Neuropsychiatric symptoms and ApoE genotype in older adults without dementia: a cross-sectional study.

BACKGROUND: The ApoE genotype and neuropsychiatric symptoms (NPS) are known risk factors for cognitive decline in older adults. However, the interaction between these variables is still unclear. The aim of this study was to determine the association between the presence of the ApoE ε4 allele and the occurrence of NPS in older adults without dementia. METHODS: In this cross-sectional investigation we determined the apolipoprotein E (ApoE) genotype of 74 older adults who were either cognitively normal (20.3% / Clinician Dementia Rating Scale (CDR): 0) or had mild cognitive impairment (MCI: 79.7% / CDR: 0.5). We used a comprehensive cognitive assessment protocol, and NPS were estimated by the Neuropsychiatric Inventory-Clinician Rating Scale (NPI-C), Mild Behavioural Impairment-Checklist (MBI-C), Hamilton Rating Scale for Depression (HAM-D), and Apathy Inventory. RESULTS: ApoE ε4 carriers had higher MBI-C total scores than ApoE ε4 noncarriers. Correlations between NPS and ApoE genotype were observed for two NPI-C domains, although in opposite directions: the ApoE ε4 allele was associated with a 1.8 unit decrease in the estimated aberrant motor disturbance score and with a 1.3 unit increase in the estimated appetite/eating disorders score. All fitted models were significant, except for the one fitted for the domain delusions from the NPI-C. Among individuals with amnestic MCI, ε4 carriers presented higher depression score (HAM-D) than noncarriers; in turn, ε4 noncarriers exhibited higher aggression score (NPI-C) than ε4 carriers. CONCLUSIONS: Our analyses showed associations between NPS and the presence of the ApoE ε4 allele in two NPI-C domains, despite the sample size. Furthermore, compared to noncarriers, the presence of the ApoE ε4 correlated positively with appetite/eating disorders and negatively with aberrant motor disturbance domain. Examination of the amnestic MCI group displayed significant, although weak, associations. Therefore, ε4 carriers exhibited higher depression scores according to the HAM-D scale compared to ε4 noncarriers. Conversely, ε4 noncarriers had higher scores in the aggression domain of the NPI-C than ε4 carriers.

Relationship between baseline plasma p-tau181 and longitudinal changes in cognition and structural brain measures in a cohort of cognitively unimpaired older adults.

INTRODUCTION: Preclinical Alzheimer's disease (AD) affects a significant proportion of cognitively unimpaired (CU) older adults. Currently, blood-based biomarkers detect very early changes in the AD continuum with great accuracy. METHODS: We measured baseline plasma phosphorylated tau (p-tau)181 using electrochemiluminescence (ECL)-based assay (MesoScale Discovery) in 533 CU older adults. Follow-up lasted up to 18 months. Cognitive performance assessment included memory and cognitive control. Structural brain measures included cortical thickness, which includes the AD magnetic resonance imaging (AD MRI) signature, and hippocampal volume. RESULTS: In this cohort of CU older adults, baseline plasma p-tau181 levels were not associated with short-term changes in cognition and structural brain measures. Also, baseline plasma p-tau levels did not influence the effects of behavioral interventions (exercise or mindfulness) on cognitive and structural brain changes. DISCUSSION: The short follow-up and healthy status of this CU cohort might have limited the sensitivity of plasma p-tau181 in detecting changes associated with AD pathology.

Diagnostic Performance of an Eye-Tracking Assisted Visual Inference Language Test in the Assessment of Cognitive Decline due to Alzheimer's Disease.

