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The emergence of sustained neuropsychiatric symptoms (NPS) among non-demented individuals in later life, defined as mild behavioral impairment (MBI), is linked to a higher risk of cognitive decline. However, the underlying pathophysiological mechanisms remain largely unexplored. A growing body of evidence has shown that MBI is associated with alterations in structural and functional neuroimaging studies, higher genetic predisposition to clinical diagnosis of Alzheimer's disease (AD), as well as amyloid and tau pathology assessed in the blood, cerebrospinal fluid, positron-emission tomography (PET) imaging and neuropathological examination. These findings shed more light on the MBI-related potential neurobiological mechanisms, paving the way for the development of targeted pharmacological approaches. In this review, we aim to discuss the available clinical evidence on the role of amyloid and tau pathology in MBI and the potential underlying pathophysiological mechanisms. Dysregulation of the hypothalamic–pituitary–adrenal (HPA) axis, disruption of neurotrophic factors, such as the brain-derived neurotrophic factor (BDNF), abnormal neuroinflammatory responses including the kynurenine pathway, dysregulation of transforming growth factor beta (TGF-β1), epigenetic alterations including micro-RNA (miR)-451a and miR-455-3p, synaptic dysfunction, imbalance in neurotransmitters including acetylcholine, dopamine, serotonin, gamma-aminobutyric acid (GABA) and norepinephrine, as well as altered locus coeruleus (LC) integrity are some of the potential mechanisms connecting MBI with amyloid and tau pathology. The elucidation of the underlying neurobiology of MBI would facilitate the design and efficacy of relative clinical trials, especially towards amyloid- or tau-related pathways. In addition, we provide insights for future research into our deeper understanding of its underlying pathophysiology of MBI, and discuss relative therapeutic implications. [ABSTRACT FROM AUTHOR]

Mild Behavioral Impairment (MBI) leverages later-life emergent and persistent neuropsychiatric symptoms (NPS) to identify a high-risk group for incident dementia. Phosphorylated tau (p-tau) is a hallmark biological manifestation of Alzheimer disease (AD). We investigated associations between MBI and tau accumulation in early-stage AD cortical regions. In 442 Alzheimer's Disease Neuroimaging Initiative participants with normal cognition or mild cognitive impairment, MBI status was determined alongside corresponding p-tau and A β. Two meta-regions of interest were generated to represent Braak I and III neuropathological stages. Multivariable linear regression modelled the association between MBI as independent variable and tau tracer uptake as dependent variable. Among A β positive individuals, MBI was associated with tau uptake in Braak I (β =0.45(0.15), p<. 01) and Braak III (β =0.24(0.07), p<. 01) regions. In A β negative individuals, MBI was not associated with tau in the Braak I region (p=0.11) with a negative association in Braak III (p=. 01). These findings suggest MBI may be a sequela of neurodegeneration, and can be implemented as a cost-effective framework to help improve screening efficiency for AD. • MBI is associated with greater tau burden in early cortical regions affected by AD. • The study provides biomarker evidence in support of MBI and its clinical utility. • MBI provides an effective framework for detecting AD early in the disease course. [ABSTRACT FROM AUTHOR]

Summary: Background: The identification of patients with an elevated risk of developing Alzheimer's disease (AD) dementia and eligible for the disease-modifying treatments (DMTs) in the earliest stages is one of the greatest challenges in the clinical practice. Plasma biomarkers has the potential to predict these issues, but further research is still needed to translate them to clinical practice. Here we evaluated the clinical applicability of plasma pTau181 as a predictive marker of AD pathology in a large real-world cohort of a memory clinic. Methods: Three independent cohorts (modelling [n = 991, 59.7% female], testing [n = 642, 56.2% female] and validation [n = 441, 55.1% female]) of real-world patients with subjective cognitive decline (SCD), mild cognitive impairment (MCI), AD dementia, and other dementias were included. Paired cerebrospinal fluid (CSF) and plasma samples were used to measure AT(N) CSF biomarkers and plasma pTau181. Findings: CSF and plasma pTau181 showed correlation in all phenotypes except in SCD and other dementias. Age significantly influenced the biomarker's performance. The general Aβ(+) vs Aβ(−) ROC curve showed an AUC = 0.77 [0.74–0.80], whereas the specific ROC curve of MCI due to AD vs non-AD MCI showed an AUC = 0.89 [0.85–0.93]. A cut-off value of 1.30 pg/ml of plasma pTau181 exhibited a sensitivity of 93.57% [88.72–96.52], specificity of 72.38% [62.51–79.01], VPP of 77.85% [70.61–83.54], and 8.30% false negatives in the subjects with MCI of the testing cohort. The HR of cox regression showed that patients with MCI up to this cut-off value exhibited a HR = 1.84 [1.05–3.22] higher risk to convert to AD dementia than patients with MCI below the cut-off value. Interpretation: Plasma pTau181 has the potential to be used in the memory clinics as a screening biomarker of AD pathology in subjects with MCI, presenting a valuable prognostic utility in predicting the MCI conversion to AD dementia. In the context of a real-world population, a confirmatory test employing gold-standard procedures is still advisable. Funding: This study has been mainly funded by Ace Alzheimer Center Barcelona, Instituto de Salud Carlos III (ISCIII), Biomedical Research Networking Centre in Neurodegenerative Diseases (CIBERNED), Spanish Ministry of Science and Innovation, Fundación ADEY, Fundación Echevarne and Grífols S.A.

Previous studies have demonstrated resilience to AD-related neuropathology in a form of cognitive reserve (CR). In this study we investigated a relationship between CR and hypometabolic subtypes of AD, specifically the typical and the limbic-predominant subtypes. We analyzed data from 59 Aβ-positive cognitively normal (CN), 221 prodromal Alzheimer's disease (AD) and 174 AD dementia participants from the Alzheimer's Disease Neuroimaging Initiative (ADNI) from ADNI and ADNIGO/2 phases. For replication, we analyzed data from 5 Aβ-positive CN, 89 prodromal AD and 43 AD dementia participants from ADNI3. CR was estimated as standardized residuals in a model predicting cognition from temporoparietal grey matter volumes and covariates. Higher CR estimates predicted slower cognitive decline. Typical and limbic-predominant hypometabolic subtypes demonstrated similar baseline CR, but the results suggested a faster decline of CR in the typical subtype. These findings support the relationship between subtypes and CR, specifically longitudinal trajectories of CR. Results also underline the importance of longitudinal analyses in research on CR. • We compared cross-sectional and longitudinal CR between hypometabolic AD subtypes. • Typical and limbic-predominant subtypes demonstrated similar CR at baseline. • Typical hypometabolic subtype seemed to benefit more from higher CR. • Results suggested a faster longitudinal decline of CR in the typical subtype. [ABSTRACT FROM AUTHOR]

