Abstract
Alzheimer's disease manifests differently across ancestral groups, with African populations showing distinct fluid biomarker levels, neuroimaging patterns, and post mortem pathology. These differences may compromise diagnostic accuracy and exacerbate health disparities. This systematic review, examined studies published from 2015 to 2025 assessing amyloid‐β and tau via fluid assays and neuroimaging. Findings reveal ancestry‐linked variation where African populations exhibit lower cerebrospinal fluid/plasma Aβ42/Aβ40 and p‐tau181 ratios, with neuroimaging showing broadly similar reduced positron emission tomography patterns but slightly elevated amyloid and reduced tau signals. Limited post mortem data suggest reduced plaque and tangle densities despite comparable dementia severity. Genetic, environmental, and sociocultural factors contribute to these disparities. Diagnostic thresholds derived from non‐African cohorts risk underdiagnosing AD in African individuals. There is an urgent need to recalibrate and validate biomarker protocols to ensure equitable and accurate dementia diagnosis across diverse populations.
Keywords: African ancestry, Alzheimer's disease, beta‐amyloid, biofluid, biomarker, diagnostic, neuroimaging, post mortem, tau
Highlights
African populations show reduced cerebrospinal fluid (CSF) and plasma Aβ42/Aβ40 and p‐tau181 levels.
Tau positron emission tomography (PET) signals are lower despite similar dementia severity across ancestries.
Apolipoprotein E (APOE) ε4 has weaker biomarker effects in African ancestry individuals.
Biomarker thresholds from non‐African cohort's risk underdiagnosing Alzheimer's disease.
Review advocates ancestry‐specific cutoffs and diagnostic recalibration.
1. BACKGROUND
Alzheimer's disease (AD), the leading cause of dementia globally, accounts for 60%–80% of cases and imposes a profound burden on individuals, families, and healthcare systems. 1 Its core neuropathological features include the accumulation of amyloid‐β plaques and neurofibrillary tangles (NFTs), extensive neuronal loss, and synaptic degradation. 2 These changes are further intensified by neuroinflammation and vascular dysfunction, which accelerate neurodegeneration and cognitive decline. 3
Emerging data from the United States of America (USA) and United Kingdom (UK) indicate that individuals of African ancestry including African American and older Black populations experience a disproportionately higher prevalence of dementia compared to non‐Hispanic White (NHW) cohorts, though the extent to which this reflects Alzheimer's pathology versus non‐AD causes remains unclear due to limited biomarker testing. 4 , 5 , 6 Further evidence reveals distinct genetic risk profiles for AD among underrepresented populations, particularly individuals of African ancestry. Variants in genes such as apolipoprotein E (APOE) and ATP‐binding cassette subfamily A 7 (ABCA7), which differ in frequency and effect across populations contribute to disease susceptibility and may influence biomarker expression and neuropathological trajectories. 7 These population‐specific genetic patterns underscore the urgent need to expand research on AD pathophysiology and validate biomarker performance within diverse ancestral groups to ensure diagnostic accuracy and equity.
Over the past decade, significant advances in biomarker discovery have transformed the landscape of AD research and clinical care. Biomarkers detected in cerebrospinal fluid (CSF) and blood such as amyloid‐β isoforms (Aβ42, Aβ40, Aβ38), phosphorylated tau species (e.g., p‐tau181, p‐tau217, p‐tau237), and neurofilament light chain (NfL) have become essential for diagnosing, staging and monitoring of prodromal AD before clinical onset. 8 , 9
CSF and blood biomarkers are used not only to detect early AD but also to explore its biological causes and find treatment targets. They track the disease's progression from amyloid buildup to tau changes and finally to neurodegeneration, following the amyloid/tau/neurodegeneration (ATN) research framework. 10 , 11 Under this framework for in vivo assessment, AD is characterized into three core biomarker categories: Aβ42, which signals amyloid beta accumulation (A); phosphorylated tau isoforms, p‐tau181 and p‐tau217, which indicate tau‐related neurofibrillary pathology (T); and NfL, a marker of neuronal injury and degeneration (N). 12 Inflammatory biomarkers, such as YKL‐40, soluble triggering receptor expressed on myeloid cells 2 (TREM2), and glial fibrillary acidic protein (GFAP), alongside other cytokines have further highlighted the role of immune modulations in AD progression. 13
Neuroimaging techniques such as magnetic resonance imaging (MRI), diffusion tensor imaging (DTI), and amyloid positron emission tomography (PET) enable in vivo visualization of Alzheimer's‐related brain changes, including structural degeneration and amyloid deposition. 14 , 15 , 16 They play a critical role in advancing biomarker‐based assessment of AD by providing spatially resolved insights into pathological changes across disease stages. 17 Amyloid PET scans using tracers such as [1 1C]PiB, [1 8F]Florbetapir, [1 8F]Flutemetamol, and [1 8F]Florbetaben quantifies amyloid deposition (A) relative to reference regions like the cerebellum or pons, yielding distribution volume ratio (DVR) or standardized uptake volume ratio (SUVR) metrics. Tau PET scan, employing tracers such as [1 8F]Flortaucipir, [1 8F]MK‐6240, and [1 8F]RO‐948, enables visualization of NFTs (T) and regional tau pathology. Fluorodeoxyglucose‐PET (FDG‐PET) assesses cerebral glucose metabolism (N), with hypometabolism interpreted as synaptic dysfunction and neurodegeneration. 17 Structural MRI, particularly T1‐weighted and diffusion‐weighted sequences, quantifies brain atrophy and subtle neurodegenerative changes, while advanced MRI modalities such as T2‑weighted fluid‑attenuated inversion recovery (T2FLAIR), arterial spin labeling, and susceptibility‐weighted imaging provide complementary data on cerebrovascular integrity. 18 Collectively, these imaging modalities refine diagnostic accuracy, enable disease staging, and allow for real‐time tracking of AD progression.
Post mortem studies remain the gold standard for confirming AD and have been instrumental in validating in vivo biomarkers. The Brain Autopsy Study (BAS) employs a 14‐region immunohistochemistry panel to assess neurodegeneration using standardized criteria for staging and diagnosis. Braak staging is used to score and categorize NFTs into four conventional groups: 0, I/II, III/IV, and V/VI while β‐amyloid plaque burden is evaluated using the Consortium to Establish a Registry for Alzheimer's Disease (CERAD) criteria, with neuritic plaque density classified as none, sparse, moderate, or frequent. 19 Recent studies indicate that post mortem outcomes of AD may differ by race. Notably, individuals of African descent demonstrate lower density of neuritic plaques and unique tau deposition patterns, with corresponding severe cognitive impairment compared to other groups. 6 These ancestral differences highlight the importance of adapting biomarker‐based diagnostic criteria to reflect population‐specific variations.
Despite advances in AD diagnostics, individuals of African ancestry remain markedly underrepresented in research and clinical trials, hindering the validation and generalizability of biomarker performance across diverse populations. This disparity persists despite their unique genetic and environmental risks, rapid progression, and more severe clinical outcomes compared to populations elsewhere. 1 , 7 Additionally, sociocultural influences including unequal access to healthcare, lower education level, and economic challenges can compound genetic and biological predispositions, thereby intensifying the complexity of AD within African ancestry populations. 20
AD diagnostic protocols and biomarker thresholds developed elsewhere are routinely applied to African cohorts. These population‐specific variations in biomarker expression can compromise diagnostic accuracy and treatment outcomes. The universal application of diagnostic thresholds may be inappropriate for African populations, thereby increasing the risk of underdiagnosis and delayed care. This underscores the urgent need for recalibrated benchmarks and culturally sensitive diagnostic platforms that reflect population diversity and improve disease detection across diverse populations. 21
This systematic review therefore synthesized recent findings on CSF and blood biomarker profiles, neuroimaging patterns, and post mortem hallmarks of AD conducted among African ancestries, highlighting how they differ relative to populations elsewhere. This further seeks to establish ancestry‐specific findings on AD biomarkers specifically among African populations, with the goal of improving diagnostic accuracy, shaping future research agenda, and advancing culturally appropriate clinical care.
2. METHODS
This systematic review was conducted following the Preferred Reporting Items for Systematic Reviews and Meta‐analyses (PRISMA) guidelines. Prior to initiating the literature search, the review protocol was registered with PROSPERO (Registration ID‐CRD42025647958).
2.1. Search strategy
Comprehensive search was conducted across multiple databases, including PubMed, Scopus and Google Scholar until 4/08/2025 using appropriate keywords to ensure a focused selection of relevant studies.
