Risk, protective, and biomarkers of dementia in Indigenous peoples: A systematic review

Abstract INTRODUCTION Dementia is an emergent health priority for Indigenous peoples worldwide, yet little is known about disease drivers and protective factors. METHODS Database searches were conducted in March 2022 to identify original publications on risk, protective, genetic, neuroradiological, and biological factors related to dementia and cognitive impairment involving Indigenous peoples. RESULTS Modifiable risk factors featured across multiple studies include childhood adversity, hearing loss, low education attainment, unskilled work history, stroke, head injury, epilepsy, diabetes, hypertension, hyperlipidemia, depression, low BMI, poor mobility, and continence issues. Non‐modifiable risk factors included increasing age, sex, and genetic polymorphisms. Education, ex‐smoking, physical and social activity, and engagement with cultural or religious practices were highlighted as potential protective factors. There is a paucity of research on dementia biomarkers involving Indigenous peoples. DISCUSSION Greater understanding of modifiable factors and biomarkers of dementia can assist in strength‐based models to promote healthy ageing and cognition for Indigenous peoples.

a greater burden of non-communicable chronic diseases, including dementia. 2ere is currently no widely available and clinically effective disease-modifying treatment for dementia and as such, modification of risk and protective factors are crucially important in strategies to promote healthy aging and prevent cognitive decline.The 2020 Lancet Commission report on dementia, prevention, intervention, and care suggests that, at a population level, up to 40% of dementia could be preventable by eliminating 12 risk factors. 4It identified less education in early life, hypertension, hearing impairment, smoking, obesity, depression, physical inactivity, diabetes, social isolation, traumatic brain injury, excessive alcohol consumption, and air pollution as key risk factors in the development of cognitive problems. 4ese risk factors feature in the health and social profile of Indigenous peoples however, a greater understanding of the risk and protective factors unique to specific Indigenous groups and those shared across First Nation populations is important in developing more effective approaches to decrease the burden and sequalae of dementia. 2e pathogenesis of dementia often begins decades before the onset of symptoms and changes in brain pathology detectable in midlife may offer insights into dementia risk in the future.Gray and white matter changes on magnetic resonance imaging (MRI) can support clinical diagnosis and assist in the differentiation of one type of dementia from another.Alzheimer's disease-specific biomarkers such as amyloid beta and tau have been demonstrated using positron emission tomography (PET) imaging and in fluids (cerebrospinal fluid and plasma). 5,6These disease-specific biomarkers, alongside microvascular and inflammatory biomarkers involved in cellular signaling, immune responses, neuronal support, and apoptosis have also been studied in peripheral blood. 7Advances in scientific understanding of genetic, neuroimaging, and biological markers augment understanding of dementia phenotype as a complex interaction between genetics, biology, and exposures across the life-course.They may, in the future, have greater utility in clinical practice to identify those at higher risk of a neurodegenerative process, improve timely and accurate diagnosis, and monitor disease progression and effects of interventions. 8Despite great strides in the field, the relationship between biomarkers and ethnoracial factors remains understudied.Large studies on cognition and aging such as the Australian Imaging Biomarkers and Lifestyle Study of Ageing (AIBL) and Alzheimer's disease neuroimaging initiative (ADNI) from North America, do not contain a broad representation of ethnoracial populations. 9,10r aim was to describe and evaluate the evidence base for risk, protective, and biomarkers associated with dementia and cognitive impairment in Indigenous peoples around the world.We also provide an update of prevalence and incidence of dementia and cognitive impairment in Indigenous populations.[13] To our knowledge, this will be the first review of risk, protective and biomarkers of dementia and cognitive impairment involving Indigenous peoples.

