Cerebral amyloid angiopathy (CAA) is a common but often unrecognized cerebrovascular condition in older adults and plays a critical role in both neurodegenerative and hemorrhagic brain pathology. It has a prevalence of about 50–93.6% in people with Alzheimer’s disease (AD) and approximately 30% of older adults without AD or other neuropathological abnormalities [1, 2]. Both CAA and AD share the same amyloid β (Aβ) pathology but have different anatomic distributions (cerebral blood vessels vs. the brain parenchyma) in Aβ deposits and different forms of Aβ (Aβ40 vs. Aβ42). The presence of CAA can lead to microhemorrhages or macrohemorrhages, potentially resulting in further cognitive impairment and even death [3–5]. CAA can be asymptomatic, but the disrupted integrity of the vessel wall from the amyloid deposits can also lead to several clinical symptoms, such as microbleeds, lobar hemorrhage (e.g., stroke), cognitive impairment, transient focal neurological episodes (TFNEs), and superficial siderosis. Risk factors for CAA include advancing age and the presence of APOE ε4 or ε2 allele. The gold standard for CAA diagnosis is through post-mortem histopathology, but that is not clinically feasible in living patients. Imaging-based Boston criteria are commonly used in living patients and have a high level of certainty. Considering the high prevalence of CAA in people with AD and similar amyloid accumulation pathology, CAA may hold a crucial role in AD management. However, current knowledge and research are limited in understanding its pathophysiology, diagnostics, reliable biomarkers, and clinical management for CAA. A comprehensive review might be a necessary step for synthesizing what is known and identifying directions for future research. This paper provides a comprehensive review of CAA pathophysiology, clinical manifestations, risk factors, diagnosis, management strategies, and directions for future research to better understand and manage CAA.

While AD primarily involves Aβ42 accumulation in the brain parenchyma, CAA involves Aβ40 accumulation in the cerebral blood vessels. CAA mainly results from impaired clearance of Aβ from the brain interstitial fluid, leading to progressive cognitive impairment and even death [6, 7]. CAA develops through the following stages: 1) accumulation of Aβ, primarily Aβ40, in cerebral vasculature such as the media, small- to medium-sized cerebral arteries, arterioles, veins, and capillaries, particularly in cortical and leptomeningeal brain vessels, 2) impaired vascular fragility, especially in posterior brain regions (e.g., occipital lobe), due to Aβ40-induced damage to vascular smooth muscle and endothelial cells, 3) non-hemorrhagic brain injury such as white matter hyperintensities (WMHs) and ischemic lesions from impaired cerebral blood flow regulations, and 4) appearance of hemorrhagic brain lesions [cortical superficial siderosis (cSS), microbleeds, intracerebral hemorrhage (ICH)] from vessel wall breakdown [8–16]. cSS occurs in approximately 60% of people with histopathologically-confirmed cases of CAA [17] and is associated with higher odds of recurrent ICH [18]. Both microbleeds and lobar ICH occur in about 50% to 57% of people with CAA [18, 19]. Elimination of the accumulated Aβ through hemorrhage may lead to a process of pathological vessel remodeling [20]. Genetic factors, such as mutations in the amyloid precursor protein (APP) gene or APOE ε4/APOE ε2 alleles, exacerbate Aβ accumulation. APOE ε4 is a major risk factor for CAA formation and progression [21–24]. It hampers Aβ clearance, promoting breakdown of blood vessels and increasing the risk of lobar ICH [23, 25]. Whereas APOE ε2 is associated with increased risk for CAA-related ICH in the presence of CAA [23, 26] and WMH multispot pattern [27]. Individuals carrying the APOE ε2 allele were found to have worse clinical outcomes compared to non-carriers, including higher mortality and poorer functional recovery after ICH [28] and a higher risk of lobar ICH (OR: 3.8, 95% CI: 1.0–14.6) if on a warfarin regimen [29]. Table 1 below describes the differences between CAA and AD.

The clinical manifestations of CAA range widely, varying from asymptomatic cases to devastating hemorrhagic strokes. It predominantly affects older adults and primarily reflects the consequences of Aβ deposition in cortical and leptomeningeal blood vessels, which weakens vascular integrity and predisposes to bleeding and ischemic change [35, 36]. The most characteristic presentation is spontaneous lobar ICH, which carries a high risk of recurrence. The recurrence rate of ICH in CAA is among the highest of all stroke subtypes, underscoring the importance of early recognition, accurate diagnosis, and tailored management strategies [36].

These hemorrhages typically occur in the cortical or subcortical regions and are most often located in the posterior areas of the brain, such as the occipital and parietal lobes. Unlike deep hemispheric hemorrhages associated with hypertension, CAA-related ICHs are typically cortical-based, and frequently recurrent. They occur due to Aβ deposition in the cortical and leptomeningeal vessels, leading to vessel fragility and rupture [37]. The lobar distribution of these hemorrhages is a distinguishing feature of CAA and helps differentiate it from other small vessel pathologies such as hypertensive arteriopathy. These lobar hemorrhages are associated with significant morbidity and mortality, often leading to long-term neurological disability and increased healthcare burden [12, 38].

