Alzheimer’s disease (AD) is reported to be the leading cause of dementia and the significant healthcare burden of the 21st century [1]. In 2015, over 46 million people were reported to be living with dementia (costing US 818 billion), a figure projected to reach 131.5 million dementia patients by the year 2050 [2]. Developed countries with an ageing population are expected to be worse hit by this burden. Typical clinical presentation of dementia includes memory impairment and executive function decline that interferes with daily activities making the elderly less independent and forcing them to engage with support services [1]. Atypical presentation of dementia consists of a more pronounced memory deficit causing language, visual, and executive problems [1]. Atypical dementia is more common in early-onset dementia, which is reported to have a strong genetic component [1].

The pathophysiology of AD is based on the accumulation of abnormally folded Aβ and Tau proteins in amyloid plaques and neuronal tangles that contribute to neurodegeneration in patients’ brains [3]. Much of this evidence comes from studying familial AD, where there exist mutations in APP genes, which alter the action of γ-secretases that cleaves Amyloid Precursor Protein (APP), causing an accumulation and aggregation of Aβ peptide [4]. Hyperphosphorylated Tau (PTau) protein, another prerequisite for AD diagnosis, accumulates intracellularly and fibrillates into paired helical filaments that form neurofibrillary tangles [5]. It has been proposed that PTau can further accelerate Aβ dysfunction [5]. A significant genetic factor for AD is APOE mutations, with the lifetime risk of AD being 50% for homozygous APOE4 carriers and 20–30% for APOE3 and APOE4 heterozygous carriers [6]. However, even without an APOE mutation at 85 yr of age, there is an 11–15% risk of developing AD, indicating there might be a significant environmental component to AD [6]. Recent evidence has suggested many lifestyle factors: diabetes, diet, socioeconomic status (SES), education, physical and mental activity, depression, tobacco use, and alcohol intake may affect the chance of developing AD and dementia [7]. The Rotterdam study even demonstrated that eliminating the seven most hazardous risk factors could reduce the incidence of dementia by 30% [8]. In the absence of a definitive clinical treatment currently, eliminating these modifiable risk factors is our best tool for reducing the burden of dementia and AD.

Coffee, the most heavily consumed caffeinated beverage, has been a popular research topic in AD, with several epidemiological studies positing its neuroprotective effect [9]. Coffee comprises a few independently neuroprotective components: caffeine, chlorogenic acid, caffeic acid, and trigonelline [10]. Chlorogenic acid has been shown to reduce blood-brain barrier (BBB) damage and improve neuronal differentiation in mice [11]. Caffeic acid and phytochemicals in coffee act as antioxidative and anti-inflammatory substances, thereby helping reduce cognitive decline [12]. Trigonelline from coffee beans has been shown to alleviate neuronal loss by reducing oxidative stress, astrocyte activity, and neuroinflammation while preserving mitochondrial integrity [13]. The neuroprotective properties of coffee have been heavily linked to its high caffeine content, but this has been difficult to demonstrate independently through epidemiological studies due to the confounding effect of other components in caffeinated beverages [9].

2. Effect of Coffee/Caffeine 

Studies by Haller et al. [25,38] showed in early cognitive decline, there is an increase in compensatory basal activity diffused through the posto-temporal region of the brain, which increases the brain’s sensitivity to the neuroprotective action of caffeine [25,38]. Furthermore, MRI studies by Ritchie et al. [35] and Haller et al. [26] showed that caffeine reduces the amount of white matter lesion/cranial volume in cognitively stable elders, contributing to cognitive decline in Dementia/AD [26,43]. Ritchie et al. [43] also showed increased cerebral perfusion in chronic coffee consumers, indicating a possible neuroprotective mechanism of coffee [43]. Moreover, Gelber et al. [39] found high caffeine levels were associated with a lower-odds of having any brain lesion types at autopsy [39]. However, an epidemiological study by Kim et al. [31] did not find any association between coffee intake and hypometabolism, atrophy of AD signature, and WMH volume; instead, it found that coffee exerted a neuroprotective effect by reducing the levels of Aβ [31].

_{3. Conclusion} 

This review found suggestive evidence in clinical studies to propose that caffeine is neuroprotective against dementia and possibly AD, but further studies are required to strengthen this link (Figure 1). The review also found strong evidence based on in vivo and in vitro studies that caffeine has some positive effects in AD models, but further studies are warranted to identify all the mechanistic pathways of the neuroprotective effect of caffeine in AD.