RESEARCH IN CONTEXT
1. Systematic review: The authors reviewed the evidence base for risk, protective and biomarkers of dementia in Indigenous peoples worldwide.This is the first review of biomarkers of dementia and cognitive impairment involving Indigenous peoples.
2. Interpretation: Database searches yielded 1567 titles for screening, 132 articles for review and 39 were included in the systematic review.Prevalence rates of dementia varied widely from 0.6% to 37.2% with rates of MCI/CIND between 4.4% and 27.4% for those aged ≥60 years.There are many shared determinants of health and illness between Indigenous populations however, appreciation of unique population profiles can assist in the development of targeted strength-based models to promote cognitive health and prevent impairment over the life-course.
3. Future directions: Increased research is needed on modifiable protective factors and biomarkers of dementia involving Indigenous peoples.

Search strategy
The protocol for this review was registered in PROSPERO (CRD42020207449).A literature search of Medline, Embase, CINAHL, Global Health, Emcare, and PsycINFO databases was conducted using the OVID platform on the 15th of March 2022.Search terms included all descriptors related to: Indigenous persons, dementia, cognitive impairment, prevalence, incidence, risk factor, protective factors, genetic markers, neuroimaging, and biomarkers.Indigenous population search terms were based on the Lancet-Lowitja Institute Global Collaboration publication on the health of Indigenous and tribal peoples and checked against works in the same canon. 2This review was limited to age-related dementias such as Alzheimer's dementia (AD), vascular dementia (VaD), Lewy body dementia (LBD), and fronto-temporal dementia (FTD), and does not address dementia secondary to primary neurological conditions (e.g., amyotrophic lateral sclerosis), retroviruses (e.g., human immunodeficiency virus), or other pathogens (e.g.,

Study selection and data extraction strategy
References from the literature search underwent screening by two reviewers (H.N. and K.B.) based on predefined inclusion and exclusion criteria.We included original studies that focused on a recognized Indigenous population that comprised >10% of the study cohort.
Indigenous peoples were chosen with reference to the UN statement and the Lancet-Lowitja Institute Global Collaboration publication on the health of Indigenous and tribal peoples across all world continents, except Antarctica, with emphasis on self-identification, connection to country, and acceptance within a cultural community.important in diagnosis as a marker of disease states of interest were also included.These encompass descriptors of regional cerebral atrophy and white matter changes on MRI as well as fluorodeoxyglucose and amyloid radiotracer avidity using functional and molecular imaging modalities.Discrepancies were resolved through discussion with a third reviewer (D.L.) to achieve consensus.

Quality assessment
Systematic appraisal of included articles was performed using a checklist adapted from the National Institute of Health (NIH) Study Quality Assessment Tool for Observational Cohort and Cross-Sectional Studies. 15Engagement, governance, or co-authorship with Indigenous people/communities/organizations and reporting of positive outcomes (strength-based model) was included to assess the reporting of Indigenous health research in line with the CONSIDER Statement and Aboriginal and Torres Strait Islander quality appraisal tool. 16,17Studies were assigned a quality rating of good, fair, or poor (Appendix SB).Discrepancies were resolved through discussion with the third reviewer (D.L.).

Data synthesis
The articles were observed to be highly heterogeneous and focused on different aspects of the research question.As such, pooling of the results in a meta-analysis was not possible due to substantial variance in focus, methods, and outcome measures employed.The findings were therefore synthesized in descriptive form.Prevalence rates were not standardized for comparison between Indigenous populations due to the lack of an appropriate reference cohort.Indeed, using any one Indigenous group as a reference would assume the sameness of all Indigenous cohorts with one another, and using a non-Indigenous cohort would omit differences between Indigenous and non-Indigenous populations.

Study selection
Database searches identified 1567 articles after removal of duplications as summarized in the PRISMA flowchart (Figure 1).After screening of titles and abstracts, 132 articles underwent full-text reviews and 39 met a priori inclusion criteria and were included in this systematic review.

