Episodic Memory Loss: When Alzheimer's Disease Is Not the Answer.

A 60-year-old man presented to a Neurology Clinic specialized in cognitive disorders to evaluate memory complaints. A comprehensive neuropsychological examination detected an isolated and severe hippocampal memory deficit. Laboratory tests, brain magnetic resonance imaging (MRI), and cerebrospinal fluid (CSF) tests, including Alzheimer's disease (AD) biomarkers, did not show remarkable results. Due to family history of cognitive impairment, we extended the study to non-Alzheimer monogenic mutations (Next Generation Sequencing) detecting a pathogenic variant of the progranulin (PGRN) gene (c.1414-1 G > T) which has been previously associated with the same phenotype. These results should be considered in patients with an Alzheimer-like presentation, negative AD biomarkers' results, and family history of dementia.

An Insertion Within SIRPß1 Shows a Dual Effect Over Alzheimer's Disease Cognitive Decline Altering the Microglial Response.

Background: Microglial dysfunction plays a causative role in Alzheimer's disease (AD) pathogenesis. Here we focus on a germline insertion/deletion variant mapping SIRPß1, a surface receptor that triggers amyloid-ß(Aß) phagocytosis via TYROBP. Objective: To analyze the impact of this copy-number variant in SIRPß1 expression and how it affects AD molecular etiology. Methods: Copy-number variant proxy rs2209313 was evaluated in GERALD and GR@ACE longitudinal series. Hippocampal specimens of genotyped AD patients were also examined. SIRPß1 isoform-specific phagocytosis assays were performed in HEK393T cells. Results: The insertion alters the SIRPß1 protein isoform landscape compromising its ability to bind oligomeric Aß and its affinity for TYROBP. SIRPß1 Dup/Dup patients with mild cognitive impairment show an increased cerebrospinal fluid t-Tau/Aß ratio (p = 0.018) and a higher risk to develop AD (OR = 1.678, p = 0.018). MRIs showed that Dup/Dup patients exhibited a worse initial response to AD. At the moment of diagnosis, all patients showed equivalent Mini-Mental State Examination scores. However, AD patients with the duplication had less hippocampal degeneration (p < 0.001) and fewer white matter hyperintensities. In contrast, longitudinal studies indicate that patients bearing the duplication allele show a slower cognitive decline (p = 0.013). Transcriptional analysis also shows that the SIRPß1 duplication allele correlates with higher TREM2 expression and an increased microglial activation. Conclusions: The SIRPß1 internal duplication has opposite effects over MCI-to-Dementia conversion risk and AD progression, affecting microglial response to Aß. Given the pharmacological approaches focused on the TREM2-TYROBP axis, we believe that SIRPß1 structural variant might be considered as a potential modulator of this causative pathway.

Correlation Between Amyloid PET Imaging and Discordant Cerebrospinal Fluid Biomarkers Results in Patients with Suspected Alzheimer's Disease.

BACKGROUND: Although the concordance between cerebrospinal fluid (CSF) Alzheimer's disease (AD) biomarkers and amyloid-PET findings is well known, there are no data regarding the concordance of amyloid-PET with inconclusive CSF values of amyloid-ß (Aß)1 - 42 and p-tau for the diagnosis of AD. OBJECTIVE: To investigate the relationship between the amyloid-PET results with discordant AD biomarkers values in CSF (Aß1 - 42+/p-tau-or Aß1 - 42-/p-tau+). METHODS: An observational retrospective study, including 62 patients with mild cognitive impairment (32/62) or dementia (30/62), suspicious of AD who had undergone a lumbar puncture to determine CSF AD biomarkers, and presented discordant values in CSF between Aß1 - 42 and p-tau (Aß1 - 42+/p-tau-or Aß1 - 42-/p-tau+). All of them, underwent an amyloid-PET with 18F-Florbetaben. An extensive neuropsychological testing as part of their diagnostic process (MMSE and TMA-93), was performed, and it was also obtained the Global Deterioration Scale. RESULTS: Comparing the discordant CSF results of each patient with the cerebral amyloid-PET results, we found that in the group with Aß1 - 42+ and p-tau-CSF values, the amyloid-PET was positive in 51.2% and negative in 48.8% of patients, while in the group with Aß1 - 42-and p-Tau+ CSF values, the amyloid-PET was positive in 52.6% of patients and negative in 47.4% of them. No significant association was found (p = 0.951) between the results of amyloid-PET and the two divergent groups in CSF. CONCLUSIONS: No significant relationship was observed between the results of discordant AD biomarkers in CSF and the result of amyloid-PET. No trend in amyloid-PET results was observed in relation to CSF biomarker values.

