Dementia Stages Of Alzheimer's Disease Research Articles

Recent advances in understanding Alzheimer's Disease: diagnosis and management strategies.

As the rates of Alzheimer's Disease (AD) increase in the world due to the aging of the population, research has made tremendous advances to target the two hallmark pathologies of AD: amyloid-β (Aβ) plaque deposition and neurofibrillary tangles of hyperphosphorylated tau. Here, we discuss recent advances in the clinical evaluation and management of AD, with a focus on new hypotheses related to the etiology of AD and new evidence related to AD-mimicking neurodegenerative diseases. Though recent clinical studies suggest anti-amyloid disease modifying agents may slow the progression of AD, there is currently no medication that stops it. Moreover, slowing the progression will result in more individuals in the mild cognitive impairment (MCI) and mild dementia stages of AD. Given this reality, we evaluate the development of non-pharmacological strategies to help sustain cognitive function and quality of life.

The time-dependent impact of type 2 diabetes mellitus on incident prodromal Alzheimer's disease: a longitudinal study in 1395 participants.

To investigate the longitudinal impact of type 2 diabetes mellitus (T2DM) on the prodromal and dementia stages of Alzheimer's disease (AD), focusing on diabetes duration and other comorbidities. 1395 dementia-free individuals aged 55-90 years with a maximum 15-year follow-up data were enrolled from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database. Cox proportional hazards regression models were used to estimate hazard ratios (HRs) of the incidence of prodromal or dementia stages of AD. Longer T2DM duration (≥5 years) (multi-adjusted HR=2.19, 95% CI=1.05-4.58), but not shorter T2DM duration (<5 years), was associated with a significantly increased risk of incident prodromal AD over a mean follow-up of 4.8 years. APOE ε4 alleles (HR=3.32, 95% CI=1.41-7.79) and comorbid coronary artery disease (CAD) (HR=3.20, 95% CI=1.29-7.95) further increased the risk of incident prodromal AD in patients with T2DM. No significant association was observed between T2DM and conversational risk of progression from prodromal AD to AD dementia. T2DM, which is characterized by a longer duration, increases the incidence risk of prodromal AD but not AD dementia. APOE ε4 allele and comorbid CAD strengthen the relationship between T2DM and prodromal AD. These findings highlight T2DM characteristics and its comorbidities as predictors for accurate prediction of AD and screening of at-risk populations.

Determinants of informal care time, distress, depression, and quality of life in care partners along the trajectory of Alzheimer's disease.

We evaluated determinants associated with care partner outcomes along the Alzheimer's disease (AD) stages. We included n = 270 care partners of amyloid-positive patients in the pre-dementia and dementia stages of AD. Using linear regression analysis, we examined determinants of four care partner outcomes: informal care time, caregiver distress, depression, and quality of life (QoL). More behavioral symptoms and functional impairment in patients were associated with more informal care time and depressive symptoms in care partners. More behavioral symptoms were related with more caregiver distress. Spouse care partners spent more time on informal care and QoL was lower in female care partners. Behavioral problems and subtle functional impairment of the patient predisposed for worse care partner outcomes already in the pre-dementia stages. Both patient and care partner determinants contribute to the care partner outcomes, already in early disease stages. This study provides red flags for high care partner burden.

Lack of association between bridging integrator 1 (BIN1) rs744373 polymorphism and tau-PET load in cognitively intact older adults.