BACKGROUND: The assessment of language changes associated with visual search impairment can be an important diagnostic tool in the Alzheimer's disease (AD) continuum. OBJECTIVE: Investigate the performance of an eye-tracking assisted visual inference language task in differentiating subjects with mild cognitive impairment (MCI) or AD dementia from cognitively unimpaired older adults (controls). METHODS: We assessed a group of 95 older adults (49 MCI, 18 mild dementia due to AD, and 28 controls). The subjects performed the same task under multiple experimental conditions which generate correlated responses that need to be taken into account. Thus, we performed a non-parametric repeated measures ANOVA model for verbal answers, and a linear mixed model (LMM) or its generalized version for the analysis of eye tracking variables. RESULTS: Significant differences were found in verbal answers across all diagnostic groups independently of type of inference, i.e., logic or pragmatic. Also, eye-tracking parameters were able to discriminate AD from MCI and controls. AD patients did more visits to challenge stimulus (Control-AD, -0.622, SE = 0.190, p = 0.004; MCI-AD, -0.514, SE = 0.173, p = 0.011), more visits to the correct response stimulus (Control-AD, -1.363, SE = 0.383, p = 0.002; MCI-AD, -0.946, SE = 0.349, p = 0.022), more fixations on distractors (Control-AD, -4.580, SE = 1.172, p = 0.001; MCI-AD, -2.940, SE = 1.070, p = 0.020), and a longer time to first fixation on the correct response stimulus (Control-AD, -0.622, SE = 0.190, p = 0.004; MCI-AD, -0.514, SE = 0.173, p = 0.011). CONCLUSION: The analysis of oculomotor behavior along with language assessment protocols may increase the sensitivity for detection of subtle deficits in the MCI-AD continuum, representing an important diagnostic tool.

Plasma Biomarkers of Alzheimer's Disease: A Review of Available Assays, Recent Developments, and Implications for Clinical Practice.

Recently, low-sensitive plasma assays have been replaced by new ultra-sensitive assays such as single molecule enzyme-linked immunosorbent assay (Simoa), the Mesoscale Discovery (MSD) platform, and immunoprecipitation-mass spectrometry (IP-MS) with higher accuracy in the determination of plasma biomarkers of Alzheimer's disease (AD). Despite the significant variability, many studies have established in-house cut-off values for the most promising available biomarkers. We first reviewed the most used laboratory methods and assays to measure plasma AD biomarkers. Next, we review studies focused on the diagnostic performance of these biomarkers to identify AD cases, predict cognitive decline in pre-clinical AD cases, and differentiate AD cases from other dementia. We summarized data from studies published until January 2023. A combination of plasma Aß42/40 ratio, age, and APOE status showed the best accuracy in diagnosing brain amyloidosis with a liquid chromatography-mass spectrometry (LC-MS) assay. Plasma p-tau217 has shown the best accuracy in distinguishing Aß-PET+ from Aß-PET-even in cognitively unimpaired individuals. We also summarized the different cut-off values for each biomarker when available. Recently developed assays for plasma biomarkers have undeniable importance in AD research, with improved analytical and diagnostic performance. Some biomarkers have been extensively used in clinical trials and are now clinically available. Nonetheless, several challenges remain to their widespread use in clinical practice.

Revisiting global cognitive and functional state 13 years after a clinical trial of lithium for mild cognitive impairment

Objectives: To re-evaluate a sample of older adults enrolled in a randomized controlled trial of lithium for amnestic mild cognitive impairment (MCI) after 11 to 15 years, re-assessing their current (or last available) global cognitive and functional state. Methods: We recalled all former participants of the Lithium-MCI trial conducted by our group between 2009 and 2012 to perform a single-blinded, cross-sectional evaluation of their global clinical state to compare the long-term outcome of those who received lithium vs. those who received placebo. Results: Of the original sample (n=61), we were able to reach 36 participants (59% of retention), of whom 22 had previously received lithium (61% of the recall sample) and 14 (39%) had received placebo. Since 30.5% of the recalled sample was deceased, psychometric data were collected only for 69.5% of the participants. We found statistically significant differences in current mean Mini Mental State Examination score according to previous treatment group (25.5 [SD, 5.3] vs. 18.3 [SD, 10.9], p = 0.04). The lithium group also had better performance in the phonemic Verbal Fluency Test than the control group (34.4 [SD, 14.4] vs. 11.6 [SD, 10.10], p < 0.001). Differences in these measures also had large effect sizes, as shown by Cohen's d values of 0.92 and 1.78, respectively. Conclusion: This data set suggests that older adults with amnestic MCI who had been treated with lithium during a previous randomized controlled trial had a better long-term global cognitive outcome than those from a matched sample who did not receive the intervention.

Revisiting global cognitive and functional state 13 years after a clinical trial of lithium for mild cognitive impairment.