Norms for the Triana Test: A Story Recall Test Based on Emotional Material.

Background: The "Triana Test" is a novel story recall test based on emotional material with demonstrated accuracy in diagnosing mild cognitive impairment patients. Objective: This study aims to obtain normative data for the "Triana Test". Methods: A normative study was conducted at a university hospital in Spain. Partners of patients were systematically recruited if eligible (age ≥50, no memory complaints, and a total TMA-93 score at or above the 10th percentile). The "Triana Test" was administered and scored. For developing the normative data, a regression-based method was followed. Results: The final sample included 362 participants (median age = 66, range = 50-88; 64.9% females). A model including age and educational level better predicted the total scores. Combinations of these variables resulted in different 10th percentile scores. Conclusions: Norms for using the "Triana Test" are now available. The provided cutoffs for the 10th percentile will aid in the diagnosis of prodromal Alzheimer's disease.

Using Cognitive Reserve to Create Norms for the TMA-93 (Relational Binding of Images).

BACKGROUND: TMA-93 examines relational binding using images. Biomarker validation has demonstrated that it is discriminative for diagnosing early AD. The effect of cognitive reserve on TMA-93 performance remains unexplored and could improve the interpretative framework for using the test. OBJECTIVE: To study the effect of cognitive reserve on TMA-93 performance and to provide new norms for the test that include its measurement. METHODS: Cognitively unimpaired people aged 55 and over were systematically recruited for this cross-sectional normative study in southern Spain. Age, sex, and scores on the Cognitive Reserve Questionnaire (CRQ; maximum score: 25 points) were collected, and the TMA-93 was administered (maximum score: 30 points). Percentile-based reference data that captured combinations of socio-demographics variables with significant effect on TMA-93 performance were calculated. RESULTS: 902 participants (62.5% female; age: median = 68, IQR = 61-75, range = 55-90) were included. CRQ total scores were globally low (median = 8, IQR = 5-13, range = 0-24). Cognitive reserve, including modifiable items as reading activity and intellectual gaming activity, and age mainly supported the TMA-93 total score variance. Sex seemed to have some influence in the elderly. TMA-93 total scores medians began to drop from 70-75 years old. Higher total score on the CRQ and, possibly, female sex determined a gentler slope. New norms based on these variables showed wide variations in scores for the 5th and 10th percentiles. CONCLUSION: Visual relational binding ability depends on cognitive reserve, including modifiable items. The age-related binding deficit is buffered by higher cognitive reserve and, at older ages, by female sex.

Design of a Non-Interventional Study to Assess Neurologists' Perspectives and Pharmacological Treatment Decisions in Early Alzheimer's Disease.

INTRODUCTION: The current therapeutic landscape of Alzheimer's disease (AD) is evolving rapidly. Our treatment options include new anti-amyloid-ß protein disease-modifying therapies (DMTs) that decrease cognitive decline in patients with early AD (prodromal and mild AD dementia). Despite these advances, we have limited information on how neurologists would apply the results of recent DMT trials to make treatment decisions. Our goal is to identify factors associated with the use of new AD DMTs among neurologists applying concepts from behavioral economics. METHODS: This non-interventional, cross-sectional, web-based study will assess 400 neurologists with expertise in AD from across Spain. Participants will start by completing demographic information, practice settings, and a behavioral battery to address their tolerance to uncertainty and risk preferences. Participants will then be presented with 10 simulated case scenarios or vignettes of common encounters in patients with early AD to evaluate treatment initiation with anti-amyloid-ß DMTs (e.g., aducanumab, lecanemab, etc.). The primary outcomes will be therapeutic inertia and suboptimal decisions. Discrete choice experiments will be used to determine the weight of factors influencing treatment choices. RESULTS: The results of this study will provide new insights into a better understanding of the most relevant factors associated with therapeutic decisions on the use of DMTs, assessing how neurologists handle uncertainty when making treatment choices, and identifying the prevalence of therapeutic inertia in the management of early AD.

Lessons learned from a sporadic FUSopathy in a young man: a case report.

