Cognitive impairment is a common symptom in the elderly population, and in severe cases it is called dementia. The prevalence of dementia increases with age [1]. Alzheimer’s disease (AD) is the most common type of dementia in old age, hence the title Alzheimer’s disease. In recent years, the understanding of AD and other cognitive impairments has deepened as research continues. 1. Neurodegeneration and cognitive impairment 1.1. Alzheimer’s disease As early as the 7th century BC, it was already noted that aging could be accompanied by cognitive decline; in the 18th century, “senile dementia” was recognized as a special pathological state different from normal aging [2]. German neuropsychiatrist Alzheimer reported a case of a female patient with progressive cognitive impairment with abnormal mental behavior, whose autopsy showed brain tissue degeneration, rich in amyloid plaques (senile plaques, SP) and neurogenic fibrillary tangles (NFT); these pathological features were similar to “senile dementia” Three years later Kraepelin cited the case in his book and gave it the name “Alzheimer’s disease”. For a long time, AD was called progeria and was considered a rare disease; it was not until the 1960s that AD was recognized as a major type of dementia in old age [3]. It was found that the genetic mutations of amyloid precursor protein (APP) and progerin 1 and 2 (PS1/2) are closely related to the genetic mutations of amyloid precursor protein (APP), while sporadic AD is associated with apolipoprotein E (ApoE) alleles. The amyloid hypothesis of AD has attracted widespread attention and a series of clinical and pathological diagnostic criteria for AD have been introduced, including Khachaturian, CERAD, Braak and Reagan, all based on histopathological changes in the brain (SP or NFT) [5 -9]. The name “Alzheimer’s disease” was first replaced by “Alzheimer’s dementia” and finally by “Alzheimer’s disease”. The main clinical symptom of AD is chronic progressive cognitive impairment, with memory loss at its core and impairment in other cognitive domains (computation, orientation, language, etc.) of sufficient severity to affect the ability to function in daily life. Screening for cognitive impairment is often done with the help of scales such as the MMSE, while scales such as the ADAS-Cog provide an accurate assessment of cognitive function. Laboratory tests are useful in the diagnosis of AD, including MRI (medial temporal lobe atrophy), cerebrospinal fluid (decreased Aβ42 and increased tau protein) and PET (decreased bilateral temporal lobe glucose metabolism). Research on AD has been conducted for more than a century, and although significant progress has been made in the pathogenesis, diagnosis and treatment of AD, it is still unsatisfactory, and there is still a long way to go in future research. 1.2. Mild cognitive impairment Although the diagnostic criteria for AD are constantly improving and meeting the needs of research and clinical practice, none of the above versions of the diagnostic criteria can avoid the fact that pathological changes similar to AD can be seen in the brain to varying degrees in people without significant cognitive impairment. In addition, a significant number of elderly people with memory or other cognitive decline, but not to the extent of dementia or AD, are often encountered in clinical practice, so the precise definition of normal aging and dementia, either pathologically or clinically, has become an urgent issue. Thus, the concept of mild cognitive impairment (MCI) was subsequently developed in the 1980s [10]. MCI is a clinical symptom cluster, a state of cognitive impairment that is intermediate between normal aging and mild dementia. Patients have a mild degree of cognitive impairment that does not reach the level of dementia (or AD) and their ability to perform daily living activities is not impaired. However, the risk of progression to AD (VaD or other dementia) is higher in MCI than in the normal elderly population. There are several subtypes of MCI, mostly amnestic MCI, and others such as purely non-amnestic and multiple cognitive impairment. The MMSE was originally used for the initial assessment of MCI, but the scale lacks sensitivity to the memory impairment domains characteristic of MCI (e.g., situational memory) and the scoring weights for each cognitive domain are not compatible with MCI; the Montreal Cognitive Assessment Scale (MoCA), which was introduced in recent years, is a comprehensive revision of the MMSE with MCI as the target, and is more suitable for clinical testing of MCI. It is important to note that MCI is relatively reversible, and it is reported that 20%-25% of MCI eventually reverses to normal cognitive function, so it is of great clinical significance to detect MCI early and provide appropriate interventions in time. 2, vascular lesions and cognitive impairment 2.1, vascular dementia As early as the end of the 19th century, vascular factors were recognized as an important cause of cognitive impairment; in 1974, Hachinski proposed the name of “multi-infarct dementia”, thus the concept of vascular dementia (VaD) was introduced. The core of VaD is the presence of both dementia and cerebrovascular disease, and the close relationship between dementia and cerebrovascular disease; cerebrovascular disease as the pathological basis includes not only multiple infarcts, but also infarcts at a single important site, extensive cerebral ischemia and hypoxia, or cerebral hemorrhage. At present, VaD has become the type of dementia with the second highest incidence after AD in old age. 2.2. Vascular cognitive impairment Just as cognitive impairment due to neurodegenerative lesions is severe in AD and mild in MCI, cognitive