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Aims: In 2018 a workgroup commissioned by the National Institute on Aging and Alzheimer’s Association (NIA-AA) published a research framework in which Alzheimer’s disease (AD) is defined by the underlying pathologic processes rather than by the presence of an etiologically non-specific syndrome or syndromes. This shifts the definition of AD from a syndromal to a biological construct.

Methods: The research framework addresses both diagnosis (definition) and staging of AD. Biomarker and cognitive staging are performed independently from each other. AD can be documented by post-mortem examination or in vivo by biomarkers. Biomarkers are grouped into those of β-amyloid deposition, pathologic tau, and neurodegeneration (AT(N). Both imaging and biofluid (CSF and plasma) biomarkers exist within each AT(N) group.

Results: Since publication of the research framework, significant advances have occurred in development of plasma AT(N) biomarkers. As a results widespread application of a biological definition of AD and AT(N) biomarker phenotyping now seem possible. This has significant implications for design of clinical trials, observational research and clinical care.

Conclusions: Many unanswered questions exist concerning the appropriate roles and the interplay between traditional expensive or invasive AD biomarkers (CSF and imaging) and newer plasma biomarkers.

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NOVEL FLUID AND PET IMAGING MARKERS FOR NEURODEGENERATIVE DISEASES

There is need for biomarkers that improve the diagnostic work-up of neurodegenerative diseases, including Alzheimer’s disease (AD), which can be used in both clinical practice and trials. In this talk I will focus on recent advances in blood-based biomarkers, and how these can be combined with other easily accessible and low-cost biomarkers to improve detection of early AD. For example, we have recently shown that combining plasma P-tau with brief cognitive tests of memory and executive function can with high accuracy predict future development of AD in patients with subjective cognitive decline or mild cognitive impairment, which outperformed the baseline clinical assessment of dementia experts. Further, I will discuss steps needed to be taken before blood-based biomarkers can be implemented in clinical practice globally. Finally, there will be a discussion on how blood and PET biomarkers can improve clinical trials evaluating disease modifying therapies, when it comes to enrichment of study participants to be included in the trials as well as when measuring relevant effects of the treatments.

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Recent studies showing that it is possible to accurately detect the core AD pathologies amyloid deposition (A), tau pathology (T), and neurodegeneration (N), using easily accessible blood tests.

For A, ultrasensitive immunoassays and immunoprecipitation - mass spectrometry (IP-MS) methods show very high concordance (up to >90%) with brain amyloidosis evaluated by PET. For T, several phosphorylated tau species (P-tau181, P-tau217) in blood, show a specific increase in AD, and high concordance with tau PET. Further, plasma P-tau is increased very early, in cognitively unimpaired elderly who have a positive amyloid PET scan. For N, blood NFL reflects axonal degeneratio, with plasma levels being increased even in early stages of the disease, but also tracks neurodegeneration during the AD continuum. These biomarkers also show very low variation in longitudinal samples, and thus promise as a tool to monitor drug therapies, but we are still awaiting data on how these blood biomarkers perform in clinical trials on drugs showing clinical benefit.

Further work is needed to standardize these assays for clinical use, especially the development of Certified Reference Measurement Procedures (“Gold Standard methods”) and Certified Reference Materials (aliquoted plasma pools with known biomarker levels) to assure batch-to-batch stability and for harmonization across assays. We also need studies validating the diagnostic performance in prospective studies using pre-set cut-offs, with samples analysed week by week as they come to the lab.

These blood biomarkers show promise for being clinically useful, easily accessible and cheap, tools for screening and possibly also diagnostics.

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Two blood-based biomarkers have been analytically and clinically validated as biomarkers for Alzheimer’s disease (AD) pathophysiology: the ratio of the 42 to 40 amino acid-long amyloid β as a marker of amyloid plaque pathology, and phosphorylated tau as a marker of AD-related tau phosphorylation and secretion. Additionally, serum neurofilament light (NfL) can be used as a general (non-specific) marker of neurodegeneration. Here, I give an updated account of the current state of the blood-based AD biomarker research field. I discuss how the new blood tests may be used in research studies, as well as in clinical trials and practice, and what role they may play in relation to more established diagnostic tests, such as cerebrospinal fluid biomarkers and amyloid and tau positron emission tomography, in the clinical work-up of patients with suspected AD.

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It is expected that tau imaging will provide a framework for staging and estimate Alzheimer’s disease (AD) progression. However, the off-target binding typically present in the first generation of tau imaging agents and the low tissue concentrations of tau typical from early Braak stages constitute a challenge for quantification of early pathophysiological phases AD. In fact, post-mortem Braak staging proposes that tau neurofibrillary tangle accumulation follows a stereotypical sequential pattern, beginning in the transentorhinal, spreading through the temporal, and then extra-temporal association and primary sensory cortices. Here we showed that high-sub-nanomolar imaging agents, due to their kinetic properties, identify individuals in the early stages of tau accumulation. We demonstrated these properties in a cohort of 301 individuals. Participants had imaging amyloid-beta PET with [¹⁸F]NAV4694, neurofibrillary tangles PET with [¹⁸F]MK-6240, magnetic resonance imaging, and clinical assessments. [¹⁸F]MK-6240 standardized uptake value ratio was quantified from 90-110 min. recapitulated the 6 hierarchical stages proposed by Braak in 98% of our population. No single region-of-interest accurately segregated individuals into the 6 Braak stages. [¹⁸F]MK-6240 SUVRs discriminated Alzheimer's disease from frontotemporal dementia patients (area under the curve = ~95-100%) with the highest accuracy in the transentorhinal, entorhinal, and hippocampal cortices. These results support that [¹⁸F]MK-6240 is suitable for staging preclinical and symptomatic AD. Tau positron emission tomography Braak staging using sub-nanomolar affinity tracers has the potential to be incorporated in the diagnosis and staging of living patients with AD.

