Regional growth rates of white matter hyperintensities are associated with beta-amyloid burden.

Internet-based recruitment holds promise for Alzheimer's disease (AD) research, but its effectiveness for engaging rural older adults with cognitive concerns remains unclear. This review synthesized existing literature on internet-based recruitment for AD research targeting rural-dwelling older adults. After searching PubMed, CINAHL, Embase, and Web of Science, 670 non-duplicate records were screened, and only one eligible study was identified. The top two reasons for exclusion were internet-based recruitment was not used or rural recruitment outcomes were not measured. Despite the expansion of digital recruitment in AD research, rural populations remain overlooked, a critical gap given their disproportionate barriers to research participation.

With the prevalence of Alzheimer's disease and related dementias (ADRD) rising, prevention and treatment clinical trials are increasingly important. Yet inadequate participant recruitment to ADRD research-a leading cause of trial delays, suspensions, or discontinuations-continues to hinder innovation and increase costs. This literature review aimed to identify ADRD recruitment strategies that are effective and ineffective, based on quantitative outcomes, with the goal of optimizing recruitment and advancing recruitment science. PubMed, Google Scholar, relevant ADRD websites, and references were searched for studies meeting inclusion criteria-those reporting quantitative outcomes aimed at improving recruitment rates, timely recruitment, or representation. Reference lists from relevant systematic reviews and meta-analyses, including publications from leading researchers, were also examined. The Mixed Methods Appraisal Tool (MMAT) was used to assess evidence quality. The search yielded 965 publications, of which 50 met inclusion criteria. Few studies reported recruitment methods for pharmacological trials, and many lacked sufficient detail or standardized reporting to assess quality using MMAT criteria, making it difficult to determine effectiveness. Recruitment efforts deemed successful by study authors often relied on multi-pronged approaches integrating community engagement, structured outreach, and digital tools. However, evidence for effective and scalable strategies remains limited. Advancing ADRD recruitment science requires progress in two key areas: embedding recruitment evaluation directly into trial protocols and encouraging broader sharing of recruitment data. Routine practices, such as publishing recruitment outcomes and adopting standardized reporting, can help close the evidence gap. These approaches enable comparison, replication, and generalizability of effective strategies, ultimately accelerating progress in ADRD research.

<p> Olfactory Dysfunction (OD) is a prevalent yet underdiagnosed sensory disorder with profound implications for quality of life and for the early detection of neurodegenerative diseases such as Parkinson's and Alzheimer's. Beyond its sensory role, OD has emerged as an early, noninvasive biomarker of neurodegenerative pathology, often preceding measurable cognitive decline in Alzheimer's Disease (AD) and Mild Cognitive Impairment (MCI). Quantitative smell loss correlates with pathological changes in the olfactory bulb and entorhinal cortex, highlighting its diagnostic potential for early screening and longitudinal monitoring. </p><p> Traditional diagnostic tools, though validated, often require specialized personnel, laboratory infrastructure, and extended testing time, limiting accessibility. This review critically examines recent innovations in the detection of olfactory dysfunction, focusing on portable, user-friendly smell test kits and their comparative performance with self-reported tools such as the Mini Olfactory Questionnaire (Self-MOQ) and 4-CAST. We synthesize evidence on diagnostic reliability, usability, and cultural adaptability, evaluating how these methods align with emerging needs in Alzheimer's and dementia research. </p><p> Portable kits such as PT-Smell and SSomix demonstrate high diagnostic precision and cultural adaptability, while self-administered and self-report tools enable scalable deployment in memory clinics and community screening programs. Within Alzheimer's research, these approaches present practical solutions for early identification of sensory biomarkers linked to cognitive decline. </p><p> To optimize diagnostic integration, a two-step framework is proposed: first-line screening with self-administered tools such as Self-MOQ or 4-CAST, followed by confirmatory psychophysical testing with portable kits such as PT-Smell or SSomix. This tiered model supports early AD and MCI detection, enhances accessibility, and promotes digital health integration for widespread olfactory monitoring. </p>.

