Abstract BACKGROUND Dementia, including Alzheimer's disease (AD), is a growing concern in Egypt, yet biomarker research in this population is scarce. Identifying serum biomarkers is essential for early diagnosis and understanding disease mechanisms in underrepresented groups. METHODS We performed serum proteomic profiling on 20 Egyptian dementia patients and 10 cognitively unimpaired controls from the Egyptian Dementia Registry using mass spectrometry. Differential protein expression and pathway enrichment analyses were conducted. RESULTS Of 260 quantified proteins, 21 were significantly different between dementia patients and controls (P < 0.05). Several serine protease inhibitor and immunoglobulin family proteins were downregulated, while apolipoprotein A‐II was upregulated in dementia. Enrichment analysis revealed associations with inflammation, complement activation, and lipid metabolism pathways. CONCLUSION This is the first serum proteomic study of dementia in an Egyptian cohort, highlighting coordinated changes in protein families involved in inflammation and lipid metabolism, and emphasizing the importance of biomarker research in diverse populations. Highlights * The study presents initial proteomic data from the Egyptian Dementia Registry. * The Egyptian population has been underrepresented in the area of dementia research. * Serine protease inhibitor G1, apolipoprotein A‐II, and lipopolysaccharide binding protein emerged as significant proteins. * The work lays the foundation for more understanding of molecular determinants in dementia in the Middle East. Keywords: Alzheimer's disease, biomarkers, dementia, Egypt, proteomic profiling, underrepresented population 1. INTRODUCTION Alzheimer's disease (AD) and related dementias (ADRD) are progressive neurodegenerative disorders that represent a growing global health concern, particularly in aging populations. AD, the most common form of dementia, is characterized by a complex pathophysiology involving the accumulation of amyloid beta plaques, tau pathology, and neuroinflammation.[58] ^1 As the burden of dementia increases, especially in low‐ and middle‐income countries, there is an urgent need for accessible and reliable biomarkers to support early diagnosis and intervention.[59] ^2 Although cerebrospinal fluid (CSF) and imaging biomarkers are well established in AD research, their invasiveness, high cost, and limited availability pose challenges for large‐scale or population‐wide screening.[60] ^3 Recently, plasma biomarkers such as phosphorylated tau proteins (p‐tau181, p‐tau217), neurofilament light chain (NfL), and glial fibrillary acidic protein (GFAP) have emerged as promising alternatives.[61] ^4 However, these low‐abundance proteins often require highly sensitive, targeted detection methods and remain underexplored in untargeted proteomic studies.[62] ^5 High‐resolution mass spectrometry (MS)–based proteomics offers an untargeted approach to profile hundreds of circulating proteins simultaneously, aiding in the identification of novel biomarkers and providing insight into disease‐related biological pathways.[63] ^6 Several proteomic studies in AD cohorts have consistently implicated inflammation, complement activation, lipid metabolism, and immune system dysregulation in disease development and progression. Yet, most of these studies have focused on European, North American, or East Asian populations, leaving significant knowledge gaps in underrepresented regions like North Africa.[64] ^7 , [65]^8 In Egypt, dementia research is still emerging, with limited epidemiological data available.[66] ^9 The estimated prevalence of dementia in Egypt ranges from 2% to 5% among those aged ≥ 65, with AD being the most common subtype.[67] ^10 Recent population‐based studies suggest that the burden of dementia in Egypt is expected to rise in parallel with the country's aging demographics.