Tauopathies and alpha-synucleinopathies play a critical role in a range of neurodegenerative diseases. Tau can accumulate in different parts of the brain, leading to several neurodegenerative disorders. Alpha-synucleinopathies are neurodegenerative disorders caused by aggregation of abnormal alpha-synuclein proteins (αSyn) with formations of insoluble fibrils in neurons and glia.
Some examples of these disorders are described below.
The Threat to Human Health
people worldwide suffer from AD
people will be diagnosed with AD by 2050
people are affected by Parkinson’s disease (PD)
AD, the most prevalent form of dementia, is characterized by progressive memory loss and cognitive deficits. Pathology is comprised of amyloid-β (Aβ) and intracellular neurofibrillary tangles composed of hyperphosphorylated tau. It is further characterized by the accumulation of 3-repeat (3R) and 4-repeat (4R) forms of tau. Progression of AD, in part, reflects the prionlike spread of Tau aggregates across brain regions, possibly along neuronal networks connected by synapses. Recent studies have shown that tau pathology is closely correlated with cognitive decline in AD patients. Thus, anti-tau immunotherapies have recently become a major emphasis of the potential treatments for AD.
There are also primary tauopathies where either the 3R or 4R forms of tau accumulate in different brain regions, leading to several neurodegenerative disorders.
FTD is the second leading cause of early-onset dementia. It is characterized by atrophy of the the frontal and temporal lobes resulting from neuronal loss, spongy changes, and gliosis. In 20% to 30% of patients, it is caused by mutations in the genes that code for tau protein or other proteins that play an important role in brain function. Clinically, patients present with behavioral and/or language impairments, but they can also present with motor impairment such as those seen in patients with PD, PSP and CBD. During the early stages, it can be difficult to differentiate among these different types of FTD.
PiD is a form of FTD characterized by specific lesions named “Pick bodies” that are found in the hippocampus and frontal cortex, resulting in progressive dementia. Pick bodies are mostly formed from the accumulation of abnormal 3R tau proteins. Therefore, more precise diagnostic approaches, such as PET imaging and plasma or cerebrospinal fluid (CSF), are needed to identify biomarkers. There are no approved treatments that change the course of the disease.
CBD is a rare condition that can cause gradually worsening problems with movement, speech, memory, and swallowing. As with other tauopathies, in the early stages it can be confused with PD, PSP, or LBD. Patients with CBD experience atrophy in frontal brain regions and basal ganglia due to accumulation of the 4R form of tau proteins.
PD is the second most common neurodegenerative disorder and results from the loss of neurons in an important brain region called the “substantia nigra,” which regulates dopamine levels in the basal ganglia, a brain region that controls motor function. PD is mainly caused by the accumulation of abnormal forms of alpha-synuclein, a protein believed to play a role in neuronal communication. As a result, the brains of patients with PD show progressive decreases in dopamine levels. Patients with PD typically present with motor impairments, such as slowing of gait, tremor, and loss of balance, but can also show nonmotor symptoms, including psychiatric and sleep disturbances. Although there are many effective treatments available for the motor symptoms of PD, there is no approved treatment that can alter the course of the disease.
LBD is another neurodegenerative disorder, which like PD, that results from the accumulation of aggregated forms of alpha-synuclein in the brain called “Lewy bodies.” Patients with LBD typically present with neuropsychiatric symptoms, often visual hallucinations, progressive decline in cognitive function, and later in the course of the disease, motor deficits similar to those seen in PD. As with the other ɑ-synucleinopathies, there are no approved treatments that can slow or stop progression of this condition.
Clinical Trial Information
APRINOIA Therapeutics Inc.
A Phase 1, Randomized, Double-Blind, Placebo-Controlled, Single Ascending Dose Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Immunogenicity of APNmAb005 in Healthy Subjects
APRINOIA Therapeutics Inc.
Evaluation of [18F]APN-1607 positron emission tomography (PET).
Uptake in AD Patients
Compared With Healthy Subjects
Suzhou APRINOIA Therapeutics Co., Ltd
A Phase 3, Multicenter Study of [18F]APN-1607 PET in Subjects With AD Compared to HC
Evaluation of [18F]APN-1607 as a PET Biomarker
Nanjing First Hospital, Nanjing Medical University
Clinical Evaluation of [18F]APN-1607 PET Uptake in Alzheimer’s Disease Patients
Chang Gung Memorial Hospital, Linkou
Topography Staging and Dual Phase Image Quantification of Tau PET in Cognitive Impairment Subjects
Chang Gung Memorial Hospital
Image Characteristic and Longitudinal
Follow-up of 18F-PMPBB3 (APN-1607) PET for Progressive Supranuclear Palsy
National Taiwan University Hospital
Establishing 18F PMPBB3 (APN 1607) PET Imaging Markers for Diagnosis of Tauopathy Parkinsonism Syndromes
The Alzheimer’s Association
225 N Michigan Ave, 17th floor,
Chicago, IL 60601
American Parkinson Disease Association
Staten Island, NY 10306
Alzheimer’s Foundation of America
322 Eighth Avenue, 16th floor
New York City, NY 10001
200 SE 1st Street, Suite 800,
Miami, FL 33131
The ALS Association
1300 Wilson Boulevard, Suite 600
Arlington, VA 22209
Cure Progressive Supranuclear Palsy
1216 Broadway, 2nd floor
New York City, NY 10001
Northeast Amyotrophic Lateral Sclerosis Consortium (NEAL)
177 E Colorado Blvd, Suite 200
Pasadena, CA 91105-1955
Lewy Body Dementia Association
912 Killian Hill Road, SW
Liburn, GA 30047
Michael J. Fox Parkinson’s Disease Foundation
New York City, NY 10163-4777
National Organization for Rare Disorders (NORD)
1900 Crown Colony Drive, Suite 310
Quincy, MA 02169