Study characteristics
Of the 39 studies included in this systematic review, 26 studies reported on risk, protective or biomarkers of dementia or cognitive impairment involving an Indigenous population (Table 1).The majority of the included articles were cross-sectional, case-control, or cohort studies, and only two involved longitudinal follow-ups.There were 18 studies on prevalence and 4 on incidence of dementia or MCI (

Prevalence and incidence of dementia and MCI
Most studies included participants aged ≥60 (±5 years).For those studies with participants aged ≥45 years, prevalence rates for ≥60 years and age-standardized prevalence rates are reported where available.Across different Indigenous populations, prevalence rates of dementia ranged from 0.6% to 37.2% and rates of MCI/CIND varied from 4.4% to 27.4%.Low rates of dementia were reported for Cree Indians (0.5%), Tibetans (1.3%), Tsimane (1.2%), and Moseten (0.6%) cohorts 19,36,56 and highest for Aboriginal and Torres Strait Islander peoples (up to 26.8% in those ≥65 years). 21Dementia incidence reported for Aboriginal and Torres Strait Islander peoples ranged from 21.0 to 35.9 per 1000 person-years for those aged ≥60 years. 22,25yeda et al. 48reported a dementia incidence of 22.2 per 1000 person-years for American Indians ≥60 years (Table 3).

Risk and protective factors
Modifiable risk factors featured across multiple (>1) studies that demonstrated a statistically significant association include childhood adversity, hearing loss, low education attainment, unskilled work history, stroke, head injury, epilepsy, diabetes, hypertension, hyperlipidemia, depression, low BMI, poor mobility, and continence issues by self-reports or using the International Consultation on Incontinence Questionnaire score.Non-modifiable risk factors across different studies were increasing age, sex, and genetic polymorphisms, including APOE ɛ4.Age was reported to be statistically significant in 11 studies, and sex differences were reported in 7 studies.Gene associations with dementia or MCI were highlighted in 13 studies (Table 4).
Potential protective factors or those negatively associated with the occurrence of dementia or MCI reported to be statistically significant in at least one study include: higher education attainment, ex-smoking (compared to never smoked or current smoker), Kowtow, turning prayer beads, physical activity by self-reports, social activities, being married or having a life partner, and eating chicken (Table 4).Low BMI was reported to be associated with a greater odds of dementia and cognitive impairment in two studies 27,29 but was associated with a lower odds of MCI in one study 30 involving Aboriginal and Torres Strait Islander peoples.Seven out of nine studies that highlighted protective factors were assessed to be of good quality, 19,22,28,30,34,35,41 and two were of fair quality 18,50 (Table 2).PAF were reported in three studies. 32,39,47MacDonald et al. produced a combined PAF for AD of 79.6% and 74.9% among on-reserve and off-reserve Indigenous peoples in Canada, respectively.The relative contributions of six modifiable risk factors were physical inactivity (32.5%), low education attainment (22.4%), smoking (19.4%), midlife obesity (16.8%) midlife hypertension (14.2%), and diabetes mellitus (6.0%). 47Ma'u et al. illustrated a PAF of 51.4% using 12 risk factors including obesity (7.3%), hearing loss (6.5%), education (5.6%), social isolation (5.1%), hypertension (5.0%), physical inactivity (5.0%), traumatic brain injury (3.5%), smoking (4.3%), depression (4.2%), diabetes (2.4%), air pollution (1.8%), and alcohol (0.7%) for M āori people of New Zealand. 32Exposure to fadang in the unique population of Chamorros on Guam was estimated to contribute between 12% and 23% to outcomes of Guam dementia and MCI, after adjusting for age, sex, and education. 39