IntroductionThe bridging integrator 1(BIN1) rs744373 risk polymorphism has been linked to increased [18F]AV1451 signal in non‐demented older adults (ie., mild cognitive impairment [MCI] plus cognitively normal [CN] individuals). However, the association of BIN1 with in vivo tau, amyloid beta (Aβ) burden, and cognitive impairment in the asymptomatic stage of Alzheimer's disease (AD) remains unknown.MethodsThe BIN1 effect on [18F]AV1451 binding was evaluated in 59 cognitively normal (CN) participants (39% apolipoprotein E [APOE ε4]) from the Flemish Prevent AD Cohort KU Leuven (F‐PACK), as well as in 66 Alzheimer's Disease Neuroimaging Initiative (ADNI) CN participants, using voxelwise and regional statistics. For comparison, 52 MCI patients from ADNI were also studied.ResultsForty‐four percent of F‐PACK participants were BIN1 rs744373 risk‐allele carriers, 21% showed high amyloid burden, and 8% had elevated [18F]AV1451 binding. In ADNI, 53% and 50% of CNs and MCIs, respectively, carried the BIN1 rs744373 risk‐allele. Amyloid positivity was present in 23% of CNs and 51% of MCIs, whereas 2% of CNs and 35% of MCIs showed elevated [18F]AV1451 binding. There was no significant effect of BIN1 on voxelwise or regional [18F]AV1451 in F‐PACK or ADNI CNs, or in the pooled CN sample. No significant association between BIN1 and [18F]AV1451 was obtained in ADNI MCI patients. However, in the MCI group, numerically higher [18F]AV1451 binding was observed in the BIN1 risk‐allele group compared to the BIN1 normal group in regions corresponding to more progressed tau pathology.DiscussionWe could not confirm the association between BIN1 rs744373 risk‐allele and elevated [18F]AV1451 signal in CN older adults or MCI. Numerically higher [18F]AV1451 binding was observed, however, in the MCI BIN1 risk‐allele group, indicating that the previously reported positive effect may be confounded by group. Therefore, when studying how the BIN1 risk polymorphism influences AD pathogenesis, a distinction should be made between asymptomatic, MCI, and dementia stages of AD.

Executive Summary of the 2021 International Conference of Korean Dementia Association: A Report From the Academic Committee of the Korean Dementia Association.

Recently, aducanumab, a beta amyloid targeted immunotherapy, has been approved by the US Food and Drug Administration for the treatment of Alzheimer’s dementia (AD). Although many questions need to be answered, this approval provides a promising hope for the development of AD drugs that could be supported by new biomarkers such as blood-based ones and composite neuropsychological tests that can confirm pathologic changes in early stages of AD. It is important to elucidate the complexity of AD which is known to be associated with other factors such as vascular etiologies and neuro-inflammation. Through the second international conference of the Korean Dementia Association (KDA), researchers from all over the world have participated in the exchange of opinions with KDA members on the most up-to-date topics. The Academic Committee of the KDA summarizes lectures to provide the depth of the conference as well as discussions. This will be an important milestone to widen the latest knowledge in the research of AD’s diagnosis, therapeutics, pathogenesis that can lead to the establishment of future directions.

Paucity of Entorhinal Cortex Pathology of the Alzheimer's Type in SuperAgers with Superior Memory Performance.

Advancing age is typically associated with declining memory capacity and increased risk of Alzheimer's disease (AD). Markers of AD such as amyloid plaques (AP) and neurofibrillary tangles (NFTs) are commonly found in the brains of cognitively average elderly but in more limited distribution than in those at the mild cognitive impairment and dementia stages of AD. Cognitive SuperAgers are individuals over age 80 who show superior memory capacity, at a level consistent with individuals 20-30years their junior. Using a stereological approach, the current study quantitated the presence of AD markers in the memory-associated entorhinal cortex (ERC) of seven SuperAgers compared with six age-matched cognitively average normal control individuals. Amyloid plaques and NFTs were visualized using Thioflavin-S histofluorescence, 6E10, and PHF-1 immunohistochemistry. Unbiased stereological analysis revealed significantly more NFTs in ERC in cognitively average normal controls compared with SuperAgers (P < 0.05) by a difference of ~3-fold. There were no significant differences in plaque density. To highlight relative magnitude, cases with typical amnestic dementia of AD showed nearly 100 times more entorhinal NFTs than SuperAgers. The results suggest that resistance to age-related neurofibrillary degeneration in the ERC may be one factor contributing to preserved memory in SuperAgers.