Abstract Background Recent evidence suggests that the failure of the glymphatic system – the brain’s waste clearance system, which is active during sleep – plays a key role in the pathophysiology of Alzheimer’s Disease (AD). Glymphatic function can be investigated using serial MRIs after intrathecal gadobutrol injection. This technique can reveal the health of the glymphatic system, but has not yet been used in participants with cognitive impairment due to AD. Case report This report describes the sleep and gadobutrol tracer clearance patterns of four participants diagnosed with mild to moderate cognitive impairment with evidence of AD pathology (pathological levels of Ab and p-tau in cerebrospinal fluid). We performed polysomnography and MRI studies before tracer injection and MRI scans at 1.5-2 h, 5–6 h, and 48 h after injection. Despite participants reporting no sleep problems, polysomnography revealed that all participants had moderate to severe sleep disturbances, including reduced sleep efficiency during the study and obstructive sleep apnea. Severe side-effects related to tracer administration were observed, impeding the completion of the protocol in two participants. Participants who finished the protocol displayed delayed and persistent tracer enrichment in the cortex and white matter, even 48 h after injection. These outcomes have not been observed in previous studies in participants without AD. Conclusion The findings suggest that brains with sleep impairment and AD pathology have poor glymphatic function, and therefore cannot clear the contrast tracer efficiently. This is likely to have caused the severe side effects in our participants, that have not been reported in healthy individuals. Our results may therefore represent the only available data acquired with this technique in participants with AD pathology.

Background: Recent evidence suggests that the failure of the glymphatic system – the brain's waste clearance system, which is active during sleep – plays a key role in the pathophysiology of Alzheimer's Disease (AD). Glymphatic function can be investigated using serial MRIs after intrathecal gadobutrol injection. This technique can reveal the health of the glymphatic system, but has not yet been used in participants with cognitive impairment due to AD. Case report: This report describes the sleep and gadobutrol tracer clearance patterns of four participants diagnosed with mild to moderate cognitive impairment with evidence of AD pathology (pathological levels of Ab and p-tau in cerebrospinal fluid). We performed polysomnography and MRI studies before tracer injection and MRI scans at 1.5-2 h, 5–6 h, and 48 h after injection. Despite participants reporting no sleep problems, polysomnography revealed that all participants had moderate to severe sleep disturbances, including reduced sleep efficiency during the study and obstructive sleep apnea. Severe side-effects related to tracer administration were observed, impeding the completion of the protocol in two participants. Participants who finished the protocol displayed delayed and persistent tracer enrichment in the cortex and white matter, even 48 h after injection. These outcomes have not been observed in previous studies in participants without AD. Conclusion: The findings suggest that brains with sleep impairment and AD pathology have poor glymphatic function, and therefore cannot clear the contrast tracer efficiently. This is likely to have caused the severe side effects in our participants, that have not been reported in healthy individuals. Our results may therefore represent the only available data acquired with this technique in participants with AD pathology. [ABSTRACT FROM AUTHOR]

Abstract Background Evidence on the relative risk of death across all stages of Alzheimer’s disease (AD) is lacking but greatly needed for the evaluation of new interventions. We used data from the Uniform Data Set (UDS) of the National Alzheimer’s Coordinating Center (NACC) to assess the expected survival of a person progressing to a particular stage of AD and the relative risk of death for a person in a particular stage of AD compared with cognitively normal (CN) people. Methods This was a retrospective observational cohort study of mortality and its determinants in participants with incident mild cognitive impairment (MCI) due to AD or AD dementia compared with CN participants. Overall survival and hazard ratios of all-cause mortality in participants ≥ 50 years of age with clinically assessed or diagnosed MCI due to AD, or mild, moderate, or severe AD dementia, confirmed by Clinical Dementia Rating scores, versus CN participants were estimated, using NACC UDS data. Participants were followed until death, censoring, or until information to determine disease stage was missing. Results Aged between 50 and 104 years, 12,414 participants met the eligibility criteria for the study. Participants progressing to MCI due to AD or AD dementia survived a median of 3–12 years, with higher mortality observed in more severe stages. Risk of death increased with the severity of AD dementia, with the increase significantly higher at younger ages. Participants with MCI due to AD and CN participants had a similar risk of death after controlling for confounding factors. Conclusions Relative all-cause mortality risk increases with AD severity, more so at younger ages. Mortality does not seem to be higher for those remaining in MCI due to AD. Findings might imply potential benefit of lower mortality if preventing or delaying the progression of AD is successful, and importantly, this potential benefit might be greater in relatively younger people. Future research should replicate our study in other samples more representative of the general US population as well as other populations around the world.

Background: Evidence on the relative risk of death across all stages of Alzheimer's disease (AD) is lacking but greatly needed for the evaluation of new interventions. We used data from the Uniform Data Set (UDS) of the National Alzheimer's Coordinating Center (NACC) to assess the expected survival of a person progressing to a particular stage of AD and the relative risk of death for a person in a particular stage of AD compared with cognitively normal (CN) people. Methods: This was a retrospective observational cohort study of mortality and its determinants in participants with incident mild cognitive impairment (MCI) due to AD or AD dementia compared with CN participants. Overall survival and hazard ratios of all-cause mortality in participants ≥ 50 years of age with clinically assessed or diagnosed MCI due to AD, or mild, moderate, or severe AD dementia, confirmed by Clinical Dementia Rating scores, versus CN participants were estimated, using NACC UDS data. Participants were followed until death, censoring, or until information to determine disease stage was missing. Results: Aged between 50 and 104 years, 12,414 participants met the eligibility criteria for the study. Participants progressing to MCI due to AD or AD dementia survived a median of 3–12 years, with higher mortality observed in more severe stages. Risk of death increased with the severity of AD dementia, with the increase significantly higher at younger ages. Participants with MCI due to AD and CN participants had a similar risk of death after controlling for confounding factors. Conclusions: Relative all-cause mortality risk increases with AD severity, more so at younger ages. Mortality does not seem to be higher for those remaining in MCI due to AD. Findings might imply potential benefit of lower mortality if preventing or delaying the progression of AD is successful, and importantly, this potential benefit might be greater in relatively younger people. Future research should replicate our study in other samples more representative of the general US population as well as other populations around the world. [ABSTRACT FROM AUTHOR]