Genetic markers
Apolipoprotein E allele4 (APOE ε4) was the most studied genetic marker and featured in 12 studies.Among the Indigenous Tsimane and Moseten peoples, the number of APOE ɛ4 alleles did not differ between those with cognitive impairment and those without; however, carrying two APOE ɛ4 alleles was associated with greater odds of cognitive impairment. 56A couple of studies looked at the relationship between APOE ɛ4, degree of American Indian ancestry and dementia.Henderson et al. found   that the prevalence of APOE ɛ4 in the Choctaw population was half that of Caucasian comparators.For those with less than 50% Choctaw ancestry, there was evidence of an association between the APOE ɛ4 genotype and disease. 38However, Rosenberg reported an inverse relationship between the genetic degree of Cherokee ancestry and AD, independent of APOE ɛ4 status. 37her genes studied include clusterin (CLU), neprilysin (NEP), microtubule-associated protein tau (MAPT) and Tau. 19,20,40Huang et al. reported that CLU genotypes AA and GA of rs2279590 were associated with a 4-fold increase in the odds of AD while CLU genotypes GG and GC of rs9331888 were negatively associated with AD in a sub-sample of 39 Tibetans with AD and 56 without. 19Chen et al.
reported two different NEP SNPs (rs701109 and rs3736187 mutation) that may add to the risk of AD among male Tibetans rather than the whole population. 20Sundar et al. reported MAPT SNPs 6, 7, and 9, homozygous genotypes (A/A, A/A, and C/C, respectively) contribute to susceptibility to Guam neurologic disorders. 40Those with SNP6 and SNP9 AC/AC diplotype had a three-fold increased risk for Guam dementia and a 4-fold increased risk for Parkinsonism dementia complex compared to those with other diplotypes, after adjusting for SNP2.
SNP2 allele carriers had a 1.6-fold increased risk of Guam dementia and a 2-fold increased risk of Parkinsonism dementia complex, after adjusting for SNPs 6 and 9. 40

Other biological and neuroradiological markers
Plasma homocysteine was a biological marker found to be higher in a small group of American Indians with AD compared to controls but did not reach statistical significance. 43,44ere were only three studies that reported on neuroimaging markers related to dementia and MCI, one using CT imaging and two using MRI. 44,52,56There were no PET imaging or cerebrospinal fluid biomarker studies.In the Bolivian cohort, poorer cognition was associated with severity of intracranial vascular calcifications, greater medial temporal atrophy, and reduced white matter volume on CT brain scans of Tsimane participants. 56In a small case-control study of 21 participants by Weiner et al., AD participants demonstrated greater volume of white matter hyperintensity as a proportion of whole brain volumes on MRI, but this did not reach statistical significance. 44

Studied variable of interest
Pu'un, 2014 18   Huang, 2016 19   Chen, 2020 20  F I G U R E 2 Geographical representation of Indigenous peoples included in this systematic review.
Indians but found no significant association between neuroradiological parameters between APOE ɛ4 carriers and non-carriers after adjusting for sociodemographic and clinical conditions. 52

Availability of evidence across Indigenous groups
Indigenous peoples live in every corner of the globe with the largest populations expected to reside in populous China, India, and Siberian regions of Russia. 58However, most of the researched Indigenous groups included in this systematic review are from Western countries with a paucity of published scientific literature from these regions (Figure 2).Compared to most world regions where age-standardized prevalence of dementia in those 60 and older lie between 5% and 7%, there was greater variance in the reported prevalence rates within and between Indigenous populations. 59Prevalence rates were lowest for Cree Indians, Tibetans, Tsimane, and Moseten (0.5%-1.3%) and highest among Aboriginal and Torres Strait Islander peoples (>20%) in those ≥60 years. 19,21,25,36,56Age-adjusted dementia rates for American Indians ranged from 6.6% to 26.8% between studies, compared to the estimated prevalence of 10.8% in the general United States population. 60This may reflect the heterogeneity of study methodologies.For instance, the study by Cotter et al. 23 based on databases reliant on routinely collected data reported no difference in dementia rates between Aboriginal and Torres Strait Islander peoples and non-Indigenous Australians, which was not congruent with cohort studies based on expert clinical diagnoses of dementia. 21,25,31The latter consistently report rates of dementia three to five times greater among different cohorts of Aboriginal and Torres Strait Islander peoples compared to non-Indigenous Australians and are more likely to reflect true prevalence of disease. 21,25,31

