Nutritional deficiency and poor sleep quality are well-established independent risk factors for cognitive decline. However, few studies have examined their combined effects on cognitive decline. This study evaluated the synergistic association between nutritional deficiency, poor sleep quality, and cognitive decline in Chinese older adults aged 65 years and above. Data from 10,152 participants were analyzed. Univariate and multivariate logistic regression analyses were conducted to determine the relationship between nutritional deficiency, poor sleep quality, and cognitive decline. Interactive effects were evaluated using the relative excess risk due to interaction (RERI), attributable proportion due to interaction (AP), and synergy index (S). The prevalence of cognitive decline was 13.02%. Multivariate analysis revealed that the odds ratios (ORs) for cognitive decline associated with nutritional deficiency and poor sleep quality were 3.587 (95% confidence interval [CI]: 3.125-4.118) and 1.174 (95% CI: 1.024-1.347), respectively. A significant synergistic interactive effect on cognitive decline was observed, with RERI (95% CI) = 1.037 (0.079-1.995), AP (95% CI) = 0.231 (0.052-0.411), and S (95% CI) = 1.424 (1.041-1.949). In the sex-stratified analysis, after full adjustment, the significant association between poor sleep quality and cognitive decline remained in women, but not in men (OR = 1.139, 95% CI: 0.917-1.415). Conversely, the significant additive interactive effects were only observed in men. Among the elderly Chinese population, nutritional deficiency and poor sleep quality are independently associated with cognitive decline, and these two variables demonstrate a synergistic effect. These findings underscore the necessity of implementing integrated interventions that simultaneously address both nutritional and sleep-related factors in this population.

BackgroundSocial isolation is a key modifiable risk factor for cognitive decline, yet its mediating mechanisms are not fully understood.ObjectiveThis study examines depression and systemic inflammation (neutrophil-to-lymphocyte ratio, NLR) as mediators between social isolation and domain-specific cognitive impairments.MethodsUsing cross-sectional data from 1272 adults aged ≥60 (NHANES 2011-2014), we constructed a social isolation index (0-4) incorporating marital status, living arrangements, functional limitations, and social participation barriers. Cognition was assessed via Alzheimer's Disease Word Learning Test (CERAD-WL) (verbal memory), Animal Fluency (executive function), Digit Symbol Substitution Test (processing speed), and composite Z-scores. Mediation analyses with PHQ-9 depression scores and NLR controlled for sociodemographic, lifestyle, and clinical factors.ResultsSevere social isolation (score = 3) showed dose-response associations with cognitive impairment, particularly in processing speed (DSST β = -11.66, p < 0.01) and global cognition (Z-score β = -0.59, p < 0.01). Depression accounted for about 14.5-20.3% of the association with executive function and processing speed, and NLR explained 25.4% of verbal memory problems. Significant direct effects persisted post-mediation (e.g., CERAD-WL β = -0.519; DSST β = -2.374, p < 0.001), suggesting unmeasured pathways.ConclusionsSocial isolation was associated with cognition through tripartite mechanisms: depression-linked processing speed/executive dysfunction, inflammation-mediated verbal memory decline, and direct neurobiological effects. Integrated interventions targeting social connectivity and depression are clinically prioritized over anti-inflammatory strategies. Findings emphasize domain-specific vulnerabilities requiring precision approaches for isolated older adults.

It is unclear whether Alzheimer disease pathology drives cognitive decline in Parkinson disease (PD) patients carrying GBA1 variants. We evaluated levels of serum phosphorylated tau 217 (p-tau217) in samples from 29 GBA1-PD, 32 idiopathic PD, 20 non-manifesting GBA1 variant carriers (GBA1-NMC) and 31 healthy controls. No differences were detected between PD groups. GBA1-NMCs showed higher levels than healthy controls, which correlated to worse cognition and subthreshold parkinsonism. Serum p-tau217 is not a marker of cognitive decline in GBA1-PD. Whether p-tau217 levels in GBA1-NMCs can predict conversion to PD or are a marker of cognitive decline, irrespective of PD, remains unknown.

