**1. Introduction**

Dementia is progressively more common disease in aging population. Worldwide, in 2015 about 46.8 million people were affected by dementia and projected to increase to about 74.7 million by 2030 [1]. The increase in dementia patients is in part due to the aging society, lack of effective prevention strategies, and curative treatments. Due to this exponential increase in dementia population, the social and economic cost of this disorder is surpassing those attributed to cancer and heart diseases [1, 2]. High global prevalence, impact of this disorder on families, caregiv‐ ers, and communities have posed significant public health challenge [3] forcing the global health community to recognize the need for action and to place dementia on the public health agenda. Recently, the World Health Organization (WHO) has identified dementia as a major public health priority [3]. Unfortunately, dementia research has not been given priority as well as funding share, which could be another reason for significant increase in dementia population. For example, in the UK, only 11% of research funding has been allocated for dementia re‐ search while 64% was spent on cancer research in 2012.

The most common forms of dementia are Alzheimer's disease (AD) and vascular dementia (VaD), with respective frequencies of 70 and 15% of all dementias [4]. However, the boundaries between the subtypes are sometimes not clear and mixed forms often coexist [5]. In past decades, research in different subtypes of dementia has failed to improve our understanding of dementia pathogenesis and to develop effective treatments or interventions for this disorder [6, 7]. The major mystery is the lack of information on the main causes of the disorder. This remains the main obstacle in developing a cure for the disorder. Therefore, an urgent inter‐ vention is needed to identify the key molecular mechanism that promotes dementia patho‐ genesis. Several theories have been put forward and only few have survived the test of time. Induction of dementia by ischemic cerebral vascular diseases or stroke was first described in clinics a century ago. However, the later discovery of aggregated β-amyloid and *tau* proteins in the brain tissues of dementia patients diverted the majority of subsequent research toward the study of these two molecules. Accordingly, it was hypothesized that this disorder is triggered by the toxicity of oligomerized protein that forms senile plaque including amyloidbeta (Aβ) and *tau* proteins [8]. However, this hypothesis failed to answer several questions regarding pathogenesis and further development in therapeutics. Although Aβ-deposition has been considered as the main cause of AD, the degree of its deposition in the brain does not correlate with dementia severity [9]. According to Arriagada et al. [10], patients without dementia have the same density of senile plaques as patients with AD. Amyloidal hypothesis could not answer questions such as why healthy elderly people have abundant senile plaques in their brains but no signs of AD [11].

The burden of senile plaques does not correlate with cognitive dysfunction in dementia indicating that protein aggregation alone is not sufficient to explain the pathology of these disorders. Accumulation of degenerative protein modifications (DPMs) triggered by nonen‐ zymatic spontaneous posttranslational modifications, loss of protein function, protein misfolding, protein aggregation, and their depositions in brain tissues could be key features of multiple neurodegenerative diseases since protein dysfunction is likely to extend beyond these Aβ and *tau* proteins alone. These deleterious protein damages can be caused by dysre‐ gulated protein repair and turnover due to hypoxia-ischemia brain injury. Recent epidemio‐ logical, clinical, and experimental studies demonstrated that cerebrovascular disease and hypoxic-ischemic brain injury are the primary causes of cognitive impairment and dementia [12–22].

Proteinopathy is the primary cause of dementia, but rarely attempts have been made to determine the complete composition of deposited protein aggregates, to find what promotes the protein aggregation, does proteins other than Aβ are the main culprit, what is the role of DPMs, and how the constituent proteins contribute to plaque formation. The state-of-the-art mass spectrometry-based proteomic technique has the potential to answer these questions. Proteomic techniques can be considered as an integral part of dementia research to identify biomarkers to detect the disorder at the early stage, understand mechanisms that lead to dementia pathogenesis, design new therapeutics, and monitor response of developed treat‐ ments. Proteomic discoveries in dementia and current published literature were used as a tool for review. To investigate our question regarding the mechanism of dementia pathogenesis and the role of degenerative protein modifications, we searched PubMed and Scopus for the literature using the following terms: dementia proteomics, amyloidal proteins, dementia proteomic biomarker, neurodegenerative diseases, degenerative protein modification, and posttranslational modification. We then review the returned articles to generate the summary of the mechanism of dementia pathogenesis and the role of degenerative protein modifications in dementia pathogenesis. We provide a review of the most significant findings in the field of dementia with a special focus on DPMs. This chapter aims at providing understanding on dementia pathogenesis through state-of-art proteomics technology and the impact of protein modifications. In the present chapter, we discussed the recent developments and novel proteomic approaches to study the mechanism of dementia pathogenesis, novel insights from neuroproteomic research, mechanism of protein aggregation, and the role of DPMs.