Core search terms encompassed dementia‐related keywords such as “Alzheimer's disease,” “dementia,” “cognitive impairment,” and “neurodegenerative diseases.” Neuropathological and biomarker terms included “amyloid‐beta,” “phosphorylated tau,” “neurofibrillary tangles,” “neuroinflammation,” “fluid biomarkers,” “neuroimaging,” “post‐mortem,” and “autopsy.” Population‐specific terms such as “African ancestry,” “African American,” “Sub‐Saharan Africa,” and relevant regional keywords were employed to ensure inclusion of studies focusing on populations of African descent. Additionally, terms related to diagnostic modalities covered “cerebrospinal fluid,” “plasma biomarkers,” “magnetic resonance imaging (MRI),” “positron emission tomography (PET),” “post mortem”, “autopsy”, “histopathological”, and “immunohistochemistry.”
The search combined medical subject headings (MeSH) and free‐text keywords linked with Boolean operators (AND, OR, NOT) to enhance sensitivity and specificity. In addition, primary sources referenced in the reviewed literature were retrieved and included in the analysis when they met the eligibility criteria, ensuring thorough and comprehensive coverage.
2.2. Eligibility and selection criteria
Studies were eligible for inclusion if they investigated neuropathological hallmarks of AD in populations of African ancestry or included stratified analyses by ancestry. The use of “African ancestry” in most studies refers to individuals of African descent, encompassing both continental Africans and members of the African diaspora, such as African American populations. To maintain consistency, this review adopted the ancestry terminology used in each study and explicitly differentiated between continental African populations and diaspora groups (e.g., African American, Afro‑Caribbean) where relevant. Studies reporting findings on fluid biomarkers (e.g., amyloid‐β, tau proteins, tau isoforms), neuroimaging (MRI, PET), or post mortem neuropathology (histological or immunohistochemical confirmation of hallmark lesions) were also included in this review. Also, studies conducted among human subjects and published in English were included. Additionally, included studies comprised original research and reputable gray literature (e.g., WHO and Alzheimer's disease International reports), provided they presented neuropathological or biomarker data rather than relying solely on clinical or cognitive diagnoses. Studies were also included if they were done within the past 10 years (2015–2025) to capture the most current advancements in fluid biomarkers, neuroimaging, and post mortem investigations relevant to AD among African ancestry populations.
Alternatively, studies were excluded if they focused on other neurodegenerative diseases aside AD, and non‐neurodegenerative disorders such as stroke, brain tumors, traumatic brain injury or were case reports, opinion pieces, conference abstracts without full reports, or preclinical studies using animal models. Studies that did not provide direct neuropathological or biomarker data were excluded accordingly. Furthermore, studies published in languages other than English were excluded due to difficulties in accurate interpretation and critical appraisal, compounded by limited resources for translation.
The selection process involved a three‐phase screening: (1) title and abstract review conducted using Zotero (version 7.0.15), with removal of duplicates; (2) full‐text screening based on inclusion and exclusion criteria; and (3) final inclusion for data extraction. Discrepancies between reviewers at each phase were resolved through discussion or adjudication by a third reviewer. The selection workflow was documented and visualized using a PRISMA flowchart (Figure 1).
FIGURE 1.
The PRISMA flow diagram visually summarizes the systematic study selection process. It traces each step, from the initial identification of records through database searches, the removal of duplicates, title and abstract screening, full‐text eligibility assessment, and the final inclusion of studies for review. PRISMA, Preferred Reporting Items for Systematic Reviews and Meta‐analyses
2.3. Data extraction
From included studies, key data were extracted systematically, including Study characteristics: authors, publication year, study design, sample size, and population demographics; Diagnostic methods: fluid biomarker assays (e.g., CSF tau or amyloid), neuroimaging modalities (MRI, PET with amyloid or tau ligands), and post mortem techniques (histology, immunohistochemistry, Thioflavin‐S, Congo Red staining), and finally neuropathological findings: presence, density, distribution, concentrations, and severity of amyloid plaques, NFTs. Reported biomarker profiles included amyloid‐β isoforms, phosphorylated tau species, neurofilament light chain, along with genetic risk factors such as APOE genotype and ancestry‐specific variants.
2.4. Quality assessment and risk of bias
To ensure a rigorous and standardized evaluation of study quality and bias, the Newcastle–Ottawa scale (NOS) and the Cochrane risk of bias tool were employed to appraise methodological rigor, assess potential sources of bias, and maintain consistency across observational and interventional studies included in the review. The NOS provides design‐specific criteria to assess the quality of observational studies, including cohort, case–control, and cross‐sectional designs. The tool evaluates three broad domains; selection of study groups, comparability of cohorts or cases/controls, and ascertainment of exposure or outcome allocating a maximum of nine stars per study.
Cohort and case–control studies were evaluated using eight sub‐criteria, with quality ratings categorized as follows: high quality (seven to nine stars), moderate quality (five to six stars), and low quality (fewer than five stars). For cross‐sectional studies, a modified assessment scale was used to account for their distinct methodological characteristics. This adapted version typically assessed domains such as sample representativeness, measurement reliability, and adjustment for confounding variables. Quality was similarly classified as high (7–10 stars on a 10‐point scale), moderate (5–6 stars), or low (fewer than five stars). In parallel, the Grading of Recommendations, Assessment, Development, and Evaluations (GRADE) framework was applied to assess the overall certainty of evidence across studies. This entailed evaluating each study for risk of bias, confounding control, exposure and outcome measurement quality, and transparency of reporting. Studies with pronounced methodological limitations were explicitly flagged, and their influence on the broader conclusions was critically appraised during synthesis. This dual‐tiered appraisal ensured that the final body of evidence reflected both methodological rigor and contextual reliability.
2.5. Ethical considerations and data synthesis
As this study is a systematic review conducted based on previously published literature, direct ethical approval was not obtained. A thematic synthesis approach was used to identify and summarize key themes and patterns within the data. Neuropathological characteristics observed in African AD cases were examined alongside global findings, with additional analysis exploring potential contributors to regional differences such as genetic predispositions, environmental exposures, and lifestyle factors.
3. RESULTS
3.1. Study characteristics
This review synthesized findings from 50 studies spanning cross‑sectional (n = 33), longitudinal (10), case‑‐control (5), and genome‑wide association designs (2). Study populations varied widely, ranging from exploratory groups of 30 or fewer participants (n = 2) 22 to extensive multi‐center datasets involving more than 30 participants (n = 48) and, in some cases, surpassing 50,000 individuals. 23 Among the selected studies, nearly 90% of the studies focused on African American/Black populations, with smaller cohorts from Hispanic/Latino, Caribbean, Peruvian, and Asian groups. Most studies were U.S.‑based and as a result, ancestry classifications largely reflect U.S. racial categories rather than genetic or continental African ancestry, and observed trends may stem from sociobiological exposures, marginalization, admixture, environment, or healthcare access rather than ancestry‑specific biology alone. Table 1 summarizes key characteristics of included studies, outlining neuropathological hallmarks of dementia and AD, diagnostic methods, biomarker modalities, and population demographics, with particular emphasis on ancestry‑linked variation across cohorts.
TABLE 1.