Abstract Objectives Participant retention is a significant challenge in ageing and dementia research. This analysis investigated (a) factors associated with retention in Insight 46, a neuroscience sub-study of the 1946 British birth cohort, and (b) clinical and cognitive changes over 2.5 years of follow-up. Results Of 502 participants assessed at baseline (mean[SD] age: 70.5[0.7] years), 442 returned for follow-up (mean[SD] interval: 2.5[0.3] years), representing a retention rate of 88%. Being β-amyloid positive (measures using positron emission tomography), female sex, and older age at baseline associated with lower odds of retention, while completion of neuroimaging and better cognitive performance at baseline– particularly on memory testing– related to higher odds of retention. By the time of follow-up, 14 participants were deceased, 12 of whom were female. Over follow-up, improvements were noted in certain cognitive tests (face-name test, logical memory delayed recall) with declines seen in others (mini-mental state examination, digit-symbol substitution test). Increases in self- and informant-reported cognitive complaints, cognitive disorder diagnoses, and motor abnormalities were also observed, alongside declines in blood pressure. These results have implications for the interpretation and generalisability of Insight 46 data and may be relevant to the planning of other longitudinal studies in this field.

Physical exercise is known to delay the cognitive decline in the elderly. However, the effect of low-impact balance exercises such as yoga or Tai chi has not been explored in detail. This cross-sectional observational study used brain magnetic resonance imaging data to quantify and compare various brain structures between neurologically healthy adults aged between 55 and 65, divided into Control Group and Balance Exercise (BE) Group based on the self-reported balance exercise status. Various brain attributes such as brain age, cortical and subcortical volume, thickness, surface area, and mean curvature were extracted and computed using machine learning algorithm software like brainageR and FreeSurfer. Clinical functional assessments (balance, vestibular and cognitive measures) were also conducted for the participants. Statistical analyses were performed to determine any differences between the groups at a significance level of 5%. The BE group showed statistically significantly higher values for the right caudal anterior cingulate thickness, left and right superior temporal volume, left entorhinal volume and mean curvature, left frontal pole thickness, left superior temporal area and left inferior temporal thickness. A statistically significant cluster after correction for multiple comparisons was found in the left rostral middle frontal gyrus with a higher volume for BE group. Clinical functional assessments (balance, vestibular and cognitive) and brain age differences were nonsignificant. The significant brain regions in the BE group are involved in memory, cognition, focus, planning, language and auditory processing, decision making, emotional regulation and mental health and could be responsible for protecting and delaying the cognitive declines in the elderly.

Introduction: There is a high prevalence of vitamin deficiency in our healthy population; however, age-related cognitive decline is an emerging global health concern, especially with an aging population and rising cases of dementia. Many trials have been performed to assess the improvement in cognitive functions of people, especially those of older age, by daily multivitamin supplementation. Studies have shown that daily multivitamin intake significantly improves memory in older adults and reduces the risk of cognitive decline. Methods: A comprehensive search was conducted across PubMed, Embase, and Google Scholar databases from 2003 to 2023. Studies were included based on predefined PICO criteria, focusing on older adults with cognitive decline receiving multivitamin supplementation compared to placebo, with cognitive improvement as the outcome. Nineteen studies meeting the inclusion criteria, comprising randomized trials, reviews, cohort, and cross-sectional designs, were analyzed. Results: The findings reveal mixed outcomes. Multivitamin supplementation was associated with cognitive improvements, particularly in memory, global cognition, and attention, mainly in individuals with baseline deficiencies or mild cognitive impairment. B-complex vitamins and antioxidant-rich formulas showed the most promising effects. However, in well-nourished or healthy populations, results were often neutral. Variability in study design, supplement composition, assessment tools, and duration were key contributors to these inconsistencies. Conclusion: The use of multivitamins shows potential cognitive benefits in specific subgroups, particularly the elderly with nutritional deficiencies or early cognitive decline. However, universal cognitive enhancement cannot be concluded. Personalized, targeted supplementation guided by nutritional status may represent the future of cognitive health strategies.

