India’s older adult population (≥60 years old) currently is comprised of 146 million people and is expected to increase to 179 million people by 2030 [1]. Southern India (including the state of Kerala) has the highest number of older adults—one-quarter of India’s older adults [2]. Kerala has had the highest life expectancy rates since the 1970s when compared with all other Indian states (Kerala: 75.2 years; India: 69.7 years) [3]. Kerala has the highest prevalence of older adults (16.5%) among all Indian states, and this number is projected to increase to 20.9% by 2031 [4]. High literacy rates, access to health care, and a relatively strong public health system in Kerala have been hypothesized to play important roles in this demographic profile.

The increase in the older adult population in Kerala is expected to be accompanied by an attendant increase in chronic age-related diseases, including dementia [5]. Only a few studies have examined the prevalence of dementia in Kerala, with prevalence rates ranging from 3.2% to 8.7% [6-9]. A dementia prevalence of 4.9% was reported in adults aged 55 years and older in Thiruvananthapuram, the capital city of Kerala [6]. Independent studies carried out in urban and rural areas of Ernakulam district in Kerala reported dementia prevalence rates of 3.36% (≥65 years old) and 3.39% (≥60 years old), respectively [7,8]. The Harmonized Diagnostic Assessment of Dementia for the Longitudinal Aging Study in India, the first cross-national study of dementia in India, reported higher dementia prevalence rates of 7.8% and 8.7% in urban and rural areas in Kerala, respectively [9]. A 10-year follow-up study in Kerala reported incidence rates per 1000 person-years for Alzheimer disease of 11.67 (95% CI 10.9-12.4) for those aged ≥55 years and 15.54 (95% CI 14.6-16.5) for those aged ≥65 years [10].

Recognizing the need for a comprehensive study of cognitive decline in this population, the Kerala Einstein Study (KES) was established in 2008 to understand the epidemiology of and risk factors for cognitive decline, Alzheimer disease, and related dementias [11-13]. The primary phase of recruitment of this study spanned from 2008 to 2016. During this initial phase, we successfully developed a clinical research center in Baby Memorial Hospital (BMH) [14] in Kozhikode City in Kerala, validated culture-fair cognitive tests, identified new dementia risk factors (eg, depression, polypharmacy, cardiovascular disease, and small vessel disease [SVD]) [12,15-17], and established magnetic resonance imaging (MRI) protocols and processing pipelines [18,19]. KES (2R01AG039330-07) was renewed by the National Institutes of Health in September 2019 and received approval from the Indian Council of Medical Research (ICMR) to start the study in June 2021.

In this KES project, we target risk factors and brain substrates of predementia syndromes, especially the motoric cognitive risk syndrome (MCR). MCR is a predementia syndrome characterized by cognitive complaints and slow gait, proposed by Verghese and colleagues in 2013 [20], and validated in multiple countries [13,21-23]. MCR predicts both Alzheimer disease and vascular dementia even after accounting for overlap with mild cognitive impairment (MCI) [13,20,21]. MCR is common; the prevalence was 9.7% in our 17-country study (including KES) [13]. Unlike MCI, complex cognitive tests or assays are not needed to diagnose MCR [13,20,21], increasing its clinical utility in resource-poor low- and middle-income countries (LMIC) like India. We have identified several potentially modifiable risk factors (depression, sedentary lifestyle, and obesity) for MCR in high-income countries [21], but their association with MCR in LMIC is unknown. In this KES project, we will study 2 novel risk factors for predementia syndromes in KES: apathy and mild traumatic brain injury (TBI). Recent investigations highlighted apathy as a separate entity from depression and uniquely associated with cognitive decline [13]. Although TBI is a leading cause of disability in LMIC, its role as a contributor to late-life cognitive decline in LMIC is underrecognized. We hypothesize that apathy and TBI will be associated with MCR and that these associations will be moderated by early-life (years of schooling) and late-life participation in cognitive activities. We also aim to explore commonalities and differences in risk factors for predementia syndromes such as MCR in urban (Kozhikode City) and rural (Kakkodi village) communities in Kozhikode district, Kerala (Figure 1).

Figure 2 shows the conceptual framework of the KES. This study will identify relationships between different risk and protective factors for MCR in this southern Indian population. This study will have a major impact on building sustainable research capacity in this region. The extensive data collected as part of this study will act as a rich resource for discovery as well as validation of risk factors of other age-associated phenotypes and syndromes.

