Abstract
Research on age-related cognitive impairment is scarce in Central America. We report factors associated with cognitive impairment among a sample of older adults in Panama diagnosed with Alzheimer’s disease (AD, n = 31), mild cognitive impairment (MCI, n = 43), or no cognitive impairment (controls, n = 185). Apolipoprotein E (ApoE) genotype was assessed in a subset of cases (n = 135). Age (OR = 2.53, 95% CI = 1.03–6.17) and ApoE ɛ4 (OR = 5.14, 95% CI = 2.11–12.52) were significantly related to cognitive impairment (AD/MCI combined). Results underscore the potential of genetic screening in Panama for identifying those at risk of dementia.
Keywords
INTRODUCTION
Latin America and the Caribbean (LAC) region is experiencing rapid population aging 1 with prevalence rates of dementia [1, 2] and cognitive impairment [3] similar to those in more developed regions. To date, there is only one published study reporting cognitive impairment among the elderly population in Panama [4], an upper middle income country in Central America. Despite its economic classification, the health status of elderly individuals is significantly affected by low income levels, poor education, and early childhood exposure to health risks [5].
Here we report the results of a cross-sectional analysis of demographic, clinical and genetic factors associated with Alzheimer’s disease (AD), mild cognitive impairment (MCI), or no cognitive impairment. The main objective was to describe the risk factors associated with AD, including the frequency of the apolipoprotein E (ApoE) genotypes, in older adults in Panama. Various clinical, community, and postmortem studies have pointed to the ApoE gene and the presence of the ɛ4 allele as the strongest genetic risk factor for sporadic AD, but this association has not been consistent for Hispanics [6–9]. Thus, to our knowledge, this is the first report of the associated risk between the ApoE ɛ4 allele and AD among Hispanics in Panama.
METHODS
Participants
Data from this study came from the Panama Aging Research Initiative (PARI) study, the first-ever study of Panamanian aging. PARI participants were recruited from the outpatient geriatric service at the largest public hospital in Panama. Participation was offered to every adult who attended the geriatric service between September 2012 and January 2013. A total of 423 adults were enrolled and screened at baseline. Inclusion criteria were being 65 years or older, availability for follow-up visits over the course of 12–18 months, and provision of informed consent. Exclusion criteria included any medical condition that required hospitalization or participation in an ongoing clinical trial at the time of enrollment. In the present analysis, only non-institutionalized individuals who had complete assessments and for whom a consensus diagnosis was established were included (N = 259). The study protocol was approved by the National Bioethics Committee of the Instituto Conmemorativo Gorgas de Estudios de la Salud and the Institutional Bioethics Committee of the CSS. All participants (or their informant) signed informed consent forms and patient confidentiality was not breached in accordance with the Declaration of Helsinki (1964).
Clinical assessments
Each participant underwent an interview (sociodemographic variables and medical history), physical evaluation, neuropsychological evaluation, and laboratory tests. A subset of individuals (n = 135) underwent a non-fasting blood draw for ApoE genotyping. Participants and/or caregivers were interviewed regarding limitations in basic (BADL) and instrumental (IADL) activities of daily living. Neuropsychological testing and assessment of depressive symptoms were conducted on the first follow-up screening (M = 4.5 months later, SD = 1.9). We report the results of the 30-item Spanish version of the Mini-Mental State Examination (MMSE) [10, 11] as a measure of global cognition [12], and results of the clock drawing test (CDT) [13] as a measure of executive function. The Spanish version of the 30-item Geriatric Depression Scale (GDS-30) [14, 15] was administered by an interviewer, and the number of depressive symptoms is reported (range 0–30, with higher numbers indicating more symptoms). Stages of cognitive function were rated according to the Global Deterioration Scale (GDS) [16]. All assessments were conducted in Spanish.
Clinical, cognitive, and functional data, as well as existing medical records and imaging studies, were reviewed by clinicians experienced in the evaluation of dementia, and each case was reviewed by consensus committee. ApoE genotypes were not available during the diagnostic process. Diagnosis of AD was based on NINCDS-ADRDA criteria [17] and required evidence of impairments in memory and at least one other cognitive domain, as well as impairments in everyday social and/or work-related activities. Participants who met criteria of possible or probable AD with a GDS score of 4 or higher (range 1–7) were considered to have a clinical diagnosis of AD. MCI diagnosis was based on core clinical criteria [18] and required deficits in at least one cognitive domain, independence in activities of daily living and GDS ≤ 3. Cognitively unimpaired participants performed within normal limits of neuropsychological assessment, and only those who scored≤10 in the GDS-30 (non-depressed individuals) were included as controls.
Assays
For ApoE analyses, DNA was extracted from whole blood and ApoE genotyping was conducted according to standardized PCR procedures [19].
Statistical analysis
Analyses were performed using SPSS 21.0 (Armonk, NY: IBM Corp.). One-way analysis of variance (ANOVA) and chi square (χ 2 ) tests were applied to continuous and categorical variables, respectively. Due to the limited number of cases with ApoE genotyping, AD and MCI groups were collapsed into a “cognitively impaired” group and included in a logistic regression model with cognitive status (impaired or not impaired) as the outcome. Coefficients of regression (B), adjusted odds ratios (OR), and 95% confidence intervals (CI) are presented for the model. Statistical significance was set at p < 0.05.
