Morris, John C.

Abstract Glial fibrillary acidic protein (GFAP) is a promising candidate blood-based biomarker for Alzheimer’s disease (AD) diagnosis and prognostication. The timing of its disease-associated changes, its clinical correlates, and biofluid-type dependency will influence its clinical utility. We evaluated plasma, serum, and CSF GFAP in families with autosomal dominant AD (ADAD), leveraging the predictable age at symptom onset to determine changes by stage of disease. Plasma GFAP elevations appear a decade before expected symptom onset, after β-amyloid accumulation and prior to neurodegeneration and cognitive decline. Plasma GFAP distinguished β-amyloid-positive from β-amyloid-negative ADAD participants and showed a stronger relationship with β-amyloid load in asymptomatic than symptomatic ADAD. Higher plasma GFAP was associated with the degree and rate of neurodegeneration and cognitive impairment. Serum GFAP showed similar relationships, but these were less pronounced for CSF GFAP. Our findings support a role for plasma GFAP as a clinical biomarker for β-amyloid-associated cognitive deterioration in AD.

Abstract Glial fibrillary acidic protein (GFAP) is a promising candidate blood-based biomarker for Alzheimer’s disease (AD) diagnosis and prognostication. The timing of its disease-associated changes, its clinical correlates, and biofluid-type dependency will influence its clinical utility. We evaluated plasma, serum, and CSF GFAP in families with autosomal dominant AD (ADAD), leveraging the predictable age at symptom onset to determine changes by stage of disease. Plasma GFAP elevations appear a decade before expected symptom onset, after β-amyloid accumulation and prior to neurodegeneration and cognitive decline. Plasma GFAP distinguished β-amyloid-positive from β-amyloid-negative ADAD participants and showed a stronger relationship with β-amyloid load in asymptomatic than symptomatic ADAD. Higher plasma GFAP was associated with the degree and rate of neurodegeneration and cognitive impairment. Serum GFAP showed similar relationships, but these were less pronounced for CSF GFAP. Our findings support a role for plasma GFAP as a clinical biomarker for β-amyloid-associated cognitive deterioration in AD.

AbstractIntroductionAs knowledge about neurological examination findings in autosomal dominant Alzheimer disease (ADAD) is incomplete, we aimed to determine the frequency and significance of neurological examination findings in ADAD.MethodsFrequencies of neurological examination findings were compared between symptomatic mutation carriers and non mutation carriers from the Dominantly Inherited Alzheimer Network (DIAN) to define AD neurological examination findings. AD neurological examination findings were analyzed regarding frequency, association with and predictive value regarding cognitive decline, and association with brain atrophy in symptomatic mutation carriers.ResultsAD neurological examination findings included abnormal deep tendon reflexes, gait disturbance, pathological cranial nerve examination findings, tremor, abnormal finger to nose and heel to shin testing, and compromised motor strength. The frequency of AD neurological examination findings was 65.1%. Cross‐sectionally, mutation carriers with AD neurological examination findings showed a more than two‐fold faster cognitive decline and had greater parieto‐temporal atrophy, including hippocampal atrophy. Longitudinally, AD neurological examination findings predicted a significantly greater decline over time.DiscussionADAD features a distinct pattern of neurological examination findings that is useful to estimate prognosis and may inform clinical care and therapeutic trial designs.

AbstractThe extent to which the pathophysiology of autosomal dominant Alzheimer's disease corresponds to the pathophysiology of ‘sporadic’ late onset Alzheimer's disease is unknown, thus limiting the extrapolation of study findings and clinical trial results in autosomal dominant Alzheimer's disease to late onset Alzheimer's disease.We compared brain MRI and amyloid PET data, as well as CSF concentrations of amyloid-β42, amyloid-β40, tau and tau phosphorylated at position 181, in 292 carriers of pathogenic variants for Alzheimer's disease from the Dominantly Inherited Alzheimer Network, with corresponding data from 559 participants from the Alzheimer’s Disease Neuroimaging Initiative. Imaging data and CSF samples were reprocessed as appropriate to guarantee uniform pipelines and assays. Data analyses yielded rates of change before and after symptomatic onset of Alzheimer's disease, allowing the alignment of the ∼30-year age difference between the cohorts on a clinically meaningful anchor point, namely the participant age at symptomatic onset.Biomarker profiles were similar for both autosomal dominant Alzheimer's disease and late onset Alzheimer's disease. Both groups demonstrated accelerated rates of decline in cognitive performance and in regional brain volume loss after symptomatic onset. Although amyloid burden accumulation as determined by PET was greater after symptomatic onset in autosomal dominant Alzheimer's disease than in late onset Alzheimer's disease participants, CSF assays of amyloid-β42, amyloid-β40, tau and p-tau181 were largely overlapping in both groups. Rates of change in cognitive performance and hippocampal volume loss after symptomatic onset were more aggressive for autosomal dominant Alzheimer's disease participants.These findings suggest a similar pathophysiology of autosomal dominant Alzheimer's disease and late onset Alzheimer's disease, supporting a shared pathobiological construct.