Summary: Lecanemab, an anti-amyloid antibody with effects on biomarker and clinical endpoints in early Alzheimer's Disease (AD), was granted accelerated approval by the FDA in 2023 and regulatory review in Europe is ongoing. We estimate the population potentially eligible for treatment with lecanemab in the 27 EU countries to 5.4 million individuals. Treatment costs would exceed 133 billion EUR per year if the drug is priced similarly as in the United States, amounting to over half of the total pharmaceutical expenditures in the EU. This pricing would be unsustainable; the ability to pay for high-priced therapies varies substantially across countries. Pricing similarly to what has been announced for the United States may place the drug out of reach for patients in some European countries. Disparities in access to novel amyloid-targeting agents may further deepen the inequalities across Europe in health outcomes. As representatives of the European Alzheimer's Disease Consortium Executive Committee, we call for pricing policies that allow eligible patients across Europe to access important innovations, but also continued investments in research and development. Infrastructure to follow up the usage of new therapies in routine care and new payment models may be needed to address affordability and inequalities in patient access.

Background: The identification of patients with an elevated risk of developing Alzheimer's disease (AD) dementia and eligible for the disease-modifying treatments (DMTs) in the earliest stages is one of the greatest challenges in the clinical practice. Plasma biomarkers has the potential to predict these issues, but further research is still needed to translate them to clinical practice. Here we evaluated the clinical applicability of plasma pTau181 as a predictive marker of AD pathology in a large real-world cohort of a memory clinic., Methods: Three independent cohorts (modelling [n = 991, 59.7% female], testing [n = 642, 56.2% female] and validation [n = 441, 55.1% female]) of real-world patients with subjective cognitive decline (SCD), mild cognitive impairment (MCI), AD dementia, and other dementias were included. Paired cerebrospinal fluid (CSF) and plasma samples were used to measure AT(N) CSF biomarkers and plasma pTau181., Findings: CSF and plasma pTau181 showed correlation in all phenotypes except in SCD and other dementias. Age significantly influenced the biomarker's performance. The general Aβ(+) vs Aβ(-) ROC curve showed an AUC = 0.77 [0.74-0.80], whereas the specific ROC curve of MCI due to AD vs non-AD MCI showed an AUC = 0.89 [0.85-0.93]. A cut-off value of 1.30 pg/ml of plasma pTau181 exhibited a sensitivity of 93.57% [88.72-96.52], specificity of 72.38% [62.51-79.01], VPP of 77.85% [70.61-83.54], and 8.30% false negatives in the subjects with MCI of the testing cohort. The HR of cox regression showed that patients with MCI up to this cut-off value exhibited a HR = 1.84 [1.05-3.22] higher risk to convert to AD dementia than patients with MCI below the cut-off value., Interpretation: Plasma pTau181 has the potential to be used in the memory clinics as a screening biomarker of AD pathology in subjects with MCI, presenting a valuable prognostic utility in predicting the MCI conversion to AD dementia. In the context of a real-world population, a confirmatory test employing gold-standard procedures is still advisable., Funding: This study has been mainly funded by Ace Alzheimer Center Barcelona, Instituto de Salud Carlos III (ISCIII), Biomedical Research Networking Centre in Neurodegenerative Diseases (CIBERNED), Spanish Ministry of Science and Innovation, Fundación ADEY, Fundación Echevarne and Grífols S.A., Competing Interests: Declaration of interests Alberto Lleó received personal fees for service on the advisory boards from Biogen, Eisai, Fujirebio-Europe, Lilly, Novartis, NovoNordisk, Nutricia, Otsuka Pharmaceutical, and Zambón, and received speaker honoraria from Lilly, Biogen, KRKA and Zambon. Juan Fortea received personal fees for service on the advisory boards, adjudication committees or speaker honoraria from AC Immune, Lilly, Lundbeck, Roche, Fujirebio and Biogen, outside the submitted work. D.A., A.L. and J.F. report holding a patent for markers of synaptopathy in neurodegenerative disease (licensed to Adx, EPI8382175.0). Marta Marquié received personal fees for service on the advisory boards from Araclon Biotech–Grifols, S.A. Marta Marquié received grants or contracts from Instituto de Salud Carlos III (ISCIII) Accion Estrategica en Salud, integrated in the Spanish National RCDCI Plan and financed by ISCIII-Subdireccion General de Evaluacion and the Fondo Europeo de Desarrollo Regional (FEDER—Una manera de hacer Europa) grant PI19/00335. Daniel Alcolea received personal fees for service on the advisory boards from Fujirebio-Europe, Roche Diagnostics, Nutricia, Krka Farmacéutica S.L., Zambon S.A.U., Grifols, S.A., Lilly, and Esteve Pharmaceuticals S.A., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Introduction: Hippocampal atrophy is an established Alzheimer's Disease (AD) biomarker. Volume loss in specific subregions as measurable with ultra-high field magnetic resonance imaging (MRI) may reflect earliest pathological alterations. Methods: Data from positron emission tomography (PET) for estimation of cortical amyloid β (Aβ) and high-resolution 7 Tesla T1 MRI for assessment of hippocampal subfield volumes were analyzed in 61 non-demented elderly individuals who were divided into risk-categories as defined by high levels of cortical Aβ and low performance in standardized episodic memory tasks. Results: High cortical Aβ and low episodic memory interactively predicted subicular volume [ F (3,57) = 5.90, p = 0.018]. The combination of high cortical Aβ and low episodic memory was associated with significantly lower subicular volumes, when compared to participants with high episodic memory (p = 0.004). Discussion: Our results suggest that low subicular volume is linked to established indicators of AD risk, such as increased cortical Aβ and low episodic memory. Our data support subicular volume as a marker of dementia-risk susceptibility in old-aged non-demented persons. [ABSTRACT FROM AUTHOR]

IntroductionHippocampal atrophy is an established Alzheimer’s Disease (AD) biomarker. Volume loss in specific subregions as measurable with ultra-high field magnetic resonance imaging (MRI) may reflect earliest pathological alterations.MethodsData from positron emission tomography (PET) for estimation of cortical amyloid β (Aβ) and high-resolution 7 Tesla T1 MRI for assessment of hippocampal subfield volumes were analyzed in 61 non-demented elderly individuals who were divided into risk-categories as defined by high levels of cortical Aβ and low performance in standardized episodic memory tasks.ResultsHigh cortical Aβ and low episodic memory interactively predicted subicular volume [F(3,57) = 5.90, p = 0.018]. The combination of high cortical Aβ and low episodic memory was associated with significantly lower subicular volumes, when compared to participants with high episodic memory (p = 0.004).DiscussionOur results suggest that low subicular volume is linked to established indicators of AD risk, such as increased cortical Aβ and low episodic memory. Our data support subicular volume as a marker of dementia-risk susceptibility in old-aged non-demented persons.

