Neuronal calcium mishandling is implicated in age-related cognitive impairment and Alzheimer's disease (AD). As neurons age, they face increased oxidative stress and impaired energy metabolism, which disrupts proteins controlling membrane excitability and intracellular calcium dynamics. Toxic forms of amyloid β-peptide (Aβ) can induce calcium influx by causing membrane-associated oxidative stress or forming oligomeric pores, leading to excitotoxicity and apoptosis. Mutations in β-amyloid precursor protein and presenilins may impair normal function of these proteins in the plasma membrane and endoplasmic reticulum, respectively. Understanding calcium signaling upstream and downstream of Aβ offers opportunities for developing novel interventions for AD. Neurons use calcium signals to control membrane excitability, neurotransmitter release, and gene expression. Calcium signaling involves complex interactions between calcium influx through voltage-gated channels and calcium release from intracellular stores. Mitochondria play a key role in regulating calcium signaling by utilizing calcium uptake mechanisms. Excessive calcium uptake can lead to mitochondrial permeability transition pore opening and apoptosis. Age-related changes in calcium-regulating systems in brain cells, including elevated intracellular calcium levels and impaired mitochondrial calcium buffering, contribute to AD pathogenesis. Aβ promotes calcium influx and calcium-mediated excitotoxicity by inducing membrane lipid peroxidation and forming pores. Aβ oligomers cause calcium overload, synaptic dysfunction, and neuronal degeneration. Aβ also disrupts calcium homeostasis by altering the production of secreted APP and affecting ER calcium release. Presenilins, which are integral membrane proteins, regulate calcium homeostasis by modulating calcium channels and signaling pathways. Mutations in presenilins can lead to increased Aβ production and altered calcium signaling, contributing to AD pathogenesis. Calcium dysregulation is linked to neurofibrillary tangles and cytoskeletal pathology in AD. Aβ can cause calcium-mediated changes in tau and microtubules, leading to tangle formation. Calcium also contributes to AD-like tau phosphorylation and Aβ accumulation. Mutations in tau that cause tangle formation alter voltage-dependent calcium channels, increasing calcium influx and contributing to cell death. Calcium acts upstream of amyloidogenesis by influencing APP processing. Environmental factors that inhibit amyloidogenesis, such as caloric restriction and antioxidants, stabilize neuronal calcium homeostasis. Direct evidence shows that calcium influences APP processing, with calcium ionophores and ischemia increasing Aβ production. Physiological calcium transients increase α-secretase cleavage of APP, decreasing Aβ production. Synaptic dysfunction and degeneration occur early in AD, with Aβ and presenilin mutations contributing to calcium-mediated degeneration. Aβ disrupts calcium homeostasis in synaptic terminals by causing membrane-associated oxidative stress. Aβ oligomers reduce the expression of NMDA and EphB2 receptors, leading to abnormal dendritic spine morphology and degeneration. Aβ immunotherapy can prevent synaptic dysfunction and restore cognitiveNeuronal calcium mishandling is implicated in age-related cognitive impairment and Alzheimer's disease (AD). As neurons age, they face increased oxidative stress and impaired energy metabolism, which disrupts proteins controlling membrane excitability and intracellular calcium dynamics. Toxic forms of amyloid β-peptide (Aβ) can induce calcium influx by causing membrane-associated oxidative stress or forming oligomeric pores, leading to excitotoxicity and apoptosis. Mutations in β-amyloid precursor protein and presenilins may impair normal function of these proteins in the plasma membrane and endoplasmic reticulum, respectively. Understanding calcium signaling upstream and downstream of Aβ offers opportunities for developing novel interventions for AD. Neurons use calcium signals to control membrane excitability, neurotransmitter release, and gene expression. Calcium signaling involves complex interactions between calcium influx through voltage-gated channels and calcium release from intracellular stores. Mitochondria play a key role in regulating calcium signaling by utilizing calcium uptake mechanisms. Excessive calcium uptake can lead to mitochondrial permeability transition pore opening and apoptosis. Age-related changes in calcium-regulating systems in brain cells, including elevated intracellular calcium levels and impaired mitochondrial calcium buffering, contribute to AD pathogenesis. Aβ promotes calcium influx and calcium-mediated excitotoxicity by inducing membrane lipid peroxidation and forming pores. Aβ oligomers cause calcium overload, synaptic dysfunction, and neuronal degeneration. Aβ also disrupts calcium homeostasis by altering the production of secreted APP and affecting ER calcium release. Presenilins, which are integral membrane proteins, regulate calcium homeostasis by modulating calcium channels and signaling pathways. Mutations in presenilins can lead to increased Aβ production and altered calcium signaling, contributing to AD pathogenesis. Calcium dysregulation is linked to neurofibrillary tangles and cytoskeletal pathology in AD. Aβ can cause calcium-mediated changes in tau and microtubules, leading to tangle formation. Calcium also contributes to AD-like tau phosphorylation and Aβ accumulation. Mutations in tau that cause tangle formation alter voltage-dependent calcium channels, increasing calcium influx and contributing to cell death. Calcium acts upstream of amyloidogenesis by influencing APP processing. Environmental factors that inhibit amyloidogenesis, such as caloric restriction and antioxidants, stabilize neuronal calcium homeostasis. Direct evidence shows that calcium influences APP processing, with calcium ionophores and ischemia increasing Aβ production. Physiological calcium transients increase α-secretase cleavage of APP, decreasing Aβ production. Synaptic dysfunction and degeneration occur early in AD, with Aβ and presenilin mutations contributing to calcium-mediated degeneration. Aβ disrupts calcium homeostasis in synaptic terminals by causing membrane-associated oxidative stress. Aβ oligomers reduce the expression of NMDA and EphB2 receptors, leading to abnormal dendritic spine morphology and degeneration. Aβ immunotherapy can prevent synaptic dysfunction and restore cognitive