Cancer-related cognitive impairment (CRCI) is a common and debilitating complication among colorectal cancer survivors, even in those without chemotherapy exposure. To identify cancer-related neural changes, we investigated spontaneous brain activity and cognition in colorectal cancer survivors using cognitive assessments and resting-state functional magnetic resonance imaging (rsfMRI). Nineteen survivors (stages I-II, cancer diagnosis < 12 months, chemotherapy-naïve) and 18 healthy controls underwent a battery of objective/subjective cognitive tests and MRI. RsfMRI data was analyzed with fractional amplitude of low-frequency fluctuations (fALFF) and functional connectivity (FC). Statistical analysis was controlled for age, sex, education, depression, and anxiety, with multiple comparison correction. Compared to controls, survivors performed significantly worse on the Hopkins Verbal Learning Test (HVLT-R) Recognition Discrimination Index (RDI) (p = 0.03) and showed slower psychomotor speed on the Trail Making Test (TMT-A) (p = 0.02). RsfMRI analysis revealed increased fALFF in the right hippocampus and bilateral inferior/middle temporal, parahippocampal, and fusiform gyri, with decreased fALFF in the bilateral superior/middle frontal gyri and left inferior frontal gyrus. RDI was negatively correlated with fALFF in right temporal regions. Survivors also exhibited reduced FC within the default mode network (DMN) (p < 0.05). This cross-sectional study shows that colorectal cancer survivors display hyperactivity in the temporal regions and disrupted DMN connectivity associated with cognitive decline, suggesting a maladaptive neural response. Our study identified the functionally altered brain regions and networks associated with colorectal CRCI using MRI. This would provide potential biological targets for developing interventions such as neuromodulation for mitigating the adverse effects of colorectal CRCI.

Microglia are pivotal regulators of neuroimmune homeostasis in the central nervous system, and their dysregulation is linked to neurodegeneration and brain aging. Among the principal sesame-seed lignans, sesamin has demonstrated robust neuroprotective effects via antioxidant and anti-inflammatory pathways, whereas the neural actions and underlying mechanisms of sesaminol remain undefined. Here, we compared sesaminol with sesamin regarding cognition, neuroinflammation, and microglial polarization in middle-aged mice, and assessed the effects of sesaminol in LPS-challenged mice. In middle-aged mice, sesaminol restored spatial and recognition memory and amplified hippocampal neurotrophic signaling, while sesamin showed only modest benefits. Sesaminol also reversed LPS-induced cognitive deficits in mice. Moreover, sesaminol suppressed oxidative stress and neuroinflammation, and shifted the microglia toward an M2-dominant phenotype, probably in a HIF-1α-dependent manner. Furthermore, sesaminol accelerated Aβ40/42 clearance by upregulating lysosomal functions. Thus, sesaminol restores microglial homeostasis and Aβ clearance to counter chronic and acute cognitive decline and might be one potential antiaging agent.

Predictive models for active suicidal ideation in cognitive decline: identifying risk factors.

Aging is accompanied by a progressive decline in immune function, known as immunosenescence, and by a chronic low-grade inflammatory state, termed inflammaging. Both conditions contribute to increased susceptibility to infections, reduced vaccine responses, and the development of age-related diseases. Emerging evidence suggests that intermittent fasting (IF), a dietary pattern that alternates between periods of fasting and feeding, may influence pathways associated with immune aging across mid-life and older adulthood. This review explores how IF may exert immunoregulatory effects through metabolic remodeling, cellular stress responses, and inflammatory signaling. Preclinical and human studies indicate that IF attenuates pro-inflammatory cytokine production, enhances autophagy, and improves immune cell function, potentially delaying immunosenescence and reducing inflammaging in middle-aged and older populations. Additionally, IF may protect against neuroinflammation and cognitive decline by reducing oxidative stress, activating AMPK-SIRT1 and ketone signaling via β-hydroxybutyrate (BHB), enhancing neuroplasticity, upregulating brain-derived neurotrophic factor, and suppressing pro-inflammatory cytokines, inflammation, and frailty in the aging brain. However, most evidence comes from short- to medium-term studies in selected, relatively healthy populations, with benefits often similar to those of continuous calorie restriction, and there is limited data on long-term safety, adverse effects, and outcomes in frail older adults. By reducing oxidative stress and inflammaging, IF may mitigate frailty in older adults or delay its progression when initiated earlier. By integrating insights from immunometabolism and gerontology, this review highlights the potential role of IF as a non-pharmacological strategy to promote healthy immune aging and support functional outcomes in older adults. However, evidence in frail older adults remains limited, and randomized trials in this population are warranted. Future research should directly compare IF with isocaloric non-fasting regimens, include long-term follow-up, and carefully characterize safety and adherence in high-risk groups before IF can be routinely recommended for immune aging.

