Monoclonal antibodies (mAbs) have made significant progress in the treatment of Alzheimer's disease (AD). However, mAbs are associated with adverse effects, including Amyloid-Related Imaging Abnormality (ARIA), which manifests as edema or effusion (ARIA-E) and hemorrhage (ARIA-H). The mechanisms behind these effects are not yet fully understood. Moreover, spontaneous ARIA has been insufficiently explored, and mAb therapies, particularly lecanemab, have mainly focused on patients with the APOE-ε4 allele carrier. This review aims to address this gap by examining the mechanisms of spontaneous ARIA, ARIA induced by mAbs, and the influence of genetic variants on ARIA development. The autoantibody-Aβ-mediated immune response targets excessive Aβ deposits, increasing immune activity through microglial reactivity. The heightened immune response, driven by Aβ accumulation in blood vessels, promotes angiopathy and inflammation, potentially contributing to spontaneous ARIA. The APOE-ε4 allele carrier is more strongly associated with ARIA-E because it redistributes Aβ deposition from the brain to blood vessels, influencing microglial reactivity. The redistribution enhances vascular integrity and reduces the risk of ARIA-H. However, it also increases the likelihood of ARIA-E due to Aβ accumulation in the vasculature, triggering inflammation. In contrast, the development of ARIA-H is linked to increased TREM2 expression and microglial reactivity, leading to impaired vascular integrity and disrupted matrix remodeling, which worsens the condition. Additionally, the adverse effects of mAbs may extend beyond the APOE-ε4 allele, possibly impacting other genetic variants involved in microglial reactivity, Aβ redistribution, and vascular integrity.

The rising incidence and death rates linked to Alzheimer's disease (AD) highlight an urgent issue. Genetic screening is celebrated as a significant advancement for its early detection capabilities, pinpointing those at risk before the emergence of symptoms. Yet, the limited availability of these technologies highlights a critical gap in widespread application. This review pivots to the potential of presymptomatic clinical assessments as a readily available, economical, and simple strategy for early detection. Traditionally, AD diagnosis relies on the late-stage identification of cognitive deterioration, functional impairments, and neuropsychiatric symptoms, coinciding with advanced brain degeneration. Conversely, emerging research identifies early indicators preceding significant degeneration, manifesting years before clinical symptoms. We introduce a mnemonic, MEMORIES, to categorize these prodromal: Metabolism changes, Eye/visual impairments, March (refer to gait disturbances), Olfactory dysfunction, Rhythm (blood pressure and heart rate), Insensitivity of the tongue, Ears (hearing loss), and Stool alterations. Recognizing these prodromal through clinical examinations provides a valuable strategy for initiating preventative actions against brain degeneration. This approach advocates for broadening the screening lens beyond genetic screening to encompass clinical evaluations, enhancing early detection and intervention opportunities for AD.

Monoclonal antibodies (mAbs) have made significant progress in the treatment of Alzheimer's disease (AD). However, mAbs are associated with adverse effects, including Amyloid-Related Imaging Abnormality (ARIA), which manifests as edema or effusion (ARIA-E) and hemorrhage (ARIA-H). The mechanisms behind these effects are not yet fully understood. Moreover, spontaneous ARIA has been insufficiently explored, and mAb therapies, particularly lecanemab, have mainly focused on patients with the APOE-ε4 allele carrier. This review aims to address this gap by examining the mechanisms of spontaneous ARIA, ARIA induced by mAbs, and the influence of genetic variants on ARIA development. The autoantibody-Aβ-mediated immune response targets excessive Aβ deposits, increasing immune activity through microglial reactivity. The heightened immune response, driven by Aβ accumulation in blood vessels, promotes angiopathy and inflammation, potentially contributing to spontaneous ARIA. The APOE-ε4 allele carrier is more strongly associated with ARIA-E because it redistributes Aβ deposition from the brain to blood vessels, influencing microglial reactivity. The redistribution enhances vascular integrity and reduces the risk of ARIA-H. However, it also increases the likelihood of ARIA-E due to Aβ accumulation in the vasculature, triggering inflammation. In contrast, the development of ARIA-H is linked to increased TREM2 expression and microglial reactivity, leading to impaired vascular integrity and disrupted matrix remodeling, which worsens the condition. Additionally, the adverse effects of mAbs may extend beyond the APOE-ε4 allele, possibly impacting other genetic variants involved in microglial reactivity, Aβ redistribution, and vascular integrity.

The rising incidence and death rates linked to Alzheimer's disease (AD) highlight an urgent issue. Genetic screening is celebrated as a significant advancement for its early detection capabilities, pinpointing those at risk before the emergence of symptoms. Yet, the limited availability of these technologies highlights a critical gap in widespread application. This review pivots to the potential of presymptomatic clinical assessments as a readily available, economical, and simple strategy for early detection. Traditionally, AD diagnosis relies on the late-stage identification of cognitive deterioration, functional impairments, and neuropsychiatric symptoms, coinciding with advanced brain degeneration. Conversely, emerging research identifies early indicators preceding significant degeneration, manifesting years before clinical symptoms. We introduce a mnemonic, MEMORIES, to categorize these prodromal: Metabolism changes, Eye/visual impairments, March (refer to gait disturbances), Olfactory dysfunction, Rhythm (blood pressure and heart rate), Insensitivity of the tongue, Ears (hearing loss), and Stool alterations. Recognizing these prodromal through clinical examinations provides a valuable strategy for initiating preventative actions against brain degeneration. This approach advocates for broadening the screening lens beyond genetic screening to encompass clinical evaluations, enhancing early detection and intervention opportunities for AD.