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Aims: The prevention of Alzheimer Disease and Related Dementias (ADRD) may be possible through multimodal interventions that combine lifestyle modification, risk reduction, health promotion, and co-morbidity management using precision medicine approaches. A driving factor in ADRD research is the search for markers of amyloid and tau deposition, however up to 40% of ADRD attributable risk may be explained by other factors and pathologies. We have reported novel non-cognitive prodromal predictors of dementia including gait and mobility impairment, sarcopenia, slowed psychomotor performance, declining physical functionality, and depression.

Methods: In a study of 400 older adults (age 75.3+9.2y; 46.9% female, 50.1% positive family history, 64.6% subjective complaints, 38.1% ApoE 4 carriers) using a comprehensive deep-phenotype evaluation to explore non-MRI/PET/CSF biomarkers to test proxy biomarkers of at-risk individuals compared with healthy controls. These proxy markers include computerized gait analyses, optical coherence tomography, dietary patterns, and serum measures of pathology

Results: Individuals at-risk for ADRD and those with mild cognitive impairment show declining gait velocity on dual cognitive-motor tasks, thinning of the retinal nerve cell layers, poorer MIND diet scores, lower “dosages” of physical and cognitive activity participation, and higher vascular risk scores measured with a modified CAIDE score compared with healthy controls. Finally, plasma ADRD biomarkers may discriminate healthy controls from individuals with pre-clinical ADRD.

Conclusions: Efforts to prevent cognitive decline may be enhanced by examining proxy biomarkers of neurodegenerative disease that are less expensive, less invasive and more accessible. Incorporating these findings into multimodal interventions may offer novel approaches to preventing ADRD.

Aims

Differentiating dementia due to small vessel disease (SVD) from Alzheimer’s disease (AD) with concomitant SVD is not optimized in clinical practice; impaired cerebral drainage due to SVD may alter cerebrospinal fluid (CSF) biomarker levels. We aimed to clarify accuracy of CSF biomarkers in patients with AD and concomitant SVD.

Methods

CSF samples from 84 patients with early AD (mild cognitive impairment [n=26]; mild dementia [n=58]) were measured by Elecsys^® CSF immunoassays (Roche Diagnostics). SVD was assessed by the extent of white matter hyperintensities (WMH) on three-dimensional fluid-attenuated inversion recovery magnetic resonance imaging using the lesion segmentation tool (LST). Spearman correlation coefficients between WMH and CSF biomarkers, age, mini-mental state examinations (MMSE) and clinical dementia rating--sum of boxes scores (CDR-SOB) were calculated. Sensitivity and specificity of Elecsys CSF immunoassays using Elecsys package inserts with AD typical metabolic pattern in fluorodeoxyglucose-positron emission tomography (FDG-PET) as comparator (58% AD-positive) were calculated for low, medium and high WMH.

Results

Observed correlations with WMH (*indicates p<0.05) were: Aβ42/Aβ40 (rho=-0.25*), tTau (0.30*), tTau/Aβ42 (0.25*), pTau (0.22), pTau/Aβ42 (0.23), age (0.37*) and MMSE (0.41*), and CDR-SOB (0.23). Sensitivity and specificity stratified by WMH tertile remained within the confidence intervals (CI) for the group point estimate (Table).

Conclusions

The results of this study demonstrate that performance of Elecsys CSF immunoassays to detect AD is not affected by concomitant SVD. Hence, Elecsys CSF assays may support clinicians in differentiating patients with SVD versus AD with concomitant SVD.

Aims

To determine whether CSF synaptic biomarkers are associated with Alzheimer’s disease (AD) pathology, and with functional and structural brain alterations in preclinical AD.

Methods

We studied 384 cognitively unimpaired participants of the ALFA+ cohort (249 A-T-, 104 A+T-, 31 A+T+). AT classification was based on CSF Aβ42/40 (A) and CSF p-tau (T). We measured the following CSF synaptic biomarkers: neurogranin (NeuroToolKit, Roche Diagnostics), GAP-43 (ELISA), SNAP-25 and synaptotagmin-1 (IP-MS). Participants underwent [¹⁸F]-flutemetamol and [¹⁸F]-FDG PET, structural MRI, and clinical and neuropsychological evaluations. Centiloid values (CL) and FDG PET and MRI AD-signatures were quantified. Synaptic biomarkers were compared between AT groups (ANCOVA adjusted by age and sex). The association between synaptic biomarkers and continuous variables was studied in linear regression models overall and stratifying by Aβ status.

Results

CSF neurogranin, GAP-43, SNAP-25, and synaptotagmin-1 were increased in the A+T+ group versus A-T-. All biomarkers increased with age, but this increase was specific for A+ participants for CSF neurogranin, GAP-43 and synaptotagmin-1 (Figure 1a).

Higher levels of the four synaptic biomarkers were associated with higher Aβ burden (i.e. lower CSF Aβ 42/40 and higher CL). CSF SNAP-25 and synaptotagmin-1 were already increased in individuals with subthreshold levels of Aβ pathology (20-40 CL).

In A+ participants, higher CSF neurogranin and GAP-43 levels were associated with higher brain metabolism and lower cortical thickness (Figure 1b, c).

Conclusions

Synaptic dysfunction is an early event in AD pathophysiology, and it is associated with metabolic and structural brain alterations in the preclinical stage of Alzheimer’s continuum.