Traumatic brain injury (TBI) represents a major global public health challenge. It is propelled by a cascade of secondary injuries. These injuries include inflammation, endothelial dysfunction, hypoxia, cerebral edema, and disruption of epigenetic homeostasis. These processes can precipitate necrosis and apoptosis. They also significantly heighten the risk of long-term cognitive deficits, dementia, and other neurodegenerative disorders. TBI progression is typically segmented into acute and chronic phases. Each phase is characterized by distinct pathological mechanisms and epigenetic alterations. The acute phase is dominated by direct tissue damage and robust inflammatory responses. In contrast, chronic TBI often evolves into long-term neurodegenerative conditions like chronic traumatic encephalopathy (CTE). CTE is marked by persistent neuroinflammation and cognitive decline. A critical gap exists in prior research. It lies in the frequent failure to disentangle the unique epigenetic reprogramming specific to each phase. This failure hinders the development of precisely timed interventions. This review systematically delineates the spatiotemporal dynamics of epigenetic regulation following TBI. It aims to construct a phase-specific framework for precision intervention. Acute-phase hallmarks involve DNA methylation. An example is DNMT3A-mediated silencing of homeostatic genes. They also include histone acetylation and m6A RNA methylation. The WTAP/YTHDF1-Lcn2 axis exemplifies this m6A regulation. Conversely, the chronic phase is defined by sustained neuroinflammation, tau hyperphosphorylation, and ferroptosis. These processes are modulated by noncoding RNAs. Examples include miR-29b and lncRNA 4933431K23Rik. Epigenetic drift also plays a regulatory role. Mitochondrial and endoplasmic reticulum stress further interact with these pathways. They amplify secondary damage. We underscore the clinical promise of time-stratified, personalized epigenetic interventions. These interventions aim to improve long-term outcomes. They forge a critical link between fundamental epigenetic discovery and precision management of neurotrauma. This work deepens the understanding of TBI pathophysiology. It also lays a conceptual and target-oriented groundwork. This groundwork advances neurotrauma care into an era of temporally tailored, individualized precision therapy.

The gut microbiota, a diverse community of trillions of microorganisms residing in the human gastrointestinal tract, plays a pivotal role in maintaining host nutrition, immunity, and metabolic function. Emerging research highlights its significant influence on the development and progression of various diseases, including obesity, type 2 diabetes, inflammatory bowel disease (IBD), and neuropsychiatric disorders. This narrative review aimed to synthesize recent findings (2020–2025) on the relationship between gut microbiota, diet, and health outcomes. A comprehensive search of databases such as PubMed, Scopus, and Google Scholar identified 110 peer-reviewed studies examining the functional roles of gut microbes, dietary interventions, and therapeutic strategies. The findings emphasize that microbial diversity and composition are influenced by factors such as diet, age, medication, birth mode, and lifestyle. High-Fiber diets, such as the Mediterranean diet, promote beneficial microbes like Bifidobacterium and Lactobacillus, while Western diets are associated with dysbiosis and chronic inflammation. Therapeutic approaches including probiotics, prebiotics, synbiotics, and faecal microbiota transplantation (FMT) demonstrated varying success in modulating gut flora to improve health. Dysbiosis was notably linked to metabolic disorders, cognitive decline, immune dysfunction, and gastrointestinal diseases. In conclusion, the gut microbiota acts as a key mediator between diet and health, influencing disease onset and therapeutic response. Personalized nutrition, combined with targeted microbial modulation, offers promising avenues for disease prevention and management. Future research should focus on standardized methods, long-term clinical trials, and multi-omics approaches to unlock the full therapeutic potential of the gut microbiome.

