Alzheimer's disease (AD) in the Hispanic/Latino population is becoming a topic of interest in AD research as Hispanics and Latinos are disproportionately affected by Alzheimer's Disease and underrepresented in clinical research. AD is a neurodegenerative disease, characterized by the presence of amyloid-beta plaques and neurofibrillary tangles, that causes memory loss and cognitive decline in its patients. However, pathology and symptoms have been shown to manifest differently in Hispanic/Latinos, as different neuroinflammatory markers are expressed and cognitive decline is more pronounced. Additionally, there is a large genetic component of AD, with mutations in the amyloid precursor protein (APP), apolipoprotein E APOE), presenilin 1 (PSEN1), bridging Integrator 1 (BIN1), SORL1, and clusterin (CLU) genes increasing one's risk to develop the condition. However, research has shown these high-risk genes have a different effect on Hispanics and Latinos then they do in other racial and ethnic groups. Additionally, this population experiences higher rates of comorbidities, that increase their risk of developing AD. Hispanics and Latinos also face socioeconomic and cultural factors, such as low income and a language barrier, that affect their ability to engage in clinical trials and receive proper care.
Alzheimer's disease
Alzheimer's disease is the most common form of dementia, accounting for 60% of all cases, and is the sixth leading cause of death in the elderly. The disease typically presents itself with intracellular aggregation of hyper-phosphorylated tau, forming neurofibrillary tangles (NFTs), and the extracellular aggregation of amyloid beta (Aβ), forming neuritic plaques. As of 2020, 5.4 million Americans have been diagnosed with Alzheimer's disease, and this number is projected to reach 15-22 million by 2050. Hispanics and Latinos account for 55 million of the population and this population is projected to rise to 97 million, accounting for 25% of the U.S. population, in 2050.
Hispanic/Latino population Hispanics and Latinos make up 18% of the U.S. population, however, they are underrepresented in clinical research. The National Institute of Health (NIH) reported that Hispanic and Latinos accounted for less than 8% of reported clinical trial participants. One proposed reason for the lack of representation is that the Hispanic/Latino population includes many people from different countries, and with this diverse background come different characteristics and comorbidities associated with AD. Hispanic and Latinos have a higher prevalence of AD compared to White non-Hispanics. Studies estimate that 12% of older Hispanic and Latino adults were diagnosed with AD, the highest proportion compared to all other ethnic groups. Hispanic and Latinos are the fastest-growing population in the U.S., and Hispanic/Latino seniors, those who are 65 and older, are expected to have the largest rise in AD and dementia cases compared to other populations, reaching 3.5 million by 2060. In 2011 the National Alzheimer's Disease Project Act was signed into law. The goal of this act was for The National Institute of Aging to accelerate research and clinical care of patients with AD; this act also has the benefit of seeking to improve the inclusion of underrepresented populations in AD research and clinical trials. This neurodegenerative disease varies across all ethnic groups. Studies show that Latinos are up to one-and-a-half times more likely to develop Alzheimer's than non-Latino whites.Manuel, G., & Patel, A. (2020). Alzheimer's Disease and Related Dementias in Hispanic and Latin Populations: A Review.* Journal of Alzheimer's Disease*, 76(4), 1219-1232. https://doi.org/10.3233/JAD-200514
Types There exist two types of Alzheimer's disease: familial Alzheimer's disease, also called early-onset Alzheimer's disease (EOAD), and sporadic Alzheimer's disease, also called late-onset Alzheimer's disease (LOAD). EOAD is the less common of the two, accounting for 5-10%, and patients with EOAD are typically diagnosed with familial AD before they turn 65 years old. LOAD is more common and accounts for 90% of AD cases and its patients experience onset after they turn 65. EOAD has been shown to have 2 types of inheritance patterns: mendelian (mEOAD) and non-mendelian (nmEOAD, sporadic) patterns. The three main genes that implicated in familial AD are amyloid precursor protein (APP), Presenilin-1 (PSEN-1), presenilin-2 (PSEN-2). Onset of sporadic AD has both genetic and environmental risk factors. Some genes of interest in LOAD are the APOE gene, specifically the ApoE4 allele, bridging Integrator 1 (BIN1), SORL1, and clusterin (CLU).
Pathology and symptoms Amyloid beta plaques and neurofibrillary tangles
Neuritic plaques and neurofibrillary Tangles (NFTs) are the main pathological component of AD. Neuritic plaques are composed mainly of the peptide Aβ, but also include other components. APP is processed through either of two pathways, the first is termed the amyloidogenic pathway and produces Aβ. The second pathway is the non-amyloidogenic pathway and does not produce Aβ. In the amyloidogenic pathway, APP (the parent protein) is trafficked to endosomes, cleaved by beta-secretase (BACE), after which it moves back to the cell surface to be cleaved by gamma secretase thus releasing the Aβ peptide. This form of APP processing produces multiple Aβ peptides, of which Aβ40 and Aβ42 peptide are most abundantly produced. APP can also be cleaved by alpha and gamma-secretase and undergo non-amyloidogenic processing. NFTs form when the tau protein, which is involved in microtubule stability, is hyperphosphorylated, dissociates from microtubules and then aggregates with other p-tau monomers forming tau oligomers, fibrils and eventually NFTs. These types of pathologies do not differ across ethnic groups.