[68] ^9 However, comprehensive national registries and longitudinal studies remain scarce, and there is a lack of large‐scale, multicenter investigations into dementia incidence, risk factors, and progression.[69] ^11 Most existing work has focused on clinical or imaging aspects, with minimal exploration of molecular or proteomic signatures.[70] ^9 Given Egypt's unique genetic background, environmental exposures, and health‐care landscape, studying this population may reveal both shared and population‐specific patterns of disease. This study presents the first serum proteomic profiling of dementia patients in an Egyptian cohort as a pilot cohort from the Egyptian Dementia Registry (EDN), aiming to identify differentially expressed proteins and disrupted biological pathways. By comparing these findings to international research, we seek to uncover regionally relevant biomarkers and contribute to a more inclusive understanding of AD pathogenesis. 1.1. Methodology This study included 20 dementia patients (13 with AD, 7 with mixed dementia) and 10 cognitively unimpaired elderly controls recruited from the EDN Registry (Table [71]S1 in supporting information). Diagnoses were established according to National Institute of Neurological and Communicative Disorders and Stroke–Alzheimer's Disease and Related Disorders Association and Diagnostic and Statistical Manual of Mental Disorders Fourth Edition criteria, supplemented by the Mini‐Mental State Examination (MMSE) and Hachinski score for mixed dementia.[72] ^12 Clinical data, including comorbidities and medication history, were collected from all participants. Blood samples were drawn at participating EDN clinics, processed within 2 hours for serum separation by centrifugation at 3000 × g for 10 minutes, aliquoted, and stored at −20°C, then sent to the American University in Cairo Biobank to be stored at −80°C until processed. High‐abundance proteins were depleted from serum before in‐solution digestion of proteins into peptides.[73] ^13 Purified peptides underwent nanoLC‐MS/MS analysis using a TripleTOF 5600+ mass spectrometer.[74] ^14 Raw data were processed and searched against the UniProt Human database. Protein inference and quantification were performed by applying probabilistic quotient normalization, exclusion of proteins with > 50% missing values, log transformation, and z scoring using R Studio.[75] ^13 Statistical analyses included group comparisons for age and sex, and linear regression models adjusting for these variables to identify differentially expressed proteins (P < 0.05). Enrichment analysis with g:Profiler was conducted against all known human genes to elucidate biological processes and pathways associated with the significant proteins. RESEARCH IN CONTEXT 1. Systematic review: We reviewed published literature on serum and plasma proteomic biomarkers in Alzheimer's disease (AD) using databases such as Embase, Scopus, PubMed, as well as meeting abstracts. Most studies have focused on European, North American, or East Asian populations, with limited research on North African cohorts. Existing Egyptian studies are few and have primarily addressed clinical and genetic aspects, with a notable lack of large‐scale biomarker or proteomic investigations. 2. Interpretation: Our study provides the first proteomic characterization of dementia in an Egyptian cohort, revealing dysregulation in inflammatory and lipid metabolism pathways. The identification of coordinated changes within protein families, such as serine protease inhibitors and apolipoproteins, supports the involvement of these biological processes in AD and highlights both shared and potentially population‐specific biomarker signatures. 