Neurodegenerative diseases affect 1 in 12 people globally and remain incurable. Central to their pathogenesis is a loss of neuronal protein maintenance and the accumulation of protein aggregates with ageing1,2. Here we engineered bioorthogonal tools3 that enabled us to tag the nascent neuronal proteome and study its turnover with ageing, its propensity to aggregate and its interaction with microglia. We show that neuronal protein half-life approximately doubles on average between 4-month-old and 24-month-old mice, with the stability of individual proteins differing among brain regions. Furthermore, we describe the aged neuronal 'aggregome', which encompasses 1,726 proteins, nearly half of which show reduced degradation with age. The aggregome includes well-known proteins linked to diseases and numerous proteins previously not associated with neurodegeneration. Notably, we demonstrate that neuronal proteins accumulate in aged microglia, with 54% also displaying reduced degradation and/or aggregation with age. Among these proteins, synaptic proteins are highly enriched, which suggests that there is a cascade of events that emerge from impaired synaptic protein turnover and aggregation to the disposal of these proteins, possibly through microglial engulfment of synapses. These findings reveal the substantial loss of neuronal proteome maintenance with ageing, which could be causal for age-related synapse loss and cognitive decline.

BackgroundEarly detection of cognitive impairment is vital for dementia management, especially in Alzheimer's disease. The Clock Drawing Test (CDT) is a widely used screening tool; however, many existing scoring methods lack comprehensive statistical validation and consistent factor structures.ObjectiveWe aimed to evaluate the validity and reliability of a novel scoring method, CDT-14, developed from items predictive of cognitive decline, and to compare its performance with three conventional scoring systems.MethodsWe enrolled 1100 outpatients undergoing cognitive assessments in a cross-sectional study. Scores from CDT-14 and the three conventional methods (Rouleau, Sunderland, Freedman) were compared. Structural validity was examined using confirmatory factor analysis (CFA), and item characteristics were analyzed via item response theory (IRT). Internal consistency was assessed with McDonald's omega. Construct validity and discriminative ability were evaluated through correlations and receiver operating characteristic (ROC) analyses. Participants were classified by Mini-Mental State Examination scores into Normal Cognition, Mild Cognitive Impairment, and Moderate-to-severe Cognitive Impairment.ResultsThe CFA results supported a three-factor model (Circle, Numbering, Hands) with good fit. The IRT analysis indicated high measurement precision in the mild cognitive decline range (θ = -1 to 0). The CDT-14 score exhibited strong internal consistency (ω = 0.835). ROC analyses showed that the CDT-14 score had comparable or superior discriminative accuracy to conventional methods, with practical cut-offs and enhanced performance when adjusted for age and education.ConclusionsThe CDT-14 is a psychometrically robust scoring method providing standardized, sensitive assessment for cognitive screening and longitudinal monitoring in dementia clinical settings.

BackgroundCognitive decline and incident dementia in ageing populations have been linked to brain parenchymal injury and the ALPS index (ALPS-I).ObjectiveThis investigation aimed to elucidate whether the baseline ALPS-I could predict incident dementia and cognitive decline in this population.MethodsIn total, 973 dementia-free participants from the Shunyi Study (mean age, 57 years; 37% male) received MRI between 2013 and 2016 to quantify the ALPS-I. The longitudinal relationships between the ALPS-I and cognitive deterioration in various cognitive areas were evaluated via linear mixed models. Cox proportional hazard models were utilized to explore the link between the index and incident dementia. Mediation assessments were carried out to identify the potential mediating effects of brain parenchymal injury on the link between the ALPS-I and cognition.ResultsThe baseline ALPS-I predicted longitudinal changes in global cognition (Montreal Cognitive Assessment), language (verbal fluency test), visuospatial perception (block design subtest of Wechsler intelligence scale), and executive function (Trail Making Test). A lower score was markedly associated with a higher incident dementia risk. Mediation analysis revealed that fractional anisotropy mediated the associations between the ALPS-I and executive function (mediation effect: 21.9%) and visuospatial perception (mediation effect: 68.8%). The white matter hyperintensity fraction was found to mediate the link between the ALPS-I and global cognition (mediation effect: 55.0%).ConclusionsThis longitudinal evidence supports a link between the ALPS-I and cognitive degeneration. Furthermore, the link is mediated by subcortical parenchymal injury.

