Down syndrome (DS) is the most common genetic cause of intellectual disability, affecting approximately six million individuals worldwide [1]. It occurs in an estimated one out of every 700 live births, with incidence rates ranging from one out of 400 to one out of 1,500 newborns [2, 3]. Karyotype analysis shows that approximately 95% of DS cases result from an extra, complete copy of chromosome 21, a condition known as trisomy 21 [4]. Around 4–5% of cases result from a translocation involving chromosomes 21 and 14 or 22, causing a partial trisomy (the duplication of only a segment of chromosome 21). A smaller proportion (1–2%) of cases result from mosaicism, wherein only a subset of cells contains an extra copy of chromosome 21 [4]. In addition to karyotype studies, the development of noninvasive methods, such as cell-free fetal DNA analysis in maternal blood, has enabled the timely identification of DS [3].

More than 250 distinctive features associated with DS have been identified phenotypically [4, 5]. The phenotypic variability observed in individuals with DS is attributed to the combined effects of multiple genes located on chromosome 21 and throughout the genome [5]. Although the exact causes of DS development remain unclear, advanced maternal age is considered a significant risk factor for trisomy 21 [6]. Environmental factors such as smokeless chewing tobacco use and oral contraceptive use also increase the risk of DS, particularly among younger and older mothers, respectively [7].

The relationship between DS and AD was first recognized in the mid-19th century when John Fraser and Arthur Mitchell studied 62 individuals with DS who experienced functional decline in adulthood. They observed that deaths in this population were often attributed to “general decay” or “premature senility”, marking the earliest recognition of early-onset senility in individuals with DS [11]. In 1929, Friedrich Struwe furthered this understanding by describing the neuropathological features of AD in individuals with DS. Struwe’s work identified isolated and perivascular plaques in the brains of individuals with DS, a hallmark of AD. His work significantly contributed to the understanding of the relationship between the two diseases [12]. In 1948, George A. Jervis published an article in the American Journal of Psychiatry that further elucidated this link, providing critical insights into the pathology of DS and AD [13]. Subsequent studies have confirmed the high risk of Alzheimer’s-like neuropathology and dementia in individuals with DS, with symptoms often appearing in the third or fourth decade of life [14]. In 1984, George G. Glenner and Cai-Wai Wong isolated and purified amyloid protein from the brain of an adult with DS and demonstrated its homology to amyloid-β (Aβ), the protein characteristic of AD. This discovery provided the first chemical evidence of the relationship between DS and AD, suggesting that DS could serve as a predictive model for AD and highlighting that the genetic defect responsible for AD is located on chromosome 21 [11]. Currently, DS is recognized as a genetically determined form of AD, similar to autosomal dominant AD [14, 15].

In this review, we explore the primary neuropathological, neuropsychological, and genetic features underlying the development of AD in individuals with DS, aiming to better understand the mechanisms of neurodegeneration in this high-risk population.

DS has been found to be strongly associated with AD, with virtually all individuals with DS developing AD-related neuropathological changes, such as amyloid plaques and neurofibrillary tangles (NFTs), by the age of 30 to 40 [16, 17]. This phenomenon is primarily attributed to the triplication of chromosome 21, which leads to the overexpression of amyloid precursor protein (APP) and subsequent Aβ plaque formation [18]. Despite the early onset of neuropathology, clinical symptoms of dementia typically do not appear until around age 50 or later. This indicates a separation between neuropathological changes and the beginning of cognitive decline [19, 20].

The progression of AD in individuals with DS is influenced by various biological and genetic factors, such as oxidative stress, neuroinflammation, the apolipoprotein E (APOE) genotype, and aging-related genes on chromosome 21 [14, 18]. The prevalence of dementia in adults with DS between the ages of 40 and 59 varies significantly, ranging from 4% to 55%. The prevalence increases considerably after age 50, reaching 75% and 90% of people over 60 years of age [14, 17]. The mean age of AD onset in this population is 53.8 years, with an estimated age of death of 58.4 years [21]. Thus, AD is classified as one of the primary causes of mortality among adults with DS.

Although cognitive deterioration in aging individuals with DS is often attributed to AD, it is important to consider other age-related conditions that may lead to functional decline. These include musculoskeletal and sensory impairments [22]. Clinically, cognitive decline is often characterized by impairments in memory, attention, language, and social functioning, which can progress to dementia [23]. Neuropathologically, AD in individuals with DS shares many features with sporadic AD, including synaptic loss, neuroinflammation, and selective neuronal degeneration in the entorhinal cortex, hippocampus, and neocortex [14, 18, 24] although they have notable differences in their origin and manifestation (Table 1). However, AD associated with DS exhibits distinctive characteristics, including earlier and more substantial amyloid accumulation, increased tangle density in the hippocampus, and a distinct M2b neuroinflammatory profile in older individuals [22, 24].