Alzheimer's disease (AD) and Parkinson's disease (PD) are the first and second most common neurodegenerative disorders, respectively. Both are proteinopathies with inexorable courses and no approved disease-modifying therapies. A substantial effort has been made to identify interventions that could slow down the progression of AD and PD; to date, with no success. The advances in biomarker research improved the identification of individuals at risk for these disorders before symptom onset, recognizing the pre-clinical stage, in which there is abnormal protein accumulation but no clinical symptoms of the disease, and the prodromal stage, in which mild symptoms are present but the clinical diagnostic criteria for disease cannot be fulfilled. The ability to detect pre-clinical and prodromal stages of these diseases has encouraged clinical trials for disease-modification at earlier phases, seeking to slow or prevent phenoconversion into clinical disease. Clinical trials at these stages have several challenges, such as the identification of the eligible population, the appropriate choice of biomarkers, the definition of clinical endpoints, the duration of follow-up, and the statistical analysis. This article aims to discuss some of the methodological challenges in the design of trials for pre-clinical and prodromal phases of AD and PD, to critically review the recent studies, and to discuss methodological approaches to mitigate these challenges in trial design. [ABSTRACT FROM AUTHOR]

Abstract Introduction The diagnosis of mild cognitive impairment (MCI) refers to cognitive impairment not meeting dementia criteria. A survey among members of the American Association of Neurology (AAN) showed that MCI was considered a useful diagnosis. Recently, research criteria have been proposed for the diagnosis of Alzheimer’s disease (AD) in MCI based on AD biomarkers (prodromal AD/MCI due to AD). The aim of this study was to investigate the attitudes of clinicians in Europe on the clinical utility of MCI and prodromal AD/MCI due to AD criteria. We also investigated whether the prodromal AD/MCI due to AD criteria impacted management of MCI patients. Methods An online survey was performed in 2015 among 102 members of the European Academy of Neurology (EAN) and the European Alzheimer’s Disease Consortium (EADC). Questions were asked on how often criteria were used, how they were operationalized, how they changed patient management, and what were considered advantages and limitations of MCI and prodromal AD/MCI due to AD. The questionnaire consisted of 47 questions scored on a Likert scale. Results Almost all respondents (92%) used the MCI diagnosis in clinical practice. Over 80% of the EAN/EADC respondents found a MCI diagnosis useful because it helped to label the cognitive problem, involve patients in planning for the future, and start risk reduction activities. These findings were similar to those reported in the AAN survey. Research criteria for prodromal AD/MCI due to AD were used by 68% of the EAN/EADC respondents. The most common reasons to use the criteria were increased certainty of diagnosis (86%), increased possibilities to provide counseling (51%), facilitation of follow-up planning (48%), start of medical intervention (49%), and response to patients’ wish for a diagnosis (41%). Over 70% of the physicians considered that a diagnosis of prodromal AD/MCI due to AD had an added value over the MCI diagnosis. Conclusions The diagnostic criteria of MCI and prodromal AD/MCI due to AD are commonly used among EAN/EADC members. The prodromal AD/MCI due to AD were considered clinically useful and impacted patient management and communication.

Abstract Introduction Free and Cued Selective Reminding Test (FCSRT) performance identifies patients with preclinical disease at elevated risk for developing Alzheimer's dementia, predicting diagnosis better than other memory tests. Methods Based on literature mapping FCSRT performance to clinical outcomes and biological markers, and on longitudinal preclinical data from the Baltimore Longitudinal Study of Aging, we developed the Stages of Objective Memory Impairment (SOMI) model. Five sequential stages of episodic memory decline are defined by Free Recall (FR) and Total Recall (TR) score ranges and years prior to dementia diagnosis. We sought to replicate the SOMI model using longitudinal assessments of 142 Einstein Aging Study participants who developed AD over 10 years. Results Average time to diagnosis was seven years if FR was intact, four years if TR was intact, and two years if TR was impaired, consistent with SOMI model predictions. The SOMI identified incipient dementia with excellent sensitivity and specificity. Discussion The SOMI model provides an efficient approach for clinical trial cognitive screening in advance of more costly biomarker studies and ultimately in clinical practice, and provides a vocabulary for understanding AD biomarker patterns and for re‐analysis of existing clinical trial data.

Background: Diagnosis of Alzheimer's disease (AD) confirmed by biomarkers allows the patient to make important life decisions. However, doubt about the fleetness of symptoms progression and future cognitive decline remains. Neuropsychological measures were extensively studied in prediction of time to conversion to dementia for mild cognitive impairment (MCI) patients in the absence of biomarker information. Similar neuropsychological measures might also be useful to predict the progression to dementia in patients with MCI due to AD.Objective: To study the contribution of neuropsychological measures to predict time to conversion to dementia in patients with MCI due to AD.Methods: Patients with MCI due to AD were enrolled from a clinical cohort and the effect of neuropsychological performance on time to conversion to dementia was analyzed.Results: At baseline, converters scored lower than non-converters at measures of verbal initiative, non-verbal reasoning, and episodic memory. The test of non-verbal reasoning was the only statistically significant predictor in a multivariate Cox regression model. A decrease of one standard deviation was associated with 29% of increase in the risk of conversion to dementia. Approximately 50% of patients with more than one standard deviation below the mean in the z score of that test had converted to dementia after 3 years of follow-up.Conclusion: In MCI due to AD, lower performance in a test of non-verbal reasoning was associated with time to conversion to dementia. This test, that reveals little decline in the earlier phases of AD, appears to convey important information concerning conversion to dementia. [ABSTRACT FROM AUTHOR]