Overview of included studies on neuropathological hallmarks of dementia and AD, showing their key features, diagnostic techniques, and population demographics
| SN | Author(s) and year | Study design/type | Sample size and demographics | Diagnostic technique/method employed | Key neuropathological features (amyloid plaques, NFT, density/quantities) | NOS score |
|---|---|---|---|---|---|---|
| 1 | Knell G et al., (2025) 24 | Cross‐sectional | Total sample size: 2358 participants
|
Plasma biomarker analysis Neuropsychological test: MMSE |
|
6 |
| 2 | Deters KD et al., (2021) 25 | Cross‐sectional | Total sample size: 3833 participants
|
Neuroimaging: 18F Florbetapir positron emission tomography (PET) Neuropsychological tests: MMSE, CDR Genetic: Genome‐wide SNP array |
|
6 |
| 3 | Royse SK et al., (2024) 18 | Cross‐sectional |
|
|
Black American (BA) participants had significantly higher UWMC than non‐Hispanic White (nHW) participants. UWMC was negatively associated with cognition (measured by MoCA scores), especially in regions affected by beta‐amyloid (Aβ) and tau pathology. The strength of the UWMC–cognition relationship did not differ by racialized group, suggesting that disparities in AD may stem more from greater UWMC burden than from differential vulnerability. |
6 |
| 4 | Morris JC et al., (2019) 26 | Cross‐sectional |
1255 participants (173 African Americans; 707 women; mean age: 70.8 ± 9.9 years) 67% cognitively normal across both racial groups |
|
|
7 |
| 5 | Jiang X et al., (2024) 27 | Longitudinal study |
|
|
|
9 |
| 6 | Hajjar I et al., (2022) 20 | Cross‐sectional |
|
|
|
6 |
| 7 | Ramanan VK et al., (2023) 28 | Cross‐sectional |
|
|
|
6 |
| 8 | Han JW et al., (2020) 29 |
|
|
|
|
8 |
| 9 | Cook JD et al., (2024) 30 | Mixed method |
|
|
|
7 |
| 10 | Xiong C et al., (2024) 31 | Longitudinal (multi‐center study assessing baseline and follow‐up plasma Aβ) |
|
|
|
8 |
| 11 | Kumar VV et al., (2020) 32 | Cross‐sectional |
|
|
|
8 |
| 12 | Dhana et al., (2025) 33 | Population‐based longitudinal cohort study (Chicago Health and Aging Project) |
|
|
|
8 |
| 13 | Kamara DM et al., (2018) 34 | Cross‐sectional |
|
|
|
5 |
| 14 | Petersen ME et al., (2024) 35 | Cross‐sectional |
|
|
|
6 |
| 15 | Sawyer RP et al., (2025) 36 | Longitudinal study |
N = 724 participants (mean age: 66.1 ± 11.7 years) 51.7% female 43.6% identified as Black; remainder White |
Biofluid (blood biomarkers: NfL, GFAP, total tau, UCH‐L1) |
Elevated GFAP, NfL, and UCH‐L1 levels at baseline were associated with higher risk of incident cognitive impairment No significant association for total tau No race‐based differences observed in biomarker associations (effects consistent across Black and White participants) |
N/A |
| 16 | Schindler SE et al., (2022) 16 | Cross‐sectional |
N = 152 (76 African American matched 1:1 with 76 non‐Hispanic White) Median age: 68.4 years 42% APOE ε4 carriers 91% cognitively normal |
Biofluid: plasma and CSF biomarkers (Aβ42/Aβ40, p‐tau181, p‐tau231, NfL) Neuroimaging: Amyloid PET in 103 participants (68%) |
|
7 |
| 17 | Budak M et al., (2024) 8 | Cross‐sectional |
N = 148 cognitively unimpaired older African Americans Mean age: 70.88 years (SD: 6.05) |
Neuroimaging: functional MRI (MTL dynamic network connectivity) Biofluid: plasma biomarkers (p‐tau231, p‐tau181, Aβ42/Aβ40) |
|
6 |
| 18 | Griswold AJ et al., (2025) 37 | Cross‐sectional |
2086 individuals Populations: African American, Caribbean Hispanic, Peruvian |
Biofluid biomarkers (Plasma) pTau181 Aβ42/Aβ40 ratio |
|
6 |
| 19 | Naslavsky MS et al., (2022) 6 | Cross‐sectional |
400 admixed Brazilians (community‐dwelling) Varied African ancestry proportions Subset analysis on 309 individuals for local APOE ancestry |
Post mortem (histological) assessment of: Neuritic plaques (NP) Neurofibrillary tangles (NFT) Clinical Dementia Rating – Sum of Boxes (CDR‐SOB) for functional cognition |
|
6 |
| 20 | Gogola A et al., (2025) 38 | Cross‐sectional |
n = 260 older adults without dementia Racialized groups: Black/African American (AA) and non‐Hispanic White (NHW) Age range: 50–90 years (mean: 68.8 ± 9.1 years) |
In vivo imaging: Aβ‐PET using [1 1C]‐PiB SUVR MRI‐based cortical thickness measurements Plasma biomarkers: Aβ42/Aβ40, p‐tau181, p‐tau217, p‐tau231, NfL, GFAP |
|
7 |
| 21 | Nayyar A et al., (2025) 39 | Cross‐sectional |
n = 217 Non‐Hispanic White (NHW): 113 Black/African American (B/AA): 66 Chinese American (ChA): 38 Recruited from two U.S. university centers |
Biofluid: Plasma p‐Tau217 (Fujirebio assay), CSF p‐Tau181 and p‐Tau217 |
|
5 |
| 22 | Koenig LN et al., (2021) 40 | Case–control |
n = 243 (81 with recent ischemic stroke) Mean age: 75 57% female 52% African American |
Neuroimaging: PET (Pittsburgh Compound B for cortical Aβ), MRI (for infarcts, WMH, microbleeds, hippocampal and WMH volumes) |
|
6 |
| 23 | Lah JJ et al., (2024) 41 | Cross‐sectional |
n = 3006 495 (16.5%) self‐identified Black/African American 2456 (81.7%) White/European ancestry |
Biofluid: Cerebrospinal fluid (CSF) Measured Aβ42, total tau (t‐tau), phospho‐181 tau (p‐tau181) Biomarker classification using ADNI cutoffs and Gaussian mixture regressions |
|
5 |
| 24 | Rajabli F et al., (2025) 23 | Cross‐ancestry genome‐wide association study (GWAS) and meta‐analysis |
Total: 56,241 individuals 37,382 non‐Hispanic White (NHW) 6728 African American (AA) 8899 Hispanic (HIS) 3232 East Asian (EAS) |
Genetic analysis of late‐onset Alzheimer's disease (LOAD) susceptibility using within‐ancestry fixed‐effects meta‐analysis and cross‐ancestry random‐effects meta‐analysis |
|
6 |
| 25 | Ferguson SA et al., (2017) 22 | Cross‐sectional |
Total: 24 AD cases (n = 6 per group: African American males, African American females, Caucasian males, Caucasian females) Age‐matched African Americans and Caucasians with Alzheimer's disease |
Post mortem (histological) analysis of brain tissue (middle temporal gyrus, BA21) Quantification of S100B, sRAGE, GDNF, Aβ40, Aβ42, and Aβ42/Aβ40 ratio |
|
7 |
| 26 | Asken et al., (2024) 42 | Cross‐sectional | 379 older adults (57% Hispanic; 88% Cuban or South American ancestry) impairment, and AD dementia stages |
Clinical diagnosis (amnestic/non‐amnestic MCI/dementia), Biofluid (plasma) biomarkers (p‐tau181, GFAP, NfL), and Neuroimaging: Aβ‐PET imaging |
|
6 |
| 27 | Misiura M et al., (2024) 43 | Cross‐sectional |
76 cognitively unimpaired, middle‐aged adults Black Americans (n = 29; 17F/12M) Non‐Hispanic Whites (n = 47; 27F/20M) |
Multimodal biomarker evaluation combining: ‐Resting‐state functional MRI (fMRI) for default mode network (DMN) connectivity ‐White matter hyperintensity (WMH) volumes ‐Hippocampal volumetry ‐CSF biomarkers: phosphorylated tau141 and Aβ42 |
|
6 |
| 28 | Graff‐Radford NR et al., (2016) 44 | Cross‐sectional |
African Americans (n = 110) Caucasians (n = 2500) All participants were clinically demented prior to death |
Neuropathological assessments from autopsy Clinical data on cognition, comorbidities, and ApoE genotype |
|
5 |
| 29 | Kunkle BW et al., (2021) 45 | Genome‐wide association meta‐analysis (case–control and family‐based) |
2784 Alzheimer's disease cases (69.8% female) 5222 controls (71.7% female) All participants of African American ancestry from multiple U.S. recruitment sites Mean age: 74.2 ± 13.6 years |
Clinical diagnosis of Alzheimer's disease Genetic analysis using African Genome Resource panel and GWAS |
New common loci identified:
|
7 |
| 30 | Shrestha S et al., (2025) 46 | Cross‐sectional |
N = 1545 Age: 76 ± 5 years 60% women 27% self‐identified as Black participants |
Biofluid biomarkers (plasma: Aβ42/Aβ40, p‐tau181, GFAP, NfL); MRI (brain volume assessment) |
|
7 |
| 31 | Giannisis A et al., (2023) 47 | Cross‐sectional |
N = 125 total participants Black/African Americans (B/AAs): n = 58 Normal cognition: n = 25 MCI: n = 24 AD dementia: n = 9 Non‐Hispanic Whites (NHWs): n = 67 Normal cognition: n = 28 MCI: n = 24 AD dementia: n = 15 |
Mass spectrometry for plasma apoE isoforms Non‐reducing Western blot for apoE monomer/dimer analysis CSF biomarkers assessed (t‐tau, Aβ) sTREM2, NfL, and plasma lipid panels (HDL, LDL, cholesterol) |