The main aims of this observational study are threefold. First, the study aims to examine clinical risk factors for predementia syndromes (MCR and MCI) in 1000 older adults from Kerala: 200 already recruited in phase 1 of KES and 800 new recruits from urban and rural sites (Aim 1). The following will be conducted to support this aim:

Second, we will explore commonalities and differences in risk factors for predementia syndromes in rural and urban Kerala older adults (Aim 2). Third, we will establish brain substrates and pathologies of MCR in Kerala older adults (Aim 3). The following activities will support this aim:

We propose a cross-sectional survey of 1000 older adults in urban and rural locations in Kozhikode district. We also propose follow-up assessments at 12-month intervals with participants at our rural site. This will be the first epidemiological survey of predementia syndromes from this region and will provide preliminary data to develop new biological hypotheses. The KES project is based in Kozhikode, a northern district in Kerala state with a metropolitan population of more than 2 million people, making it the 19th largest urban agglomeration in India. The initial phase (2008-2016) of the KES was based in BMH—one of the leading providers of medical care in Kozhikode City [14]. Participants (n=200) were identified from patients and caregivers attending the neurology clinic at BMH.

An additional 800 new participants will be recruited in this phase of KES. Brain MRI will be performed with 400 participants (180 completed in the initial phase of KES and 220 new studies in this project), and up to 154 repeat MRIs will be obtained at 12-month intervals. Large-scale neuroimaging investigations are limited in India. The KES will create a unique MRI database to examine brain substrates of cognitive decline in this population.

A new component included in this KES study is the addition of rural and exurban recruitment sites in Kozhikode district. The rural site will be in Kakkodi village (population: 42,866 people) [24]. Kakkodi village differs from Kozhikode City in several indicators such as socioeconomic status (lower), occupational types (agricultural and household work are the major occupations), health care access (no hospitals nor specialty clinics), educational institutions (only primary school and middle school), and transportation (limited bus service and no trains). These rural-urban differences disproportionately affect rural-dwelling older adults who may be less mobile. There are no hospitals in Kakkodi, but BMH maintains a community health center where 500 to 600 Kakkodi adult residents receive routine medical care annually. Patients with more acute or serious complaints are referred to BMH and other hospitals in Kozhikode City. We will utilize this BMH community health center to recruit rural-dwelling older adults. The second new site will be Meitra Hospital [25], located in an exurban (beyond the suburbs) location outside Kozhikode city. As in BMH, potential participants will include patients attending neurology and other specialty clinics as well as older caregivers or family members who meet KES eligibility criteria. Meitra Hospital is a multidisciplinary institution with outpatient and inpatient facilities. Although BMH and Meitra Hospital are in urban and exurban locations, respectively, the patient population in both hospitals includes a mix of urban and rural patients who are referred from all over Kozhikode district as well as neighboring districts. We will track urban or rural residency for our analyses (regardless of study site) based on participants’ home addresses.

Inclusion criteria are (1) age of 60 years or older and (2) being able to provide informed consent. Exclusion criteria are (1) refusal to complete the study tasks (ie, we had <5% refusal rate in the initial KES phase), (2) previous physician-diagnosed dementia, and (3) presence of acute or terminal illnesses or (4) presence of severe auditory or visual loss that would make it difficult for the participant to complete cognitive tasks. In addition, for neuroimaging studies, standard exclusion criteria apply, such as presence of pacemakers; aneurysm clips; artificial heart valves; ear implants; and metal fragments or foreign objects in the eyes, skin, or body.

Study protocols were collaboratively developed by the KES team in India and the United States over the past decade. Study procedures, testers, and supervision will be uniform and harmonized across all 3 field centers in Kozhikode district. Several culturally appropriate strategies approved by the local institutional review board (IRB) are in place to optimize recruitment and retention. For instance, all testing will be administered in Malayalam (local language) or English, as preferred by participants [11,26-28]. Results of electrocardiogram (ECG) and neuroimaging studies will be provided to the participants to share with their medical providers.

Once participants provide informed consent, they and their caregiver, if appropriate, will complete a standardized interview with the research assistant (RA) to obtain demographic characteristics, comprehensive medical history including TBI history, current medications, functional status, and mood states. Participants also complete robust measures of cognitive and physical functioning and undergo ECGs. Those who consent for the neuroimaging substudy will also complete MRIs of the brain. KES assessments are described in detail in the following sections.

Neuropsychological measures will be completed to evaluate cognitive function and to diagnose cognitive impairment or dementia in this cohort. Table 1 provides a catalog of the neuropsychological tasks conducted in KES. All KES tests have established Malayalam and English versions.