Another notable clinical feature of CAA is TFNEs, also referred to as “amyloid spells” [39]. These episodes are characterized by brief, recurrent, and stereotyped neurological symptoms, such as sensory disturbances, motor deficits, or visual phenomena. Although they often mimic transient ischemic attacks (TIAs), TFNEs typically differ in their slow progression, affecting adjacent cortical areas in a sequential manner and spreading pattern. This evolution pattern is more characteristic of CAA and is rarely seen in vascular TIAs. TFNEs are distinguished by their association with cSS and convexity subarachnoid hemorrhage (cSAH) on neuroimaging, both of which are key markers of underlying CAA pathology [30]. The prevailing hypothesis is that these episodes result from cortical spreading depolarizations or small cortical hemorrhages, leading to temporary disruptions in neuronal activity of cortical territories. Importantly, the presence of TFNEs—particularly when associated with cSS—is associated with increased risk of major lobar ICH, making them valuable early warning signs for clinicians. Due to their subtle presentation and overlap with other conditions, TFNEs are often under-recognized, yet they represent a hallmark clinical manifestation of CAA that warrants further diagnostic evaluation [40].

Cognitive impairment is also prevalent among individuals with CAA, ranging from mild cognitive impairment to dementia [12, 41]. The cognitive deficits are often multifactorial, resulting from a combination of microhemorrhages, cortical microinfarcts, and white matter changes. Patients with CAA may experience a gradual decline in cognitive function, a step-wise deterioration following recurrent hemorrhages, or a rapidly progressive decline in cases of CAA-related inflammation (CAA-ri) [12]. The accumulation of Aβ in cerebral vessels contributes to chronic cerebral hypoperfusion and microinfarctions, leading to deficits in executive function, processing speed, and memory [42, 43]. This cognitive decline can occur independently or concomitantly with AD, complicating the clinical picture. Seizures and headaches are less common but may occur, particularly in CAA-ri [44].

CAA-ri is a rare but distinct subtype of CAA characterized by an immune-mediated inflammatory response to vascular Aβ deposits. It encompasses two subtypes: inflammatory CAA and Aβ-related angiitis [45, 46]. It is a rare syndrome of reversible encephalopathy, and unlike sporadic CAA, which typically progresses gradually, CAA-ri often presents with subacute or rapidly progressive cognitive decline, seizures, headaches, behavioral changes, or focal neurological deficits [45, 47]. Magnetic resonance imaging (MRI) findings in CAA-ri are notably different, with characteristic asymmetric cortical or subcortical T2/fluid-attenuated inversion recovery (FLAIR) hyperintensities reflecting vasogenic edema—often described as “gyral edema”—which is not typically seen in non-inflammatory CAA [45, 46, 48]. Unlike the hemorrhagic markers predominant in sporadic CAA (e.g., lobar microbleeds, cSS), CAA-ri may also show leptomeningeal enhancement or patchy contrast enhancement on MRI. Prompt recognition is critical because, unlike classic CAA, CAA-ri responds to immunosuppressive treatment—typically corticosteroids—with many patients experiencing clinical and radiological improvement [46, 48]. Brain biopsy is sometimes required to confirm the diagnosis, particularly when imaging is inconclusive. Early treatment can significantly alter the disease trajectory and prevent irreversible deficits [46, 48].

Neuroimaging often reveals cerebral microbleeds (CMBs) and cSS in patients with CAA. CMBs are small, chronic hemorrhages visible on susceptibility-weighted imaging (SWI) or T2*-weighted MRI sequences, predominantly located in lobar regions [41, 49]. cSS, indicative of chronic bleeding into the subarachnoid space, appears as linear hypointensities on MRI and is associated with an increased risk of future ICH [39].

Accurate diagnosis of CAA relies on a combination of clinical assessment supported by neuroimaging and, in some cases, cerebrospinal fluid (CSF) biomarkers. The Boston criteria, recently updated to version 2.0, provide a framework for diagnosing probable CAA based on clinical and imaging findings without the need for histopathological confirmation [30]. MRI is the modality of choice, with SWI sequences being particularly sensitive in detecting CMBs and cSS, hallmark features of CAA [49].