3. Future directions: Future research should include larger, multicenter studies with longitudinal follow‐up; use targeted assays for established low‐abundance biomarkers; and investigate genetic, environmental, and lifestyle factors unique to the Egyptian and regional context to validate and expand upon these findings. 2. RESULTS 2.1. Cohort characteristics The study cohort comprised 10 cognitively unimpaired controls and 20 dementia patients, including 13 with AD and 7 with mixed dementia. Dementia patients were significantly older than controls (mean age 74.3 ± 7.7 vs. 62.5 ± 12.0 years, P = 0.0025). Sex distribution was comparable, with 70% females among controls and 60% among patients (Fisher exact test, P = 0.702). Dementia patients had an average MMSE score of 9.26, 10% had positive family history, and 35% used dementia medication. Additional clinical features are summarized in Table [76]S1. 2.2. Proteomic profiling MS‐based proteomic analysis identified 5410 non‐redundant serum proteins. After rigorous data processing and filtering (requiring proteins to be present in at least 50% of samples within a group), 260 proteins remained for downstream quantitative analysis (Table [77]S2 in supporting information). Principal component analysis demonstrated clear separation between dementia and control samples (Figure [78]1A). Statistical comparison using linear regression models revealed 42 differentially significant proteins (P value < 0.05). Model correction for age and sex identified 21 proteins as significantly differentially expressed (P < 0.05; Table [79]1). FIGURE 1. FIGURE 1 [80]Open in a new tab Differentially expressed proteins in dementia using mass spectrometry quantification. A, PCA analysis of all proteins identified in the study cohorts (patients and controls). B, Volcano plot showing the difference in protein expression profiles between patients and controls. The plot shows the fold change in proteins NSAF (log2 [patient/control]) versus P value (−log10[P value]). Significantly expressed proteins are highlighted in red (upregulated) or blue (downregulated; P value < 0.05, and log2 fold change ≥ ± 0.5). C, Heatmap with hierarchical clustering of significantly expressed proteins across samples showing the altered pattern of expression between patients and controls. The relative expression of each protein is shown based on the z score of the protein's NSAF. D, Box plots show expression levels (NSAF) of the top significant proteins. E, Functional enrichment analysis with GO annotations of the 21 significant differentially expressed proteins (P value < 0.05) between patients and control. GO annotations, according to the biological process, molecular function, and cellular localization, are shown on the x axis, whereas the y axis represents the number of proteins. GO, Gene Ontology; NSAF, normalized spectral abundance factor; PCA, principal component analysis TABLE 1. Differentially expressed proteins between patients and controls using simple regression analysis (lm) and lm corrected for age and sex. P ∼ dementia status P ∼ dementia status+ age + sex Accession ID Protein names Protein family FC log2 FC Estimate SE P value Estimate SE P value Significance [81]P05155 Plasma protease C1 inhibitor (C1 Inh) (C1Inh) (C1 esterase inhibitor) (C1‐inhibiting factor) (Serpin G1) Serpin family 0.511299877 −0.967758416 −0.9677584 0.35156412 0.01043606 −1.455033616 0.39256436 0.00104852 Down E9KL26 Epididymis tissue protein Li 173 (Serpin peptidase inhibitor clade G member 1 isoform 1) Serpin family 0.511299877 −0.967758416 −0.9677584 0.35156412 0.01043606 −1.455033616 0.39256436 0.00104852 Down A0A348GSH7 Serpin peptidase inhibitor clade G member 1 Serpin family 0.511299877 −0.967758416 −0.9677584 0.35156412 0.01043606 −1.455033616 0.39256436 0.00104852 Down V9HWP0 Pentraxin family member Pentraxin family 0.563963077 −0.826327384 −0.8263274 0.4102177 0.05695713 −1.269326664 0.388145788 0.00402633 Down A0A5C2GNP8 IG c202_light_IGLV8‐61_IGLJ3 0.487634901 −1.036126709 −1.0361267 0.42459543 0.02756306 −1.361616451 0.432365537 0.00768309 Down [82]P01011 Alpha‐1‐antichymotrypsin (ACT) (Cell growth‐inhibiting gene 24/25 protein) (Serpin A3) [Cleaved into: Alpha‐1‐antichymotrypsin His‐Pro‐less] Serpin family 0.58548472 −0.772296575 −0.7722966 0.3661361 0.0439874 −1.176085948 0.418350565 0.00925896 Down B3KS79 cDNA FLJ35730 fis, clone TESTI2003131, highly similar to ALPHA‐1‐ANTICHYMOTRYPSIN Serpin family 0.58548472 −0.772296575 −0.7722966 0.3661361 0.0439874 −1.176085948 0.418350565 0.00925896 Down [83]Q6MZX7 Uncharacterized protein DKFZp686M24218 2.112450157 1.078917301 1.0789173 0.36043923 0.00692641 1.242960294 0.43685912 0.01034993 Up A0A5C2FY00 IGL c1841_light_IGLV8‐61_IGLJ3 0.485935842 −1.041162246 −1.0411622 0.43637968 0.03171279 −1.3257221 0.440016955 0.01080477 Down A0A5C2FZD1 IGL c2321_light_IGLV8‐61_IGLJ3 (IGL c2807_light_IGLV8‐61_IGLJ3) 0.485935842 −1.041162246 −1.0411622 0.43637968 0.03171279 −1.3257221 0.440016955 0.01080477 Down A0A5C2H228 IG c1006_light_IGLV8‐61_IGLJ3 0.52293414 −0.935298834 −0.9352988 0.43992377 0.05051298 −1.296193033 0.439995852 0.01136054 Down A0A5C2GU70 IG c951_light_IGLV8‐61_IGLJ3 0.52293414 −0.935298834 −0.9352988 0.43992377 0.05051298 −1.296193033 0.439995852 0.01136054 Down A0A7I2V2D2 Serpin family G member 1 Serpin family 0.594392788 −0.750511485 −0.7505115 0.37070587 0.05290879 −1.113310024 0.43960705 0.01797801 Down A0A7S5C4C6 IGH c1615_heavy_IGHV1‐69_IGHD6‐19_IGHJ4 0.528546067 −0.919898876 −0.9198989 0.40489419 0.03427928 −1.185652332 0.455671047 0.01802373 Down A0A087WW49 Ig‐like domain‐containing protein 2.025188512 1.018056205 1.01805621 0.34400797 0.00620941 0.956058619 0.396581194 0.02328647 Up [84]Q14520 Hyaluronan‐binding protein 2 (EC 3.4.21.‐) (Factor VII‐activating protease) (Factor seven‐activating protease) (FSAP) (Hepatocyte growth factor activator‐like protein) (Plasma hyaluronan‐binding protein) [Cleaved into: Hyaluronan‐binding protein 2 50 kDa heavy chain; Hyaluronan‐binding protein 2 50 kDa heavy chain alternate form; Hyaluronan‐binding protein 2 27 kDa light chain; Hyaluronan‐binding protein 2 27 kDa light chain alternate form] Peptidase S1 family 1.939177504 0.955444868 0.95544487 0.35036334 0.01090496 0.949863237 0.409716388 0.02855924 Up A0A5C2GV40 IG c653_light_IGLV8‐61_IGLJ2 0.471618012 −1.084309278 −1.0843093 0.45684219 0.03371565 −1.158695635 0.501307139 0.04120076 Down [85]P01023 Alpha‐2‐macroglobulin (Alpha‐2‐M) (C3 and PZP‐like alpha‐2‐macroglobulin domain‐containing protein 5) Protease inhibitor I39 (alpha‐2‐macroglobulin) family 0.732157958 −0.449773162 −0.4497732 0.38487958 0.25241543 −0.918709942 0.433173703 0.04362926 Down V9GYM3 Apolipoprotein A‐II (Apolipoprotein A2) Apolipoprotein A2 family 1.582493856 0.662199898 0.6621999 0.37375944 0.08732408 0.931472523 0.443053558 0.04535376 Up [86]P02652 Apolipoprotein A‐II (Apo‐AII) (ApoA‐II) (Apolipoprotein A2) [Cleaved into: Proapolipoprotein A‐II (ProapoA‐II); Truncated apolipoprotein A‐II (Apolipoprotein A‐II(1‐76))] Apolipoprotein A2 family 1.582493856 0.662199898 0.6621999 0.37375944 0.08732408 0.931472523 0.443053558 0.04535376 Up A0A0U4BCF5 Complement factor I 1.852711936 0.889638585 0.88963859 0.35649801 0.01874374 0.902176121 0.433277902 0.04730531 Up [87]P18428 Lipopolysaccharide‐binding protein (LBP) BPI/LBP/Plunc superfamily, BPI/LBP family 0.716663154 −0.480632912 −0.4806329 0.44765198 0.29641559 −1.032694265 0.488144799 0.049447 Down A8K8Z4 Complement component C6 Complement C6/C7/C8/C9 family 1.782681094 0.834048641 0.83404864 0.36126577 0.02855833 0.880814974 0.437789718 0.05469365 [88]P04217 Alpha‐1B‐glycoprotein (Alpha‐1‐B glycoprotein) 1.965578142 0.97495372 0.97495372 0.34843862 0.00919793 0.828424672 0.418483279 0.05842846 [89]P05156 Complement factor I (EC 3.4.21.45) (C3B/C4B inactivator) [Cleaved into: Complement factor I heavy