The Addenbrooke Cognitive Examination (ACE) [28] and picture-based memory impairment screen [11] will be used to provide estimates of global cognition and memory function, respectively. For those participants who agree to complete more comprehensive testing, neuropsychological measures will include those chosen from the ICMR-Neurocognitive Toolbox (NCTB), a validated battery created in India and translated into various Indian languages including Malayalam [42]. The following ICMR-NCTB measures will be selected: Verbal Learning Test (verbal learning and memory), Modified Taylor Complex Figure Test (visuospatial and visual memory), Trail Making Test Black and White (A and B; visuospatial attention, cognitive speed, and set-shifting), Category Fluency Test (verbal fluency), and Phonemic Fluency Test (verbal fluency). The Wechsler Memory Scale-Revised Digit Span Task, which was previously used and validated in Kerala, will be used to assess auditory attention and working memory [43].

Participants will complete validated self-report questionnaires assessing depressive symptoms (Geriatric Depression Scale-30 [GDS-30] [42]), anxiety (Generalized Anxiety Disorder [GAD-7] [36]), apathy (Apathy Evaluation Scale [AES] by Marin et al [44]), social networks (Social Network Index [45] and Medical Outcomes Study Social Support Survey [46]), happiness (Subjective Happiness Scale [39]), and current leisure activities (Leisure Activity Scale [47]).

Level of independent functioning will be measured using the Instrumental Activities of Daily Living Scale for elderly people, which was developed in Kerala as a scale of functional abilities [37]. Subjective cognitive complaints will be operationalized using the 20-item Cognitive Change Index [48] and Subjective Cognitive and Motoric Complaint Questionnaire. The latter instrument was developed by our team to ascertain participant concerns regarding their cognition and motoric function.

All cognitive tasks and questionnaires will be administered by KES RAs, trained and supervised by the KES clinical neuropsychologists (EFW and MS). RAs in Kerala are trained in the administration and scoring of neuropsychological measures via televideo by a licensed clinical neuropsychologist (MS) based in the United States. Training includes review and explanation of each of the neuropsychological measures, modeling of test administration, and practice administration and scoring. RAs will be cleared by the neuropsychologist (MS) to evaluate participants following acceptable televideo practice administration. Quality control measures include regular meetings with the neuropsychologist (MS) and RAs to refresh and review procedures as well as periodic review of scored protocols by the neuropsychologist. In addition, all study protocols are double scored by a single dedicated RA (who did not administer the tests) to ensure consistency in scoring across RAs and to identify and correct any observed errors in administration and/or scoring procedures.

A standard 12-lead ECG (Tricog Health) will be performed by a certified cardiac physiologist at BMH and Meitra Hospital [12,41]. Standard 12-lead ECG will be analyzed following the Minnesota code classification by a study clinician, blinded to neurological status including normal, MCR, or dementia diagnoses. Based on our previous KES projects, the following abnormalities will be reported: rhythm abnormalities, left ventricular hypertrophy, significant ST and T wave changes, Q waves, heart block, and bundle branch block [12]. Major ECG abnormalities are defined as the presence of any one of the following: Q-QS wave abnormalities, left ventricular hypertrophy, Wolff-Parkinson-White syndrome, complete bundle branch block or intraventricular block, atrial fibrillation or atrial flutter, or major ST-T changes.

Over the 5 years of this project, we will seek to recruit approximately 400 urban-dwelling and 400 rural-dwelling participants. Of the 800 new participants, 220 from all sites will undergo neuroimaging, which, along with the 180 studies from the first KES phase, will provide a database of 400 neuroimaging studies. Participants from all 3 sites will be recruited for imaging studies. Given the restricted geographic location of our rural site (Kakkodi village) and very low rates of out-migration by older residents, we propose to follow up rural participants every 12 months. In our urban sites, we will attempt to conduct 12-month follow-up assessments with all participants undergoing neuroimaging. Given the larger catchment area, follow-up will be more challenging, but we will also consider home assessments to improve retention.

This study will be conducted in accordance with the Helsinki Declaration. The informed consent and recruitment processes follow local socially and culturally appropriate practices. The assessments and procedures have been approved by the IRB at BMH (BMH/IEC/02/2022), which also served as the local IRB for the first phase of KES. In addition, study design and consent procedures have also been approved by the ICMR (2020-10058), which is a requirement for epidemiological and experimental studies conducted in India. The study protocols have also been reviewed and approved by the Albert Einstein College of Medicine IRB (2006-368).