Alzheimer's Disease in Down Syndrome: Progress in the Design and Conduct of Drug Prevention Trials.

Individuals with Down syndrome (DS) are at high risk for developing Alzheimer's disease (AD) pathology and this has provided significant insights into our understanding of the genetic basis of AD. The present review summarizes recent clinical, neuropathologic, imaging, and fluid biomarker studies of AD in DS (DSAD), highlighting the striking similarities, as well as some notable differences, between DSAD and the more common late-onset form of AD (LOAD) in the general population, as well as the much rarer, autosomal-dominant form of AD (ADAD). There has been significant progress in our understanding of the natural history of AD biomarkers in DS and their relationship to clinically meaningful changes. Additional work is needed to clearly define the continuum of AD that has been described in the general population, such as the preclinical, prodromal, and dementia stages of AD. Multiple therapeutic approaches, including those targeting not only β-amyloid but also tau and the amyloid precursor protein itself, require consideration. Recent developments in the field are presented within the context of such efforts to conduct clinical trials to treat and potentially prevent AD in DS.

Functional connectome and neuropsychiatric symptom clusters of Alzheimer's disease

Neuropsychiatric symptoms (NPSs) are important aspects of Alzheimer's disease (AD). Investigation of the effect of functional network abnormalities on clustered NPSs may uncover loci of altered connectivity for more targeted pharmacological and behavioral interventions in AD. The study aimed to investigate functional connectivity in AD and the clustered NPSs, as assessed by the Neuropsychiatric Inventory (NPI). In one hundred and fifty-nine patients with mild dementia stage of AD, graph metrics measuring functional connectivity at global network- and local network-level were assessed by closeness-centrality, betweenness-centrality, average-path-length, local-efficiency, and clustering-coefficient, respectively. The relationship between the NPI composite score and functional connectivity was assessed. In AD, an increase in behavioral composite score was associated with changes in functional connectivity at local network-level, and regions displayed the changes was left lingual gyrus, left sub-genual ACC nodes, and left supra-genual ACC nodes (P < 0.05). An increase in affective composite score was associated with changes in functional connectivity at global network-level, and regions displayed the change was right caudate (P=0.014). An increase in psychotic composite score was associated with changes in functional connectivity at global network-level, and regions displayed the change was left precuneus and right dorsolateral superior frontal gyrus (P < 0.05). Cognitively normal elderly subjects and longitudinal follow-up will be needed to see the evolution of NPS clusters and pathological changes in the functional connectivity at global or local network-level. Different NPS clusters corresponded to distinct changes in functional connectivity at global and local network-level.

TREATMENT PARAMETERS AND RATIONALE FOR THE USE OF ELECTROCONVULSIVE THERAPY FOR THE MANAGEMENT OF TREATMENT-REFRACTORY AGITATION IN ALZHEIMER'S DISEASE

TREATMENT PARAMETERS AND RATIONALE FOR THE USE OF ELECTROCONVULSIVE THERAPY FOR THE MANAGEMENT OF TREATMENT-REFRACTORY AGITATION IN ALZHEIMER'S DISEASE

Intrinsic functional connectivity, CSF biomarker profiles and their relation to cognitive function in mild cognitive impairment.