chain; Complement factor I light chain] Peptidase S1 family 1.722654015 0.784632973 0.78463297 0.36519814 0.04046664 0.810977643 0.443949964 0.07924318 A0A5C2GD17 IGL c483_light_IGKV3D‐20_IGKJ1 0.522314718 −0.937008738 −0.9370087 0.39511302 0.02689119 −0.831647275 0.458450533 0.08470404 A0A5C2GD19 IGH + IGL c588_light_IGLV2‐23_IGLJ2 0.498968042 −1.002980679 −1.0029807 0.41547335 0.02603139 −1.096554086 0.612692425 0.09132586 A0A5C2FZC4 IGL c2272_light_IGLV2‐23_IGLJ2 0.498968042 −1.002980679 −1.0029807 0.41547335 0.02603139 −1.096554086 0.612692425 0.09132586 [90]P01008 Antithrombin‐III (ATIII) (Serpin C1) Serpin family 1.923888354 0.94402508 0.94402508 0.37737557 0.01992573 0.738642513 0.424546588 0.09652448 A0A5C2G1K3 IGL c2336_light_IGLV2‐23_IGLJ2 0.512272546 −0.96501652 −0.9650165 0.424563 0.03551556 −1.079180902 0.628403512 0.10520767 A0A5C2GLP7 IG c571_light_IGLV2‐23_IGLJ2 0.518592874 −0.947325713 −0.9473257 0.44884936 0.04906337 −1.079274289 0.630262542 0.10612816 A0A5C2FZT6 IGL c1185_light_IGLV2‐23_IGLJ2 0.518592874 −0.947325713 −0.9473257 0.44884936 0.04906337 −1.079274289 0.630262542 0.10612816 A0A5C2FWM1 IGL c1212_light_IGLV2‐23_IGLJ3 (IGL c463_light_IGLV2‐23_IGLJ3) (IGL c749_light_IGLV2‐23_IGLJ3) 0.518592874 −0.947325713 −0.9473257 0.44884936 0.04906337 −1.079274289 0.630262542 0.10612816 A0A5C2FVZ9 IGL c1244_light_IGLV2‐23_IGLJ2 (IGL c260_light_IGLV2‐23_IGLJ2) (IGL c425_light_IGLV2‐23_IGLJ2) 0.518592874 −0.947325713 −0.9473257 0.44884936 0.04906337 −1.079274289 0.630262542 0.10612816 A0A5C2FT63 IGL c161_light_IGLV2‐23_IGLJ1 0.518592874 −0.947325713 −0.9473257 0.44884936 0.04906337 −1.079274289 0.630262542 0.10612816 A0A5C2G6L0 IGL c1857_light_IGLV2‐23_IGLJ3 (IGL c2063_light_IGLV2‐23_IGLJ3) 0.518592874 −0.947325713 −0.9473257 0.44884936 0.04906337 −1.079274289 0.630262542 0.10612816 A0A5C2G202 IGL c2944_light_IGLV2‐23_IGLJ2 0.518592874 −0.947325713 −0.9473257 0.44884936 0.04906337 −1.079274289 0.630262542 0.10612816 A0A5C2FW60 IGL c340_light_IGLV2‐23_IGLJ1 0.518592874 −0.947325713 −0.9473257 0.44884936 0.04906337 −1.079274289 0.630262542 0.10612816 A0A5C2FUG2 IGL c392_light_IGLV2‐23_IGLJ3 0.518592874 −0.947325713 −0.9473257 0.44884936 0.04906337 −1.079274289 0.630262542 0.10612816 A0A5C2FYY0 IGL c467_light_IGLV2‐23_IGLJ1 0.518592874 −0.947325713 −0.9473257 0.44884936 0.04906337 −1.079274289 0.630262542 0.10612816 A0A5C2G841 IGL c537_light_IGLV2‐23_IGLJ1 0.518592874 −0.947325713 −0.9473257 0.44884936 0.04906337 −1.079274289 0.630262542 0.10612816 A0A5C2FXJ2 IGL c920_light_IGLV2‐23_IGLJ1 0.518592874 −0.947325713 −0.9473257 0.44884936 0.04906337 −1.079274289 0.630262542 0.10612816 A0A5C2G191 IGL c93_light_IGLV2‐23_IGLJ3 0.518592874 −0.947325713 −0.9473257 0.44884936 0.04906337 −1.079274289 0.630262542 0.10612816 A0A0K0Q2Z1 Antithrombin‐III (Serpin C1) Serpin family 1.916454055 0.938439412 0.93843941 0.3779808 0.02076754 0.691601391 0.414885693 0.11036679 [91]P02749 Beta‐2‐glycoprotein 1 (APC inhibitor) (Activated protein C‐binding protein) (Anticardiolipin cofactor) (Apolipoprotein H) (Apo‐H) (Beta‐2‐glycoprotein I) (B2GPI) (Beta(2)GPI) 1.783650579 0.834833016 0.83483302 0.36120106 0.02839536 0.695650992 0.434665016 0.12158551 A0A384NKM6 Beta‐2‐glycoprotein 1 (Apolipoprotein H) (Beta‐2‐glycoprotein I) 1.783650579 0.834833016 0.83483302 0.36120106 0.02839536 0.695650992 0.434665016 0.12158551 [92]P01042 Kininogen‐1 (Alpha‐2‐thiol proteinase inhibitor) (Fitzgerald factor) (High molecular weight kininogen) (HMWK) (Williams–Fitzgerald–Flaujeac factor) [Cleaved into: Kininogen‐1 heavy chain; T‐kinin (Ile‐Ser‐Bradykinin); Bradykinin (Kallidin I); Lysyl‐bradykinin (Kallidin II); Kininogen‐1 light chain; Low molecular weight growth‐promoting factor] 1.70260525 0.767743984 0.76774398 0.36647789 0.04534678 0.520556674 0.40712211 0.21232497 B2R6W1 cDNA, FLJ93143, highly similar to Homo sapiens complement component 7 (C7), mRNA