impairment due to vascular lesions also includes cases that do not reach the level of dementia, and they are quite common in clinical practice, neither normal nor classifiable as VaD, leading to the concept of vascular cognitive impairment (VCI) in the 1990s. VCI is a general term for cognitive impairment of varying degrees due to various cerebrovascular diseases and their risk factors, and is of great interest because of its high prevalence (estimated at 5% in the elderly) and relative treatability. vCI is clinically classified into non-dementia VCI (VCIND), VaD, and mixed dementia. Because of its deep and broad connotation, it provides a huge space for research. However, precisely because of the large coverage and high heterogeneity of the two major elements that make up VCI – etiology (vascular factors) and symptoms (cognitive impairment) – it adds to the difficulty of correctly grasping the connotation of VCI. For example, non-infarct ischemic lesions in the brain are one of the causes of VCI, but the white matter hyper-signal (WMH) on MRI is commonly seen in normal elderly people, which makes it difficult to differentiate them from VCI; the spectrum of cognitive impairment in VCI spans a wide range, and although cortical (e.g., single significant site) infarcts often affect certain specific cognitive impairment spectrum, the more common subcortical lesions in VCI The VCIND subtype of VCI is sometimes difficult to distinguish from the non-amnesic subtype of MCI because the latter may have a vascular origin. Therefore, it is urgent and important to accurately identify VCI in the clinical setting. In recent years, the VCI neuropsychological test protocol jointly recommended by the United States and Canada covers all domains of cognitive function with emphasis on the detection of executive functions, and involves depression and other emotional symptoms common to VCI, which increases the accuracy and operability of VCI diagnosis and has greater clinical guidance significance. The relationship between degenerative and vascular factors in cognitive impairment For a long time, AD has been considered a “pure” degenerative disease, while VaD is a “pure” vascular disease. As research has progressed, these views have been challenged. In 1997, a pathological study of elderly nuns (Nun study) found that the intracerebral SP and NFT loads of the deceased did not coincide with the severity of cognitive impairment during life, whereas lacunar infarct foci were able to focalize the correlation between load and cognitive function [11], thus reawakening the importance of the relationship between cerebral blood supply and cognitive impairment [12]. center longitudinal study in 2001 showed that a number of patients with late-onset dementia had dual AD and cerebrovascular lesions [13]. Patients with only mild subclinical (silent) AD pathology or mild subclinical cerebrovascular disease progressed to dementia later than those with both pathologies. Recent studies have shown that the degree of SP and NFT loading in older adults with dementia (30%) is similar to that in those without cognitive impairment (24.2%); in the former, AD lesions in the brain often coexist with vascular lesions and Lewy vesicles. The likelihood of conversion from normal cognition to MCI and from MCI to dementia is significantly higher in those with multiple coexisting pathological alterations [14]. Late-onset dementia (late-life dementia) often has multiple pathological alterations in the cortex and hippocampus [15,16]. Even minor vascular damage can have a significant impact on brain function, thus shaking the previous belief that the severity of AD dementia is only related to the characteristic pathological changes of AD; the accuracy of AD diagnosis in previous cohort studies has also been questioned. The study confirmed that if only dementia without any vascular lesions were defined as “pure” AD, more than half of the cases previously diagnosed as AD would be rejected. The occurrence of dementia under 75 years of age has been reported to be strongly associated with SP and NFT, but not in those over 90 years of age [17]. It is evident that the previous view that late onset dementia is exclusively attributed to changes in the SP and NFT of the brain is too absolute. In recent years, Fotuhi et al. proposed the dynamic polygon hypothesis for the pathogenesis of dementia, suggesting that the pathogenesis of late-onset dementia is very different from that of early-onset AD, which is mainly due to the toxic effects of SP and NFT, whereas late-onset dementia has a complex pathogenesis and is closely related to cortical and hippocampal volumes, depending on the SP and NFT are only two of the many factors that influence cortical and hippocampal volume and synaptic density and ultimately determine cognitive function in later life [2]. This hypothesis rejects the previous tendency to overemphasize the influence of SP and NFT on the onset of AD, and takes into account many factors such as brain function, cardiovascular function, neuroplasticity, and ultimately cognitive impairment in later life, emphasizing the dynamic interplay between inherited intrinsic pathological processes and environmental variables, suggesting that the balance between favorable and unfavorable genetic factors, and between favorable and unfavorable environmental factors may persist throughout early and mid-life, continue to affect brain function, and play a role in determining whether cognitive function is impaired in later life [2]. Amyloid plaque load is determined to some extent by genetic background, but can be modified by environmental factors such as diet, exercise or traumatic brain injury; like the degree of microangiopathy