Mild cognitive impairment (MCI) often precedes Alzheimer's Dementia (AD), and in a high proportion of individuals affected by MCI, there are already neuropathological processes ongoing that become more evident when patients progress to AD. Accordingly, there is a need for reliable biomarkers to distinguish between normal aging and incipient AD. Recent research suggests that, in addition to established biomarkers such as CSF Aß42, total tau and hyperphosphorylated tau, resting state connectivity established by functional magnetic resonance imaging might also be a feasible biomarker for prodromal stages of AD. In order to explore this possibility, we investigated resting state functional connectivity as well as cerebrospinal fluid (CSF) biomarker profiles in patients with MCI (n = 30; age 66.43 ± 7.06 years) and cognitively healthy controls (n = 38; age 66.89 ± 7.12 years). CSF Aß42, total tau and hyperphosphorylated tau concentrations were correlated with measures of cognitive performance (immediate and delayed recall, global cognition, processing speed). Moreover, MCI-related alterations in intrinsic functional connectivity within the default mode network were investigated using functional resting state MRI. As expected, MCI patients showed decreased CSF Aß42 and increased total tau concentrations. These alterations were associated with cognitive performance. However, there were no differences between MCI patients and cognitively healthy controls regarding intrinsic functional connectivity. In conclusion, our results indicate that CSF protein profiles seem to be more closely related to cognitive decline than alterations in resting state activity. Thus, resting state connectivity might not be a reliable biomarker for early stages of AD.

Brain Metabolic Dysfunction in Early Neuropsychiatric Symptoms of Dementia.

Neuropsychiatric symptoms (NPS) including behavioral and psychiatric symptoms are common in the dementia stages of Alzheimer's disease (AD) and are associated with poorer outcomes in cognition, functional states, quality of life, and accelerated progression to severe dementia or death. NPS are also increasingly observed in the mild cognitive impairment stage of AD and may predict incipient dementia. As such, there is an emerging conceptual framework, which support NPS as early non-cognitive symptoms of dementia. [18F]fluorodeoxyglucosepositron emission tomography is a technique that is sensitive in detecting resting metabolism associated with NPS in neuropsychiatric conditions, and there is a growing body of literature evaluating the role of NPS as early indicators of brain metabolic dysfunctions in AD. In this mini-review, we examine the frequency and associations of NPS with metabolic dysfunction in the AD continuum, including preclinical, prodromal, and dementia stages of AD. We will also present the validated neurobehavioral syndrome, mild behavioral impairment describes the later life emergence of sustained NPS as an at-risk state for incident cognitive decline and dementia, and an early presentation of neurodegenerative diseases in some. Lastly, we will discuss future directions in the field so as to better understand the neurobiological basis of NPS in the early stages of the AD continuum, and their role in predicting AD pathophysiological progression and incident dementia.

Timing of Dysphagia Screening in Alzheimer's Dementia.

Dysphagia is an important and frequent symptom in Alzheimer's dementia (AD). We hypothesized that dysphagia could be seen in the early stages of AD and sarcopenia presence rather than the severity of the AD affecting dysphagia. The main aim of this study was to investigate swallowing functions in AD patients according to stages. The second aim was to investigate the correlation between sarcopenia and dysphagia in AD. This study involved 76 probable AD patients. For all participants, diagnosis of sarcopenia was based on definitions from the revised version of European Working Group on Sarcopenia in Older People at 2018. Dysphagia symptom severity was evaluated by the Turkish version of the Eating Assessment Tool, a videofluoroscopic swallowing study (VFSS) was performed for instrumental evaluation of swallowing. The patients were divided into 3 groups according to the clinical dementia rating (CDR) scale as CDR 1 (mild dementia), CDR 2 (moderate dementia), and CDR 3 (severe dementia). Swallowing evaluation parameters were analyzed between these groups. Mean age was 78.9 ± 6.4 years, and 56.4% were female. Twenty-six patients had mild dementia, 31 patients had moderate dementia, 19 patients had severe dementia (CDR 3). We found that sarcopenia rates were similar between AD stages according to CDR in our study population and dysphagia could be seen in every stage of AD. In a multivariate analysis, polypharmacy and sarcopenia were found to be independently associated factors for dysphagia, irrespective of stage of AD (OR: 6.1, CI: 1.57-23.9, P = 0.009; OR: 4.9, CI: 1.24-19.6, P = 0.023, respectively). Aspirations may be subtle so that AD patients and caregivers may not be aware of swallowing difficulties. Therefore, all AD patients, especially those who have polypharmacy and/or sarcopenia (probable-sarcopenia-severe sarcopenia), should be screened for dysphagia in every stage.