OBJECTIVES: To re-evaluate a sample of older adults enrolled in a randomized controlled trial of lithium for amnestic mild cognitive impairment (MCI) after 11 to 15 years, re-assessing their current (or last available) global cognitive and functional state. METHODS: We recalled all former participants of the Lithium-MCI trial conducted by our group between 2009 and 2012 to perform a single-blinded, cross-sectional evaluation of their global clinical state to compare the long-term outcome of those who received lithium vs. those who received placebo. RESULTS: Of the original sample (n=61), we were able to reach 36 participants (59% of retention), of whom 22 had previously received lithium (61% of the recall sample) and 14 (39%) had received placebo. Since 30.5% of the recalled sample was deceased, psychometric data were collected only for 69.5% of the participants. We found statistically significant differences in current mean Mini Mental State Examination score according to previous treatment group (25.5 [SD, 5.3] vs. 18.3 [SD, 10.9], p = 0.04). The lithium group also had better performance in the phonemic Verbal Fluency Test than the control group (34.4 [SD, 14.4] vs. 11.6 [SD, 10.10], p < 0.001). Differences in these measures also had large effect sizes, as shown by Cohen's d values of 0.92 and 1.78, respectively. CONCLUSION: This data set suggests that older adults with amnestic MCI who had been treated with lithium during a previous randomized controlled trial had a better long-term global cognitive outcome than those from a matched sample who did not receive the intervention.

Impact of Cognitive Demand on Eye Movement Pattern in Patients with Alzheimer's Disease.

BACKGROUND: Eye-movement behavior has been used as a reliable tool to identify cognitive and behavioral patterns in individuals with different neuropsychiatric disorders including Alzheimer's disease (AD). Most studies in the field have been dedicated to evaluating eye-movement behavior during cognitive tasks in different protocols using multiple parameters. OBJECTIVE: We aimed to evaluate the differences of eye-movement behavior in healthy subjects, subjects with mild cognitive impairment (MCI), and those with AD in a simple color task with and without cognitive demand. METHODS: 91 subjects: 18 AD, 47 MCI, and 26 healthy controls had their oculomotor parameters assessed during baseline (no cognitive demand involved) and during a simple computational color memory task using an eye-tracker. RESULTS: Baseline showed statistically different and heterogeneous results between normal cognition and MCI groups. Familiarization phase of the task could not discriminate between groups in any of the analyzed parameters. AD subjects made longer fixations and visits on distractors, and more frequent fixations and visits on the target areas than other groups during the response phase. CONCLUSION: Eye-tracking time-related parameters differentiate AD subjects from other groups under cognitive demand even in a simple color memory task.

Decision tree-based classification as a support to diagnosis in the Alzheimer's disease continuum using cerebrospinal fluid biomarkers: insights from automated analysis

Objective: Cerebrospinal fluid (CSF) biomarkers add accuracy to the diagnostic workup of cognitive impairment by illustrating Alzheimer's disease (AD) pathology. However, there are no universally accepted cutoff values for the interpretation of AD biomarkers. The aim of this study is to determine the viability of a decision-tree method to analyse CSF biomarkers of AD as a support for clinical diagnosis. Methods: A decision-tree method (automated classification analysis) was applied to concentrations of AD biomarkers in CSF as a support for clinical diagnosis in older adults with or without cognitive impairment in a Brazilian cohort. In brief, 272 older adults (68 with AD, 122 with mild cognitive impairment [MCI], and 82 healthy controls) were assessed for CSF concentrations of Aβ1-42, total-tau, and phosphorylated-tau using multiplexed Luminex assays; biomarker values were used to generate decision-tree algorithms (classification and regression tree) in the R statistical software environment. Results: The best decision tree model had an accuracy of 74.65% to differentiate the three groups. Cluster analysis supported the combination of CSF biomarkers to differentiate AD and MCI vs. controls, suggesting the best cutoff values for each clinical condition. Conclusion: Automated analyses of AD biomarkers provide valuable information to support the clinical diagnosis of MCI and AD in research settings.

Decision tree-based classification as a support to diagnosis in the Alzheimer's disease continuum using cerebrospinal fluid biomarkers: insights from automated analysis.