Chronic inflammation Neuroinflammation is another pathological component of AD pathology, and is associated with an increase in levels of inflammatory markers. Researchers have also identified many genes linked to immune function that are risk factors for AD, such as TREM2. TREM2 are highly expressed in microglia, the immune cell of the brain, tying the progression of AD with dysfunction in microglial activity. Neuroinflammation, Aβ and tau pathologies interact in Alzheimer's disease, and their progress can be monitored with biomarkers. For example, studies have found the neuroinflammatory marker YKL-40 in the cerebrospinal fluid (CSF) of AD patients. This protein increases years before the onset of AD symptoms and correlates with other neurodegenerative biomarkers, which suggests a potential to predict disease progression. While YKL-40 has not been shown to associate with the APOE -ε4 allele, there is research to link this biomarker to AD in the Hispanic population.
Neurodegeneration Along with the plaques and inflammation, patients with AD also suffer from neurodegeneration, characterized by loss of neurons and synapses (the communication tool for neurons). As a result, the entire brain shrinks in volume (termed brain atrophy), the ventricles grow larger, and the hippocampus and cortex shrink in size. As all these pathologies progress, patients begin to experience a decline in memory, cognitive abilities, and independence. The accumulation of neurofibrillary tangles and loss of synaptic fields correlate most closely with cognitive loss.
Mild cognitive impairment Mild cognitive impairment (MCI) precedes the overt diagnosis of AD. To be diagnosed with MCI a patient must show memory impairment, a progressive decline in cognitive abilities without presenting symptoms of Parkinson's disease, cerebrovascular diseases, and behavioral or language disorders. Studies show that older Hispanic/Latinos exhibit a higher prevalence of dementia than caucasians. Demographic and linguistic factors can prevent a proper MCI diagnosis. For instance, subjects for whom English might not be the primary language require use of a translator to perform the cognitive testing, which could affect testing results, but such experimental weaknesses are frequently not described.
Brain imaging Positron emission tomography (PET) is a brain imaging technique that uses a small amount of radioactive substance, called a tracer, to measure energy use or a specific molecule in different brain regions. In AD research, tracers can be used to detect neuritic plaques (containing Aβ) and tau. Depending on the tracer used, the signal can be used to determine the presence of neuritic plaques and NFTs.
Biomarkers Establishing biomarkers for the early detection of AD is an ongoing are of research because pathological changes occur years before symptoms become apparent. Common biomarkers for AD include amyloid beta and hyperphosphorylated tau, both of which can be found in brain tissue and cerebrospinal fluid (CSF). Aβ provides a biomarker of neuritic plaques, which form when APP cleavage results in an increase in the Aβ42/Aβ40 ratio. Hyperphosphorylated tau serves as a biomarker of neurofibrillary tangles (NFTs), with the presence of NFTs indicating a disruption in microtubule stability and neuronal injury. Researchers have begun investigating other markers in the CSF, such as markers of neuronal injury, like Visinin-Like-Protein-1 (VILIP-1), YKL-40, and Neurogranin (NGRN). Due to the low use of CSF sampling in most countries, efforts have been made to study biomarkers in blood. Through work on blood biomarkers, researchers have been able to find proteins that are elevated in AD patients and have predictive potential. The predictive potential of these plasma markers increases further when coupled with the presence of genetic risk factors, such as the APOE E4 allele. Examples of plasma biomarkers include interleukin, TGF, and micro-RNA.
Genetic risk factors being considered for integration with biomarkers includes ApoE, PSEN1, Bin1, CLU, and SORL1.
APOE gene Apolipoprotein E (APOE) is a lipoprotein, composed of 299 amino acids, that is expressed throughout the body but particularly important in the brain where it is involved in cholesterol metabolism, specifically in the intracellular and extracellular transport, delivery, and distribution. APOE associates with high-density lipoproteins (HDL). The gene for APOE is located on chromosome 19 and exhibits polymorphisms in the population defined by three alleles of APOE: 𝜀2, 𝜀3, and 𝜀4. These alleles differ by only two single nucleotide polymorphisms in exon 4, rs429358 and rs7412 (amino-acid position 112 and 158). APOE𝜀3 is the more common of the three and is present in 50-90% of the general population. APOE 𝜀4 is the most common risk factor for LOAD, increasing genetic risk up to 33-fold, depending on the population (see the table below). Over 50% of LOAD patients have the 𝜀4 allele and that having even one copy of the 𝜀4 allele increases the risk of developing Alzheimer's by a factor of 4. APOE 𝜀2 has been shown to have a neuroprotective effect with carriers of the allele showing a lower prevalence of AD. The neuropathological effects of APOE ε4 are pleiotropic; APOE ε4 impairs uptake of cholesterol by neurons, promotes microglial dysfunction, promotes beta-amyloid aggregation and is increases cerebral angiopathy (CAA). The increased incidence of AD associated with the APOE ε4 allele has been proposed to be directly linked to Aβ because it modulates Aβ aggregation and clearance, although increasing evidence points to a multitude of actions.
+The risk of developing AD with two copies of the APOE𝜀4 allele across various racial-ethnic groupsPopulationAPOE𝜀4 Association with ADCaucasian12.5African Americans5.7Hispanic2.2Japanese33.1