There are multiple potential pharmaceutical targets for the treatment of AD, as currently documented in the Common Alzheimer's Disease Research Ontology (CADRO) , including amyloid beta (Aβ) peptide, tau protein, apolipoprotein E4 (APOE4), lipids, lipoprotein and neurotransmitter receptors, enzymes, and many other regulators, and multitarget interventions. Amyloid beta and tau proteins are the major undisputed pharmacological targets for disease modifying therapies of AD (Figure , lower panel). The fastest growing target according to the CAS data is the transactive response DNA binding protein of 43 kDa (TDP-43), a nuclear protein involved in the regulation of gene expression (Figure , upper panel). Cytoplasmic inclusion bodies comprising phosphorylated and truncated forms of TDP-43 have been found in multiple AD cases, as well as in other proteinopathies including amyotrophic lateral sclerosis, frontotemporal dementia. TDP-43 deposits have been also found in neurons with neurofibrillary tangles. There is emerging evidence that TDP-43 may spread in a prion-like manner, which means it could propagate from cell to cell, potentially contributing to the progression of neurodegenerative diseases like AD. The most common genetic risk factor for AD, apolipoprotein E4 (APOE4), is associated with increased frequency of TDP-43 pathology. Angiotensin-converting enzyme (ACE) is another pharmacological target of AD exhibiting rapid growth in the number of publications included in the CAS Content Collection (Figure , upper panel). Indeed, among the Aβ degrading enzymes such as neprilysin, insulin-degrading enzyme, endothelin-converting enzyme, and ACE, the last one is the most commonly targeted enzyme by inhibitors, mainly because it plays central role in the regulation of blood pressure and hypertension. 121, 122 However, genetic, pathological and biochemical studies have associated ACE with AD. ACE has been shown able to convert neurotoxic β-amyloid protein Aβ42 to Aβ40. Aβ42 is believed to play a causative role in the development of AD, whereas Aβ40 exhibits neuroprotective activities against Aβ42 aggregation as well as against metalinduced oxidative damage. 124 Genetic factors play a major role in the development of AD. In the late-onset type of AD, which applies to 95% of cases, the underlying etiology is supposedly caused by a combination of genetic and environmental factors in the approximate ratio of 70:30, respectively. In the rare cases of early onset AD, the disease etiology is allegedly almost exclusively genetic. Hence, genetics seem to play a major role in all types of AD.