The manifestation of AD in individuals with DS is influenced by intellectual disability and reduced cognitive reserve. This often results in non-amnestic symptom patterns and a complicated trajectory of decline due to comorbid health conditions [25]. The early and frequent emergence of AD in this population intersects with broader challenges, including accelerated aging, increased dependence on care, and a growing burden on aging family caregivers [26]. These factors give rise to substantial clinical, familial, and public health concerns. Consequently, regular health screenings, timely diagnoses, and multidisciplinary interventions are crucial for enhancing quality of life and postponing functional deterioration in individuals with DS at risk for or living with AD [27].

Conventionally, DS has been diagnosed primarily through karyotype analysis and prenatal screening using biochemical and ultrasound markers [28]. Recently, advanced genetic and molecular techniques, such as next-generation sequencing and whole-exome sequencing, have significantly improved the accuracy and efficiency of diagnoses, with sensitivities exceeding 99% [29]. Additionally, non-invasive prenatal testing, which analyzes cell-free fetal DNA in maternal blood, has achieved detection rates above 98%. Proteomic and metabolomic studies have identified additional promising DS biomarkers in maternal serum, placental tissue, and amniotic fluid [30]. These studies have revealed numerous differentially expressed proteins and metabolic alterations.

In contrast, diagnosing AD in individuals with DS requires a multifaceted approach. This approach includes physical and neurological examinations, cognitive assessment batteries, and caregiver and informant questionnaires. It also involves neuroimaging techniques such as magnetic resonance imaging (MRI) and positron emission tomography (PET). PET scans targeting amyloid, tau, and fluorodeoxyglucose (FDG) detect changes in cognitive, behavioral, and functional domains [31]. These scans facilitate the identification of different stages of cognitive decline and dementia.

Biomarker studies in DS show progression similar to that of sporadic AD: early reductions in cerebrospinal fluid (CSF) Aβ42 and elevated plasma neurofilament light chain (NfL) levels are followed by amyloid PET changes, tau accumulation, brain atrophy, and hypometabolism [15]. Cognitive decline in DS correlates closely with regional glucose metabolism, as assessed by FDG-PET [31]. The most extensively studied biomarkers are amyloid and tau. DS individuals exhibit elevated baseline plasma Aβ levels due to APP overexpression [32].

In addition to imaging and clinical evaluations, established AD biomarkers, such as Aβ40, Aβ42, total tau, and phosphorylated tau 181 (pTau181), can now be measured in the blood of individuals with DS [33]. Emerging biomarkers, including pTau217, NT1-Tau, NfL, and glial fibrillary acidic protein (GFAP), have also demonstrated the potential to enhance diagnostic accuracy [34]. Furthermore, metabolomic biomarkers reflecting alterations in glucose metabolism, oxidative stress, cholesterol pathways, inflammation, and amino acid metabolism are being investigated for their potential to facilitate early AD detection in DS [34, 35].

Early diagnosis is critical for improving quality of life; however, it is often complicated by comorbidities, pre-existing intellectual disability, and functional variability [36–38]. Studies suggest that artificial intelligence and machine learning methods could improve the early detection of AD in individuals with DS. Algorithms such as k-nearest neighbors, Naive Bayes, decision trees, and ensemble methods have shown potential in enhancing diagnostic precision when applied to MRI and PET imaging data [30, 39–41].

Research into anti-Aβ antibodies in DS continues to reveal the complexity of disease mechanisms. Individuals with DS exhibit elevated plasma levels of Aβ1-42 and corresponding antibodies with higher affinity and titers than observed in the general population. These findings suggest a potential state of autoimmunization against Aβ [42, 43]. Higher plasma Aβ40/42 ratios and increased anti-fibril antibody titers have been associated with a greater risk of dementia [44]. Postmortem brain analyses confirm the presence of soluble Aβ protofibrils and insoluble Aβ40 and Aβ42, resembling the pathology seen in sporadic AD [45]. These findings reinforce the therapeutic potential of targeting Aβ pathology in individuals with DS and AD [46].