|
5 |
| 32 | Li X et al., (2023) 11 | Longitudinal study |
N = 307 women (209 with HIV, 98 without HIV) 53% African American or Black 96% aged ≥50 years |
Biofluid (plasma biomarkers: Aβ40, Aβ42, Aβ42/Aβ40 ratio, t‐tau, p‐tau231, GFAP, NFL) |
|
7 |
| 33 | Deniz K et al., (2021) 10 | Cross‐sectional |
N = 321 African Americans 159 with AD, 162 controls |
Biofluid (plasma biomarkers: Aβ42, tau, IL6, IL10, TNFα) |
|
6 |
| 34 | Modeste ES et al., (2023) 48 | Cross‐sectional |
N = 203 total (105 controls, 98 AD patients) 100 Caucasians, 103 African Americans |
Biofluid (CSF proteomic analysis via TMT‐MS and SRM) |
|
7 |
| 35 | Misiura MB et al., (2020) 49 | Cross‐sectional | Total sample size: 137 stratified into Normal cognition, MCI, and AD |
Neuroimaging (functional MRI ‐ default mode network connectivity) Biofluid (CSF: amyloid β1–42, total tau) Neuropsychological tests: MMSE |
|
6 |
| 36 | Howell JC et al., (2017) 50 | Prospective cohort |
Total: 135 participants African Americans: 65 (mean age = 69.1 years) Caucasians: 70 (mean age = 70.8 years) |
Biofluid (CSF: Aβ42, Aβ40, total tau, p‐tau181, α‐synuclein, NfL) Neuroimaging (MRI: hippocampal atrophy, white matter hyperintensity [WMH] volume) |
|
6 |
| 37 | Simons RL et al., (2024) 9 | Longitudinal |
Total: 255 participants Population: Black Americans followed over 17 years (from midlife into 60s) |
Biofluid (serum biomarkers: p‐tau181, neurofilament light [NfL], GFAP) |
|
8 |
| 38 | Garrett SL et al., (2019) 51 | Case–control |
Total: 362 participants African American: 152 (42.0%) Mean age: 65.6 years 63.5% female 52.2% had mild cognitive impairment (MCI) |
Biofluid (CSF biomarkers: Aβ1‐42, total tau, p‐tau181) Neuroimaging (MRI – hippocampal volume) |
|
8 |
| 39 | Kjaergaard et al., (2025) 52 | Cross‐sectional | ‐ 1170 memory clinic patients from 91 countries; 539 had CSF or amyloid PET confirmation | Plasma p‐tau217 measurement; supplemented by CSF or amyloid PET for diagnostic validation |
|
7 |
| 40 | Xu X et al., (2025) 1 | Longitudinal study |
Total: 4592 individuals African ancestry: 119 Asian ancestry: 52 European ancestry: 4421 Mean age: 70.8 years (SD: 10.2) Sex: 52.8% female |
Biofluid (CSF biomarkers: Aβ42, p‐tau181, total tau) |
|
8 |
| 41 | Meeker KL et al., (2021) 21 | Cross‐sectional |
Total: 816 cognitively normal participants African American: 131 White: 685 Age: 45 years and older |
Neuroimaging: (amyloid PET Tau PET) Structural MRI Resting‐state functional connectivity (rs‐fc) |
|
5 |
| 42 | Butts B et al., (2024) 53 | Longitudinal study |
Total: 82 adults Age: 45–65 years All had a parental history of Alzheimer's disease Racial groups: Black/African American (B/AA) and non‐Hispanic White (NHW) |
Biofluid biomarkers: Cerebrospinal fluid (CSF) and blood (baseline and year 2) |
|
7 |
| 43 | Gottesman RF et al., (2016) 15 | Cross‐sectional |
329 participants aged 67–88 years Dementia‐free at enrollment Recruited from 3 U.S. community sites 141 Black participants (43%) |
Amyloid PET imaging using Florbetapir Global cortical SUVR > 1.2 defined as elevated amyloid burden |
|
5 |
| 44 | Schwinne M et al., (2024) 2 | Cross‐sectional | 81 Congolese participants |
Blood‐based biomarkers: Plasma Aβ42/40 and p‐tau181 Cognitive assessments: Alzheimer's questionnaire (AQ) and community screening interview for dementia (CSID) |
|
6 |
| 45 | Walker KA et al., (2018) 3 | Longitudinal study | 339 non‐demented older adults (mean age: 75 ± 5 years) from the ARIC–PET Study |
Florbetapir PET imaging to assess brain amyloid (SUVR >1.2 = elevated deposition) Systemic inflammation assessed via C‐reactive protein (CRP) at three time points (midlife and late‐life, over a 22‐year span) |
|
7 |
| 46 | Ennis GE et al., (2025) 5 | Cross‐sectional |
233 predominantly cognitively unimpaired Black adults from the African Americans Subsamples: 137 participants had creatinine/eGFR data 65 participants underwent amyloid PET (16 positive) 70 participants underwent tau PET |
Plasma p‐tau217 measured using ALZPath, Inc. assay Neuroimaging: Amyloid‐ and tau‐PET for confirming pathology |
|
6 |
| 47 | Simino J et al., (2025) 54 | Mixed method with plasma amyloid‐β (Aβ) concentrations at multiple time points (mean ages: 59, 77, and over ∼18 years) |
1414 African American and European American participants Internal replication sample: 1014 participants (exome chip data) External replication sample: 725 participants |
Plasma Aβ42 and Aβ40 concentrations measured Genetic analysis: Single‐variant and gene‐based association analyses (MAF ≥1% and ≥5%, respectively) Statistical tools: seqMeta, T5 burden test, and SKAT |
|
7 |
| 48 | Bonomi et al., (2024) 4 | Cross‐sectional study | 3095 participants (495 Black, 2600 White) from four harmonized aging studies |
CSF biomarkers (Aβ42/40, total tau, p‐tau181, NfL), Neuroimaging: amyloid PET, MRI, cognitive assessments |
|
7 |
| 49 | Duara et al., (2019) 14 | Cross‐sectional | ‐ 159 Hispanic and non‐Hispanic participants (classified as CN, MCI, or Dementia) | Neuroimaging: [18‐F]florbetaben PET scans (visual assessment and SUVR quantification), ROC analysis, Genetic analysis: APOE ε4 genotyping |
|
5 |
| 50 | Ali et al., (2023) 55 | Prospective genome‐wide association study (GWAS) | 13,409 participants across multiple ethnicities from multicenter cohorts |
Neuroimaging: amyloid PET Genome analysis: SNP genotyping; sex‐ and race‐stratified genetic analyses |
|
5 |
Note: Table 1 summarizes key characteristics of studies included in the systematic review, detailing neuropathological hallmarks of dementia and Alzheimer's disease. It highlights diagnostic methods used, biomarker modalities assessed, and population demographics, with emphasis on ancestry‐linked variation across cohorts.
3.2. Biomarkers and neuroimaging findings
Evidence from fluid biomarker studies revealed a recurring pattern where African American participants present with lower CSF, plasma p‐tau, and total tau compared to NHW individuals, despite similar degrees of cognitive impairment. 26 , 32 , 41 In contrast, Hispanic cohorts frequently demonstrated equal or elevated p‐tau levels compared to non‐Hispanic participants. 35 , 37 Amyloid biomarkers demonstrated greater variability where several studies reported lower amyloid‐β (Aβ42/Aβ40) ratios and reduced PET‐amyloid signals in African American populations, 16 , 25 , 31 while others found no significant racial differences. 34 , 56 , 57 Genetic variation contributed to the observed patterns, as APOE ε4 was strongly associated with amyloid burden in NHW individuals, 25 whereas its association was comparatively weaker in cohorts of African ancestry. 6 , 26 Neuroimaging findings revealed insignificant ancestral differences in amyloid or tau PET burden compared with fluid biomarkers. However, markers of neurodegeneration were consistently more pronounced in African American participants. Several studies reported reduced cortical thickness, greater white‐matter hyperintensities (WMH), smaller hippocampal volumes, and accelerated brain aging. 38 , 58 Studies reporting comparable amyloid burden across racial groups found that vascular and structural brain alterations were more pronounced in African American individuals. 40 , 44
3.3. Methodological quality and rigor of included studies
There was variation of quality across the included studies, with most (n = 39) demonstrating moderate rigor (scores 6–8), reflecting adequate participant selection and reasonable comparability through adjustment for age, sex, and APOE genotype, but often lacking broader control for social determinants such as education or cardiovascular risk. A smaller group of studies (n = 2) achieved high quality (scores ≥9), characterized by robust biomarker measurement, standardized protocols, and comprehensive outcome ascertainment, while lower‑quality studies (n = 9) with scores ≤5 were limited by small sample sizes, incomplete reporting of biomarker assays, or inadequate adjustment for confounders.