Machine learning enables scalable quantification of neuropathology, offering deeper phenotyping of Alzheimer's disease (AD). In this validation study, we quantified amyloid-beta (Aβ) deposits, evaluating multiple brain regions across institutions, and evaluated associations with clinical, demographic, and genetic factors in persons pathologically diagnosed with AD. All linear models were adjusted for sex, age of death, ethnicity, and center. We analyzed densities (#/mm2) of cored plaques, diffuse plaques, and cerebral amyloid angiopathy (CAA) in 273 individuals from 3 Alzheimer's Disease Research Centers. Formalin-fixed paraffin-embedded sections of frontal, temporal, and parietal cortices were immunostained and digitized, generating 799 whole-slide images (WSIs). Following log transformation, mixed-effects modeling revealed the parietal cortex had the highest cored plaque densities (P < .001); the temporal cortex had the highest diffuse plaque (P < .001); CAA showed no regional differences. Wilcoxon rank-sum test, and covariates adjusted linear models showed ApoE ε4- status was associated with higher cored plaque densities in the temporal lobe (P = .04). ApoE ε4+ status was associated with diffuse plaques in the temporal lobe (P = .001), and CAA in the frontal lobe (P = .004). These findings provide further validation and provide exploratory associations advancing deeper phenotyping of AD.

Oligodendrocyte dysfunction in alzheimer's disease: Integrating spatial epigenomics and metabolic circuitry in demyelination - A critical review.

Elucidating the molecular targets in Alzheimer's disease: Advances and therapeutic implications.

Advances in molecular-level research proposed the Amyloid-β (Aβ) pathway as a pathophysiological centre of Alzheimer's Disease (AD) progression. The biochemical alterations within the Aβ cycle represent a core biological hallmark of AD and offer promising targets for the development of disease-modifying therapies. However, the precise molecular mechanisms of the Aβ pathway, as well as the spatial and temporal dynamics that drive synaptic dysfunction, neurodegeneration, and the clinical onset of AD, remain active and intensive current research areas. In this work, we provide a comprehensive review and update of the extensive body of research in the field. We analyze data that highlights the differential relationships between various species of Amyloid-β (Aβ) and several biological mechanisms relevant to Alzheimer's Disease (AD), including tau-mediated processes, neuroimmune responses, inflammatory changes, and neurochemical imbalances. This review explores the role of amyloid β, clinical symptoms and mortality, FDA-approved drugs, immunotherapy, and different phytoconstituents used for Aβ-targeting therapy. Phytochemicals show potential in Alzheimer's disease treatment through their antioxidant, anti-inflammatory, and anti-amyloid properties, but challenges with bioavailability and blood-brain barrier permeability remain significant obstacles to their clinical effectiveness.

A cross-consortium, stakeholder-driven model for implementing a modern electronic data capture and submission system across the Alzheimer's Disease Research Centers Program.

Integrating real-world data with gold-standard longitudinal clinical and genomic data to advance precision medicine for the Alzheimer's Disease Research Center Program and beyond: a proof-of-concept data platform.

Residential segregation of Black and Latinx older adults and brain imaging outcomes.

Alzheimer's disease pathology (ADP) and Lewy body pathology (LBP) are traditionally associated with distinct cognitive profiles. However, growing evidence highlights the role of behavioral and psychological symptoms of dementia (BPSD) in shaping clinical presentations. The combined influence of cognitive and behavioral symptoms across neuropathologically confirmed ADP, LBP, and mixed AD-LBP has not been systematically examined. This study aimed to identify clinically meaningful subtypes by jointly analyzing cognitive performance and BPSD profiles in individuals with autopsy-confirmed dementia pathology. This retrospective longitudinal cohort study used data from the National Alzheimer Coordinating Center (NACC), collected across multiple U.S. Alzheimer's Disease Research Centers. Participants had a Clinical Dementia Rating (CDR) Global score ≤1 at baseline and autopsy-confirmed ADP, LBP, or mixed AD-LBP. Cognitive outcomes included standardized tests of memory, executive function, and language. BPSD were assessed using the Neuropsychiatric Inventory Questionnaire (NPI-Q), which captures ten symptom domains: agitation, apathy, depression, delusions, disinhibition, auditory and visual hallucinations, irritability, personality change, and REM sleep behavior disorder. Cluster analysis was applied to identify subtypes based on combined cognitive and BPSD data. The study included 1,028 participants (mean age at baseline 76.4 years; 47.6% female): 521 with ADP, 96 with LBP, and 411 with mixed AD-LBP. A three-cluster clinical subtype (CS) solution best fit the data. The most symptomatic group (CS-3) had the youngest age at first visit (mean 72.1 years), the highest BPSD burden, and the fastest cognitive and functional decline across ADP and AD-LBP groups. CS-1 and CS-2 exhibited milder early cognitive impairment and lower BPSD burden. Within ADP and AD-LBP, CS-2 showed slower progression than CS-1, fewer APOE ε4 carriers (41% vs. 58%), and better memory scores, despite reporting a higher frequency of agitation. These findings reveal distinct clinical subtypes that cut across traditional pathological boundaries, emphasizing the need to incorporate both cognitive and behavioral features into early dementia characterization. This multidimensional approach can improve guide personalized prognosis and care planning and enhance clinical trial design by considering disease heterogeneity. The study supports integrated clinical profiling as important factor in robust evaluation of dementia outcomes.