Evidence of risk and protective factors of dementia or cognitive impairment
Despite the diversity of Indigenous peoples worldwide, there are many similarities in the determinants of health and illness.Study of risk factors predominate the literature and emphasize medical factors such as head injury, epilepsy, diabetes, hypertension, and stroke.
However, protective factors associated with dementia or MCI are less well understood.Poor mobility, falls, and continence issues found to be associated with dementia in cross-sectional studies likely reflect syndromes related to a dementia diagnosis rather than its precipitant.This may have a bearing on the association between BMI and dementia across different studies.This relationship is proposed to be J-shaped, whereby high BMI and obesity in middle age may increase the risk of dementia but low BMI is more likely to accompany cognitive impairment or dementia in the older population. 61sk and protective factors associated with dementia for Indigenous peoples are congruent with the evidence available for non-Indigenous populations. 4,57However, the significance of social determinants of health across the life-course (childhood adversity, education attainment, skilled work history) and engagement with cultural or religious practices (Kowtow, turning prayer beads) were highlighted in this review of Indigenous peoples.As Radford et al. proposed, cultural connection and support from extended family may help mitigate experiences of trauma and adversity in childhood. 28Male sex was associated with a greater risk of dementia in certain Indigenous cohorts, 22,35,39,41,46 in contrast to most non-Indigenous populations where dementia is more common in women. 62,63Higher rates of cluster risk factors such as stroke, head injury, and cardiac disease among men compared to women have been described in studies involving Aboriginal and Torres Strait Islander peoples. 22,29,35Sex differences in exposure to other lifestyle and social risk factors such as heavy alcohol use, history of police custody and incarceration, and low education may also contribute to the higher rates of dementia and cognitive impairment among men in these communities.Among the Chamorros, there was slightly higher prevalence of parkinsonism-dementia complex in men, but sex was not significantly associated with Guam dementia after adjusting for age and education. 39,41Studies involving First Nations people of North America included in this review were equivocal and contained insufficient data on rates of risk factors to offer plausible explanations on sex differences.More work is required to delineate the differential risk factors for dementia for Indigenous men and women and to ascertain whether adjustments for education, cardiometabolic disease, and competing risk of death modifies these sex differences. 64F calculations utilize the strength of each risk factor, its prevalence in a population, and overlap within the same person.Combined PAF for AD for First Nations people of Canada (79.6% for on-reserve and 74.9% for off-reserve) and M āori (51.4%) were considerably higher than global estimates (40%) and suggests that the preventable burden of dementia may be greater for certain Indigenous communities. 4,32,47,57This is in keeping with the breadth of studies demonstrating higher prevalence of health and psychosocial factors associated with dementia in different Indigenous, compared to non-Indigenous, populations.ε4/ε4 OR: 11.8-33.1)and non-Hispanic White populations (ε3/ε4 OR: 3.2; ε4/ε4 OR: 14.9) compared to African Americans and Hispanic peoples (ε3/ε4 OR:1.1-2.2;ε4/ε4 OR: 2.2-5.7). 65Most studies of APOE ɛ4 involving Indigenous peoples were small and may be poorly powered to discern an association.Where an association was reported, APOE ɛ4 carriers had increased odds of dementia or cognitive impairment comparable to other high-risk ethnic groups, except among American Indians where the degree of Choctaw or Cherokee ancestry may modify this effect.The genotype ɛ2/ɛ3 that has been demonstrated to be protective across ethnic groups has not demonstrated in studies involving Indigenous peoples. 65nome-wide association studies involving Indigenous peoples are limited and more work is required to elucidate genetic polymorphisms of significance to individual populations and across different cohorts.There was a notable absence of studies on AD susceptibility genes such as amyloid precursor protein, presenilin, presenilin 2, phosphatidylinositol-binding clathrin assembly protein, or inflammatory markers (e.g., C-reactive protein, interleukin-6) that have been the subject of dementia research in non-Indigenous populations. 66