Association of hippocampal volume with gait variability in pre-dementia and dementia stages of Alzheimer disease: Results from a cross-sectional study.

Decreased hippocampal volume is a biomarker of Alzheimer disease (AD). The association of hippocampal volume with gait variability across the spectrum of AD, especially in early stages, has been few studied. The study aims to examine the association of hippocampal volume with the coefficient of variation (CoV) of stride time in individuals with mild and moderate to severe subjective cognitive impairment (SCI), non-amnestic mild cognitive impairment (na-MCI), amnestic mild cognitive impairment (a-MCI), and mild to moderate AD dementia. 271 individuals (79 mild SCI, 68 moderate to severe SCI, 47 na-MCI, 42 a-MCI and 35 mild to moderate AD dementia) were included in this cross-sectional study. Hippocampal volume was quantified from a three-dimensional T1-weighted MRI. CoV of stride time was recorded at self-selected pace with an electronic walkway. Age, sex, body mass index, number of drugs daily taken, history of falls, walking speed, type of MRI scanner, total intracranial volume, and white matter volume abnormality were used as covariates. Participants with moderate to severe SCI had a higher CoV of stride time compared to those with mild SCI and na-MCI (P < 0.010), and a higher hippocampal volume compared to other groups (P ≤ 0.001). Participants with moderate to severe SCI had increased hippocampal volume associated with increased CoV of stride time (coefficient of regression β = 0.750 with P = 0.041), while the other groups did not show any significant association. A positive association between greater hippocampal volume (i.e., better brain morphological structure) and an increased stride time variability (i.e., worse gait performance) in individuals with moderate to severe SCI is reported. This association confirms the key role of the hippocampus in gait control and suggests an inefficient compensatory mechanism in early stages of pathological aging like AD.

CSF biomarkers of neuroinflammation and cerebrovascular dysfunction in early Alzheimer disease.

ObjectiveTo measure CSF levels of biomarkers reflecting microglia and astrocytes activation, neuroinflammation, and cerebrovascular changes and study their associations with the core biomarkers of Alzheimer disease (AD) pathology (β-amyloid [Aβ] and tau), structural imaging correlates, and clinical disease progression over time.MethodsThe study included cognitively unimpaired elderly (n = 508), patients with mild cognitive impairment (MCI, n = 256), and patients with AD dementia (n = 57) from the longitudinal Swedish BioFINDER cohort. CSF samples were analyzed for YKL-40, interleukin (IL)–6, IL-7, IL-8, IL-15, IP-10, monocyte chemoattractant protein 1, intercellular adhesion molecule 1 (ICAM-1), vascular adhesion molecule 1 (VCAM-1), placental growth factor, and fms-related tyrosine kinase 1 (Flt-1). MRI data were available from 677 study participants. Longitudinal clinical assessments were conducted in control individuals and patients with MCI (mean follow-up 3 years, range 1–6 years).ResultsCSF levels of YKL-40, ICAM-1, VCAM-1, IL-15, and Flt-1 were increased during the preclinical, prodromal, and dementia stages of AD. High levels of these biomarkers were associated with increased CSF levels of total tau, with the associations, especially for YKL-40, being stronger in Aβ-positive individuals. The results were similar for associations between phosphorylated tau and YKL-40, ICAM-1, and VCAM-1. High levels of the biomarkers were also associated with cortical thinning (primarily in the precuneus and superior parietal regions) and with subsequent cognitive deterioration in patients without dementia as measured with Mini-Mental State Examination (YKL-40) and Clinical Dementia Rating Sum of Boxes (YKL-40, ICAM-1, VCAM-1 and IL-15). Finally, higher levels of CSF YKL-40, ICAM-1, and Flt-1 increased risk of development of AD dementia in patients without dementia.ConclusionsNeuroinflammation and cerebrovascular dysfunction are early events occurring already at presymptomatic stages of AD and contribute to disease progression.