OBJECTIVE: Cerebrospinal fluid (CSF) biomarkers add accuracy to the diagnostic workup of cognitive impairment by illustrating Alzheimer's disease (AD) pathology. However, there are no universally accepted cutoff values for the interpretation of AD biomarkers. The aim of this study is to determine the viability of a decision-tree method to analyse CSF biomarkers of AD as a support for clinical diagnosis. METHODS: A decision-tree method (automated classification analysis) was applied to concentrations of AD biomarkers in CSF as a support for clinical diagnosis in older adults with or without cognitive impairment in a Brazilian cohort. In brief, 272 older adults (68 with AD, 122 with mild cognitive impairment [MCI], and 82 healthy controls) were assessed for CSF concentrations of Aß1-42, total-tau, and phosphorylated-tau using multiplexed Luminex assays; biomarker values were used to generate decision-tree algorithms (classification and regression tree) in the R statistical software environment. RESULTS: The best decision tree model had an accuracy of 74.65% to differentiate the three groups. Cluster analysis supported the combination of CSF biomarkers to differentiate AD and MCI vs. controls, suggesting the best cutoff values for each clinical condition. CONCLUSION: Automated analyses of AD biomarkers provide valuable information to support the clinical diagnosis of MCI and AD in research settings.

Neuropsychiatric symptoms and cerebrovascular risk in non-demented elders: cross-sectional study using the mild behavioural impairment checklist (MBI-C).

BACKGROUND: Neuropsychiatric symptoms (NPS) may represent early clinical manifestations of evolving brain diseases. Studies underpin the occurrence of NPS in the context of mild cognitive impairment (MCI) and prodromal Alzheimer's disease, where symptoms referred to as 'mild behavioural impairment' (MBI) have been shown to predict conversion to dementia and to hasten cognitive/functional decline. However, the association between NPS and cerebrovascular risk factors has been poorly investigated, despite the high prevalence of the latter among individuals with MCI. The aim of the present study was to investigate the association between MBI and cerebrovascular risk in a clinical sample of non-demented elders. METHODS: Sixty-five MCI and 15 cognitively unimpaired older adults were cross-sectionally assessed with the Mild Behavioural Impairment Checklist (MBI-C), using the cut-off score > 6.5 to define positive screening. Participants were submitted to the Hachinski Ischaemic Score (HIS) to account for cerebrovascular symptoms, vascular risk, and related comorbidities. Neuroimaging scans (magnetic resonance imaging and/or 18F-fluorodeoxyglucose-positron emission tomography) and apolipoprotein E genotype were obtained. RESULTS: Positive associations were found between total MBI-C scores and increasing number of comorbidities present (0-2 comorbidities), but not with three comorbidities. Two domains of the MBI-C-impulse dyscontrol and social inappropriateness-followed the same trend of the MBI-C total score, with higher scores with the increasing numbers of comorbidities. No significant associations were found between MBI symptoms and HIS or cerebrovascular burden in neuroimaging assessment. CONCLUSION: We found weak associations between MBI-C total score and the presence of comorbidities with cerebrovascular risk, but not with structural or functional neuroimaging abnormalities or HIS. This finding may represent that the presence of comorbidities adds limited risk to the occurrence of MBI in this sample of non-demented elders.

Heterogeneity of Cerebrospinal Fluid Biomarkers Profiles in Individuals with Distinct Levels of Cognitive Decline: A Cross-Sectional Study.

BACKGROUND: Decreased cerebrospinal fluid (CSF) concentrations of the amyloid-ß (Aß), along with increased total (T-tau) and phosphorylated tau protein (P-tau), are widely accepted as core biomarkers of Alzheimer's disease (AD) pathology. Nonetheless, there are a few remaining caveats that still preclude the full incorporation of AD biomarkers into clinical practice. OBJECTIVE: To determine the frequency of clinical-biological mismatches in a clinical sample of older adults with varying degrees of cognitive impairment. METHODS: 204 participants were enrolled for a cross-sectional assessment and allocated into diagnostic groups: probable AD (n = 60, 29.4%); MCI (n = 84, 41.2%); or normal cognition (NC, n = 60, 29.4%). CSF concentrations of Aß42, T-tau, and 181Thr-P-tau were determined, and Aß42/P-tau ratio below 9.53 was used as a proxy of AD pathology. The AT(N) classification was further used as a framework to ascertain the biological evidence of AD. RESULTS: The majority (73.7%) of patients in the AD group had the Aß42/P-tau ratio below the cut-off score for AD, as opposed to a smaller proportion in the MCI (42.9%) and NC (23.3%) groups. In the latter, 21 subjects (35%) were classified as A+, 28 (46.7%) as T+, and 23 (38.3%) as N + . In the AD group, 66.7%of the cases were classified as A+, 78.3%as T+, and 80%as N+. CONCLUSION: Analysis of CSF biomarkers was able to discriminate between AD, MCI, and NC. However, clinical-biological mismatches were observed in a non-negligible proportion of cases.