White matter tract alterations have been consistently described in Alzheimer's disease (AD). In particular, limbic fronto-temporal connections, which are critical to episodic memory function, may degenerate early in the course of the disease. However the relation between white matter tract degeneration, hippocampal atrophy and episodic memory impairment at the earliest stages of AD is still unclear. In this magnetic resonance imaging study, white matter integrity and hippocampal volumes were evaluated in patients with amnestic mild cognitive impairment due to AD (Albert et al., 2011) (n = 22) and healthy controls (n = 15). Performance in various episodic memory tasks was also evaluated in each participant. Relative to controls, patients showed a significant reduction of white matter fractional anisotropy (FA) and increase of radial diffusivity (RD) in the bilateral uncinate fasciculus, parahippocampal cingulum and fornix. Within the patient group, significant intra-hemispheric correlations were notably found between hippocampal grey matter volume and FA in the uncinate fasciculus, suggesting a relationship between atrophy and disconnection of the hippocampus. Moreover, episodic recognition scores were related with uncinate fasciculus FA across patients. These results indicate that fronto-hippocampal connectivity is reduced from the earliest pre-demential stages of AD. Disruption of fronto-hippocampal connections may occur progressively, in parallel with hippocampal atrophy, and may specifically contribute to early initial impairment in episodic memory.

Introduction: It is a challenge to find participants for Alzheimer's disease (AD) prevention trials within a short period of time. The European Prevention of Alzheimer's Dementia Registry (EPAD) aims to facilitate recruitment by preselecting subjects from ongoing cohort studies. This article introduces this novel approach. Methods: A virtual registry, with access to risk factors and biomarkers for AD through minimal data sets of ongoing cohort studies, was set up. Results: To date, ten cohorts have been included in the EPAD. Around 2500 participants have been selected, using variables associated with the risk for AD. Of these, 15% were already recruited in the EPAD longitudinal cohort study, which serves as a trial readiness cohort. Discussion: This study demonstrates that a virtual registry can be used for the preselection of participants for AD studies. [ABSTRACT FROM AUTHOR]

Lecanemab, an anti-amyloid antibody with effects on biomarker and clinical endpoints in early Alzheimer's Disease (AD), was granted accelerated approval by the FDA in 2023 and regulatory review in Europe is ongoing. We estimate the population potentially eligible for treatment with lecanemab in the 27 EU countries to 5.4 million individuals. Treatment costs would exceed 133 billion EUR per year if the drug is priced similarly as in the United States, amounting to over half of the total pharmaceutical expenditures in the EU. This pricing would be unsustainable; the ability to pay for high-priced therapies varies substantially across countries. Pricing similarly to what has been announced for the United States may place the drug out of reach for patients in some European countries. Disparities in access to novel amyloid-targeting agents may further deepen the inequalities across Europe in health outcomes. As representatives of the European Alzheimer's Disease Consortium Executive Committee, we call for pricing policies that allow eligible patients across Europe to access important innovations, but also continued investments in research and development. Infrastructure to follow up the usage of new therapies in routine care and new payment models may be needed to address affordability and inequalities in patient access., Competing Interests: No specific funding was received for the preparation of this manuscript. Authors have completed separate CoI forms. The authors declare the following Conflicts of Interest: LJ received research grants (paid to institution) by Vinnova, FORTE and Novo Nordisk, license fees for the RUD instrument paid to European Health Economics, advisory board honorarium from Laboratoires Servier, travel support from BioArctic AB. AW received grants from Vinnova and EU (PREDEM, MOPEAD, PRODEMOS, EURO-FINGER, PROMINENT, PMI-AD, ADDITION, paid to institution), and is a license holder of the RUD instrument. Member of MSAP for ADI (un-paid). RH received research grants from JPND, ZonMW, IMI, H2020 (paid to institution), consulting fees from Lilly Nederland, iMTA, Biogen Nederlands, Biogen MA Inc, Eisai Inc (paid to institution), member of ISPOR modeling SIG and IPECAD modeling group (un-paid). MB is Member of the Advisory Boards Grifols, Roche, Lilly, Araclon Biotech, Merck, Zambon, Biogen, Novo- Nordisk, Bioiberica, Eisai, Servier, Schwabe Pharma. SE received research grants from Interreg Vlaanderen-Nederland, Research Foundation Flanders (FWO), VLAIO, GSKE/FMRE (paid to institution), consulting fees from Icometrix, Novartis, Eisai (paid to institution), personal consulting fees from Roche and Biogen, personal honoraria from Eisai, Roche, travel support to institution from Biogen, Patent EP3452830B1 (institution), member of SMB/SAB for EU-H2020 project RECAGE. VP of Belgian Dementia Council (unpaid). LF received grants from EU (RADAR-AD, RECAGE, FRAILBRAIN, paid to institution), personal consulting fees from Biogen, Eisai, Grifols, Hummingbird, Infecto-Pharm, Janssen-Cilag, MSD, Neurimmune, Functional Neuromodulation, Noselab, NovoNordisk, Roche, TauRX, Schwabe, lecture honoraria from Hoffmann-LaRoche and Schwabe, personal advisory board honorarium from Avanir/Otsuka, Pharmatropix, FZ Jülich, Charité Berlin, Neuroscios, reMYND, Vivoryon. FJ received personal consulting fees and lecture honoraria from Eisai, Biogen, Lilly, and personal honoraria for participation in advisory board from AC Immune. PJO received grants from Alector, Alzheon, Araclon Biotech, Biogen, Avanir Pharmaceuticals, Cortexyme, Eisai, Eli Lilly, Green Valley Pharmaceutical, Hoffman-La Roche, Janssen, Novartis Pharmaceuticals, NovoNordisk, TauRx, UCB Biopharma (paid to institution). NS received grants from EU (EPAD) and NovoNordisk (paid to institution). Personal fee as member of SAB from Albert Einstein College of Medicine – NIH funded. PJV received grants from EU (AMYPAD, RADAR-AD, EPND), Zon-MW, Biogen, Amyloid biomarker study (paid to institution), honoraria from workshop grant writing by Stiftung Synapsis, Alzheimer Forschung Schweiz. Patent holder (PCT/NL2020/050216) on AD subtypes (all paid to institution). GW received research grant from Danish Ministry of Health (paid to institution). BW received personal honorarium for a 2 h meeting with BioArctic, member of SMB for Alzinova, member of SAB for Resverlogix, stocks in AlzeCure pharma. GJ, PK, MK and AM declare no conflicts of interest., (© 2023 The Author(s).)