BACKGROUND: In frontotemporal dementia (FTD) spectrum, younger patients may correspond to fusopathy cases, and cognitive decline could be rapidly progressive. We present a clinical and neuropathological description of a patient. CASE PRESENTATION: A 37-year-old man, without a family history of neurodegenerative diseases, was brought by his family to consult for dysarthria and behavioural change. Initial exploration showed spastic dysarthria and disinhibition. He progressively worsened with a pseudobulbar syndrome, right-lateralized pyramidal signs, left hemispheric corticobasal syndrome and, finally, lower motor neuron signs in his right arm. He died four years after the initiation of the syndrome from bronchopneumonia. Laboratory tests (including blood and cerebrospinal fluid (CSF)) were normal. Magnetic resonance imaging (MRI) and fluorodeoxyglucose-containing positron emission tomography (PET-18F-FDG) showed left fronto-insular atrophy and hypometabolism. Subsequently, 123I-ioflupane (DaT-SCAN®) single-photon emission computed tomography (SPECT) was pathologic, manifesting bilaterally decreased activity with greater affection on the left side. Only a third electromyogram (EMG) detected denervation in the last year of evolution. No mutations were found in genes such as Tau, progranulin, C9orf72, FUS, TDP-43, CHMP2B, or VCP. In necropsy, severe frontotemporal atrophy with basophilic neuronal cytoplasmic and intranuclear inclusions, negative for tau and TAR DNA binding protein 43 (TDP-43), but positive for fused in sarcoma (FUS) consistent with specifically basophilic inclusions body disease (BIBD) type was found. CONCLUSIONS: In patients affected by FTD, particularly the youngest, with rapidly progressive decline and early motor affection, fusopathy must be suspected. These cases can include motor signs described in the FTD spectrum. Lower motor neuron affection in EMG could be detected late.

Mendelian Randomisation Confirms the Role of Y-Chromosome Loss in Alzheimer's Disease Aetiopathogenesis in Men.

Mosaic loss of chromosome Y (mLOY) is a common ageing-related somatic event and has been previously associated with Alzheimer's disease (AD). However, mLOY estimation from genotype microarray data only reflects the mLOY degree of subjects at the moment of DNA sampling. Therefore, mLOY phenotype associations with AD can be severely age-confounded in the context of genome-wide association studies. Here, we applied Mendelian randomisation to construct an age-independent mLOY polygenic risk score (mloy-PRS) using 114 autosomal variants. The mloy-PRS instrument was associated with an 80% increase in mLOY risk per standard deviation unit (p = 4.22 × 10-20) and was orthogonal with age. We found that a higher genetic risk for mLOY was associated with faster progression to AD in men with mild cognitive impairment (hazard ratio (HR) = 1.23, p = 0.01). Importantly, mloy-PRS had no effect on AD conversion or risk in the female group, suggesting that these associations are caused by the inherent loss of the Y chromosome. Additionally, the blood mLOY phenotype in men was associated with increased cerebrospinal fluid levels of total tau and phosphorylated tau181 in subjects with mild cognitive impairment and dementia. Our results strongly suggest that mLOY is involved in AD pathogenesis.

Medical help-seeking intentions among patients with early Alzheimer's disease.

Background: Limited information is available on the active process of seeking medical help in patients with Alzheimer's disease (AD) at early stages. The aim of this study was to assess the phenomenon of medical help-seeking in early AD and to identify associated factors. Methods: A multicenter, non-interventional study was conducted including patients of 50-90 years of age with prodromal or mild AD (National Institute on Aging/Alzheimer's Association criteria), a Mini-Mental State Examination (MMSE) score ≥ 22, and a Clinical Dementia Rating-Global score (CDR-GS) of 0.5-1.0. A multivariate logistic regression analysis was conducted. Results: A total of 149 patients were included. Mean age (SD) was 72.3 (7.0) years, 50.3% were female, and 87.2% had a CDR-GS score of 0.5. Mean disease duration was 1.4 (1.8) years. Ninety-four (63.1%) patients sought medical help, mostly from neurologists. Patients with help-seeking intentions were mostly female (60.6%) with a CDR-GS score of 0.5 (91.5%) and had a greater awareness of diagnosis, poorer quality of life, more depressive symptoms, and a more severe perception of their condition than their counterparts. Lack of help-seeking intentions was associated with male sex (p = 0.003), fewer years of education (p = 0.005), a low awareness of diagnosis (p = 0.005), and a low emotional consequence of the condition (p = 0.016). Conclusion: Understanding the phenomenon of active medical help-seeking may facilitate the design of specific strategies to improve the detection of cognitive impairment, especially in patients with a lower level of educational attainment and poor awareness of their condition.

Quality of Life and the Experience of Living with Early-Stage Alzheimer's Disease.

