Abstract Body

Several papers show that the core AD pathophysiologies amyloid deposition (A), tau pathology (T), neurodegeneration (N), as well as glial activation (G) can accurately be identified and monitored using CSF and blood tests. For amyloid deposition, the Ab42/40 ratio, shows high concordance (AUCs of 80-90%) with brain amyloidosis evaluated by PET, but despite high AUCs, the fold change in PET positive cases is lower in plasma than in CSF. Several plasma P-tau species (181, 217, and 231), show a specific increase in plasma in AD, high concordance with tau PET, and increase also in elderly people with PET evidence of brain amyloidosis but with negative tau PET scans. Recent studies show high correlations between these P-tau species in both CSF and plasma, suggesting that differences are minor.

To implement the blood biomarkers in clinical routine diagnostics, full analytical validation of the analytical methods is needed, and optimally also Reference Measurement Procedures and Certified Reference Materials to assure batch-to-batch stability and comparable results across laboratories. In addition, data on the robustness, defined as the difference between the biomarker variability [combined effects of patient-related, biological, pre-analytical, analytical, and longitudinal bias] and the fold change [percent difference between patients and controls]. For a biomarker to be robust and clinically useful, the variability needs to be substantially lower than the fold change. In summary, although more data on assay performance and the certainty of classification into normal/abnormal is needed, blood tests show great promise as easily accessible screening tools for AD in the clinic.

Abstract Body

There is increasing interest in conducting disease-modification trials in the presymptomatic stage of AD- when there is the greatest potential to save cognitive function and better chances of slowing progression.

Presymptomatic trials rely on recruiting individuals on a course towards symptomatic disease. The ability to stage participants is important for the selection of those most likely to benefit and to reduce heterogeneity and improve power.

Familial Alzheimer’s disease (FAD) caused by APP or PSEN mutations genes offer a means of studying presymptomatic disease and understanding the sequence of biomarker changes that may help predict where an individual is in on the disease trajectory and how far they are from symptom onset.

I will review the insights from presymptomatic FAD studies about the timing of fluid (CSF, blood) biomarker changes relative to symptom onset and discuss their relevance to sporadic and familial AD. I will describe the special case of measurement of plasma Aβ peptides (and ratios) in FAD. In a study of 66 family members (39 carriers vs 27 non-carriers) we found elevations in plasma Aβ42:40 ratios in carriers compared to non-carriers and differences in Aβ ratios across genotypes: Aβ42:38 ratios were higher in PSEN1 vs. APP, Aβ38:40 ratios were higher in APP vs. PSEN1. Importantly, more aggressive PSEN1 mutations (earlier AAO) had higher Aβ42:40 and Aβ42:38 ratios: in-vivo evidence of pathogenicity of peptide profiles. Plasma Aβ profiles may improve prediction of an FAD individual's likely age at onset and thereby help in trial inclusion and staging.

Abstract Body

The Parkinson Progression Marker Initiative (PPMI) is a longitudinal, observational, multi-center study to assess progression of clinical outcomes, and imaging, biologic and genetic biomarkers of Parkinson’s disease (PD) progression. The PPMI study has established a robust clinical and biomarker dataset. PPMI has now expanded the number of participants across the PD continuum from prodromal to moderate PD and identify and explore the use of biomarkers to examine the underlying molecular pathobiology of PD, enable modeling of PD progression to identify data driven PD progression sub-sets, and inform studies testing PD therapeutics.

The PPMI prodromal cohort will enroll 2000 participants at high risk of developing PD during the next 3-5 years based on a staged risk paradigm. We plan to enroll approximately 100000 participants in to PPMI online, a customized online platform, to identify those at some risk using questionnaires followed by remote olfactory, genetic and digital testing. Those eligible will be further evaluated in clinic with DAT imaging and then if eligible, enrolled at PPMI study sites in a five-year comprehensive observational, longitudinal clinical study.

We will demonstrate proof of concept for this eligibility paradigm and will provide exploratory data identifying clinical subsets of PD that may predict disease progression. PPMI will expand the existing data set and biorepository already available from PPMI. he PPMI expansion has the potential to establish an algorithm for developing a prodromal PD cohort and to identify meaningful clinical and biomarker outcomes that could accelerate clinical trials of both manifest and prodromal PD.