Diagnosing cognitive impairment and AD in individuals with DS presents unique clinical challenges due to the baseline presence of intellectual disability and atypical symptoms [47, 48]. Early indicators of AD in this population include visual memory decline, diminished learning capacity, and reduced social functioning [49]. Reliable diagnostic tools such as the Cambridge Examination for Mental Disorders of Older People with Down’s Syndrome and Others with Intellectual Disabilities (CAMDEX-DS) have demonstrated high accuracy in detecting the prodromal and dementia stages of AD [50]. Other effective instruments include the Modified Cued Recall Test and the Dementia Questionnaire for People with Learning Disabilities [51]. An accurate diagnosis requires a multidimensional approach that integrates observer-rated assessments, direct neuropsychological testing, and evaluations of functional abilities in daily life [48]. Longitudinal assessment and exclusion of alternative causes of cognitive decline are important, even among individuals with severe baseline impairments [49].

The cognitive and behavioral phenotype of individuals with DS evolves throughout life, showing greater decline with age [47, 52]. Neuropsychologically, individuals with DS who develop AD often follow a similar trajectory to individuals with sporadic or autosomal dominant AD. The initial clinical hallmark is typically a decline in episodic memory, especially among individuals who are amyloid-positive at diagnosis or become so over time [53]. Early impairments in attention and executive functioning are also common, followed by deficits in visuospatial skills, verbal fluency, motor coordination, and planning abilities (Figure 1) [54]. Nonverbal skills tend to remain relatively stable in adulthood, while verbal skills typically decline more steeply [54–56].

Language is one of the cognitive domains most severely affected in DS, with expressive abilities typically being more impaired than receptive ones [23, 57]. In adulthood, language impairments become a central component of the cognitive decline associated with AD-like dementia (Figure 1). These deficits have been shown to negatively impact behavior, social relationships, and overall quality of life. Although relatively stable during earlier stages of life, receptive language abilities tend to decline with age, particularly in older adults with DS. Figueroa and Darbra [57] found that older individuals with DS performed significantly worse on the Token and Peabody tests, suggesting that receptive language may be more vulnerable to age-related decline than expressive abilities. However, declines in verbal fluency and expressive language have also been documented in individuals without AD, while comprehension often remains intact [9, 23, 58].

Deficits in working memory, particularly in the verbal domain, are well-documented in individuals with DS and tend to persist across the lifespan (Figure 1) [59, 60]. Long-term memory is also compromised, with difficulties in encoding and retrieval processes becoming evident in adolescence and early adulthood [16, 61, 62]. These memory issues are linked to temporal lobe and hippocampus dysfunctions [63] and progressively worsen with age [64]. Episodic memory remains relatively intact in early adulthood but deteriorates significantly with the onset and progression of dementia. Some studies suggest that episodic memory is the first cognitive domain to deteriorate during aging in individuals with DS [65]. As cognitive decline progresses, explicit memory, including verbal and visual encoding, also deteriorates [66].

Executive functions, including inhibitory control, cognitive flexibility, and working memory, are essential for self-regulation, planning, and goal-directed behavior [67]. Adults with DS exhibit significant impairments in these domains and score lower than their typically developing peers on standardized executive function measures such as the Global Executive Composite, Plan/Organize, Working Memory, Task Monitor, and Metacognition Index scales [68, 69]. However, it remains unclear whether these neuropsychological changes follow a distinct progression, occur independently, or converge over time to culminate in AD.

Neuroanatomical changes, particularly in the hippocampus and corpus callosum, are also linked to cognitive deterioration. Additionally, psychosocial factors may influence cognitive function and AD progression in DS [49, 70]. Therefore, a comprehensive diagnostic approach that incorporates clinical, imaging, and biomarker data is crucial for the early detection of AD in this population [34, 35].

Despite the clinical heterogeneity observed in older individuals with DS, age-related AD neuropathology is a consistent and defining feature. Postmortem studies of DS brains have identified structural abnormalities such as reduced total brain weight, hypoplasia of the frontal and temporal lobes, a simplified gyral pattern with fewer sulci, generalized cortical atrophy, ventricular enlargement, and cerebellar and brainstem atrophy, particularly in the middle cerebellar lobe [71]. Interestingly, while subcortical regions such as the lenticular nuclei and posterior parietal and occipital cortices often retain relatively normal volumes, the hippocampus shows disproportionately severe volume reduction, and the amygdala exhibits shrinkage consistent with overall brain size reduction [72].

Neuroimaging studies have further elucidated these structural changes. For instance, MRI findings reported by Pujol et al. [73] revealed significant volume reductions in the hippocampus, basal forebrain (specifically the substantia innominata), and the temporal and parietal lobes in adults with DS and dementia. Similarly, Mullins et al. [74] observed an increased lateral ventricular volume in individuals with DS, even in those without dementia. Fortea et al. [15] corroborated these findings, describing a distinctive DS brain morphology characterized by diminished frontal lobe, hippocampus, cerebellum, and brainstem volumes. These patterns closely mirror the neurodegeneration seen in sporadic AD.

