Ca²⁺ dysregulation may happen early and could be a proximal driver of Alzheimer’s pathology

Alzheimer’s disease (AD) is the most common form of dementia and is classically defined by two hallmark brain pathologies: extracellular amyloid beta (Aβ) plaques and intracellular neurofibrillary tangles formed by hyperphosphorylated tau. For decades, major drug development efforts have focused on amyloid centered approaches, but many of these strategies have shown limited success in improving cognitive outcomes in patients. This gap has pushed researchers to re examine what might be happening upstream of plaques and tangles, and whether a more proximal driver exists.

One increasingly supported idea is that neuronal calcium (Ca²⁺) dysregulation is not just a downstream consequence of AD pathology, but may occur early and contribute directly to synaptic dysfunction, abnormal protein processing, mitochondrial stress, impaired clearance pathways, and ultimately neurodegeneration. Ca²⁺ is a fundamental second messenger in neurons. It shapes electrical excitability, neurotransmitter release, synaptic plasticity, learning, and memory. Because Ca²⁺ signaling sits at the center of so many essential processes, even subtle long term disruption can gradually shift neurons toward vulnerability and degeneration.

In healthy neurons, intracellular Ca²⁺ homeostasis is tightly maintained through coordinated control across multiple compartments. Cytosolic Ca²⁺ is normally kept low at rest, while intracellular stores such as the endoplasmic reticulum (ER) hold much higher Ca²⁺ levels. When neurons are activated, Ca²⁺ signals can be generated either by influx from outside the cell through plasma membrane channels, or by release from internal stores, especially the ER. After signaling, Ca²⁺ must be rapidly cleared or redistributed to avoid chronic overload and toxic downstream effects.

Neurons rely on a network of Ca²⁺ handling proteins to maintain this balance. The ER refills Ca²⁺ using ATP dependent pumps, while the plasma membrane removes Ca²⁺ through extrusion systems. When ER Ca²⁺ stores become depleted, cells can trigger store operated Ca²⁺ entry (SOCE) to bring Ca²⁺ back in from outside and replenish the ER. Meanwhile, mitochondria and lysosomes also participate in Ca²⁺ storage and signaling, linking Ca²⁺ balance to energy metabolism and protein clearance.

In AD, evidence suggests that Ca²⁺ imbalance can appear before the major visible hallmarks of plaques and tangles. Familial AD (FAD) mutations, especially those involving presenilin (PS1 and PS2), have been strongly linked to altered Ca²⁺ handling. Presenilins are part of the γ secretase complex that processes APP, but they also influence Ca²⁺ regulation. In several AD related models, ER Ca²⁺ release becomes exaggerated, often through enhanced activity or expression of key ER release channels such as the inositol 1,4,5 trisphosphate receptor (InsP3R) and the ryanodine receptor (RyR). This exaggerated ER Ca²⁺ release can elevate cytosolic Ca²⁺ and drive downstream stress responses.

At the synaptic level, Ca²⁺ dysregulation can shift neurons toward abnormal excitability and impaired plasticity. Ca²⁺ signaling is essential for long term potentiation (LTP), which supports learning and memory. When Ca²⁺ dynamics become distorted, neurons may become more susceptible to maladaptive signaling patterns, weakening synaptic stability and contributing to cognitive decline. Importantly, Ca²⁺ disruption can also interact with the amyloid and tau pathways. Aβ can affect Ca²⁺ signaling through multiple routes, including influencing Ca²⁺ entry at the plasma membrane and altering Ca²⁺ release from internal stores. At the same time, elevated cytosolic Ca²⁺ can influence APP processing and kinase driven tau phosphorylation, strengthening the idea that Ca²⁺ dysregulation can sit upstream and amplify multiple pathological loops.

Beyond the ER and synapses, lysosomal Ca²⁺ signaling has gained attention because of its connection to autophagy and clearance of toxic proteins. Lysosomes are acidic organelles required for degradation and recycling, and they also act as Ca²⁺ stores. In AD, impaired autophagy and lysosomal dysfunction are frequently observed. Disrupted lysosomal Ca²⁺ handling can interfere with normal lysosomal pH regulation and fusion processes, reducing the efficiency of autophagosome lysosome degradation and contributing to accumulation of intracellular waste, including aggregated proteins.

Mitochondria also sit at a critical intersection of Ca²⁺ signaling and neuronal survival. Under normal conditions, Ca²⁺ transfer from ER to mitochondria supports ATP production. However, excessive mitochondrial Ca²⁺ loading can suppress energy metabolism, increase reactive oxygen species (ROS), and promote apoptosis. In AD models, exaggerated ER Ca²⁺ release can overload mitochondria, creating a cycle of oxidative stress and further Ca²⁺ instability. This is one reason why Ca²⁺ dysregulation is often linked to early bioenergetic decline and vulnerability in neurons.

Because Ca²⁺ disruption appears to be involved across multiple AD related pathways, correcting abnormal Ca²⁺ signaling has been proposed as a therapeutic strategy. Existing approved treatments such as memantine act partly by limiting excessive Ca²⁺ influx through NMDA receptors, helping reduce excitotoxic stress. However, many candidate approaches are now looking beyond plasma membrane channels and toward intracellular Ca²⁺ handling systems, including ER release channels, store operated Ca²⁺ entry pathways, lysosomal Ca²⁺ channels, and mitochondrial Ca²⁺ uptake mechanisms. The overall challenge is that Ca²⁺ signaling is essential throughout the body, so therapies must be precise enough to correct pathological Ca²⁺ imbalance without disrupting normal physiological signaling.

Overall, the Ca²⁺ hypothesis offers a framework that connects amyloid, tau, synaptic failure, mitochondrial dysfunction, and impaired clearance under a shared upstream driver. While no single pathway fully explains AD, Ca²⁺ dysregulation remains one of the most promising integrative targets because it intersects with so many core features of the disease. Continued research into Ca²⁺ handling proteins and compartment specific signaling may help define more effective intervention points, especially if therapies can be applied early enough to prevent irreversible neurodegeneration.

Source
Tong BCK, Wu AJ, Li M, Cheung KH. Calcium signaling in Alzheimer’s disease & therapies☆. Biochimica et Biophysica Acta (BBA) Molecular Cell Research. 2018;1865(11 Pt B):1745-1760. doi:10.1016/j.bbamcr.2018.07.018