SEQUENCE OF COGNITIVE DECLINE IN ADULTS WITH DOWN SYNDROME DURING PROGRESSION FROM PRECLINICAL TO PRODROMAL ALZHEIMER'S DISEASE

Down syndrome (DS, trisomy 21) is associated with a high risk of Alzheimer's disease (AD) due to triplication of the APP gene on chromosome 21. DS is therefore an important population in which to test the efficacy of drugs aimed at preventing or delaying onset of disease, before neurodegeneration occurs. However, there is lack of data on the early progression of AD in DS. We aimed to define the progression of aging-related decline associated with AD in DS using detailed cognitive phenotyping in a large cohort of older individuals with DS to identify tests that could be used as outcome measures, and to understand the sequence of cognitive decline, as well as effect of the APOE gene. Using cognitive test data and informant-rated questionnaires from 316 adults with DS aged 16 and older, we firstly compared individuals in the preclinical, prodromal and dementia stage of AD to identify cognitive domains most affected in each group and to estimate effect sizes of potential cognitive outcome measures for trials. We also used a data-driven approach, the Event-Based Model (EBM), to estimate the sequence of AD-related cognitive decline and assign participants to a disease stage. We demonstrated that individuals with DS experience significant cognitive decline before the onset of clinical dementia, with large effect sizes on several cognitive measures for the transition from preclinical to prodromal, and from prodromal to dementia stages. Decline in visuospatial memory and sustained attention are implicated as early events in AD in DS; informant measures defined later events. A staging model was identified, with older adults with an AD diagnosis and those with APOE e4 status being more likely to be staged later. We estimated sample sizes required for clinical trials to prevent or delay decline. Significant cognitive change occurs during the prodromal stages of AD in DS, highlighting the necessity for early assessment. Sample size calculations suggest that trials of treatment to prevent or delay dementia are feasible in DS individuals.

Left lateralized cerebral glucose metabolism declines in amyloid-β positive persons with mild cognitive impairment.

BackgroundPrevious publications indicate that Alzheimer's Disease (AD) related cortical atrophy may develop in asymmetric patterns, with accentuation of the left hemisphere. Since fluorodeoxyglucose positron emission tomography (FDG PET) measurements of the regional cerebral metabolic rate of glucose (rCMRgl) provide a sensitive and specific marker of neurodegenerative disease progression, we sought to investigate the longitudinal pattern of rCMRgl in amyloid-positive persons with mild cognitive impairment (MCI) and dementia, hypothesizing asymmetric declines of cerebral glucose metabolism.MethodsUsing florbetapir PET and cerebrospinal fluid (CSF) measures to define amyloid-β (Aβ) positivity, 40 Aβ negative (Aβ-) cognitively unimpaired controls (CU; 76 ± 5y), 76 Aβ positive (Aβ+) persons with MCI (76 ± 7y) and 51 Aβ + persons with probable AD dementia (75 ± 7y) from the AD Neuroimaging Initiative (ADNI) were included in this study with baseline and 2-year follow-up FDG PET scans. The degree of lateralization of longitudinal rCMRgl declines in subjects with Aβ + MCI and AD in comparison with Aβ- CU were statistically quantified via bootstrapped lateralization indices [(LI); range − 1 (right) to 1 (left)].ResultsCompared to Aβ- CU, Aβ + MCI patients showed marked left hemispheric lateralization (LI: 0.78). In contrast, modest right hemispheric lateralization (LI: −0.33) of rCMRgl declines was found in Aβ + persons with probable AD dementia. Additional comparisons of Aβ + groups (i.e. MCI and probable AD dementia) consequently indicated right hemispheric lateralization (LI: −0.79) of stronger rCMRgl declines in dementia stages of AD. For all comparisons, voxel-based analyses confirmed significant (pFWE<0.05) declines of rCMRgl within AD-typical brain regions. Analyses of cognitive data yielded predominant decline of memory functions in both MCI and dementia stages of AD.ConclusionsThese data indicate that in early stages, AD may be characterized by a more lateralized pattern of left hemispheric rCMRgl declines. However, metabolic differences between hemispheres appear to diminish with further progression of the disease.

