Coffee and Alzheimer's Disease: A Literature Review on the Neuroprotective Effects of Caffeine, Polyphenols and Interaction with the Gut Microbiome

Abstract

Alzheimer’s Disease (AD) is a chronic, debilitating neurodegenerative disorder and the most common cause of dementia, characterized by progressive cognitive decline and memory impairment [1]. It represents a rapidly growing global health crisis. According to recent epidemiological data, the global number of AD cases has risen significantly, increasing from approximately 4.08 million in 1992 to 9.84 million in 2021 [2]. Projections indicate that this burden will continue to escalate due to population aging, with the total number of cases expected to nearly double to 19.12 million by 2036 [2]. In the United States alone, an estimated 6.9 million individuals aged 65 and older are currently living with Alzheimer’s dementia, a number projected to reach 13.8 million by 2060 [3]. The disease is also a leading cause of mortality; between 2000 and 2021, while deaths from heart disease decreased, reported deaths from AD increased by more than 140% [3].

The socioeconomic burden of AD is staggering. It is one of the costliest conditions to society, imposing immense financial pressure on healthcare systems and families [3]. In 2024, the total payments for health care, long-term care, and hospice services for people with dementia in the US are estimated at $360 billion [3]. On a global scale, the economic impact is equally profound, with spending estimated at USD 305 billion in 2020 and projected to exceed USD 1 trillion by 2050 [2]. Beyond direct medical costs, there is a substantial social burden borne by informal caregivers. In 2023, more than 11 million unpaid caregivers provided an estimated 18.4 billion hours of care, valued at approximately $346.6 billion [3]. This caregiving responsibility often results in significant emotional distress and negative physical health outcomes for family members [3].

Despite the escalating prevalence and costs, the development of effective pharmacological treatments remains a major challenge. AD drug development is characterized by an exceptionally high failure rate. Between 2004 and 2021, approximately 98 unique compounds failed in phase II and III clinical trials, resulting in a success rate of only 2.0% for disease-modifying therapies [1]. Current treatments are largely symptomatic and do not halt the progression of the disease [1], [4]. The repeated failures of clinical trials have been attributed to several factors, including an incomplete understanding of the complex pathophysiology of AD, inappropriate drug dosages, and the initiation of treatment too late in the disease process when neurodegeneration is already irreversible [4]. Recent approvals of anti-amyloid therapies offer some hope, but their clinical efficacy in broader populations remains to be fully validated in real-world settings [1].

Given the lack of an effective cure and the limitations of current pharmacotherapy, research focus has increasingly shifted toward primary prevention strategies, specifically targeting modifiable lifestyle factors [5]. Epidemiological evidence suggests that a healthy lifestyle is associated with a substantially lower risk of developing dementia. A composite score of healthy behaviors—including a high-quality diet, regular physical activity, cognitive engagement, and abstention from smoking—has been shown to reduce the risk of Alzheimer’s dementia by 60% [6]. In particular, dietary patterns such as the Mediterranean diet (MD) and the MIND diet (Mediterranean-DASH Intervention for Neurodegenerative Delay) have demonstrated significant potential in reducing AD risk [5]. For instance, high adherence to the MIND diet has been associated with a 53% reduction in AD rates [5]. Consequently, identifying and promoting these protective lifestyle factors has become a critical public health priority to mitigate the looming burden of Alzheimer’s Disease [6].