RESULTS
Groups did not differ in gender, relationship status, monthly household income, or chronic conditions. Controls were significantly younger than AD (p = 0.001) and MCI groups (p = 0.015) and more educated (ps < 0.05). AD and MCI groups did not differ in either age or education. Highly significant differences in cognitive performance were noted among the groups: (ps < 0.001). The AD group reported greater BADL and IADL difficulties than control and MCI groups (ps < 0.001), which did not differ from each other. The MCI group endorsed more depressive symptoms (GDS-30) than AD and control groups (ps < 0.05), which did not differ from one another. BMI in AD subjects was significantly lower than controls (p < 0.05). At least half of AD (57%) and MCI (50%) groups expressed one or two copies of the ApoE ɛ4 allele. Table 1 summarizes the frequencies for the five ApoE genotypes observed. The logistic regression analysis (Table 2) indicated that age (OR = 2.53, 95% CI = 1.03–6.17, p = 0.042) and ApoE ɛ4 expression (OR = 5.14, 95% CI = 2.11–12.52, p < 0.001) were significant predictors of cognitive impairment, whereas educational level was marginally associated with cognitive impairment.
DISCUSSION
This study suggests that the ApoE ɛ4 allele is a significant factor associated with AD and MCI in elderly individuals in Panama. The frequency of ApoE ɛ4 expression as well as the strength of the association between ApoE ɛ4 expression and risk for AD in Hispanics has varied across studies [6–9, 21]. Among Mexican Americans, there is a lower frequency of ApoE ɛ4 expression [6, 21] that may explain the difference in etiology of dementia in this population. Moreover, the strength of the association between ApoE ɛ4 expression and risk for AD in Hispanics also has varied across studies within and outside the U.S. [6–9, 22]. To our knowledge, our study shows one of the highest ApoE ɛ4 allele frequencies among Hispanics diagnosed with AD, and underscores the association between AD and the ApoE ɛ4 allele in Panamanian older adults. The only study reporting a similarly high frequency was conducted in Hispanics in Colombia [7]. In that study, 51% of individuals with AD expressed ApoE ɛ4, and the odds of expressing at least one copy of ApoE ɛ4 among subjects diagnosed with sporadic AD was also comparable to our results (6.8, 95% CI 2.1–21.5). The variation among studies is likely due to the fact that Hispanics are a mixture of Amerindian, African, and European descent with relative compositions varying by country [23]. In light of this, the genetic admixture of Panamanians is likely very different from other Hispanic populations and this is a line of investigation we are beginning to examine.
An important limitation to the present study is its sample size, particularly in regard to ApoE genotyping. In addition to being able to analyze the association between ApoE ɛ4 expression and AD and MCI groups separately, an increased sample size will allow us to determine whether there is a correlation between the number of copies of ApoE ɛ4 allele and the severity of cognitive impairment. Also, the study is cross-sectional so we cannot draw causal inference about the variables measured and cognitive function. Despite these limitations, the current study adds to the debate regarding ApoE risk and AD among Hispanics. Little is known about the factors associated to cognitive health at old age in Central American populations. In Panama, cognitive impairment is seen as a normal part of the aging process. Affected individuals do not seek formal medical services until advanced stages of impairment, and care for the elderly is typically carried out at home by family members, factors that increase the burden of aging on healthcare services and individuals. In U.S. population studies, compared with non-Hispanics, Hispanics are more burdened with dementia risk factors and there is less awareness, treatment and control of risk factors [24, 25]. Thus, our study adds to the effort to document the cognitive status of older adults in Central America and constitutes a contribution to our understanding of the risk factors of cognitive outcomes among Hispanics both within and outside LAC. Our results underscore also the potential of genetic screening for the identification of those at highest risk for dementia.
United Nations, Population Division, World Population Prospects: The 2012 Revision (Geneva: UN, 2013).
Footnotes
ACKNOWLEDGMENTS
The following Panama Aging Research Initiative (PARI) collaborators assisted with data collection and provided valuable input to the study logistics: Aquiles Aguilar, M.D.; Aron Benzadón, M.D., Vanessa Castillo, M.T.; José A. Cedeño, M.S.; Lissette Chang, M.D.; David Dondis, M.D., Frank Ferro, M.D.; Josefina Fletcher, M.D., Patricia González, M.D.; Vanessa González, M.D.; Luis Lee, M.D.; María Mendieta, M.D.; Ribana Molino, M.D.; Josué Morales, M.D.; Nelson Novarro, M.D.; Viterbo Osorio, M.D.; Luis Sotillo, M.D.; Vivian Vásquez, M.D.; Ramón Zarak, M.D. Research reported in this publication was supported by NIA grant AG039389, the Melo Brain Project and by the National Secretariat of Science, Technology and Innovation (SENACYT) of Panama. The National Institutes of Health had no role in the design and conduct of the study: collection, management, analysis, and interpretation of the data; and preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