Introduction The objective of this study was to determine the utility of subjective memory decline (SMD) to predict episodic memory change and rates of clinical progression in cognitively normal older adults with evidence of high β-amyloid burden (CN Aβ+). Methods Fifty-eight CN Aβ+ participants from the Australian Imaging, Biomarkers, and Lifestyle study responded to an SMD questionnaire and underwent comprehensive neuropsychological assessments. Participant data for three follow-up assessments were analyzed. Results In CN Aβ+, subjects with high SMD did not exhibit significantly greater episodic memory decline than those with low SMD. High SMD was related to greater rates of progression to mild cognitive impairment or Alzheimer's disease (AD) dementia (hazard ratio = 5.1; 95% confidence interval, 1.4–20.0, P = .02) compared with low SMD. High SMD was associated with greater depressive symptomatology and smaller left hippocampal volume. Discussion High SMD is a harbinger of greater rates of clinical progression in preclinical AD. Although SMD reflects broader diagnostic implications for CN Aβ+, more sensitive measures may be required to detect early subtle cognitive change. [ABSTRACT FROM AUTHOR]

Decay of the temporoparietal cortex is associated with prodromal Alzheimer’s disease (AD). Additionally, shrinkage of the temporoparietal cerebral area has been connected with an increase in α3/α2 electroencephalogram (EEG) power ratio in prodromal AD. Furthermore, a lower regional blood perfusion has been exhibited in patients with a higher α3/α2 proportion when contrasted with low α3/α2 proportion. Furthermore, a lower regional blood perfusion and reduced hippocampal volume has been exhibited in patients with higher α3/α2 when contrasted with lower α3/α2 EEG power ratio. Neuropsychological evaluation, EEG recording, and magnetic resonance imaging were conducted in 74 patients with mild cognitive impairment (MCI). Estimation of cortical thickness and α3/α2 frequency power ratio was conducted for each patient. A subgroup of 27 patients also underwent single-photon emission computed tomography evaluation. In view of α3/α2 power ratio, the patients were divided into three groups. The connections among cortical decay, cerebral perfusion, and memory loss were evaluated by Pearson’s r coefficient. Results demonstrated that higher α3/α2 frequency power ratio group was identified with brain shrinkage and cutdown perfusion inside the temporoparietal projections. In addition, decay and cutdown perfusion rate were connected with memory shortfalls in patients with MCI. MCI subgroup with higher α3/α2 EEG power ratio are at a greater risk to develop AD dementia. [ABSTRACT FROM AUTHOR]

Background: In the field of Alzheimer's disease (AD), the validation of biomarkers for early AD diagnosis and for use as a surrogate outcome in AD clinical trials is of considerable research interest.Objective: To characterize the clinical profile and genetic, neuroimaging and neurophysiological biomarkers of prodromal AD in amnestic mild cognitive impairment (aMCI) patients enrolled in the IMI WP5 PharmaCog (also referred to as the European ADNI study).Methods: A total of 147 aMCI patients were enrolled in 13 European memory clinics. Patients underwent clinical and neuropsychological evaluation, magnetic resonance imaging (MRI), electroencephalography (EEG) and lumbar puncture to assess the levels of amyloid β peptide 1-42 (Aβ42), tau and p-tau, and blood samples were collected. Genetic (APOE), neuroimaging (3T morphometry and diffusion MRI) and EEG (with resting-state and auditory oddball event-related potential (AO-ERP) paradigm) biomarkers were evaluated.Results: Prodromal AD was found in 55 aMCI patients defined by low Aβ42 in the cerebrospinal fluid (Aβ positive). Compared to the aMCI group with high Aβ42 levels (Aβ negative), Aβ positive patients showed poorer visual (P = 0.001), spatial recognition (P < 0.0005) and working (P = 0.024) memory, as well as a higher frequency of APOE4 (P < 0.0005), lower hippocampal volume (P = 0.04), reduced thickness of the parietal cortex (P < 0.009) and structural connectivity of the corpus callosum (P < 0.05), higher amplitude of delta rhythms at rest (P = 0.03) and lower amplitude of posterior cingulate sources of AO-ERP (P = 0.03).Conclusion: These results suggest that, in aMCI patients, prodromal AD is characterized by a distinctive cognitive profile and genetic, neuroimaging and neurophysiological biomarkers. Longitudinal assessment will help to identify the role of these biomarkers in AD progression. [ABSTRACT FROM AUTHOR]

Background: Dubois et al. proposed the criteria for prodromal Alzheimer's disease (AD) to detect dementia in its very early stage. Because detection requires magnetic resonance imaging and 18F‐fluorodeoxyglucose‐positron emission tomography (PET), the prevalence and prognosis have not been fully investigated. Methods: Our database included 346 healthy participants (Clinical Dementia Rating (CDR) 0), 119 with questionable dementia (CDR 0.5), and 32 dementia participants (CDR 1+) and was applied to investigate the prevalence of prodromal AD. Forty‐four CDR 0.5 participants (37%) were randomly selected to undergo 18F‐fluorodeoxyglucose‐PET. The same percentage was applied to select 128 CDR 0 and 12 CDR 1 + participants (total: n = 184) to calculate the prevalence. A neuroradiologist classified the PET images in a blinded manner based on the criteria of Silverman et al. Participants were considered to have prodromal AD if they exhibited ‘parietal/temporal +/− frontal hypometabolism’ (PET) with hippocampal atrophy (magnetic resonance imaging). Results: Eighteen CDR 0.5 participants (40.9%) met the criteria for prodromal AD, which was a prevalence rate of 9.8% among older adults aged ≥65 years. Thirteen prodromal AD participants (72%) converted to AD during the 5‐year follow‐up period. Discussion: The concept and criteria for prodromal AD are useful for predicting which subjects in a community will convert to AD. [ABSTRACT FROM AUTHOR]