4. DISCUSSION
4.1. Alzheimer's disease overview and pathogenesis among individuals of African ancestry
Individuals of African ancestry with AD exhibit a neuropathological profile characterized by key biomarkers including amyloid plaques and soluble isoforms such as Aβ42, Aβ40, and Aβ38, as well as tau proteins including Total tau (T‐tau) and phosphorylated variants like p‐tau181, p‐tau217, and p‐tau243 which align with patterns observed in other global populations. 2 , 37 , 46 However, evidence suggests that the diagnostic thresholds for these biomarkers may differ, reflecting ancestry‐specific variations in expression and disease manifestation. 20 , 24 , 26 , 50 , 51
These reported disparities and pathogenesis of AD among African ancestries involve a multifactorial interplay of genetic, vascular, sociocultural, and inflammatory factors leading to progressive synaptic and neuronal loss, cognitive decline, and ultimately dementia. 13 , 17 Notably, genetic variations in APOE ε4 allele and novel ancestry‐specific loci such as ABCA7 and TREM2 may exert weaker effect on amyloid accumulation and tau formation in African ancestries compared to populations elsewhere, which contribute to the differential susceptibility of AD. 7 , 23 , 45 Additionally, vascular comorbidities, including hypertension, diabetes, and chronic kidney disease, are disproportionately prevalent and have been shown to exacerbate neurodegeneration through mechanisms involving cerebrovascular dysfunction and neuroinflammation. 5 , 15 , 34 , 53 Sociocultural determinants such as systemic racism, reduced access to healthcare, educational disparities, and chronic psychosocial stress further modulate disease progression by influencing both biological vulnerability and diagnostic access. 12
4.2. Anatomical distribution and burden of amyloid and tau in African ancestry brains
The anatomical distribution of key AD biomarkers among African cohorts generally mirrors patterns observed in other populations. 49 Amyloid plaques initially accumulate in neocortical regions including the frontal, temporal, parietal, and occipital lobes and progressively extend to the hippocampal and entorrhinal areas. Tau pathology follows the established Braak staging sequence, beginning in the transentorhinal cortex and hippocampus, and advancing into limbic and isocortical regions as the disease progresses (Figure 2). 59
FIGURE 2.
Illustrates the anatomical distribution of AD biomarkers using the Thal amyloid‐beta staging and Braak NFT staging systems. Thal phases (I–V) depict the sequential accumulation and spread of amyloid‐beta plaques, originating in the neocortex and subsequently spreading through the hippocampus, subcortical regions, brainstem, and cerebellum. Braak stages (I–VI) illustrate the spread of tau pathology (NFTs), which begins in the entorhinal cortex and hippocampus, progresses to the limbic regions, and ultimately involves widespread neocortical areas. 59 AD, Alzheimer's disease; NFT, neurofibrillary tangle
4.3. Cerebrospinal fluid and blood biomarker dynamics in neurodegeneration
During AD, the integrity of the blood–brain barrier (BBB) becomes compromised, allowing proteins, nanoparticles, and extracellular vesicles such as exosomes to cross into peripheral circulation. 33 Concurrently, neurodegenerative biomarkers leak into the CSF and blood, reflecting pathological changes within the brain (Figure 3). 60 Advances in ultrasensitive detection technologies have significantly enhanced the ability to identify and quantify these biomarkers in CSF and blood, supporting their use and offer promising platforms for diagnosis and disease monitoring.
FIGURE 3.
Illustrate the movement of key brain‐derived AD biomarkers—GFAP, Aβ, P‐Tau, and NfL—into the CSF and blood. The transport occurs primarily through two mechanisms: disrupted blood–brain barrier pathways and extracellular vesicle trafficking. 60 AD, Alzheimer's disease; CSF, cerebrospinal fluid; GFAP, glial fibrillary acidic protein; NfL, neurofilament light chain
4.4. Fluid biomarkers: profiles and ancestral differences
Across fluid biomarker studies, African American participants frequently exhibited lower CSF and plasma tau concentrations, 26 , 32 , 41 yet greater markers of neurodegeneration and vascular pathology, 38 , 40 , 58 while Hispanic cohorts often showed elevated phosphorylated tau (p‑tau) levels. 35 , 37 Amyloid burden was more variable, with some studies reporting reduced Aβ42/Aβ40 ratios and PET‑amyloid signal in African American individuals, 16 , 25 , 31 while other studies found no significant differences, 34 , 56 , 57 and one reporting higher Aβ42 levels with greater neuroinflammation. 22 These findings reaffirm existing reports of lower tau burden despite comparable cognitive impairment in African American individuals 26 and highlight the prominent role of vascular pathology. 40 Elevated p‑tau levels in Hispanic cohorts align with emerging evidence of heterogeneity across Latino populations, 35 , 37 while variability in amyloid burden further confirms earlier mixed findings. 16 , 25 , 57
4.4.1. CSF amyloid and tau profiles
Across populations, CSF amyloid biomarkers generally demonstrated broadly consistent concentrations, supporting the view of a shared biological pathway in early stages of AD. Several studies have reported minimal racial differences in CSF Aβ‐analyte levels, with no significant differences in Aβ42 concentrations among Black and other cohorts elsewhere, 4 , 12 , 16 , 20 , 26 , 48 , 51 , 53 suggesting a comparable amyloid deposition across groups. In contrast, findings from African cohorts reveal a divergent pattern with multiple studies reporting significantly lower concentrations of CSF amyloid isoforms including Aβ38, Aβ40, and Aβ42, particularly in those with mild cognitive impairment or AD. 31 , 39 , 41 , 50 Yet, other studies have reported elevated levels of amyloid biomarkers in African‐descended groups, 4 , 20 , 49 indicating heterogeneity not only across populations but potentially within African cohorts themselves.
This variability underscores that amyloid expression may differ by ancestry, disease stage, or methodological approach. These results suggest that, while amyloid deposition follows a relatively conserved trajectory across ancestries, subtle differences emerge in certain African populations. Such variations may reflect methodological sensitivity, cohort characteristics or underlying socio‐genetic factors.
Genetic diversity within African populations may play a predominant role in the observed disparities. Ancestry‐specific variants in genes such as APOE and ABCA7, including pathogenic haplotypes and elevated expression levels, have been associated with increased risk of neurodegeneration. For example, Giannisis et al. 47 reported that Black African American individuals exhibited a 2.6‐fold increase in APOE protein levels compared to NHW individuals, highlighting ancestry‐related differences in biomarker expression relevant to AD pathogenesis. These mechanisms influence amyloid processing and clearance, contributing to distinct patterns of AD pathogenesis. 44 , 47 Beyond genetics, additional factors such as sociocultural diversity, comorbid health conditions, disparities in healthcare access and methodological inconsistent sample collection and assay platforms further influence CSF amyloid variation within African ancestry populations. Notably, a longitudinal study by Simons et al. 9 reported that experiences of racial discrimination among Black American individuals in midlife (around age 40) were predictive of elevated AD biomarkers nearly two decades later, highlighting the long‐term impact of social determinants on neurodegenerative risk. 9 , 12
Studies investigating CSF tau concentrations across African populations further reveal mixed and sometimes contrasting patterns. A number of reports describe insignificant differences compared to other populations, thereby supporting the continued application of uniform diagnostic thresholds across ancestries in clinical and research settings. 12
However, several studies have consistently identified significantly lower concentrations of CSF tau biomarkers particularly total tau and p‐tau181 among African ancestries, independent of amyloid status. 16 , 26 , 49 , 50 , 51 This implies that tau‐related neurodegeneration may manifest differently across populations, raising concerns about the sensitivity of current diagnostic protocols in detecting AD among African individuals. Conversely, a smaller subset of studies has reported disproportionately higher tau concentrations in African ancestry participants, particularly in subgroups with advanced cognitive impairment or comorbid conditions, 39 , 48 highlighting possible intra‐population variability.
The diagnostic potential of combining tau and amyloid isoform ratios has been widely investigated across multiple studies. Notably, Garrett et al. 51 demonstrated that tau/Aβ42 and p‐tau181/Aβ42 ratios showed statistically significant discriminatory power for tau‐related neurodegeneration among African American individuals compared to other populations. These findings underscore the importance of establishing robust biomarker thresholds that reflect population diversity and support equitable diagnostic accuracy. 51
The disparities in CSF tau concentrations in African ancestries may stem from a combination of vascular, structural, and genetic factors. African American populations may experience more subclinical endothelial dysfunction and ischemic damage, reflected in their higher MRI WMH and differences in brain network integrity and connectivity which heightens vulnerability to neurodegeneration. 50 Additionally, genetic influences such as the attenuated association between the APOE ε4 allele and tau pathology as well as variation in expression of tau‐related genes like TREM2 and rare microtubule‑associated protein tau (MAPT) gene (H2 haplotype) in African ancestries compared to populations elsewhere may influence tau aggregation and CSF levels, though current evidence is inconclusive. 10 , 45 Together, these factors suggest a complex interplay that may affect tau pathology and diagnostic interpretation across populations.