Neuroradiological and biomarkers for dementia and cognitive impairment
This systematic review yielded few studies involving biological or imaging markers of dementia or MCI.Many of these studies were small scale, case-control studies with limited statistical power. 44,56In the broader literature, a study of 786 American Indian participants from the Strong Heart study (not included in this review) found that general cognitive functioning correlated with hippocampal volumes while processing speed was associated with brain volumes as well as cerebral vascular burden (infarcts and white matter disease). 67In studies comparing ethnoracially diverse groups, cognitive decline was most associated with global gray matter atrophy in African American participants, volume of white matter hyperintensities in Hispanic participants, while regional temporal atrophy had greater relevance for White American participants. 68This suggests t differences in the importance of neuroimaging markers as a reflection of the heterogenous brain changes driving cognitive change and dementia between ethnoracial groups.
Larger studies on neuroimaging markers of dementia and MCI involving Indigenous peoples are needed to greater understand the brain changes relevant to these populations.

Indigenous perspectives in dementia research
The dementia prevention discourse is largely framed by a Western biomedical model with emphasis on risk factors and pathology. 69ough this model allows for greater recognition of those at risk of cognitive decline and dementia, it often de-emphasizes the cultural, historic, and psychosocial influences that are crucial in comprehensive understanding of possible determinants and correlates of health for Indigenous peoples.This biomedical model also reinforces a deficits approach that can negatively impact on the empowerment of people to strive for healthy ageing.Alternatively, a greater focus on proactive factors across the life-course may be more conducive to a strengths-based approach and the promotion of cognitive health and ageing for Indigenous peoples and their communities.There is increasing awareness of the Ethics around research involving Indigenous peoples evident in approaches to study design and governance of research teams.Some research groups are explicit in their engagement of Indigenous researchers and stakeholders to ensure that research involving Indigenous people serves to strengthen capacity, improve syphilis).Cognitive impairment encompassed cognitive impairment not dementia (CIND) and mild cognitive impairment (MCI) diagnoses and pertained to those with evidence of cognitive decline from baseline without functional loss to meet a diagnosis of dementia.CIND and MCI were included in this review as they may represent an early stage of dementia with shared risk or protective factors.The full search strategy is detailed in Appendix SA.The review is reported according to the Preferred Reporting Items for Systematic Reviewsand Meta-Analyses (PRISMA).14 Suchy-Dicey et al. described MRI-defined brain, hippocampal, and intracranial volumes against cognitive test scores in a larger cohort of 811 American TA B L E 4 Compilation of studied risk factors with measures of association.

4 . 3
Genetic factors associated with dementia or cognitive impairmentAPOE ɛ4 is the most well recognized genetic risk-factor for AD.The association of APOE allele with AD risk differs across ethnoracial groups with stronger effects observed in East Asian (ε3/ε4 OR: 3.1-5.6;

Study Prevalence and/or incidence Risk, protective, genetic, and/or biomarkers Both
). Indigenous populations studied included Aboriginal and Torres Strait Islander peoples of Australia, First Nations people of Canada, Choctaw and Cherokee Indians in the United States, Native Hawaiians, Chamorros of Guam, Melanau people of East Malaysia, Tibetans residing in the Qinghai-Tibet plateau, the Otomi tribe native to Mexico, the Mamirauá and Amanã peoples of the Amazonian Basin in Brazil, and the Tsimane and Moseten tribespeople Indigenous to Bolivia.A Peruvian cohort with high Amerindian genetic ancestry was also included.Odds ratios (ORs) were the most frequent means of assessing the relationship between variables of interest and dementia or cognitive impairment.MacDonald et al. and Ma'u et al. 50 56

Author, year Title Study design Indigenous population Age; mean/ median age (SD) Outcomes of interest Risk or protective factors Genetic or biomarker QA
defined as deficits (1.5 SD below mean) in leaning and retention tasks in multidomain psychometric tests such as the California Verbal Learning Test, Weschler Adult Intelligence Scale, Controlled Oral Word Association, and Modified Mini Mental Status Examination.

TA B L E 3
Prevalence and incidence.