AbstractINTRODUCTIONAs the number of biomarkers used to study Alzheimer's disease (AD) continues to increase, it is important to understand the utility of any given biomarker, as well as what additional information a biomarker provides when compared to others.METHODSWe used hierarchical clustering to group 19 cross‐sectional biomarkers in autosomal dominant AD. Feature selection identified biomarkers that were the strongest predictors of mutation status and estimated years from symptom onset (EYO). Biomarkers identified included clinical assessments, neuroimaging, cerebrospinal fluid amyloid, and tau, and emerging biomarkers of neuronal integrity and inflammation.RESULTSThree primary clusters were identified: neurodegeneration, amyloid/tau, and emerging biomarkers. Feature selection identified amyloid and tau measures as the primary predictors of mutation status and EYO. Emerging biomarkers of neuronal integrity and inflammation were relatively weak predictors.DISCUSSIONThese results provide novel insight into our understanding of the relationships among biomarkers and the staging of biomarkers based on disease progression.

AbstractBackgroundRecent advances in the development of novel Alzheimer’s disease (AD) measures of amyloid, tau, and neurodegeneration in cerebrospinal fluid (CSF) and blood have enabled a better understanding of the links between amyloid‐beta (Aβ), tau species and neurodegeneration in the brain, CSF, and blood. The discoveries of novel tau species in CSF and blood, including specific phospho‐tau (p‐tau) and truncated species containing the microtubule binding region of tau (MTBR‐tau) which aggregates in tau tangles, have greatly expanded our understanding of tau biology and tau target development. The longitudinal Aβ, tau, and neurofilament light chain (NfL) changes previously measured in CSF are now being measured accurately in blood, enabling interpretation and understanding of AD progression in much larger and more robust populations.MethodWe analyzed longitudinal CSF and/or blood plasma mass spectrometry measures of Aβ42/Aβ40, multiple p‐tau species (including p‐tau217, 231, 181, 205, etc.), total tau, MTBR‐tau (e.g., MTBR‐tau243, MTBR‐tau299, and MTBR‐tau354), and NfL in sporadic AD and dominantly inherited AD cohorts. Mass spectrometry results were compared to amyloid and tau aggregation measures by Positron Emission Tomography (PET) scans and clinical and cognitive measures in local and international clinical cohorts including ADNI, AIBL, BioFINDER, Mayo Clinic, the Knight ADRC, and the DIAN.ResultThe longitudinal results indicate that a pathophysiological cascade of events begin with altered CSF and blood plasma Aβ42/Aβ40 ratio, followed by increases in amyloid plaques as measured by amyloid PET, associated with increased phosphorylation of specific CSF tau species (e.g., p‐tau217, p‐tau181, etc.), before increases in p‐tau205, NfL, total tau concentrations, hypometabolism, and atrophy. Finally, some species of MTBR‐tau increase before or with tau aggregation by tau PET and onset of clinical symptoms and correlate with longitudinal tau aggregation and clinical progression.ConclusionThese findings indicate that CSF and blood plasma Aβ, p‐tau, MTBR‐tau and NfL measures are highly precise biomarkers of brain amyloidosis, tauopathy, and neurodegeneration and can accurately identify stages of preclinical and clinical AD.

Abstract The Worldwide Alzheimer's Disease Neuroimaging Initiative (WW‐ADNI) is a collaborative effort to investigate imaging and biofluid markers that can inform Alzheimer's disease treatment trials. It is a public‐private partnership that spans North America, Argentina, Australia, Canada, China, Japan, Korea, Mexico, and Taiwan. In 2004, ADNI researchers began a naturalistic, longitudinal study that continues today around the globe. Through several successive phases (ADNI‐1, ADNI‐GO, ADNI‐2, and ADNI‐3), the study has fueled amyloid and tau phenotyping and refined neuroimaging methodologies. WW‐ADNI researchers have successfully standardized analyses and openly share data without embargo, providing a rich data set for other investigators. On August 26, 2020, the Alzheimer's Association convened WW‐ADNI researchers who shared updates from ADNI‐3 and their vision for ADNI‐4.

AbstractAs prevention trials advance with autosomal dominant Alzheimer disease (ADAD) participants, understanding the similarities and differences between ADAD and “sporadic” late‐onset AD (LOAD) is critical to determine generalizability of findings between these cohorts. Cognitive trajectories of ADAD mutation carriers (MCs) and autopsy‐confirmed LOAD individuals were compared to address this question. Longitudinal rates of change on cognitive measures were compared in ADAD MCs (n = 310) and autopsy‐confirmed LOAD participants (n = 163) before and after symptom onset (estimated/observed). LOAD participants declined more rapidly in the presymptomatic (preclinical) period and performed more poorly at symptom onset than ADAD participants on a cognitive composite. After symptom onset, however, the younger ADAD MCs declined more rapidly. The similar but not identical cognitive trajectories (declining but at different rates) for ADAD and LOAD suggest common AD pathologies but with some differences.