APOE-mediated sex differences in microvascular pathology and AD-associated proteinopathies in the medial temporal lobe.

The emergence of Alzheimer's disease (AD) pathology has been the focus of multiple hypotheses, with amyloid β (Aβ) playing a central role due to its presence in both familial and sporadic AD. Therefore, a crucial aspect of AD research is understanding the generation of different Aβ species. Aβ peptides result from the proteolytic processing of Amyloid Precursor Protein (APP) by β- and γ-secretases, with BACE1 being the most prominent β-secretase. However, BACE1-overexpressing mouse models exhibit disadvantages, making them limited for AD research. Importantly, N-terminally truncated Aβ species, which constitute up to 70% of Aβ in AD brains, are not generated by BACE1. In recent years, alternative proteases capable of cleaving APP have been identified, bridging the gap between N-terminally truncated Aβ species and BACE1-derived Aβ. Among these novel players, the metalloprotease meprin β has emerged as a risk factor in AD pathology, generating both N-terminally truncated and full-length Aβ species. Our primary objective was to develop a mouse model that more accurately resembles the pathology of AD beyond BACE1-overexpressing models, while simultaneously confirming APP cleavage of meprin β in the hippocampus and cerebral cortex. Overexpression of meprin β led to a marked increase in soluble Aβ levels, particularly in the hippocampus, indicating a higher vulnerability or elevated meprin β activity in this region compared to the cerebral cortex. Notably, this biochemical change occurred without any observable behavioral deficits, suggesting a region-specific role of meprin β in AD pathology that may extend beyond immediate functional impairment.

Bibliometric analysis of neuroinflammation in Alzheimer's Disease: Insights from APP/PS1 mouse model research in the past two decades.

From cradle to cortex: An exposome- and equity-centered perspective of neurocognitive aging and dementia risk in the era of climate change.

Alzheimer disease (AD) and its related disorders (ADRDs) are characterized by a high frequency of copathologies. We aimed to determine the specificity of plasma pTau217, glial fibrillary acidic protein (GFAP), and neurofilament light chain (NfL) for AD neuropathological change (ADNC) in the presence of common ADRD copathologies. pTau217, GFAP, and NfL were measured using S-PLEX immunoassays from Meso Scale Discovery in banked plasma samples from 2 groups of participants in the Massachusetts Alzheimer's Disease Research Center (MADRC) Longitudinal Cohort study: (1) participants spanning the cognitive spectrum, who underwent brain autopsy, and blood collection within 6 years before death, and (2) participants with normal cognition and no neurologic diagnosis during 5 years of follow-up, but no autopsy data (normal controls [NCs]). Cross-sectional associations between biomarker levels and ADNC, primary neuropathologic diagnosis (NPDx1), and presence of non-AD copathologies were evaluated using linear regression models controlling for age, sex, and time to death. One hundred eighty-seven participants with brain autopsy (NPDx1: AD n = 85; other n = 102; mean age: 74.3 years, 38.5% female; interval blood collection-death [mean ± SD]: 2.8 ± 1.6 years) and 67 NC without brain autopsy (mean age: 66.5 years, 71.6% female) were included. pTau217, but not GFAP, levels increased stepwise with increasing Thal phases (β = 0.61; 95% CI [0.24-0.97] to β = 0.91 [0.55-1.27]) and Braak stages (β = 0.59; [0.16-1.01] to β = 0.74 [0.33-1.15]). Although 23% of individuals with a non-AD NPDx1 had increased pTau217 levels using a cutoff defined by the contrast between ADNC and NC, the majority (62%) had intermediate/high ADNC copathology and the remaining pTau217+ individuals had borderline increased levels. By contrast, 48% of individuals without ADNC had increased GFAP levels. pTau217 and GFAP were not different in the presence or absence of cerebral amyloid angiopathy, α-synuclein or TDP-43 proteinopathies, or primary tauopathies. NfL was not specifically associated with ADNC. Plasma pTau217, but not GFAP or NfL, levels accurately reflect the presence of ADNC in the brain even in individuals with an NPDx1 of a non-AD dementia. Thus, a positive plasma pTau217 test in an individual with a suspected non-AD dementia should not necessarily be considered a misdiagnosis of the presumed non-AD dementia or as a false positive, but rather as evidence of ADNC copathology.