Cerebral small vessel disease (CSVD) significantly contributes to cognitive decline and poses potential risk factors for both dementia and acute cerebrovascular events. Tai Chi has been recognized as an effective mind-body intervention for enhancing cognitive function and promoting neural plasticity. However, the neurobiological mechanisms that underlie how Tai Chi exercises affect cognitive improvement in patients with CSVD remain unclear. We recruited 51 patients with CSVD, randomly assigning them to either a 24-week Tai Chi exercise group (n = 26) or a health education control group (n = 25). We collected and analyzed data on neuropsychological assessments, plasma homocysteine levels, and brain structural and functional connectivity (SC and FC). Additionally, we employed network-based statistics along with correlational and mediation effect analyses to analyze the intervention process. Patients in the intervention group demonstrated a significant improvement in cognitive function. Furthermore, they demonstrated an increased FC pattern in the frontal-parietal-occipital regions, along with a significant rise of structural-functional coupling within the frontal network and a reduction in the occipital network. The enhanced structural-functional coupling in the frontal network partially mediated the reduction in homocysteine levels and the improvement in cognitive function.

There is growing interest in non-invasive brain stimulation (NIBS) as a safe and practical method to support cognitive function during ageing. NIBS using rhythmic sensory stimuli entrains brain oscillations and synchronizes functional networks, but the choice of NIBS frequency to enhance performance in cognitive tasks remains unclear. We adopt a network neuroscience approach to NIBS, linking network connectivity, EEG oscillatory frequencies and behavioural performance to test the effects of personalized rhythmic auditory stimulation (RAS) on an inhibitory control task (Simon task) in older adults aged 60-75 years. Simon task trials were preceded by ≈1.7-3.2 s of personalized RAS (clicks) at each individual's theta oscillation frequency (fθ), a slightly faster variant (fθ+), a fixed low-frequency control at 2 Hz (f2Hz) or a non-rhythmic control (NR). Reaction times (RTs) after personalized stimulation were faster than f2Hz and NR, with stronger brain entrainment to rhythmic stimulation linked to faster RTs. Task-related EEG signals showed enhanced attentional processes and more efficient cortical responses following the personalized stimulation. Individuals with lower baseline performance had the greatest benefits. The findings suggest personalized RAS enhances cognitive performance in ageing and provides a cost-effective neurorehabilitation approach to mitigate age-related cognitive decline.

INTRODUCTIONThe Active Gains in Brain Using Exercise During Aging (AGUEDA) trial examined the effects of a 24 week resistance exercise (RE) intervention on executive function (EF) and other cognitive domains in cognitively normal older adults.METHODSNinety participants (mean age, 71.8 years; 57.8% female) were randomized to an RE or control group. At baseline and 24 weeks, EF and other cognitive domains were assessed.RESULTSThe RE group showed significant improvements in overall EF (standardized mean difference [SMD] = 0.39, 95% confidence interval = 0.14, 0.65), with no significant between‐group difference (SMD = 0.13, p = 0.37). The RE group showed a significant improvement in attentional/inhibitory control (SMD = 0.43, p < 0.001) compared to the control group, while no effects were observed in other domains (all p > 0.12). Moderation by age, education, and subjective cognitive decline was observed.DISCUSSIONAlthough no overall EF benefit was observed, RE improved attentional/inhibitory control in cognitively normal older adults. RE may yield greater benefits in vulnerable subgroups.CLINICAL TRIAL REGISTRATIONThe trial was registered on ClinicalTrials.gov (ClinicalTrials.gov Identifier: NCT05186090).HighlightsCognitive effects of resistance exercise (RE) may vary across different cognitive domains in cognitively healthy older adults.Twenty‐four week RE produced selective improvements in attention/inhibitory control.RE did not improve executive function (EF), or other cognitive domains (episodic memory, processing speed, visuospatial processing, and working memory).RE improved muscular strength, which were associated with gains in EF, episodic memory and working memory.There is value in personalized exercise interventions tailored to individual risk populations, such as those with higher subjective cognitive decline.

