Since Alois Alzheimer documented the first report of Alzheimer’s disease (AD) in the early 1900s, much progress has been made in the treatment of patients with this disease. While we do not yet have a complete understanding of disease mechanisms, patient care has continued to advance. For example, understanding the utility of biomarkers for the diagnosis of AD and incorporating disease-modifying drugs to slow the progression of cognitive decline are some of the more recent tools that are expected to improve patient outcomes.

AD is a progressive neurodegenerative disease, and it is the most common cause of dementia in older adults. AD dementia is estimated to occur in approximately 1 in 9 people aged 65 years and older, with the proportion increasing with age. A 2023 epidemiologic study estimated the global prevalence of AD dementia, prodromal AD, and preclinical AD to be 32 million, 69 million, and 315 million individuals, respectively. With the increase in life expectancy and in the number of adults aged 65 years and older in the coming years, it has been estimated that the number of AD cases will triple by 2050. Accordingly, the current and projected high numbers of affected individuals are exerting a serious disease burden on patients, families and informal caregivers, and society in general.

The exact cause of AD is not entirely understood; however, it is known to have an insidious onset that is thought to begin years—or even decades—before the occurrence of identifiable behavioral and cognitive impairments that may affect language, memory, comprehension, attention, judgment, and reasoning. Some of the most prominent features of AD are the development of neuropathologic accumulation of beta-amyloid plaques outside of brain neurons and neurofibrillary tangles of the tau protein inside of brain neurons, which are accompanied by neuronal death and brain tissue damage. The reasons for these changes cannot be entirely explained, which have led to multiple hypotheses attempting to identify the root cause of disease. The amyloid hypothesis implicates the production, accumulation, or disposal of beta-amyloid as the primary cause of AD, whereas the tau hypothesis supports a role for the tau-mediated development of neurofibrillary tangles as the causative source of disease. While these are the 2 primary hypotheses that are used to explain the potential causes of AD, other hypotheses have been proposed and are being considered. Therefore, additional investigation is necessary to understand the exact mechanisms that are involved in the development of disease.

Clinically, AD typically progresses from a preclinical, asymptomatic state to mild cognitive impairment to, finally, AD dementia, and the duration within each stage may vary. Early in the course of AD, symptoms may include difficulty remembering recent conversations, names, or events; apathy; and depression. Later-onset symptoms may include impaired communication, disorientation, confusion, poor judgment, and behavioral changes. As the disease progresses, neurons that enable a person to carry out basic bodily functions such as speaking, swallowing, and walking are affected, ultimately resulting in individuals becoming bedbound and requiring around-the-clock care. AD is ultimately fatal.

There is no single test for AD dementia; however, several diagnostic tools are available. An initial diagnosis is typically predicated on the determination of the presence and severity of cognitive impairment, along with an evaluation of the patient’s medical and psychiatric history. A neurologic examination with or without brain imaging may be performed to rule out other causes of impaired memory or thinking. In addition, cognitive, functional, and behavioral tests may provide a more detailed assessment of memory, thinking, and simple problem-solving skills, as well as insight into the effects of the disease on activities of daily living. While not always used to diagnose disease, positron emission tomography–based and fluid-based biomarkers derived from cerebrospinal fluid and, more recently, plasma have demonstrated an ability to accurately identify AD amyloid and tau pathology. Among experts in the field, the confirmation of AD with biomarkers is becoming a consensus requirement for a clinical diagnosis of AD.

Although symptoms can be temporarily relieved by individualized care and medication, there are currently no specific measures to prevent or cure AD. Most of the available pharmacologic treatments aim to improve symptoms or alter disease progression. Cholinesterase inhibitors and NMDA antagonists are US Food and Drug Administration (FDA) approved for the symptomatic treatment of various stages of AD. Cholinesterase inhibitors prevent the breakdown of acetylcholine, which is considered important for memory and cognitive functions, and NMDA antagonists promote a neuroprotective effect by inhibiting the intracellular influx of calcium and reducing neuronal excitotoxicity. Accordingly, these treatments may lessen or stabilize symptoms such as impaired memory, impaired cognition, and dementia-related behaviors. More recently, disease-modifying therapies that alter disease progression by removing beta-amyloid plaques from the brain and slowing cognitive and functional decline have become available. The FDA approval of the first disease-modifying therapy for AD in 2023 will significantly impact the way that the disease is treated in the near and long-term future.

Over the past few decades, research on the pathophysiology of AD has led to an evolution in the management of the disease. Indeed, progress in our understanding of disease pathology and subsequent improvements in the way that patients with AD are clinically evaluated, diagnosed, and treated have significantly improved patient care. Much is still being learned about AD, and the goal is that this increasing knowledge will continue to improve patient outcomes in the future.

Expert Perspectives in Alzheimer’s Disease will include a series of articles exploring current progress and future directions in the pathophysiology, assessment, diagnosis, and management of AD, with a focus on the emerging science and the potential implications for clinical practice.