Potential Role of Neuroimaging Markers for Early Diagnosis of Dementia in Primary Care.

The use of imaging markers for the diagnosis of predementia and early dementia stages of Alzheimer's disease (AD) has widely been explored in research settings and specialized care. The use of these markers in primary care has yet to be established. Summarize current evidence for the usefulness of imaging markers for AD in primary compared to specialized care settings. Selective overview of the literature, and pilot data on the use of MRI-based hippocampus and basal forebrain volumetry for the discrimination of AD dementia and mild cognitive impairment (MCI) cases from healthy controls in 58 cases from a primary care cohort and 58 matched cases from a memory clinic's sample. Molecular imaging marker of amyloid pathology, and volumetric markers of regional and whole brain atrophy support the diagnosis of AD dementia and MCI due to AD, and contribute to confidence in the differential diagnosis of AD and non-AD related dementias in specialized care. Limited evidence from the literature and our primary care cohort suggests that the diagnostic accuracy of volumetric imaging markers may be similar in the dementia stage of AD, but may be inferior for cases with MCI in primary compared with specialized care. Evidence is still widely lacking on the use of imaging markers for early and differential diagnosis of AD dementia, and detection of prodromal AD in primary care. Further progress to fill this gap will depend on the availability of international multimodal data from well-defined primary care cohorts.

VALIDATING NON-AMYLOID, NON-TAU CSF BIOMARKERS FOR ALZHEIMER'S DISEASE IN THE PRE-SYMPTOMATIC, MCI, AND DEMENTIA STAGES: A MULTI-CENTER STUDY

Amyloid- and tau-related cerebrospinal fluid (CSF) biomarkers for Alzheimer's disease (AD) accurately reflect the presence of neuritic plaques and neurofibrillary tangles in the brain, but their levels remain stable throughout the disease course and do not mirror the degree of cognitive and functional decline. Previous studies have examined whether non-amyloid, non-tau (NANT) CSF biomarkers can improve the fluid biomarker-based staging of AD, but few biomarkers have been validated in multi-centered studies other than the Alzheimer's Disease Neuroimaging Initiative or used independent assays. We reviewed findings from published multi-analyte profiling studies and identified the top nine CSF NANT biomarkers associated with AD. Using CSF collected from subjects with normal cognition (NC), very mild dementia/CDR0.5/mild cognitive impairment (MCI), AD dementia, and other non-AD dementia (OD) recruited from three Alzheimer's Disease Centers, we qualified nine immunoassays to identify stage-dependent biomarkers of AD. Each of the 125 subjects was examined according to clinical diagnosis and CSF AD biomarker profiles. Symptomatic subjects with AD had greater CSF levels of fatty acid binding protein 3, neurofilament light chain (NfL), and interleukin 7 than asymptomatic subjects with AD. Regardless of CSF AD biomarker profiles, NfL levels were highest in dementia and lowest in NC. When combined with amyloid and tau levels, CSF NANT biomarkers can distinguish between pre-symptomatic, MCI, and dementia stages of AD and non-AD disorders.