Advancing age is the most significant risk factor for CAA, with prevalence increasing markedly in individuals over 70 years [1, 2]. Genetic predisposition also plays a role; the APOE ε4 allele correlates with increased amyloid deposition and cognitive decline, while the presence of the APOE ε2 allele is associated with a higher risk of lobar ICH and cSS [37, 72–74]. A study from the National Alzheimer’s Coordinating Center (NACC) reported APOE ε4 carriers having a higher risk for CAA development [χ²(3) = 150.6, p < 0.001] [75]. Another study also reported APOE ε4/APOE ε4 carriers having severe CAA in the meninges of the occipital lobe among 371 autopsy samples [76]. A study from the ROSMAP demonstrated that APOE ε4 carriers showed threefold higher odds (OR = 3.55, 95% CI = 2.73–4.63, p < 0.001) of having more severe meningeal/parenchymal CAA than the APOE ε3/APOE ε3 carriers [72]. While hypertension is a well-established risk factor for deep hemispheric hemorrhages [12], its role in CAA-related lobar hemorrhages is less clear. Some studies suggest that hypertension may exacerbate the risk of hemorrhagic events in CAA, although the association is not as robust as with other forms of small vessel disease [12, 13]. CAA and AD frequently co-occur, with amyloid pathology contributing to both conditions. While CAA can develop independently of AD, its presence often modifies the clinical trajectory of cognitive decline and increases the risk of cerebral hemorrhages [44]. Table 4 below is the list of key studies in CAA.

Although there are no proven treatments for CAA, current management focuses on preventing complications and exploring experimental therapies aimed at enhancing amyloid clearance and vascular health. Potential promising approaches include Aβ-degrading enzymes [e.g., neprilysin, insulin-degrading enzyme (IDE)], vascular receptor-mediated clearance [e.g., low-density lipoprotein receptor-related protein-1 (LRP1)], and the perivascular drainage pathway (i.e., an Aβ clearance route) [64, 79, 80]. Studies found both neprilysin and IDE promote Aβ degradation and clearance [81–83]. LRP1, highly present in cerebrovascular walls, plays a role in the clearance of Aβ from the brain [84, 85]. Perivascular drainage pathway, also known as intramural periarterial drainage (IPAD), is impaired in CAA, leading to Aβ accumulation in vessel walls. IPAD relies on vascular smooth muscle cell contraction [86]. Potential strategies to restore IPAD pathway include anti-inflammatory agents or antioxidants, as well as pulsation-based therapies such as physical activity and medications affecting heart rate [86, 87]. Optimizing control of vascular risk factors, such as hypertension, diabetes, and hyperlipidemia, may support perivascular drainage and reduce secondary damage [86].

This review provides a comprehensive and state-of-the-art review of CAA, focusing on pathophysiology, clinical presentations, diagnostic approaches, risk factors, and management strategies. CAA is a complicated cerebrovascular disease and a major cause of vascular dysfunction, lobar ICH, and cognitive impairment in older adults.

Despite much progress in CAA research, significant limitations remain. Brain histopathology remains the gold standard of CAA diagnosis, but not practical. Both the Boston criteria and the Edinburgh criteria enable early detection of symptomatic CAA but are limited in the identification of asymptomatic CAA. The need for innovative biomarkers in consideration of APOE genes to diagnose asymptomatic CAA is emphasized, especially as anti-amyloid therapies become more widely used in AD management.

This review also acknowledges that while plasma biomarker and proteomics studies have yielded valuable insights, their translation to routine practice remains limited by methodological heterogeneity and small cohort sizes. A balanced appraisal underscores that current findings, though encouraging, are preliminary. Future research should emphasize standardization of measurement protocols, replication across diverse populations, and correlation with clinical outcomes. Such rigor will be vital for establishing reliable biomarkers that inform diagnosis, prognosis, and therapeutic monitoring in CAA.

Up-to-date management strategies for CAA include Aβ enzymatic degradation, vascular receptor-mediated, and perivascular drainage [64, 79]. However, age-related decline in enzyme activity and arterial stiffening may limit Aβ breakdown and clearance [93, 94], emphasizing the complexity of Aβ clearance in older adults and the necessity of therapeutic regimens to minimize progression of AD and CAA. Most biomarkers and therapeutic strategies targeting amyloid clearance have been conducted in animal models, underscoring validation studies in human studies. In addition, plasma-based biomarkers and proteomics analysis are gaining recognition as promising avenues for understanding the underlying CAA pathophysiology, refining diagnostic approaches via identifying biomarkers and therapeutic targets, which warrant future studies. Furthermore, current diagnostic gaps in asymptomatic or mixed pathologies (CAA and AD) heighten the need for further studies.

Future studies should prioritize longitudinal cohort tracking for early detection of asymptomatic CAA and clarify the mechanisms of vessel wall degeneration. Integrating genetic, imaging, and fluid biomarkers into multimodal diagnostic frameworks will be key for improving diagnostic precision. Translational research bridging animal and human studies is also crucial to validate mechanistic insights and develop targeted therapies aimed at halting or reversing amyloid deposition. Ultimately, these efforts will support the creation of comprehensive risk stratification tools that combine genetic, imaging, and clinical data for individualized management.

CAA frequently coexists with AD and contributes significantly to adverse cognitive and cerebrovascular outcomes in older adults. Much progress has been made in diagnosing and managing CAA. The Boston criteria and the Edinburgh criteria are both reliable in vivo methods to diagnose symptomatic CAA. Emerging CSF, plasma, and proteomic biomarkers offer promise for earlier detection. Several experimental agents effective in animal models require validation in human trials. This review provides up-to-date research and future directions for CAA management.