Complement C6/C7/C8/C9 family 2.674445067 1.419239571 1.41923957 0.41267797 0.00275002 0.823170566 0.720571092 0.26912851 A0A5C2GWS3 IG c120_light_IGLV6‐57_IGLJ2 2.50704802 1.32598963 1.32598963 0.43139209 0.00825157 0.70379336 0.65681067 0.30500841 [93]Q8NFP4‐2 MAM domain‐containing glycosylphosphatidylinositol anchor protein 1 (GPI and MAM protein) (GPIM) (Glycosylphosphatidylinositol‐MAM) (MAM domain‐containing protein 3) 1.824481011 0.867486136 0.86748614 0.39588281 0.03837625 0.469242506 0.478240283 0.33716902 [94]Open in a new tab Abbreviations: FC, fold change; SE, standard error. A volcano plot (Figure [95]1B) showed the distribution of all proteins, highlighting the 21 significant proteins with upregulation of six proteins in dementia with a magnitude of ≥ 1.5‐fold change, such as complement factor I, apolipoprotein A‐II (ApoA‐II), and hyaluronan‐binding protein 2. Fifteen proteins were downregulated including plasma protease C1 inhibitor (serine protease inhibitor [serpin] G1), serpin peptidase inhibitor clade G member 1, alpha‐1‐antichymotrypsin (ACT), lipopolysaccharide‐binding protein (LBP), serpin family G member 1, pentraxin family member, and other immunoglobulin proteins. Exact protein expressions are displayed by box plots (Figure [96]1D), showing selected top significant proteins. Heatmap analysis showed individual protein expression differences among the two cohorts (Figure [97]1C). 2.3. Enrichment and pathway analysis Functional enrichment analysis, performed using g: Profiler with all human genes as the background, revealed that the 21 differentially expressed proteins were strongly associated with biological processes, including inflammatory response, complement activation, coagulation cascade, and acute‐phase signaling. At the molecular function level, these proteins also showed enrichment for roles in immune effector processes, complement regulation (especially within the lectin pathway), serine‐type endopeptidase inhibition, and lipid metabolism. At the pathway level, key associations included complement and coagulation cascades, platelet degranulation, plasma lipoprotein assembly, and fibrin clot formation, reinforcing the central roles of inflammation and metabolism in dementia observed globally (Figure [98]1E, Table [99]S3 in supporting information). 3. DISCUSSION This study presents the first serum proteomic analysis of dementia patients in an Egyptian cohort using MS, addressing a significant gap in our understanding of AD and ADRD in North Africa. The Egyptian context, characterized by distinctive genetic backgrounds, environmental exposures, and rapidly aging demographics, brings urgency to locally relevant biomarker research.[100] ^15 Although epidemiological and biomarker studies of dementia in Egypt are scarce, our work provides new evidence of proteomic alterations consistent with findings from established AD cohorts worldwide. We identified 21 significantly differentially expressed proteins between dementia patients and controls, many of which have been reported in European and Asian studies, suggesting that core mechanisms, such as inflammation and lipid dysregulation, are conserved across populations. For example, upregulation of ApoA‐II and complement factor I, and downregulation of serpin G1 (C1 inhibitor) and LBP, mirror global signatures of AD pathology.[101] ^7 , [102]^16 Importantly, several altered proteins clustered into major families, indicating coordinated shifts in biological pathways. Multiple members of the serpin family (e.g., serping1, serpina3) were consistently downregulated, which points to impaired regulation of inflammation and protease activity.[103] ^17 Reductions in immunoglobulin family proteins mark broader changes in immune defense, while the upregulation of ApoA‐II within the apolipoprotein family suggests disruption of lipid metabolism.