BACKGROUND: There is a need to better understand the experience of patients living with Alzheimer's disease (AD) in the early stages. OBJECTIVE: The aim of the study was to evaluate the perception of quality of life in patients with early-stage AD. METHODS: A multicenter, non-interventional study was conducted including patients of 50-90 years of age with prodromal or mild AD, a Mini-Mental State Examination (MMSE) score ≥22, and a Clinical Dementia Rating-Global score (CDR-GS) of 0.5.-1.0. The Quality of Life in Alzheimer 's Disease (QoL-AD) questionnaire was used to assess health-related quality of life. A battery of self-report instruments was used to evaluate different psychological and behavioral domains. Associations between the QoL-AD and other outcome measures were analyzed using Spearman's rank correlations. RESULTS: A total of 149 patients were included. Mean age (SD) was 72.3 (7.0) years and mean disease duration was 1.4 (1.8) years. Mean MMSE score was 24.6 (2.1). The mean QoL-AD score was 37.9 (4.5). Eighty-three percent (n = 124) of patients had moderate-to-severe hopelessness, 22.1% (n = 33) had depressive symptoms, and 36.9% (n = 55) felt stigmatized. The quality of life showed a significant positive correlation with self-efficacy and negative correlations with depression, emotional and practical consequences, stigma, and hopelessness. CONCLUSION: Stigma, depressive symptoms, and hopelessness are frequent scenarios in AD negatively impacting quality of life, even in a population with short disease duration and minimal cognitive impairment.

Awareness of Diagnosis in Persons with Early-Stage Alzheimer's Disease: An Observational Study in Spain.

INTRODUCTION: Limited information is available on people's experiences of living with Alzheimer's disease (AD) at earlier stages. This study assessed awareness of diagnosis among people with early-stage AD and its impact on different person-centered outcome measures. METHODS: We conducted an observational, cross-sectional study in 21 memory clinics in Spain. Persons aged 50-90 years, diagnosed with prodromal or mild AD (NIA/AA criteria), a Mini Mental State Examination (MMSE) score ≥ 22, and a Clinical Dementia Rating-Global score (CDR-GS) of 0.5 or 1.0 were recruited. The Representations and Adjustment to Dementia Index (RADIX) was used to assess participants' beliefs about their condition and its consequences. RESULTS: A total of 149 persons with early-stage AD were studied. Mean (SD) age was 72.3 (7.0) years and 50.3% were female. Mean duration of AD was 1.4 (1.8) years. Mean MMSE score was 24.6 (2.1) and 87.2% had a CDR-GS score of 0.5. Most participants (n = 84, 57.5%) used a descriptive term related to specific AD symptoms (e.g., memory difficulties) when asked what they called their condition. Participants aware of their diagnosis using the term AD (n = 66, 45.2%) were younger, had more depressive symptoms, and poorer life satisfaction and quality of life compared to those without awareness of their specific diagnosis. Practical and emotional consequences RADIX scores showed a significant negative correlation with Quality of Life in Alzheimer's Disease score (rho = - 0.389 and - 0.413, respectively; p < 0.0001). Years of education was the only predictor of awareness of AD diagnosis [OR = 1.04 (95% CI 1.00-1.08); p = 0.029]. CONCLUSIONS: Awareness of diagnosis was a common phenomenon in persons with early-stage AD negatively impacting their quality of life. Understanding illness representations in earlier stages may facilitate implementing optimized care that supports improved quality of life and well-being.

Testing Visual Binding by the TMA-93 in People Aged 75 and Over.

BACKGROUND: TMA-93 examines relational binding using images. The test has been proven to be discriminative for diagnosing early Alzheimer's disease by biomarkers. Norms for this test are available, but the elderly, at high risk for Alzheimer's disease, have not yet been widely represented. OBJECTIVE: To extend normative data on the TMA-93 for people aged 75 and over. METHODS: An extension of the Spanish TMA-93 normative study was undertaken. Only cognitively unimpaired people aged 75 and over were included. Age, gender, and educational attainment were registered as socio-demographic variables. Using histograms analysis, median comparisons, and linear regression analysis, we selected variables that demonstrated influence on TMA-93 total scores and provided percentile-base reference data according to combinations of those variables. RESULTS: We included 431 new participants, resulting in a total sample of 657 individuals (median age = 78, interquartile range = 76-81, range = 75-93). Percentile-base reference data stratified by a combination of age ranges (75-79, n = 428; and ≥80 years, n = 229), and educational attainment (< first grade, n = 253; first grade, n = 209; > first grade, n = 195) revealed that participants achieved a minimum TMA-93 total score of 26/30 at the 50th-percentile regardless of stratum. At the 10th-percentile, a maximum of 24/30 was achieved in the more educated stratum contrasting with a minimum of 19/30 in the less educated stratum. CONCLUSION: Although mitigated by lower levels of education, performance on the TMA-93 is widely preserved in cognitively unimpaired people aged 75 and over. The test could facilitate the screening of elderly patients with memory complaints.