Crucially, evidence suggests that some neuropathological differences in DS originate developmentally rather than degeneratively. Pinter et al. [64] found that children with DS have smaller hippocampal volumes than their typically developing peers, indicating early neurodevelopmental alterations. Neuropsychological evaluations of school-aged individuals with DS reveal hippocampal-specific dysfunctions alongside broader cognitive impairments [75]. In adults with DS without clinical dementia, age-related atrophy affects the hippocampus and corpus callosum, suggesting changes in allocortical and neocortical structures [72].

Advancements in pediatric medical care, particularly surgical interventions for congenital heart defects, have significantly increased the life expectancy of individuals with DS. Life expectancy rose from an average of four years in 1950 to approximately 60 years by 2010 [4, 76–78]. However, this extended lifespan has not been matched by proportional improvements in overall health outcomes. By age 30, many individuals with DS exhibit clear signs of accelerated aging. This is characterized by the early onset of age-related conditions and premature physical decline compared to the general population [79–81].

This is reflected by the high prevalence of comorbidities, including early menopause, osteopenia, osteoporosis, hypothyroidism, abnormal fat distribution, obesity, atherosclerosis, hypertension, and immune system dysfunction [16, 19, 82–84]. Furthermore, there is a possibility of the development of neurological or psychiatric disorders, including anxiety, depression, conduct disorder, epilepsy, cognitive impairment, and early-onset AD [16, 65].

Notably, the accelerated aging process in DS begins prenatally, as evidenced by epigenetic age acceleration observed in newborns with the condition [85]. Studies using epigenetic clocks have shown that individuals with DS have a biological age approximately 6.6 years older than their chronological age, based on blood and brain tissue [86].

Premature aging in DS is associated with multiple established hallmarks of aging, including Aβ accumulation, oxidative stress, and chronic neuroinflammation [87]. Additional mechanisms, such as cellular senescence and disruptions in metal homeostasis (e.g., copper imbalance), are believed to contribute to accelerated aging, age-related diseases, and cognitive decline in this population [80, 81].

AD is an incurable and progressive neurological disorder that ranks as the sixth leading cause of death worldwide and is the most common form of dementia, accounting for approximately 80% of all diagnoses [88]. The disease typically progresses over a period of 8 to 10 years during its clinical stages, following prodromal and preclinical phases that may span up to two decades [89]. The annual incidence of the condition ranges from 1% to 3%, with a prevalence that varies from 10% to 30% among individuals over the age of 65 [90]. Globally, the number of individuals affected is expected to reach approximately 152 million by 2050, with the most significant increase occurring in developing countries [88].

The main relationship between DS and AD is due to the overexpression of the APP gene located on chromosome 21 [91]. This genetic alteration leads to the excessive production and accumulation of Aβ peptides, particularly Aβ42. Intraneuronal Aβ deposits can be detected at an early age in individuals with DS and precede the formation of extracellular amyloid plaques [92, 93]. This early accumulation triggers a cascade of pathological events, including oxidative stress, mitochondrial dysfunction, chronic neuroinflammation, glial alterations, vascular abnormalities, and the formation of NFTs, hallmark features of AD pathology (Figure 2) [20, 93, 94].

The pathological cascade of AD in DS begins early, with intracellular Aβ accumulation detectable in endosomes and lysosomes as early as 28 weeks of gestation [18]. By age eight, extracellular Aβ deposits are present, with a dramatic increase in deposition occurring between the ages of 35 and 45 [53, 92]. Diffuse Aβ plaques begin forming between ages 20 and 30 and evolve into neuritic plaques during the fourth decade of life. NFTs appear after Aβ deposition, reflecting the progressive nature of AD pathology [15]. Individuals with DS over the age of 40 exhibit AD-associated neuropathological hallmarks, including extracellular senile plaques, perivascular Aβ deposits (amyloid angiopathy), intraneuronal NFTs, and neuritic plaques, regardless of dementia symptoms [15, 20, 53, 95]. This pathology typically begins in the entorhinal cortex, then progresses to the hippocampus, and eventually spreads to the neocortical association areas [72]. Together, these interconnected mechanisms contribute to the accelerated onset and progression of AD in individuals with DS.

