered mental status (aHR = 1.36 [1.16, 1.59]), and first-time fall (aHR = 1.34 [1.09, 1.65]). Conclusions: COVID-19 increases the risk of mortality and other adverse health outcomes in dementia patients. These findings highlight the need for closer follow-up and management strategies for dementia patients post-COVID-19.
Xia Chen, Cong Lin, Chengfen Ha, Kaikai Li, Jianmei Gao, Qihai Gong, Fei Li
Icariin improves learning and memory function by enhancing HRD1-mediated ubiquitination of amyloid precursor protein in APP/PS1 mice
Abstract: Background: One of the hallmark pathological characteristics of Alzheimer’s disease (AD) is amyloid-β (Aβ) accumulated in brain, which is mainly derived from the proteolytic processing of amyloid-β protein precursor (AβPP). The ubiquitin-proteasome system is able to reduce Aβ generation by ubiquitination and degradation of AβPP. Icariin (ICA), a flavonoid isolated from Epimedium brevicornum Maxim., has been reported that it could regulate the metabolism of AβPP and reduce the Aβ level in AD in vivo and in vitro models. Objective: To investigate whether the effect of ICA on AβPP and Aβ is related to AβPP ubiquitination. Methods: We used in vivo and in vitro models to observe the effect of ICA on AβPP ubiquitination as well as to investigate the effect of HMG-CoA reductase degradation protein 1 (HRD1), an E3 ubiquitin-protein ligase, on the processing of AβPP ubiquitination. Results: This study showed that ICA improved the cognitive abilities of APP/PS1 AD mice in Morris Water Maze and Y-maze tests, upregulated HRD1 expression, subsequently elevated the total ubiquitination and K48-linked polyubiquitination of AβPP level, as well as increased AβPP degradation. Moreover, silenced HRD1 gene abolished the aforementioned effects of ICA. Furthermore, ICA decreased the location of AβPP in the early endosome, where AβPP is cleaved into Aβ, evidenced by reducing the co-localization of AβPP and early endosome antigen 1 (EEA1). Conclusions: This study demonstrated that ICA increased AβPP degradation by upregulating HRD1 mediated ubiquitination.
Ryszard Pluta, Janusz Kocki, Jacek Bogucki, Anna Bogucka-Kocka, Stanisław J Czuczwar
Apolipoprotein (APOA1, APOE, CLU) genes expression in the CA3 region of the hippocampus in an ischemic model of Alzheimer’s disease with survival up to 2 years
Abstract: Background: Changes in the Alzheimer’s disease-related apolipoprotein genes expression, occurring parallel with brain ischemia-induced neurodegeneration in the hippocampal CA3 area, may be crucial for the development of memory loss and dementia. Objective: The aim of the study was to investigate changes in genes expression of apolipoprotein A1 (APOA1), apolipoprotein E (APOE), and clusterin (CLU) in CA3 area post-ischemia with survival of 2 years. Methods: The gene expression was evaluated with the use of an RT-PCR protocol after 2, 7, and 30 days and 6, 12, 18, and 24 months post-ischemia. Results: The expression of the APOA1 gene (encoding apolipoprotein A1) was below the control values at 2 days, 6 and 12 months while at 7 and 30 days and 18 and 24 months post-ischemia this gene expression exceeded the control values. In the case of the CLU gene (encoding clusterin) expression, it was above the control values at all times post-ischemia. Similar expression was observed for the APOE gene (encoding apolipoprotein E) except on day 7 after ischemia where its expression was below the control value. Conclusions: The results seem to indicate that the observed changes in the gene expression may reflect the activation and inhibition of a variety of processes involved in ischemia-induced neurodegeneration. The enhanced expression of APOA1 and CLU genes may be associated with induction of neuroprotective mechanisms while increased expression of the APOE gene may produce detrimental effects.