Fecal Volatile Organic Compounds and Microbiota Associated with the Progression of Cognitive Impairment in Alzheimer's Disease.

Metabolites produced by an altered gut microbiota might mediate the effects in the brain. Among metabolites, the fecal volatile organic compounds (VOCs) are considered to be potential biomarkers. In this study, we examined both the VOCs and bacterial taxa in the feces from healthy subjects and Alzheimer's disease (AD) patients at early and middle stages. Remarkably, 29 fecal VOCs and 13 bacterial genera were differentiated from the healthy subjects and the AD patients. In general, higher amounts of acids and esters were found in in the feces of the AD patients and terpenes, sulfur compounds and aldehydes in the healthy subjects. At the early stage of AD, the most relevant VOCs with a higher abundance were short-chain fatty acids and their producing bacteria, Faecalibacterium and Lachnoclostridium. Coinciding with the development of dementia in the AD patients, parallel rises of heptanoic acid and Peptococcus were observed. At a more advanced stage of AD, the microbiota and volatiles shifted towards a profile in the feces with increases in hexanoic acid, Ruminococcus and Blautia. The most remarkable VOCs that were associated with the healthy subjects were 4-ethyl-phenol and dodecanol, together with their possible producers Clostridium and Coprococcus. Our results revealed a VOCs and microbiota crosstalk in AD development and their profiles in the feces were specific depending on the stage of AD. Additionally, some of the most significant fecal VOCs identified in our study could be used as potential biomarkers for the initiation and progression of AD.

Genomic Characterization of Host Factors Related to SARS-CoV-2 Infection in People with Dementia and Control Populations: The GR@ACE/DEGESCO Study.

Emerging studies have suggested several chromosomal regions as potential host genetic factors involved in the susceptibility to SARS-CoV-2 infection and disease outcome. We nested a COVID-19 genome-wide association study using the GR@ACE/DEGESCO study, searching for susceptibility factors associated with COVID-19 disease. To this end, we compared 221 COVID-19 confirmed cases with 17,035 individuals in whom the COVID-19 disease status was unknown. Then, we performed a meta-analysis with the publicly available data from the COVID-19 Host Genetics Initiative. Because the APOE locus has been suggested as a potential modifier of COVID-19 disease, we added sensitivity analyses stratifying by dementia status or by disease severity. We confirmed the existence of the 3p21.31 region (LZTFL1, SLC6A20) implicated in the susceptibility to SARS-CoV-2 infection and TYK2 gene might be involved in COVID-19 severity. Nevertheless, no statistically significant association was observed in the COVID-19 fatal outcome or in the stratified analyses (dementia-only and non-dementia strata) for the APOE locus not supporting its involvement in SARS-CoV-2 pathobiology or COVID-19 prognosis.

Evaluation of aquaporins in the cerebrospinal fluid in patients with idiopathic normal pressure hydrocephalus.

Brain aquaporin 1 (AQP1) and AQP4 are involved in cerebrospinal fluid (CSF) homeostasis and might participate in the origin of hydrocephalus. Studies have shown alterations of perivascular AQP4 expression in idiopathic normal pressure hydrocephalus (iNPH) and Alzheimer's disease (AD). Due to the overlapping of clinical signs between iNPH and certain neurological conditions, mainly AD, specific biomarkers might improve the diagnostic accuracy for iNPH. The goal of the present study was to analyze and quantify the presence of AQP1 and AQP4 in the CSF of patients with iNPH and AD to determine whether these proteins can be used as biomarkers of iNPH. We examined AQP1 and AQP4 protein levels in the CSF of 179 participants (88 women) classified into 5 groups: possible iNPH (81 participants), hydrocephalus associated with other neurological disorders (13 participants), AD (41 participants), non-AD dementia (32 participants) and healthy controls (12 participants). We recorded each participant's demographic and clinical variables and indicated, when available in the clinical history, the record of cardiovascular and respiratory complications. An ELISA showed virtually no AQP content in the CSF. Information on the vascular risk factors (available for 61 patients) confirmed some type of vascular risk factor in 86% of the patients with possible iNPH and 58% of the patients with AD. In conclusion, the ELISA analysis showed insufficient sensitivity to detect the presence of AQP1 and AQP4 in CSF, ruling out the possible use of these proteins as biomarkers for diagnosing iNPH.