AD-Related CSF Biomarkers Across Distinct Levels of Cognitive Impairment: Correlations With Global Cognitive State.

AIM: Associations between cerebrospinal fluid (CSF) biomarkers of Alzheimer's disease (AD) with the severity of cognitive impairment are unclear. We examined the correlations between CSF biomarkers and cognitive performance in the AD continuum. METHODS: We studied 143 elderly patients: cognitively unimpaired (n = 51), mild cognitive impairment (MCI) amnestic (n = 55) and nonamnestic (n = 20), and mild AD (n = 17) assessed with the Cambridge Cognitive Test (CAMCOG). We correlated total CAMCOG and its subdomains with CSF Aß42, T-tau, p-tau levels, and Aß42/p-tau. RESULTS: In the total sample, T-tau and Aß42/p-tau correlated with the total CAMCOG (P < .01); all biomarkers correlated with memory (P < .001); T-tau correlated with language (P < .01). CONCLUSION: Memory and T-tau levels may be the most suitable parameters to reflect cognitive/CSF biomarker correlations. At present, such correlations are of little use in routine clinical practice.

Mental Health Status of Psychogeriatric Patients During the 2019 New Coronavirus Disease (COVID-19) Pandemic and Effects on Caregiver Burden.

Introduction: There is a growing awareness about the noxious effects of the 2019 Coronavirus Disease (COVID-19) pandemic on the mental health of the elderly. However, there is limited information from clinically driven research. The objectives of the present study were to examine the magnitude of psychiatric symptoms and to determine their association with caregiver distress, in a cross-section of community-dwelling older adults and a subsample of aging adults with Down syndrome (DS) attending a psychogeriatric service in São Paulo, Brazil. Method: Telephone-based interviews and electronically filled self-assessment questionnaires were used to collect information from patients and caregivers, addressing their impressions and concerns about the pandemic and related effects on the patient's emotional state and behavior. Clinical information was obtained from hospital charts, medical records, and psychometric tests administered through telephone interviews [Hospital Anxiety and Depression Scale (HADS) and Neuropsychiatric Inventory Questionnaire (NPI-Q)]. Results: We included 100 consecutive participants, comprising 71 older adults with psychogeriatric/neurocognitive disorders and 29 aging adults with DS. Higher HADS and NPI-Q scores were significantly associated with caregiver distress (p < 0.05) in both groups. Correlation analyses indicated strong, positive associations between caregiver burden and scores in HADS anxiety (HADS-A) and HADS depression (HADS-D) scales in the subsamples of euploid and DS subjects. Higher NPI-Q scores in the former group were also correlated with caregiver distress, with stronger associations for neuropsychiatric symptoms. Similar findings were observed among DS subjects. ANOVA tests indicated significant associations between NPI-Q scores and caregiver distress among dementia patients, as well as with HADS scores. Similar results were found after multiple linear regressions; as such, among the elderly subsample, higher scores in HADS-A (p = 0.002) and HADS-D (p = 0.001) predict a significant impact on caregiver burden (p < 0.00001, R 2 0.46); taking into consideration caregiver burden as a dependent variable and NPI-Q total score as an independent variable, we obtained significant strong prediction values for either DS (p < 0.00001, R 2 0.95) or elderly adults (p < 0.00001, R 2 0.88). Conclusion: During the COVID-19 pandemic, patients with neurocognitive disorders present with clinically relevant neuropsychiatric symptoms, with significant impact on caregiver distress. Apathy, aberrant motor behavior, sleep disorders, and psychoses were the main psychopathological domains, which had determined caregiver burden worsening.

Early diagnosis and treatment of Alzheimers disease: new definitions and challenges

The prevalence of Alzheimer's disease (AD), a progressive neurodegenerative disorder, is expected to more than double by 2050. Studies on the pathophysiology of AD have been changing our understanding of this disorder and setting a new scenario for drug development and other therapies. Concepts like the "amyloid cascade" and the "continuum of AD," discussed in this article, are now well established. From updated classifications and recommendations to advances in biomarkers of AD, we aim to critically assess the literature on AD, addressing new definitions and challenges that emerged from recent studies on the subject. Updates on the status of major clinical trials are also given, and future perspectives are discussed.