Immune checkpoint inhibitors (ICIs) have revolutionized cancer treatment but are associated with a range of immune-related adverse events, including neurological complications. We report the case of a 64-year-old man diagnosed with small-cell lung cancer who developed AMPA2 antibody-positive autoimmune encephalitis after receiving tislelizumab combined with chemotherapy. The patient presented with a 3-week history of cognitive decline following the second cycle of treatment. Extensive testing confirmed the presence of a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid 2 (AMPA2) antibodies in the cerebrospinal fluid and serum. The patient was treated with corticosteroids and intravenous immunoglobulin, resulting in significant improvement within 1 month. This case highlights the potential of ICIs to induce autoimmune encephalitis, which is a rare but serious complication. This finding underscores the importance of early recognition and prompt intervention in patients undergoing immunotherapy.

Blood biomarkers have the potential to revolutionize Alzheimer's disease (AD) diagnosis, offering advantages over cerebrospinal fluid (CSF) and positron emission tomography (PET) due to their accessibility, scalability, and cost-effectiveness. This study evaluated the effectiveness of individual plasma biomarkers, such as phosphorylated Tau (pTau) 217, as well as biomarker combinations, with a focus on the pTau 217/β-Amyloid (Aβ) 1-42 ratio to predict amyloid positivity. To improve clinical utility, a dual threshold approach was applied to maximize predictive values and positive likelihood ratios while minimizing the proportion of indeterminate results. Plasma samples from two hundred eight (208) participants (including 7 with Subjective Cognitive Decline, 150 with Mild Cognitive Impairment, 12 with Alzheimer's disease dementia, and 39 with other cognitive conditions) from three cohorts (BioFINDER2, BIOCARD, and MissionAD) were analyzed to measure Aβ 1-42, Aβ 1-40, and pTau 217 levels using the Fujirebio LUMIPULSE® G1200 platform. Amyloid status was determined by FDA-cleared PET imaging and/or CSF biomarker ratios. Logistic regression modelling evaluated biomarkers either individually or in combination to identify those that best distinguished amyloid positivity. Clinically applicable thresholds were established through likelihood ratio analysis and further evaluated based on predictive values. When assessing the ability of individual plasma biomarkers to differentiate between amyloid-positive and amyloid-negative participants, plasma pTau 217 (p < 0.001) and plasma Aβ 1-42 (p = 0.0056) demonstrated significant discriminative power, whereas Aβ 1-40 (p = 0.30) did not. Notably, the integration of these biomarkers into the plasma pTau 217/Aβ 1-42 ratio, demonstrated enhanced classification performance (p < 0.001). Using a two-threshold approach based on positive and negative likelihood ratios (PLR/NLR) targets of 14/20, respectively, the plasma pTau 217/Aβ 1-42 ratio achieved a PPV of 94.44% and NPV of 94.28%, in the parametric model, comparable to plasma pTau 217 alone (PPV: 94.44%, NPV: 94.28%), but yielded fewer indeterminate results (26.5% vs. 38.6%). Using a non-parametric model, the plasma ratio achieved a PPV and NPV of 94.62% and 91.78%, respectively, while plasma pTau 217 alone achieved 92.41% and 92.86%; the ratio once again reduced the proportion of indeterminate results (20.2% vs. 35.1%). The plasma pTau 217/Aβ 1-42 ratio demonstrated superior performance in identifying amyloid pathology and reduced the frequency of indeterminate results compared to plasma pTau 217 alone. These findings support the evaluation of the clinical utility of the plasma pTau 217/Aβ 1-42 ratio as a tool for identifying amyloid pathology in patients presenting with cognitive complaints.