Common variants in Alzheimer's disease and risk stratification by polygenic risk scores.

Genetic discoveries of Alzheimer's disease are the drivers of our understanding, and together with polygenetic risk stratification can contribute towards planning of feasible and efficient preventive and curative clinical trials. We first perform a large genetic association study by merging all available case-control datasets and by-proxy study results (discovery n = 409,435 and validation size n = 58,190). Here, we add six variants associated with Alzheimer's disease risk (near APP, CHRNE, PRKD3/NDUFAF7, PLCG2 and two exonic variants in the SHARPIN gene). Assessment of the polygenic risk score and stratifying by APOE reveal a 4 to 5.5 years difference in median age at onset of Alzheimer's disease patients in APOE ɛ4 carriers. Because of this study, the underlying mechanisms of APP can be studied to refine the amyloid cascade and the polygenic risk score provides a tool to select individuals at high risk of Alzheimer's disease.

Preliminary Validation of the Triana Test: A New Story Recall Test Based on Emotional Material.

OBJECTIVE: To first validate the diagnostic accuracy of the "Triana Test," a new story recall test based on emotional material. METHOD: A phase I study of validation. We included 55 patients with amnestic Mild Cognitive Impairment and 69 healthy controls, diagnosed according to the "Memory Associative Test of the district of Seine-Saint-Denis" (TMA-93), and matched by age, gender, and educational level. The Triana Test's diagnostic accuracy was calculated by ROC curve analysis and Spearman correlations estimated its convergent validity with a hippocampal memory test, the Free and Cued Selective Reminding Test with Immediate Recall (FCSRT+IR). RESULTS: The "Triana Test" immediate and delayed recalls showed adequate diagnostic accuracy (AUC ≥ 0,74). The delayed free recall showed the highest diagnostic accuracy (AUC = 0.86). Correlations with the FCSRT+IR were moderate to strong. CONCLUSIONS: The "Triana Test" demonstrated accuracy for discriminating amnestic Mild Cognitive Impairment patients from healthy controls and convergent validity with the FCSRT+IR.

TMA-93 Validation by Alzheimer's Disease Biomarkers: A Comparison with the Free and Cued Selective Reminding Test on a Biobank Sample.

BACKGROUND: The Memory Associative Test TMA-93 examines visual relational binding, characteristically affected in early-AD stages. OBJECTIVE: We aim to validate the TMA-93 by biomarkers determination and compare its diagnostic characteristics with the Free and Cued Selective Reminding Test (FCSRT). METHODS: Retrospective analysis of a Biobank database. Patients' records initially consulted for memory complaints, scored MMSE≥22, had TMA-93 and FCSRT tested, and AD biomarker determination (Amyloid-PET or CSF), either positive or negative, were selected. As cutoffs, we considered the 10-percentile for TMA-93 (P10/TMA-93), and "total free recall" (TFR) 21/22, total recall (TR) 43/44, and Cued Index < 0.77 for FCSRT from previous Spanish validation and normative studies. Diagnostic utilities were calculated using ROC curves and compared by the DeLong method. We studied if one test improved the other test's prediction, following a forward stepwise logistic regression model. RESULTS: We selected 105 records: 64 "positive" and 41 "negative" biomarkers. TMA-93 total score diagnostic utility (AUC = 0.72; 95%CI:0.62-0.82) was higher than those of the FCSRT: TFR (AUC = 0.70; 95%CI: 0.60-0.80), TR (AUC = 0.63; 95%CI:0.53-0.74), and Cued Index (AUC = 0.62; 95%CI:0.52-0.73). The P10/TMA-93 cutoff showed 86%sensitivity, similar to that of the most sensitive FCSRT cutoff (TFR21/22, 89%) and 29%specificity, lower than that of the most specific FCSRT cutoff (Cued Index < 0.77, 57%). 32.8%of the positive-biomarker group scored above CI/0.77 but below p10TMA-93. The addition of TMA-93 total score to FCSRT variables improved significantly the biomarkers results' prediction. CONCLUSION: TMA-93 demonstrated "reasonable" diagnostic utility, similar to FCSRT, for discriminating AD biomarker groups. TMA-93 total score improved the AD biomarker result prediction when added to FCSRT variables.