in the brain, amyloid levels may be influenced by lifestyle. Studies have confirmed that factors associated with the cognitive impairment that accompanies aging, including obesity, depression, hypertension, diabetes, high cholesterol, smoking, alcohol abuse, ApoE genotype, high homocysteine levels, silent stroke, obstructive sleep apnea, chronic stress, traumatic brain injury, abnormal insulin responsiveness, and folate and vitamin B12 deficiency, all transiently or persistently alter brain structure to varying degrees at the cellular and molecular levels or persistently alter brain structure at the cellular and molecular levels, ultimately affecting hippocampal volume and cognitive function. Therefore, unlike early-onset AD, late-onset dementia is somewhat preventable; access to education, exercise, moderate alcohol consumption, mental effort, and consumption of fish, fruits, and vegetables reduce the risk of late-onset dementia. It is believed that these factors may increase synaptic density by promoting angiogenesis or by increasing brain-derived nerve growth factor (BDNF) levels in the brain, leading to enhanced cognitive reserve [18]. 4. Outstanding issues Studies have found that the annual rate of amyloid deposition in normal subjects, MCI or AD patients does not always correspond to the rate of neurodegeneration and brain volume reduction [19], corresponding to the previously observed inconsistency between the rate of dementia progression and the degree of amyloid deposition [14]. Thus, the relationship between late-onset dementia and early-onset AD, i.e., whether late-onset dementia is a sequel to early-onset AD or another disease, remains to be further explored. Perhaps, late-onset dementia is triggered by some unknown gene or protein. The marked atrophy of the cortex and hippocampus in late-onset dementia is more closely related to the severity and rate of progression of dementia than are white matter lesions, infarct foci, SP, NFT, or Lewy bodies. The pathogenetic basis of this atrophy is unknown and it remains to be investigated whether it originates from lesions other than stroke, AD, inflammation or Lewy bodies [17]. Aβ has been used as an important therapeutic target for AD, but whether this remains true for late-onset dementia needs to be further determined. If NFT pathological changes are more closely related to the degree of cognitive impairment than Aβ, the therapeutic focus should seem to shift to the dissociation of tau protein aggregates. As research on cognitive impairment and dementia continues, new insights into the classification of dementia continue to emerge. Traditionally, dementia has been classified according to etiology, involved brain regions or clinical symptoms [1,20], and the currently followed classification is based on etiology, classifying dementia into AD, VaD, mixed dementia and other types of dementia. In recent years, Emre et al. proposed a classification based on pathogenesis, dividing dementia into two main categories: primary degenerative and secondary (symptomatic) [21]. Primary degenerative dementia is characterized by the selective loss of susceptible neurons, and the functionally corresponding brain regions and sites of predilection vary with the disease. It is subdivided into dementia simplex (including AD, Pick’s disease, etc.) and dementia-plus (dementia-plus) disorders. In the former, dementia is the only manifestation; in the latter, symptoms of other systems such as extrapyramidal, pyramidal, or autonomic systems are present in addition to dementia, and these symptoms may occur first, second, or simultaneously with the onset of cognitive impairment, including PD dementia, Lewy body dementia, progressive supranuclear palsy, corticobasal ganglion degeneration, and Huntington’s disease. Secondary dementia is further divided into 3 main subgroups: diseases that directly damage brain tissue; diseases that cause increased intracranial pressure and thus structural brain damage; and abnormal brain function due to lack of certain essential substances in the body or high or low levels of normal components in the blood, such as endocrine, toxic, and metabolic diseases. This classification helps to understand how different diseases have harmful effects on the brain and lead to dementia, and facilitates the development of a logical framework for diagnostic thinking. The diagnostic process of cognitive impairment consists of two major steps. The first is a detailed history, a systematic physical examination and neuropsychological tests to determine the presence of cognitive impairment or dementia; the second is the classification and differentiation of various cognitive impairments and dementias, and finally the identification of the cause. The understanding of cognitive impairment is constantly changing and deepening, and some old ideas have been or are being discarded, while some new ideas have reached consensus. For example, late onset cognitive impairment over the age of 80 years may be associated with multiple pathological changes in the brain such as degeneration and vasculopathy, while a single lesion in the brain (e.g., “pure” AD, LBD, or hippocampal sclerosis) is rare [2]. Many factors influence the development of cognitive impairment, including genetic and environmental factors, which may be beneficial or detrimental to cognitive function. Further elucidation of the role of these factors in the process of cognitive impairment, early intervention for those at risk of cognitive impairment, and reversal of vascular and AD pathological changes in the brain through lifestyle changes and the use of targeted medications are undoubtedly important for the prevention and treatment of cognitive impairment.