CSF BIOMARKERS OF NEUROINFLAMMATION ARE ELEVATED IN PRECLINICAL AND PRODROMAL AD AND CORRELATE WITH TAU PATHOLOGY

Neuroinflammation has been implicated in the pathophysiology of Alzheimer's disease (AD). Here we investigated if neuroinflammatory changes occur in the early stages of the disease, e.g. preclinical and prodromal AD. The study population included a cohort of 875 individuals (the Swedish BioFINDER study), including patients with subjective cognitive decline (SCD), mild cognitive impairment (MCI), AD and cognitively healthy elderly. Cerebrospinal fluid (CSF) concentrations of a panel of inflammatory biomarkers were measured using ultrasensitive MSD immunoassay. We also analyzed CSF levels Aβ42, Aβ40 and p-tau. Study participants were categorized into groups with normal (N) or pathological (P) Aβ status using the CSF Aβ42/Aβ40 ratio cutoff<0.1. Inflammatory biomarkers, YKL-40, ICAM-1, VCAM-1 and IL-15 were already increased in preclinical AD stage (control-P group) and remained elevated in prodromal (SCD-P, MCI-P) and dementia stages of AD compared to control-N groups. IL-8 was higher in SCD-P, MCI-P and AD but not in control-P group. The inflammatory biomarkers correlated with CSF p-tau. Furthermore, correlations between p-tau and YKL-40, ICAM-1, VCAM-1 and IL-15 were stronger in CSF Aβ-positive than in Aβ-negative individuals. In this large clinical study we demonstrate that in AD, neuroinflammatory responses are activated early in the disease course, long before the onset of clinical symptoms. Our data also indicate that neuroinflammation may partially trigger AD-related tau pathology especially in cases with amyloid pathology.

THE FINANCIAL CAPACITY INSTRUMENT–SHORT FORM IS A NOVEL, PERFORMANCE-BASED MEASURE THAT MAY HELP DIFFERENTIATE MILD COGNITIVE IMPAIRMENT AND MILD DEMENTIA DUE TO ALZHEIMER’S DISEASE POPULATIONS IN CLINICAL TRIALS

Mild cognitive impairment (MCI) represents a pre-dementia stage of Alzheimer's disease (AD) that immediately precedes mild AD dementia (mAD) on the disease continuum. As both MCI and mAD populations are now commonly included in AD clinical trials, effective differentiation of these two clinical subgroups has key relevance to defining clinical trial populations. We have previously shown that MCI and mAD subgroups at baseline share substantial overlap on traditional clinical measures, suggesting no clear subgroup boundary when using measures such as the Mini Mental State Examination (MMSE). Thus, new measures are needed to better differentiate these subgroups based on clinical score. The Financial Capacity Instrument—Short Form (FCI-SF) is a novel, performance-based measure of clinically relevant financial skills shown to be sensitive to preclinical, prodromal (MCI), and mild dementia stages of AD. In this study, we assessed the ability of FCI-SF performance and processing speed variables to distinguish MCI and mAD groups at baseline. Baseline clinical scores were summarized using descriptive statistics for baseline MCI (n=65) and mAD (n=51) participants from the NIH-funded Cognitive Observations in Seniors Study 2 (COINS2; co-author Marson, PI). The SAS KDE procedure was used to quantify the degree of overlap (OVR) between the two populations on FCI-SF Total Performance, FCI-SF Total Time, and MMSE scores. MCI and mAD populations in COINS2 showed low overlap on baseline FCI-SF total performance scores (OVR=0.41), and high overlap on FCI-SF time to completion scores (OVR=0.78). Consistent with previous work, MMSE overlap was low and similar to FCI-SF performance score overlap when MMSE was used to define clinical subgroup diagnosis (OVR=0.431). The FCI-SF is a novel, performance-based measure that effectively distinguishes MCI and mAD clinical subgroups using baseline performance scores, and in this regard, appears to outperform traditional clinical measures. Previous findings indicate that MMSE overlap is dependent on the use of MMSE at inclusion, where overlap is substantially higher when it is not used to define the clinical subpopulations (OVR=0.72). The FCI-SF represents an emerging new generation of clinically relevant functional performance instruments that may better differentiate early AD populations in clinical trials.