4.4.2. Plasma amyloid, tau, and neurodegeneration markers
Plasma biomarkers have emerged as a more accessible and less invasive diagnostic alternative for AD, with strong sensitivity in detecting key pathological changes. 28 Plasma concentrations of amyloid‐β and tau closely mirror the CSF biomarker profiles described earlier, supporting their potential utility in scalable screening and monitoring strategies. Thus, comparable plasma biomarkers, specifically Aβ and tau isoforms, have been documented both in African populations and in cohorts elsewhere. However, their diagnostic performance may vary due to population‐specific factors, including genetic diversity, comorbidities, and environmental influences. 7 Most studies have reported no significant differences in plasma amyloid levels, especially Aβ42/Aβ40 in African populations compared to populations elsewhere, 20 , 28 , 31 , 37 , 38 suggesting broad comparability. This general observation may reflect ancestral genetic variation and overlap or limitations in the sensitivity of the assay technique used, which may have failed to detect subtle population‐level differences. 37
However, multiple studies have reported markedly reduced concentrations of amyloid and its isoforms in individuals of African ancestry compared to other population groups. 20 , 24 , 27 These discrepancies may limit the applicability of biomarker thresholds established elsewhere, raising concerns about potential underdiagnosis in African‐ancestry groups. Importantly, lower Aβ42/Aβ40 ratios have been consistently associated with increased dementia risk among individuals of African ancestry, 20 , 27 and a study in native Congolese participants confirmed their discriminatory value by linking reduced plasma Aβ42/Aβ40 ratios to poorer cognitive performance. 2
Conversely, a few studies have observed significant elevations of plasma amyloid levels in African populations compared to populations elsewhere, 16 , 31 pointing to heterogeneity within and across cohorts. Several reasons have been suggested for these differences including distinct peripheral amyloid metabolism or clearance, possibly influenced by liver and kidney function disparities prevalent in African American populations. 31 Additionally, the variable influence of the APOE ε4 allele on plasma amyloid levels in African populations relative to other groups underscores the role of ancestry‐specific genetic modifiers in lipid metabolism and amyloid regulation. 18 , 25
Patterns in plasma tau biomarkers also parallel CSF findings. Plasma tau biomarkers particularly p‐tau181, p‐tau217, and p‐tau231 have shown similar reduced levels in individuals of African ancestry 8 , 39 , 41 which may also limit the sensitivity for early detection when universal thresholds are applied. Among these, plasma p‐tau181, though not associated with significant cognitive performance, has demonstrated relative stability and reliability across populations and underscores its potential as a target biomarker for early AD diagnosis. 28 , 37 , 51 Another tau isoform, p‐tau217, has shown strong stability and consistent detectability in plasma‐based assays. Studies by Kjaegaard et al. 52 and Ennis et al. 5 demonstrated reliably measurable p‐tau217 levels across diverse populations, with minimal intergroup variation. This was evidenced by a high area under the curve (AUC) of 0.98, indicating strong diagnostic performance and consistency. 5 , 52 Due to their reproducible diagnostic accuracy in racially diverse populations, p‑tau217 and p‑tau181 are increasingly recognized as candidates for clinical application. However, additional population‐level validation studies are needed to confirm their generalizability and support broader clinical implementation. Low plasma tau concentrations may limit the sensitivity and early AD detection in African ancestry populations when universal thresholds are applied. This challenge is further compounded by comorbidities, such as chronic kidney disease, which are prevalent in African populations and can independently elevate tau levels, thereby obscuring the accurate interpretation of biomarker data. 5
4.4.3. Diagnostic potential of CSF and blood NfL and GFAP in AD
NfL, a structural axonal protein released during neuronal injury, has emerged as a sensitive and scalable blood‐based marker of neurodegeneration. Across studies, elevated NfL concentrations in both CSF and plasma are strongly associated with AD and mild cognitive impairment, supporting its role as a minimally invasive biomarker for early detection and longitudinal disease monitoring. Importantly, recent analysis reveals ancestral variation, with African American participants often showing differences in NfL levels compared to non‐Hispanic White individuals. These findings suggest that while NfL is broadly applicable across neurodegenrative disorders, standardization of measurement and careful adjustment for confounders such as age, dementia stage, and comorbidities are essential in African populations. The ability of NfL to complement AD‐specific markers such as p‑tau217 highlights its value as a strategic biomarker for molecular epidemiology and screening, particularly in resource‑limited settings where access to advanced imaging is constrained.
GFAP released during astrocyte activation near amyloid plaques, reflects neuro‐inflammatory processes and early tau pathology. GFAP has demonstrated strong associations with tau pathology and cognitive decline, independent of amyloid burden, in dementia cohorts with closely matched serum and post mortem assessments. However, its interpretation may be affected by ancestry‑related biological variation and broader social determinants of health. 28 One study demonstrated that elevated baseline levels of GFAP and NfL predicted incident cognitive impairment, while total tau showed no significant association. Importantly, these biomarker effects were consistent across Black and White participants, indicating no race‐based differences in predictive performance. 36 However, given the heterogeneity in comorbidities and cohort characteristics, further research is needed to clarify GFAP's diagnostic utility in diverse populations and its relationship to other temporal lobe pathologies such as hippocampal sclerosis and argyrophilic grain disease.
4.5. Neuroimaging biomarkers of amyloid and tau
Neuroimaging biomarkers such as amyloid and tau PET, alongside structural and functional MRI, offer in vivo insights into AD. Comparative studies across African ancestry and in other cohorts revealed both convergent and divergent patterns, with underlying genetic, vascular, and sociocultural factors contributing to observed variations. Studies revealed fewer race‑specific differences in amyloid or tau PET burden, yet consistently demonstrated greater vascular pathology and structural brain changes in African American individuals, 38 , 40 , 58 suggesting that non‑amyloid mechanisms disproportionately contribute to cognitive decline.
4.5.1. Amyloid PET imaging
Across studies, amyloid PET imaging generally revealed similar cortical burden and spatial distribution among African American and White populations, with several investigations reporting no significant racial differences in amyloid deposition among cognitively normal individuals. For example, Morris and colleagues found comparable cortical amyloid burden and spatial distribution between groups, suggesting that amyloid accumulation follows a broadly conserved neuroanatomical trajectories across ancestries [cortical SUVR: 1.69(0.12) vs. 1.80(0.04) p = 0.38)]. 26 However, findings from the Atherosclerosis Risk In Communities (ARIC) study deviated, reporting higher florbetapir uptake in African American participants. These discrepancies may be due to methodological differences. For instance, Morris and colleagues used partial volume‐corrected SUVR with [11C]PiB and dichotomized the data, while ARIC used [18F]florbetapir and treated uptake as a continuous variable. Additionally, the ARIC cohort was, on average, 5 years older and included individuals with mild cognitive impairment within the non‐demented group. 3 , 26 Subtle differences may stem from underlying factors such as genetic variation in the APOE ε4 allele, which exerts a stronger influence on amyloid accumulation among other populations than those of African ancestry. 6 , 18 , 25
Also, individuals of Black race and African ancestry have been linked to lower levels of amyloid deposition, with a notable interaction observed among APOE ε4 carriers. Specifically, non‐Hispanic Black participants with APOE ε4 allele showed reduced amyloid accumulation compared to their NHW counterparts with the same genetic profile. 25 They emphasize that social determinants such as neighborhood disadvantage and chronic stress likely influenced brain health, underscoring the importance of incorporating these factors into future research on dementia risk in Black populations. Moreover, more prevalent vascular comorbidities and chronic stress in African ancestry populations could impact neurodegeneration through inflammation and synergistic interactions with amyloid. 22 , 30 , 32 , 40 This suggests that amyloid deposition, which is an early core AD biomarker, follows a similar neuroanatomical progression across ancestries.
At the same time, emerging evidence from other studies presents a contradictory perspective. One study found that Black race was independently associated with elevated amyloid SUVRs, with an odds ratio (OR) of 2.08 (95% CI 1.23–3.51), even after adjusting for APOE ε4 genotype, vascular risk factors, cognition, and WMH. 15 Consistent with expectations, the APOE ε4 allele increased amyloid burden substantially (OR 2.65; 95% CI 1.61–4.39), while age was also positively associated with amyloid load (OR 1.63 per decade). These findings underscore the multifaceted nature of racial differences in amyloid pathology. While earlier large‐scale studies reported comparable amyloid burden across racial groups, further analyses suggest that individuals of African descent may exhibit slightly elevated amyloid deposition, even after accounting for established risk factors.
4.5.2. Tau PET imaging
Tau PET also offers a detailed, region‐specific assessment of NFT accumulation, yet studies in individuals of African ancestry remain limited. Available evidence generally suggests minimal racial disparities in total tau burden or its regional distribution when compared to White populations. 18 While earlier research by Meeker and colleagues identified lower CSF concentrations of total tau and p‐tau181 in African American participants compared to White cohorts, the PET scan study found no racial differences in tau deposition when measured. 12 This contrast suggests that CSF and PET biomarkers may capture different stages or dimensions of tau pathology, with tau PET potentially less sensitive to early or subtle changes particularly in cognitively normal individuals. Notably in the same study, mediation analysis revealed that socioeconomic factors, as measured by the Area Deprivation Index (ADI), significantly contributed to racial disparities in neurodegeneration. These findings highlight the importance of integrating both biological and social determinants in Alzheimer's research to enhance diagnostic performance across diverse populations. 12
Another plausible explanation involves genetically mediated differences. Ancestry‐specific genetic variants, including those in loci such as APOE, ABCA7, and TREM2, are known to influence tau pathology and its clinical impact. 23 , 45 For instance, the APOE ε4 allele, the strongest common genetic risk factor for AD has a demonstrably weaker association with tau accumulation in African descent populations relative to those in other populations, possibly due to differences in linkage imbalance and haplotype structures. 1 , 6 , 18 , 25 These genetic distinctions may attenuate tau aggregation or alter its biochemical kinetics, contributing to reduced tau PET signal despite comparable neurodegeneration.