Based on their ability to analyze methylation differences genome-wide in a large number of samples at a reasonable cost and time, microarrays were rapidly adopted by Alzheimer's disease (AD) researchers to isolate CpG sites with methylation levels that were changed in the blood of AD patients. However, concerns gradually arose about the reproducibility of these methylation markers. I attribute the cause to the lack of confirmation of methylation changes detected by DNA methylation arrays. Only by simply plotting an individual's methylation distribution can some false methylation differences be avoided. Furthermore, we may need to set a realistic, minimum threshold for methylation changes for clinical purposes. The prospect of using DNA methylation as a diagnostic marker for AD may be compromised by the increasing number of irreproducible markers. Therefore, establishing minimum guidelines for the search and presentation of AD-associated methylation markers is necessary when publishing. Some empirically useful guidelines are outlined in this Perspective, and applications for diagnosing AD using reliable methylation markers are also presented. One of the most desired applications of methylation markers will be to identify individuals whose cognitive abilities decline before memory problems appear, a task that has not yet been accomplished with protein markers or imaging.

Abnormal synaptic plasticity is an early pathological feature of Alzheimer disease (AD). Synaptic damage and dysfunction initiate neuronal degeneration and death, ultimately leading to cognitive impairment. Traditional Chinese medicine (TCM) can effectively ameliorate cognitive dysfunction through multitarget regulation of synaptic plasticity. This review summarizes the mechanisms by which TCM, including active components, single herbs, and classical formulas, modulates synaptic plasticity, offering new insights for future research and clinical applications. Relevant experimental studies published between 2020 and 2024 were retrieved from major databases, including China National Knowledge Infrastructure, the National Science and Technology Library, Wanfang Data, Elsevier, ScienceDirect, PubMed, SpringerLink, and Web of Science. Network pharmacology and bioinformatics approaches were used to predict the therapeutic effects and mechanisms of TCM on AD-related synaptic plasticity. In total, 15 TCM single herbs and 11 TCM formulas were identified as enhancing AD-related synaptic plasticity. Additionally, 15 active ingredients targeting synaptic plasticity in AD were retrieved from TCM databases over the past decade. This review provides novel perspectives and strategic directions for future AD research and therapeutic development.

GSK-3β has been a key target in Alzheimer's disease (AD) research for over two decades. To identify novel GSK-3β inhibitors, 333 compounds from the National Cancer Institute (NCI) database were screened using a validated ligand-based pharmacophore model with four essential features (two hydrogen bond acceptors, one hydrophobic, and one aromatic ring). After tapering screening with refined boundaries, two top compounds (NSC 275 and NSC 3198) were identified. Molecular docking and simulation studies confirmed their strong binding affinity to GSK-3β. ELISA analysis revealed that their half maximal inhibitory concentration (IC50) values were comparable to the standard GSK-3β inhibitor, CHIR99021. Subsequent in-vivo studies assessed the efficacy of these chemical entities in tested mouse model. Acute toxicity studies demonstrated no observed adverse effect level (NOAEL). Whereas behavioral tests, using the Morris water maze, the tested compounds (5mg/kg and 10mg/kg) exhibited cognitive improvements comparable to those of the donepezil group (1mg/kg), an approved AD treatment. Further analysis of oxidative stress, histopathology, and immune responses in the hippocampus (CA1) indicated that the NSC 275 and NSC 3198 reversed cognitive deficits similarly to the donepezil treated group. The results suggested that combination of in-silico, in-vitro, and in-vivo approaches demonstrates the potential of NSC 275 and NSC 3198 as promising GSK-3β inhibitors for AD treatment.