Studies have linked the overexpression of superoxide dismutase 1 (SOD1) to the accumulation of reactive oxygen species (ROS) and the oligomerization of Aβ in individuals with DS [96]. Trisomy 21, a characteristic of DS, leads to the overexpression of SOD1 and APP, contributing to increased oxidative stress and neural dysfunction [97]. An imbalance between SOD1 and glutathione peroxidase activity has been associated with increased free radical production [96]. High levels of oxidative damage, particularly the accumulation of 4-hydroxy-2-nonenal (HNE)-bound proteins, have been observed in the frontal cortex of individuals with DS and correlate with Aβ levels [98]. Additionally, increased SOD and catalase activity have been reported in plasma samples from adults with DS and cognitive impairment [99, 100]. SOD1 deficiency in an AD mouse model has been shown to accelerate Aβ oligomerization and worsen memory impairment, suggesting that cytoplasmic superoxide plays a critical role in Alzheimer’s pathogenesis [101]. Similarly, neurons obtained from the brains of individuals with DS have been shown to be highly sensitive to oxidative stress [102]. Taken together, these findings underscore the intricate relationship between SOD1 overexpression, oxidative stress, and Aβ aggregation in DS and AD, highlighting the potential of antioxidant-based therapeutic strategies.

Mitochondrial abnormalities have been linked to various clinical manifestations in DS, including intellectual disability, premature aging, and AD-like dementia [103–105]. Studies have demonstrated that mitochondrial DNA (mtDNA) mutations accumulate with age and are notably higher in the brains of individuals with DS and AD [104, 106]. This leads to a reduction in mtDNA copy number and impaired mitochondrial function [107, 108]. This dysfunction contributes to increased oxidative stress, elevated ROS production, and neuronal cell death in DS [102, 106, 109]. Overproduction of Aβ is also associated with mitochondrial dysfunction, suggesting that energy deficits in DS may contribute to altered processing of Aβ [110, 111]. Furthermore, the relationship between mitochondrial dysfunction and autophagy has been investigated in DS, revealing that autophagy can lead to inflammation and the development of a redox imbalance, as well as changes in protein homeostasis and signal transduction [112]. Consequently, therapeutic strategies that correct mitochondrial defects and enhance autophagy are being investigated as potential interventions to improve cognitive function and quality of life in individuals with DS and AD [106, 112].

Microvascular dysfunction is a critical contributor to the development and progression of AD, particularly in individuals with DS. Postmortem studies of brains from individuals with both conditions reveal significant vascular abnormalities, such as reduced microvessel density and compromised endothelial integrity [113]. These findings closely resemble those observed in sporadic AD. They also contribute to decreased cerebral blood flow, impaired nutrient delivery, and reduced metabolic waste clearance. These factors exacerbate neurodegeneration [113].

Additionally, the excessive accumulation of Aβ in individuals with DS leads to cerebral amyloid angiopathy (CAA). In CAA, Aβ deposits within cerebral vessel walls promote further vascular injury and accelerate AD pathology [114, 115]. Despite the absence of typical systemic vascular risk factors, such as hypertension or atherosclerosis, individuals with DS frequently exhibit cerebrovascular lesions, including white matter hyperintensities and microbleeds. These lesions increase with age and disease progression [116, 117]. These vascular injuries may intensify astrocytosis, promoting tau hyperphosphorylation and amplifying neurodegeneration [118].

The interplay among vascular pathology, Aβ accumulation, and neuroinflammation creates a reinforcing cycle that drives cognitive decline in DS. The mechanisms of vascular amyloidosis, endothelial dysfunction, and chronic inflammation are shared by sporadic and familial forms of AD. This underscores the value of DS as a model for studying the early and aggressive pathogenesis of AD [119, 120].

Understanding this complex network is essential for developing targeted preventive and therapeutic strategies that address vascular health, inflammation, and Aβ pathology for individuals with DS and the broader population affected by AD [118, 120].

Postmortem studies reveal significant reductions in neurons, astrocytes, and oligodendrocytes in the cortex and basal ganglia of adults with DS, indicating widespread cellular degeneration [121, 122]. Glial dysfunction disrupts key metabolic and homeostatic processes, including Aβ clearance, oxidative stress regulation, and inflammatory control, thereby amplifying neurodegeneration [123, 124].

The triplication of Hsa21 genes in individuals with DS alters gene dosage and regulation. This leads to widespread disruptions in cellular homeostasis. These changes affect multiple biological processes, including protein aggregation, mitochondrial function, inflammation, and synaptic signaling. Collectively, these changes accelerate the onset and progression of AD. Understanding the molecular mechanisms linking DS to early-onset AD requires knowledge of the specific contributions of Hsa21 genes and their interactions with genes on other chromosomes [4, 148].