Furthermore, among individuals of African ancestry, the interplay of cerebrovascular disease, systemic inflammation, and chronic conditions like hypertension, diabetes, and kidney disease may drive neurodegeneration through mechanisms that support or vary from tau pathology. 22 These factors can intensify clinical symptoms even when tau burden is relatively low, while elevated inflammatory markers suggest that altered tau phosphorylation and clearance may further contribute to distinct disease trajectories in these populations.
Nonetheless, divergent viewpoints highlight the need for caution when interpreting reduced tau PET burden, given the potential confounding factors and methodological variability. Some studies reported no significant racial differences in regional or overall tau deposition when accounting for demographic and clinical variables. 12 , 18 Variability in sample sizes, PET tracer sensitivity, and methodological approaches may contribute to inconsistent findings. Moreover, the heterogeneity within African ancestry populations exhibiting diverse geographic, cultural, and genetic backgrounds complicates direct comparisons with those elsewhere. 2 , 29 , 50 , 55 It is also possible that lower tau PET signals reflect differences in tau isoform expression or conformational diversity that current imaging ligands may not fully detect.
These disparities in neuroimaging findings underscore the imperative for larger, longitudinal, and multi‐ethnic studies employing harmonized imaging protocols and integrating vascular and inflammatory assessments to unravel ancestry‐specific AD mechanisms and improve diagnostic accuracy.
4.5.3. MRI assessment of neurodegeneration
Several studies have found consistent neurodegeneration outcomes across racial groups. For example, Misiura et al., 43 reported no significant association between total WMH volume and race or brain connectivity. In their cohort, WMH volumes were comparable across cognitive groups for Caucasian [3984.40 mm3 (SD = 4110.10)] and African American [3886.03 mm3 (SD = 4964.93)] individuals. However, the potential influence of region‐specific WMH patterns remains unexplored. Baseline differences in connectivity point to underlying variations in brain function that may be independent of disease mechanisms and possibly linked to vascular factors. Yet, the exact nature of these differences is unclear, and adjusting for vascular disease in the regression models did not change the findings.
Studies examining the association between AD biomarkers and neuroimaging outcomes have yielded divergent findings across racial groups. For instance, Misiura et al. 49 identified race‐specific neuroimaging patterns in a high‐risk cohort where cognitively healthy Black American participants with lower CSF Aβ42 levels were associated with increased WMH volumes in the parietal, temporal, and occipital lobes, a relationship not observed in NHW participants. 49 These findings suggest that disparities in vascular health may modulate the interaction between amyloid pathology and cerebrovascular burden, potentially contributing to distinct AD trajectories across racial populations.
4.6. Post mortem neuropathological findings of AD
Autopsy studies using standard neuropathological techniques including Bielschowsky silver stain, Congo red, Thioflavin‐S, and immunohistochemistry have consistently confirmed the presence of core AD histomorphological features, such as Aβ plaques and NFTs, in individuals of African descent, mirroring findings in other populations. 34 While these hallmark lesions are reliably observed across groups, the quantitative and qualitative characteristics of AD pathology in African populations remain underexplored, highlighting a critical gap in comparative neuropathological research. Few post mortem studies from African brain tissues have demonstrated reduced densities and frequencies of neuritic plaques and NFTs within the frontal, temporal, and parietal cortices, as well as the hippocampus, despite presenting similar levels of clinical dementia severity. 6 , 26 , 34 Additionally, cerebral amyloid angiopathy (CAA), characterized by amyloid buildup in brain vessels showed similar patterns and severity in both African and Caucasian counterparts. 34
In contrast, a cross‐sectional protein assay using immunoassay analysis of homogenized brain tissue from African American and Caucasian individuals with AD revealed significantly higher Aβ42 levels and Aβ42/Aβ40 ratios in African American individuals (p < 0.011 and p = 0.0002, respectively; Cohen's d = 0.88, indicating a large effect size). Additionally, African American participants exhibited elevated neuro‐inflammatory markers, despite showing comparable levels of plaque and tangle pathology to their Caucasian counterparts. 22 Notably, the study reported that Aβ42 levels were 121% higher in African American individuals with AD (p < 0.02), and the Aβ42/Aβ40 ratio was elevated by 493% (p < 0.002). These pronounced differences suggest substantial accumulation or altered processing of Aβ peptides in African American AD brains, potentially reflecting increased amyloidogenic activity or divergent clearance mechanisms. These disparities could stem from ancestry‐linked biological variation, including differences in peptide metabolism, immune modulation, or elimination pathways. Additionally, study‐specific factors such as participant selection, comorbid conditions, and anatomical sampling sites may contribute to the observed variation.
Again, an autopsy‐based study conducted by Graff‐Radford et al. 44 revealed that African American individuals with AD exhibited higher Braak and CERAD scores compared to Caucasian individuals, along with a greater burden of infarcts, hemorrhages, atherosclerosis, and cerebral angiopathy (OR: 2.69; 95% CI: 1.37–5.23). However, after adjusting for APOE genotype status, the association between race and AD neuropathology was attenuated to a non‐significant level (OR = −1.86; 95% CI: 0.80–4.28). This was attributed to the fact that African American individuals had a higher prevalence of the APOE ε4 allele, consistent with prior clinical studies, suggesting that APOE ε4 may mediate the observed racial differences in AD neuropathology. 44 Additionally, African American individuals had a greater history of hypertension and elevated systolic blood pressure, aligning with increased vascular pathology. Cultural, social, and behavioral factors such as dietary patterns and psychosocial stress may further contribute to racial disparities in vascular neuropathology, even after controlling for hypertension. These findings underscore the potential impact of early intervention targeting vascular risk factors, which may yield greater benefits for brain health in African American populations compared to Caucasian populations.
4.7. Genetic and comorbid influences on Alzheimer's pathology in African populations
Genetic studies provide critical molecular insights into the relationships between AD biomarkers and underlying genetic profiles, identifying novel loci 23 and ancestry‑specific variants, 45 underscoring the importance of diverse recruitment. Notably, APOE ε4 showed the strongest amyloid‑related effect in NHW individuals, 25 but demonstrating weaker influence in African ancestry cohorts. 6 , 26 Recent advances in genetic and molecular studies have highlighted the complex interplay between genetic variants and comorbid conditions in influencing AD, particularly in African ancestries.
4.7.1. Genetic variation and its impact on AD pathology
Genomic analyses reveal a nuanced and dynamic regulation of AD, particularly plasma Aβ concentrations, mediated by both common and rare variants with variable prevalence across ancestries. A key study found that midlife plasma Aβ42 levels were significantly associated with genetic variants in vascular‐related genes, specifically KLKB1 (rs3733402) and F12 (rs1801020). Notably, a similar association involving KLKB1 was observed in independent replication analyses, reinforcing the reliability and robustness of the finding. 54 Additionally, ITPRIP, PLIN2, and TSPAN18 genes were associated with the Aβ42:Aβ40 ratio, a key marker of amyloid pathology, with TSPAN18 demonstrating relevance across racial groups, ITPRIP and PLIN2 were primarily linked to amyloid dynamics in European American populations, while NCOA1 and NT5C3B emerged as ancestry‐specific signals influencing longitudinal Aβ patterns in African American populations. 54 These findings suggest a temporal and ancestry‐aware genetic regulation of plasma amyloid levels, emphasizing the importance of stratified analyses by age and population when interpreting biomarker data.