Abstract Body

Disparities in AD health care are a major problem. Blacks and Latinos are more as likely to develop AD compared to non-/Latino Whites, but racial and ethnic Under-Represented Populations (URPs) remain less likely to be participants in AD research. Until recently, the Alzheimer’s Disease Neuroimaging Initiative (ADNI)had relatively low enrollment of URPs, which greatly limited generalizability of our data. In 2020, we launched culturally-tailored recruitment initiatives at 13 ADNI sites, together with a digital advertising/social media marketing campaign aimed specifically at URPs. Prior to the campaign, rate of enrollment was 1.1 URP/month. The campaign increased enrollment to 4 URP/month, a 264% increase in the “monthly rate.” New participant enrollment, the URP enrollment went from 89 (16.8%) to 126 (21.1%) representing a 25% increase in percent enrollment during the last year. In the last 6 months, there have been 43 new enrollments into ADNI3. Of these 43 participants, 33 (77%) were from URPs. For ADNI4, a new Engagement Core which will deploy a culturally-informed community engaged research approach using a Community-Scientific Partnership Advisory Board and ethnoculturally-concordant, recruiters and retention support. Their efforts will be facilitated by culturally-tailored digital advertising and locally-branded racial and ethnic websites. The goal is to reach ~20,000 individuals (50-60% who are URPs) to complete an online, digital screener with the goal to identify 4,000 participants for a plasma AD biomarker study, leading to in-clinic enrollment of 500 participants (50-60% URPs). We expect these efforts to serve as a potential new model for AD clinical research.

Abstract Body

Objectives: The Alzheimer Disease Neuroimaging Initiative (ADNI) aims to validate clinical diagnoses and molecular biomarkers of Alzheimer disease (AD) to inform the design of clinical trials of anti-AD investigational therapies. We examined the accuracy of these diagnoses and biomarkers for predicting the presence of neuropathological AD.

Methods: All ADNI participants who had completed neuropathological assessments through January 31, 2022, were included in the analyses. The clinical diagnosis of AD, with or without other dementing disorders, at the last ADNI assessment before death was correlated with the presence or absence of neuropathological AD, defined as “intermediate” or “high” AD Neuropathologic Change (ADNC; NIA-AA criteria). Similar correlations were examined using the last amyloid positron emission tomography (PET) results and/or amyloid-beta₄₂, total tau, and p-tau₁₈₁ measurements from the last cerebrospinal fluid (CSF) collection.

Results: In 76 ADNI participants with a clinical diagnosis of AD dementia alone (N=66) or AD dementia with other dementing disorders (N=10), intermediate or high ADNC was present in 64 (84%). AD was the sole neuropathological dementing disorder in 12 (16%) of the 76 cases. In 8 participants who were not diagnosed with AD dementia, 7 (88%) had low or absent ADNC. The predictive accuracy of amyloid PET and CSF biomarkers will be reported.

Conclusions: The ADNI clinical diagnostic accuracy of 84% for neuropathologic AD is acceptable but can be improved with the incorporation of biomarker results. Non-AD biomarkers are also needed as most neuropathologic AD cases have non-AD pathologies that could contribute to dementia and compromise anti-AD trials.

Abstract Body

Abstract Body

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. Both plasma Ab42/40, particularly mass spec methods, and pTau perform well diagnostically against clinical, PET, CSF or autopsy standards. Most of these data, however, were generated from highly selected samples.

Conclusions: Due to advances in plasma biomarkers, widespread application of a biological definition of AD and AT(N) biomarker phenotyping now seems possible. This has significant implications for design of clinical trials, observational research, and clinical care. However, 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. In particular, it is less clear how well plasma biomarkers perform at the earliest, most subtle stages of disease progression, and in community settings.

Abstract Body

Aims: The goal of this study was to identify the molecular bases of dementia in Lewy body diseases, and highlight ways to detect them in life.

Background: Dementia early in the course of disease is one of the defining features of DLB; cognitive impairment and dementia occur later in the course of idiopathic PD but eventually affect >80% by the time of death. As a prelude to developing neuroprotective treatment, it is necessary to identify the putative causes as early as possible.

Methods & Results: We have performed amyloid PET scans in subjects with PD, PDD and DLB, and conducted autopsies on 20 of these. Amyloid Abeta burden is high in most DLB and in many PDD patients; it is associated with faster cognitive decline. Abeta burden is significantly correlated with the extent of tau positive neurofibrillary tangles and alpha-synuclein positive Lewy bodies measured at autopsy.

Conclusions: We conclude that Abeta is a substantial risk factor for developing dementia in Lewy body diseases, that the combination of Abeta, tau and alpha-synuclein is especially neurotoxic, and speculate that efforts to reduce brain Abeta burden may retard cognitive loss in Lewy body diseases.