Cognitive impairment in remitted late-life depression is not associated with Alzheimer's disease-related CSF biomarkers.

BACKGROUND: Cognitive impairment is a common feature of late-life depression (LLD). Early studies using Alzheimer's disease (AD) biomarkers inferred a biological link between AD pathology and LLD, but recent findings have challenged this association. The aim of this investigation was to determine a panel of AD-related cerebrospinal fluid (CSF) biomarkers in a cross-section of elders with mild cognitive impairment (MCI) with and without LLD. METHODS: Subjects comprised 102 older adults: 27 with 'pure' amnestic MCI (aMCI), 53 with major depression and cognitive impairment - encompassing 22 late-onset (LOD) and 31 early-onset depression (EOD), and 22 euthymic elders without cognitive impairment (controls). Participants underwent lumbar puncture for determination of CSF concentrations of Aß1-42, T-tau, and P-tau. Cut-off scores for suspected AD were: Aß1-42 < 416p g/mL, P-tau > 36.1 pg/mL and Aß/P-tau ratio < 9.53 (O. V. Forlenza et al. 2015). Statistical analyses consisted of analyses of variance (ANOVA), analyses of covariance (ANCOVA), Bonferroni post-hoc tests, and Pearson's chi-squared tests. RESULTS: ANCOVA (age and schooling as covariates) displayed statistically significant results with respect to CSF biomarkers' profiles regardless of the socio-demographic divergencies previously identified by one-way ANOVA. Mean Aß1-42 values (pg/mL) were: aMCI, 360.3 (p < 0.001); LOD, 486.6 (p < 0.001); EOD, 494.2 (p < 0.001); controls, 528.3 (p < 0.001); p< 0.05. Mean Aß1-42/P-tau ratio: aMCI, 7.9 (p < 0.001); LOD 14.2 (p < 0.001); EOD, 15.3 (p < 0.001); controls, 17.1 (p < 0.001); p < 0.05. Post-hoc tests indicated that patients with aMCI showed significant differences in biomarker profile compatible with AD signature. LIMITATION: The main limitation is the relatively small sample. CONCLUSION: Our findings suggest that, distinctively from aMCI, cognitive impairment in LLD is not associated with AD's CSF pathological signature.

Passive antiamyloid immunotherapy for Alzheimer's disease.

PURPOSE OF REVIEW: Antiamyloid therapy of Alzheimer's disease tackles the overproduction and clearance of the amyloid-beta peptide (Aß). Immunotherapeutic compounds were tested in large-scale trials. We revisit the recent literature focusing on randomized-controlled trials (RCT) using monoclonal anti-Aß antibodies. RECENT FINDINGS: Forty-three articles on anti-Aß passive immunotherapy for Alzheimer's disease were published between January 2016 and October 2019 regarding 17 RCTs: 13 phase III trials using the monoclonal antibodies bapineuzumab, solanezumab, gantenerumab, crenezumab, and aducanumab; three phase II with crenezumab and aducanumab; and one phase I trial with BAN2401. Studies resulted largely negative considering the effect of the treatment on primary and secondary outcome variables. The incidence of the most important adverse effect, amyloid-related imaging abnormalities (ARIAs) ranged between 0.2 and 22%, in treatment groups. Primary endpoints were not met in eight trials, and five trials were discontinued prior to completion. SUMMARY: Passive immunotherapy RCTs failed to show clinically relevant effects in patients with clinically manifest or prodromal dementia. The high incidence of ARIAs indicates that the risk of adverse events may outweigh the benefits of these interventions. Ongoing studies must determine the benefit of such interventions in preclinical Alzheimer's disease, addressing the effect of antiamyloid immunotherapy in samples of asymptomatic carriers of autosomal-dominant mutations related to early-onset Alzheimer's disease.

Early diagnosis and treatment of Alzheimer's disease: new definitions and challenges.

The prevalence of Alzheimer's disease (AD), a progressive neurodegenerative disorder, is expected to more than double by 2050. Studies on the pathophysiology of AD have been changing our understanding of this disorder and setting a new scenario for drug development and other therapies. Concepts like the "amyloid cascade" and the "continuum of AD," discussed in this article, are now well established. From updated classifications and recommendations to advances in biomarkers of AD, we aim to critically assess the literature on AD, addressing new definitions and challenges that emerged from recent studies on the subject. Updates on the status of major clinical trials are also given, and future perspectives are discussed.