Objectives: To investigate arterial spin-labelling (ASL) cerebral blood flow (CBF) changes in predementia stages of Alzheimer's disease (AD).Methods: Data were obtained from 177 patients with subjective complaints, mild cognitive impairment and AD from the Amsterdam Dementia Cohort. AD stages were based on diagnosis and cerebrospinal fluid biomarkers amyloid-β (Aβ) and total-tau (tau). General-linear-models were used to assess relationships between AD stages and total and regional CBF, correcting for age and sex.Results: Decreasing CBF was related to more advanced AD stages in all supratentorial regions (p for trend < 0.05). Post-hoc testing revealed that CBF was lower in AD compared to controls and stage-1 predementia patients (i.e. abnormal Aβ and normal tau) in temporal and parietal regions, and compared to stage-2 predementia patients (i.e. abnormal Aβ and tau) in temporal regions. CBF values of stage-2 predementia patients were numerically in between those of stage-1 predementia patients and AD.Conclusion: The continuing decrease of CBF along the continuum of AD indicates the potential of ASL-CBF as a measure for disease progression.Key Points: • Decreasing CBF relates to more advanced AD stages in all supratentorial regions. • The reduction of CBF does not reach a bottom level. • ASL-CBF has potential as a measure for disease progression in AD. [ABSTRACT FROM AUTHOR]

Prodromal Alzheimer's disease (AD) is a neurodegenerative condition typically progressing to dementia within 3 years. We describe a case of a mild cognitive impairment (MCI) patient with biomarker evidence for amyloidosis, tau, and neurodegeneration who had minimal changes in clinical phenotype during an 11-year period. AD biomarkers were obtained with cerebrospinal fluid analysis and amyloid PET imaging, both of which supported a biological diagnosis of AD. However, the patient's neuropsychological profile remained stable over 11 years except for mild memory-retrieval changes. This case provides evidence that MCI with supportive AD biomarkers may have an atypically minimal progression., Competing Interests: The authors have no conflict of interest to report., (© 2023 – The authors. Published by IOS Press.)

Abstract: The aim of this perspective article is to stimulate radical shifts in thinking and foster further discussion on the effective discovery, development, validation, and qualification process of biological markers derived from all available technical modalities that meet the complex conceptual and pathophysiological challenges across all stages of the complex, nonlinear, dynamic, and chronically progressive sporadic Alzheimer’s disease (AD). This perspective evaluates the current state of the science regarding a broad spectrum of hypothesis-driven and exploratory technologies and “markers” as candidates for all required biomarker functions, in particular, surrogate indicators of adaptive to maladaptive and compensatory to decompensatory, reversible to irreversible brain “systems failure.” We stress the future importance of the systems biology (SB) paradigm (next to the neural network paradigm) for substantial progress in AD research. SB represents an integrated and deeper investigation of interacting biomolecules within cells and organisms. This approach has only recently become feasible as high-throughput technologies and mass spectrometric analyses of proteins and lipids, together with rigorous bioinformatics, have evolved. Existing high-content data derived from clinically and experimentally derived neural tissues point to convergent pathophysiological pathways during the course of AD, transcending traditional descriptive studies to reach a more integrated and comprehensive understanding of AD pathophysiology, derived systems biomarkers, and “druggable” system nodes. The discussion is continued on the premise that the lack of integration of advanced biomarker technologies and transfertilization from more mature translational research fields (e.g., oncology, immunology, cardiovascular), which satisfy regulatory requirements for an accurate, sensitive, and well-validated surrogate marker of specific pathophysiological processes and/or clinical outcomes, is a major rate-limiting factor for the successful development and approval of effective treatments for AD prevention. We consider the conceptual, scientific, and technical challenges for the discovery-development-validation-qualification process of biomarker tools and analytical algorithms for detection of the earliest pathophysiological processes in asymptomatic individuals at elevated risk during preclinical stages of AD. The most critical need for rapid translation of putative markers into validated (performance) and standardized (harmonized standard operating procedures) biomarker tools that fulfill regulatory requirements (qualify for use in treatment trials: e.g., safety, target engagement, mechanism of action, enrichment, stratification, secondary and primary outcome, surrogate outcome) is the availability of a large-scale worldwide comprehensive longitudinal database that includes the following cohorts: (a) healthy aging, (b) people at elevated risks (genetic/epigenetic/lifestyle/comorbid conditions), and (c) asymptomatic–preclinical/prodromal–mild cognitive impairment/syndromal mild, moderate, or severe AD. Our proposal, as initial strategic steps for integrating markers into future development of diagnostic and therapy trial technologies, is to work toward: (a) creating the essential research and development infrastructure as an international shared resource, (b) building the organizational structure for managing such a multinational shared resource, and (c) establishing an integrated transsectoral multidisciplinary global network of collaborating investigators to help build and use the shared research resource. [Copyright &y& Elsevier]

Background: Higher mild cognitive impairment (MCI) prognostic variability has been related to sample characteristics (community-based or specialized clinic) and to diverse operationalization criteria. The aim of the study was to evaluate the trajectory of MCI of Alzheimer type in a population-based elderly cohort in Southern Brazil. We also estimated the risk for the development of probable Alzheimer's disease (AD) in comparison with healthy subjects.Methods: Data were derived from a population-based cohort (the PALA study). MCI outcomes were sub-classified into three categories: conversion, stabilization, and reconversion. The risk of progression to dementia was compared between MCI and normal participants. The analysis was based on 21 MCI subjects and 220 cognitively intact participants (N = 241).Results: Of the 21 MCI subjects, 38% developed dementia, 24% remained stable and 38% improved. The MCI annual conversion rate to AD was 8.5%. MCI was associated with significantly higher risk of conversion to AD (HR = 49.83, p = 0.004), after adjustment for age, education, sex and Mini-Mental State Examination score.Conclusions: Independent of the heterogeneity of the outcomes, MCI of the Alzheimer type participants showed significantly higher risk of developing probable AD, demonstrating the impact of the use of these MCI criteria that emphasize long-term episodic memory impairment. [ABSTRACT FROM PUBLISHER]