[104] ^18 The pentraxin family and LBP, involved in innate immunity, were also affected.[105] ^19 This pattern of family‐wide alterations supports the notion that dementia pathogenesis involves broad disruptions across interacting protein networks, particularly those tied to inflammation, immunity, and lipid transport.[106] ^19 Pathway enrichment analysis, using all known human genes as the background, further linked these proteins to inflammation, complement activation, coagulation, and lipid metabolism cascade.[107] ^20 The robustness of these associations, even in a small and underrepresented cohort, illustrates both the universality of these pathological pathways and the potential for uncovering population‐specific nuances that may be clinically significant. However, there are important limitations to consider. Our untargeted proteomic platform was not sensitive enough to detect several established low‐abundance plasma biomarkers, such as p‐tau, NfL, or GFAP, which are increasingly used in AD research but remain below the detection thresholds of standard discovery proteomics.[108] ^5 This limitation underscores the need for future work using targeted, highly sensitive assays. Additional limitations include small sample size, cross‐sectional design, and incomplete data on participant co‐morbidities and medications. The absence of an external replication cohort and the potential influence of unmeasured confounders, such as dietary or socioeconomic differences, further limit the generalizability of our findings. In summary, this study expands the global dementia biomarker landscape by highlighting both shared and potentially unique serum proteomic signatures in Egyptian patients. The observed coordinated changes across protein families involved in inflammation, immunity, and lipid metabolism underscore both universal and population‐specific mechanisms underlying dementia. Ongoing research in larger, longitudinal, and ethnically diverse cohorts, coupled with more sensitive, targeted biomarker measurement, will be essential for validating these findings and translating them into clinical strategies tailored for underrepresented populations like Egypt. AUTHOR CONTRIBUTIONS Conceptualization and design: Shimaa A. Heikal and Mohamed Salama. Data acquisition: Shimaa A. Heikal, Eman M. Khedr, Mai Othman, Nesma G. Elsheikh, Heba M. Tawfik, Hany I. Hassanin, Nouran Al‐Shehaby, Ashraf Eltaher, Samir Shamma, Ahmed S. Mohamed, Mostafa Saber, Abdullah A. Lomomba, Esraa Ali, Shady M. Safwat, Noha Abo Elfetoh, and Gharib Fawi. Drafting of manuscript: Shimaa A. Heikal and Mohamed Salama. Critical revision of manuscript for intellectual content: all authors. Data analysis: Shimaa A. Heikal, Nouran Al‐Shehaby, Ashraf Eltaher, Noha A. Yousri, and Mohamed Salama. Administrative, technical, or material support: Mohamed Salama. Supervision: Mohamed Salama. Data management: Shimaa A. Heikal, Noha A. Yousri, and Mohamed Salama. Funding acquisition: Shimaa A. Heikal and Mohamed Salama. All authors have read and approved the final manuscript version. CONFLICT OF INTEREST STATEMENT The authors declare no conflicts of interest. Author disclosures are available in the [109]Supporting Information ETHICS STATEMENT All participants or legal guardians provided written informed consent following the Declaration of Helsinki. All protocols were approved by the institution review board at the American University in Cairo (IRB‐AUC# 2024‐2025‐028). CONSENT TO PARTICIPATE DECLARATION All human participants consented for participation and publication of this study. Supporting information Supporting Information [110]DAD2-17-e70172-s001.docx^ (15KB, docx) Supporting Information [111]DAD2-17-e70172-s004.xlsx^ (96.8KB, xlsx) Supporting Information [112]DAD2-17-e70172-s002.xlsx^ (32.1KB, xlsx) Supporting Information [113]DAD2-17-e70172-s003.pdf^ (1.6MB, pdf) ACKNOWLEDGMENTS