Abstract: Neurodegenerative diseases, including Alzheimer’s disease (AD), frontotemporal dementia, Parkinson’s disease, and dementia with Lewy bodies, represent tremendous unmet clinical needs. A common feature of these diseases is the aberrant cerebral accumulation of pathological protein aggregates, affecting selectively vulnerable circuits in a disease-specific pattern. Earlier studies have established a relationship between abnormal aggregation and neuronal dysfunction or loss, suggesting multifactorial pathogenesis mechanisms in these neurodegenerative disorders. Developing disease-modifying drugs requires a thorough molecular understanding of how the proteinopathies progressively spread and the link to neurodegeneration and cognitive impairment. Preventing and removing pathological protein aggregates has shown potential as an effective therapeutic strategy for these proteinopathies. Immunotherapies have demonstrated slowing the rate of cognitive decline by effectively removing pathological amyloid-beta (Aβ) deposits in patients with AD. Several immunotherapeutic approaches targeting tau, alpha-synuclein, and TAR DNA-binding protein 43 for the treatment of neurodegenerative disorders, including AD, primary tauopathies, alpha-synucleinopathies, and amyotrophic lateral sclerosis, are currently in clinical trials. Advances in neuroimaging technology have enabled the noninvasive detection of physiopathological events in the brains of living patients and disease animal models. Positron emission tomography (PET) and single-photon emission computed tomography (SPECT) with radioactive ligands for protein aggregates such as Aβ, tau, and alpha-synuclein with β-sheet structures have facilitated the early and differential detection of AD and primary tauopathies. Aβ and tau PET have demonstrated their clinical utility and validity and are considered surrogate efficacy endpoints in clinical trials of pharmacological or emerging nonpharmacological treatments. In the era of disease-modifying therapy, imaging biomarkers are expected to play an increasingly important role in early diagnosis, patient stratification, and monitoring, in addition to fluid biomarkers.