The role of the APOE gene, particularly the ε4 allele (APOE4), remains a cornerstone in AD genetics but exhibits different effects across racial groups. Plasma APOE is predominantly monomeric irrespective of race or cognitive status, however, plasma APOE levels among APOE ε4/ε4 carriers were found to be approximately 2.6 times higher in Black/African American (B/AA) than NHW individuals. 47 Notably, among B/AA individuals carrying the APOE ε3/ε4 genotype, higher APOE4 protein levels were associated with elevated total cholesterol and low density lipoprotein (LDL) concentrations, suggesting distinct lipid metabolism pathways in this population. 47 Also in NHW individuals, APOE4 concentrations were positively correlated with CSF tau, whereas in B/AA individuals, the relationship was reversed. This contrast underscores race‐modified effects of APOE4 on tau pathophysiology and may suggest disparities in AD risk and biomarker expression. Such divergent patterns indicate that APOE may interact differently with tau‐related neurodegeneration across ancestry groups, potentially reflecting underlying genetic, environmental, or sociocultural modifiers that influence disease progression and diagnostic accuracy. 1 , 15 , 47
Furthermore, large‐scale genome‐wide association studies (GWAS) have discovered both known and novel loci influencing AD risk among African cohorts, with some genes overlapping among other populations while others unique. Notably, newly identified AD loci include EDEM1 (3p26), which regulates intracellular glycoprotein trafficking; ALCAM (3q13), a key mediator of immune cell adhesion and signaling; GPC6 (13q31), involved in recruiting glutamatergic receptors; and VRK3 (19q13.33), associated with glutamate‐induced neurotoxicity. 45 Additionally, rare variant associations such as IGF1R (15q26) and genes like API5 and RBFOX1 suggest complex contributions to AD. Gene expression studies have associated these loci (ALCAM, ARAP1, GPC6, and RBFOX1) with brain Aβ burden in African American individuals, suggesting unique molecular mechanisms underlying neuropathology in this population.
Further cross‐population genetic analyses identified thirteen loci with genome‐wide significance including classical AD genes APOE, ABCA7, TREM2, BIN1, and CLU alongside two novel loci LRRC4C (11p12) and LHX5‐AS1 (12q24.13) which were implicated in neuronal development, potentially influencing neurodegeneration trajectories. 23 In the same study, population‐specific genome‐wide significant loci such as PTPRK and GRB14 in Hispanic individuals, KIAA0825 in NHW individuals, and SHARPIN in multi‐ancestry cohorts highlight the diversity and specificity of genetic risk factors across ethnicities. 23 These genetic insights show the partial overlap with European ancestry loci, but also considerable ancestry‐specific variation, which may underlie observed differences in biomarker profiles, neuropathological burden, and clinical manifestation of AD in African ancestry populations.
4.7.2. Influence of vascular and metabolic comorbidities
Genetic predisposition interacts with prevailing comorbidities to shape Alzheimer's pathology in African ancestry groups. Many identified genes such as KLKB1, F12, and PLIN2 are involved in vascular biology, implicating cerebrovascular integrity and lipid metabolism as modulatory factors. 48 , 54 The higher burden of hypertension, diabetes mellitus, and chronic kidney disease in African American individuals profoundly influences AD pathogenesis independent of classical amyloid and tau mechanisms.
For example, impaired renal function has been shown to correlate with elevated plasma p‐tau217 levels even after adjusting for amyloid burden, indicating that kidney dysfunction may independently augment neurodegenerative biomarker concentrations and complicate clinical interpretation of AD. 5 This suggests that systemic organ impairment can alter fluid biomarker levels, potentially confounding disease diagnosis or progression assessment. Similarly, alterations in lipid metabolism associated with APOE genotype exhibit differential effects on CSF tau among individuals of African descent, implying that vascular and metabolic pathways modulate tauopathy distinctly across ancestries. 47 These ancestry‐specific interactions between genetic risk factors and systemic health highlight the intricate biological mechanisms influencing tau pathology beyond classical amyloid‐dependent processes, necessitating consideration of comorbidities such as kidney disease and dyslipidemia when interpreting tau biomarkers in diverse populations.
4.7.3. Implications for diagnosis, clinical care, and research
Given the divergent biomarker profiles in African ancestry populations, the application of universal biomarker cutoffs risks underdiagnosis and could introduce bias in the diagnosis of AD and related dementia. For example, lower CSF tau in African American individuals compared to Caucasian individuals could lead to lower sensitivity of tau‐based biomarkers for AD diagnosis. Neuroimaging biomarkers, including amyloid PET, appear more consistent across ancestries but still require further validation within these groups. Equitable clinical care mandates ancestry‐specific diagnostic algorithms and biomarker thresholds that incorporate genetics, vascular comorbidities, and social determinants.
To advance diagnostic equity and identify multifactorial mechanisms underlying AD, research efforts must prioritize large‐scale, prospective, multi‐ethnic cohorts with harmonized biomarker measurements and diverse sampling including underrepresented native African populations. Establishing longitudinal cohorts with standardized CSF, plasma, neuroimaging, and genomic data and detection cut‐offs across ancestries, particularly among diaspora and continental African populations, is also critical. Incorporating environmental and social variables will enable more accurate modeling of disease risk and progression. Ancestry‐specific or genetically adjusted diagnostic biomarker thresholds should be developed using population genetics and social determinant data. Finally, capacity building and investment in Brain Health research infrastructure must be prioritized in resource‐limited African settings to ensure sustainable and inclusive scientific advancement.
5. CONCLUSION
This systematic review projects compelling evidence that the neuropathological hallmarks of AD, particularly fluid and neuroimaging biomarkers, manifest distinct profiles in individuals of African ancestries compared to populations elsewhere. Across different studies, concentrations of CSF and plasma amyloid‐beta (Aβ) biomarkers in African populations are consistently similar to, and sometimes even lower than those found in Caucasian populations. Despite a comparable amyloid burden, however, tau‐related biomarkers like total tau and p‐tau isoforms are remarkably lower in individuals of African ancestry who have the same disease severity. Neuroimaging and post mortem findings support the variation in tau protein concentrations across different populations. These studies consistently show greater differences in indicators of brain damage, such as hippocampal atrophy, cortical thinning, and elevated WMHs, which are more prevalent in individuals of African ancestry.
This review is tempted to speculate that the biomarker differences could stem from a combination of complex genetic and environmental factors. Genetic distinctions include a weaker effect of the APOE ε4 allele on tau and amyloid accumulation in African populations, as well as the presence of ancestry‐specific risk genes like ABCA7, TREM2, and LRRC4C. These genetic factors interact with highly prevalent vascular comorbidities (hypertension, diabetes, and chronic kidney disease) and other elements such as systemic racism and chronic psychosocial stress. These influences can affect neuroinflammation, vascular health, and neurodegeneration pathways. This complex interplay likely contributes to a unique form of AD in African populations and complicates the accuracy and interpretation of current biomarkers.
The findings advocate for the development and validation of ancestry‐specific biomarker cutoffs and diagnostic frameworks that integrate genetic diversity, vascular comorbidities, and social determinants of health.
5.1. Strength and limitation
This review's strength lies in its thorough integration of multimodal biomarker and neuropathological evidence from African ancestry cohorts, complemented by detailed comparisons with other populations. It covers critical perspectives on AD biomarker cut‐offs, particularly in African American groups, and highlights the risks of applying universal thresholds. In addition, it provides guidance for future recruitment strategies, stressing the importance of broader diversity to ensure biomarker thresholds are validated across populations. However, a key limitation is that most AD biomarker studies focus on African American cohorts, with far fewer incorporating other diaspora groups or native African populations. This imbalance reduces generalizability and hampers direct extrapolation of tau and amyloid pathology to continental African populations. Additionally, differences in assay platforms limit cross‐study comparability, while the lack of ancestry‐specific quantitative biomarker cutoffs in some studies increases the risk of misclassification.
5.2. Recommendations
Optimization and validation of platforms for AD biomarker diagnostic cutoffs for populations of African ancestry to improve diagnostic accuracy, integrate genetic, vascular, and social determinant data into biomarker interpretation and clinical algorithms, integrate multimodal diagnostic approaches including neuroimaging, biofluid biomarkers, and clinical assessments to validate biomarker levels and enhance evaluation of their prognostic relevance and increase recruitment and participation of native African ancestry individuals in clinical trials and observational studies to enhance research equity.
AUTHOR CONTRIBUTIONS
Conceptualization – Linus Kpelle, Ansumana Bockarie, and David Larbi Simpong; Methodology and Investigation– Linus Kpelle, Maxwell Hubert Antwi, George Nkrumah Osei, David Brodie‐Mends, David Mawutor Donkor and Albertha Maku Adu; Supervision – Ansumana Bockarie and David Larbi Simpong; Writing – original draft –Linus Kpelle, Maxwell Hubert Antwi, George Nkrumah Osei, David Brodie‐Mends, David Mawutor Donkor, and Albertha Maku Adu. All authors revised the manuscript critically for important intellectual content. All authors read and agreed with the final manuscript.
CONFLICT OF INTEREST STATEMENT
The authors declare no conflict of interest. Author disclosures are available in the Supporting information.
Supporting information
Supporting Information
ACKNOWLEDGMENTS
The authors have nothing to report.
Kpelle L, Bockarie A, Antwi MH, et al. Population disparities in Alzheimer's disease: A systematic review of fluid and neuroimaging biomarkers. Alzheimer's Dement. 2026;18:e70263. 10.1002/dad2.70263
DATA AVAILABILITY STATEMENT
No primary data were used for the research described in the article.
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Data Availability Statement
No primary data were used for the research described in the article.