Background/Aims: To prospectively follow up a group of amnesic patients at risk for Alzheimer’s disease (AD), to characterize a group of patients whose features were intermediate between amnesic mild cognitive impairment (aMCI) and probable AD, prodromal AD (Prd-AD), and to investigate if these patients were at higher risk for AD conversion. Methods: A total of 109 subjects were assessed by neuropsychological evaluation and by 1H magnetic resonance spectroscopy (1H-MRS): 27 controls, and 16 aMCI, 34 probable AD and 32 Prd-AD patients. Results: Episodic memory and frontal test scores resulted lower in Prd-AD compared to aMCI patients. Prd-AD patients obtained significantly higher scores than AD ones in language, perception, praxis and frontal functions. Although Prd-AD and AD patients had distinct 1H-MRS features from aMCI ones, there were no 1H-MRS differences between Prd-AD and AD patients. The AD annual conversion rate after 1 year of follow-up for Prd-AD (57.1%) was higher than in aMCI patients (20%; p < 0.01). A logistic regression, in which all amnesic patients were treated as a single group, showed that the Visual Memory Test was a significant neuropsychological predictor for AD conversion. Conclusions: Prd-AD patients are a clinically distinguishable group, with distinct neuropsychological and 1H-MRS features and a higher conversion rate to probable AD than aMCI patients. Copyright © 2007 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) and Parkinson's disease (PD) are the first and second most common neurodegenerative disorders, respectively. Both are proteinopathies with inexorable courses and no approved disease-modifying therapies. A substantial effort has been made to identify interventions that could slow down the progression of AD and PD; to date, with no success. The advances in biomarker research improved the identification of individuals at risk for these disorders before symptom onset, recognizing the pre-clinical stage, in which there is abnormal protein accumulation but no clinical symptoms of the disease, and the prodromal stage, in which mild symptoms are present but the clinical diagnostic criteria for disease cannot be fulfilled. The ability to detect pre-clinical and prodromal stages of these diseases has encouraged clinical trials for disease-modification at earlier phases, seeking to slow or prevent phenoconversion into clinical disease. Clinical trials at these stages have several challenges, such as the identification of the eligible population, the appropriate choice of biomarkers, the definition of clinical endpoints, the duration of follow-up, and the statistical analysis. This article aims to discuss some of the methodological challenges in the design of trials for pre-clinical and prodromal phases of AD and PD, to critically review the recent studies, and to discuss methodological approaches to mitigate these challenges in trial design., Competing Interests: The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Aquino.)

Prodromal AD clinical trial methodology is advancing rapidly. It is now possible to more accurately identify MCI patients with underlying AD pathology at an earlier stage of the disease through the use of amyloid imaging and CSF biomarkers. Measurement of decline in these early stage clinical trials using continuous clinical and cognitive outcome measures is conceptually more appealing and adds greater efficiency compared to the classical outcome of 'conversion' to dementia used in prior MCI clinical trials. Nevertheless, the fact that many prodromal AD patients who are likely to be recruited to these early stage studies are not taking acetylcholinesterase inhibitors at the time of enrollment, but are poised to start taking them over a multi-year period of follow-up, is a potential confound that needs to be addressed. [ABSTRACT FROM AUTHOR]

Introduction: The recent failure of several late-stage Alzheimer's disease (AD) clinical trials focused on amyloid beta (Aβ) highlights the challenges of finding effective disease-modifying therapeutics. Despite major advances in our understanding of the genetic risk factors of disease and the development of clinical biomarkers, and that not all Aβ-based approaches are equivalent, these failures may engender skepticism regarding the value of the AD pipeline., Methods: To investigate these concerns, we compiled a database of current Phase 2 and 3 trials based on disease-modifying targets through a query of the National Institutes of Health's ClinicalTrials.gov. We then assessed the financial value of the pipeline. Financial modeling utilized risk-adjusted net present value (rNPV) measurements and included sensitivity analyses to help inform the drug development process., Results: Results indicate that the preponderance of current Phase 3 trials were indeed targeting Aβ, with only 15% addressing other targets. In contrast, the pipeline of Phase 2 trials was more diverse. The estimated rNPV of Phase 2 and 3 therapeutics was estimated to be $338 billion over 10 years. This figure increased to a theoretical cumulative value of $788 billion when incorporating the assumption that diagnostics will be developed to identify individuals at high risk for developing AD. Results from model sensitivity analyses showed that speed of market penetration and patient access contributed the most weight to financial value. In contrast, decreasing drug development costs had minimal impact on rNPV., Discussion: These findings argue in favor of conducting thorough biomarker-driven Phase 2 proof of concept studies to avoid prematurely advancing assets into Phase 3. Insights from these analyses are also discussed in the context of the financial ecosystem needed to maintain a healthy AD pipeline., (© 2020 The Authors. Alzheimer's & Dementia: Translational Research & Clinical Interventions published by Wiley Periodicals, Inc. on behalf of Alzheimer's Association.)

Background: Apolipoprotein E (ApoE) ε 4 has been identified as the strongest genetic risk factor for Alzheimer's disease (AD). However, the importance of ApoE ε 4 on clinical and biological heterogeneity of AD is still to be determined, particularly at the prodromal stage. Here, we evaluate the association of ApoE ε 4 with clinical cognition and neuroimaging regions in mild cognitive impairment (MCI) participants based on the AT (N) system, which is increasingly essential for developing a precise assessment of AD., Methods: We stratified 178 A+T+MCI participants (prodromal AD) into ApoE ε 4 (+) and ApoE ε 4 (-) according to ApoE genotype from the Alzheimer's Disease Neuroimaging Initiative (ADNI). We determined Aβ-positivity (A+) by the standardized uptake values ratios (SUVR) means of florbetapir-PET-AV45 (the cut-off value of 1.1) and fibrillar tau-positivity (T+) by cerebrospinal fluid (CSF) phosphorylated-tau at threonine 181 position (p-Tau) (cut-off value of 23 pg/mL). We evaluated the effect of ApoE ε 4 status on cognitive conditions and brain atrophy from structural magnetic resonance imaging (MRI) scans. A multivariate analysis of variance was used to compare the differences of cognitive scores and brain atrophy from structural MRI regions of interest (ROIs) between both groups. Furthermore, we performed a linear regression model to assess the correlation between signature ROIs of structural MRI and cognitive scores in the prodromal AD participants., Results: ApoE ε 4 (+) prodromal AD participants had lower levels of CSF Aβ 1-42, higher levels of t-Tau, more memory and global cognitive impairment, and faster decline of global cognition, compared to ApoE ε 4 (-) prodromal AD. ApoE ε 4 (+) prodromal AD participants had a thinner cortical thickness of bilateral entorhinal, smaller subcortical volume of the left amygdala, bilateral hippocampus, and left ventral diencephalon (DC) relative to ApoE ε 4 (-) prodromal AD. Furthermore, the cortical thickness average of bilateral entorhinal was highly correlated with memory and global cognition., Conclusions: ApoE ε 4 status in prodromal AD participants has an important effect on clinical cognitive domains. After ascertaining the ApoE ε 4 status, specific MRI regions can be correlated to the cognitive domain and will be helpful for precise assessment in prodromal AD., Competing Interests: Conflicts of Interest: The authors have no conflicts of interest to declare., (2020 Quantitative Imaging in Medicine and Surgery. All rights reserved.)