Is dolichol pathway dysfunction a significant factor in Alzheimer’s disease?

Alzheimer’s disease (AD) is one of the most common forms of incurable, progressive senile dementia, with a complex pathophysiology featuring brain inflammatory processes (Twarowski and Herbet 2023). An early indication of AD is loss of the sense of smell (Doty 2019). Anosmia is also an early indicator for COVID-19 (Amadoro et al. 2023). SARS‑CoV‑2 infection morbidity, mortality, and impaired humoral response correlate with a deficiency in free zinc, distinct from most zinc, which is an integral, tightly bound part of proteins (Heller et al. 2021; Chillon et al. 2022). Zinc deficiency, induced by viral infection, is a likely cause of anosmia associated with acute SARS-CoV-2 infections and Long COVID (Schloss 2023). Post-COVID, the survivors are at substantially higher risk of developing AD (Aleman et al. 2025). SARS-CoV-2 infection and AD seem to share zinc deficiency, manifest as anosmia, as an early indicator of disease and an underlying contributing factor to disease progression. Zinc dietary supplements seem to benefit patients who have AD (Rivers-Auty et al. 2021). The basis for Zn²⁺-deficiency-induced anosmia can be linked to the dolichol pathway (Fig. 1). An enzyme essential to olfaction, UDP-glucuronosyltransferase (e.g., UGT2A1), requires N-glycosylation and has been linked to anosmia associated with COVID-19 and zinc deficiency (Neiers et al. 2021; Shelton et al. 2022; Schloss 2023). Deficiencies in pyridine nucleotides (derived from niacin) and zinc, both essential to proper functioning of the dolichol pathway, can result directly from infections or due to stress related to the pandemic and its aftermath (Schloss 2023; Lopresti 2020).

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How can levels of free zinc impact the progression of AD? AD patients have even higher levels of dolichol in their brains than the increases normally associated with aging (Wolfe et al. 1985; Bergamini et al. 2004). Paradoxically, polyprenol precursors to dolichol improve cognition in AD animal models and in preliminary clinical trials (Fedotova et al. 2016a, b; Soultanov et al. 2017; Fedotova et al. 2016a, b; Fedotova et al. 2012, 2010). A possible explanation for this paradox involves the dolichol kinase (DOLK). DOLK requires free zinc and CTP to phosphorylate dolichol (Sakakihara and Volpe 1985). Expression of DOLK is highest in the human brain, during fetal development and in the adult, indicating an important role for DOLK in the central nervous system (Farooqi et al. 2023). Only the brain DOLK is selective for zinc, since the enzyme in other tissues is less restrictive in its metal requirement. Mutations that reduce the levels of DOLK or polyprenol dehydrogenase/reductase (SRD5A3 and DHRSX) result in congenital disorders of glycosylation (CDG) (Wilson et al. 2024; Paprocka et al. 2021). CDG is manifested, in part, by devastating intellectual disability and other neurological problems. Among the glycosylated proteins affected by CDG are the amyloid precursor protein (APP), tau protein, and voltage-gated calcium channels (Schedin-Weiss et al. 2014; Lazniewska and Weiss 2017). Glycosylation disorders correlate with the development of AD.

Zinc is known to regulate the transcription factor nuclear factor erythroid 2-related factor 2, known as Nrf2 (Vali et al. 2025). The Nrf2 pathway modulates oxidative stress and regulates antioxidant defenses, which is critical in the pathogenesis of neurological diseases. The Kelch-like ECH-associated protein 1, known as Keap1, regulates Nrf2 by facilitating its ubiquitination and proteolysis (Song et al. 2024). Together, the Nrf2–Keap1 axis regulates oxidative stress and inflammation. Both Keap1 and Nrf2 are subject to O-GlcNAcylation that affects their activity-dependent protein folding and can prevent phosphorylation-dependent inactivation of Nrf2 by kinases. There are only two enzymes that either glycosylate (O-GlcNAcylation, O-GlcNAc transferase, OGT) Keap1 (Ser104, Chen et al. 2017) or Nrf2 (Ser103, Zhang et al. 2024) or remove carbohydrates from either enzyme (O-GlcNAcase, OGA). The Keap1–Nrf2 axis is intimately interrelated with the inflammatory signaling pathway primarily governed by nuclear factor-kappa B (NF-κB). While Nrf2 activation is generally anti-inflammatory, NF-κB activation is pro-inflammatory (Gao et al. 2022). Like Keap1 and Nrf2, NF-κB is also regulated by O-GlcNAcylation (Liu and Ramakrishnan 2021). Glycosylation of NF-κB regulates cancer cell proliferation, survival, and metastasis, providing a nutrient-dependent link between inflammation and cancer. Although Nrf2, Keap1, and NF-κB are subject to O-glycosylation, they are not directly modified by zinc- and dolichol phosphate-dependent N-glycosylation.

The regulation of the Nrf2–Keap1 axis by zinc is thought to involve direct interaction of Zn²⁺ with Keap1 (McMahon et al. 2018). However, zinc deficiency may have other, indirect effects on Nrf2–Keap1, O-glycosylation, oxidative stress, and inflammation, through the magnesium-dependent dolichyl-phosphate N-acetylglucosaminephosphotransferase (DAPGT1)-mediated link between N- and O-glycosylation (Fig. 2). Transfer of N-acetylglucosamine-1-phosphate from UDP-N-acetyl-d-glucosamine to dolichol phosphate produces N-acetyl-d-glucosaminyl-diphosphodolichol, which is essential for N-glycosylation (Fig. 2). Reducing the flux between N- and O-glycosylation pathways by zinc-limited production of dolichol phosphate or magnesium-limited reduction of DAPGT1 activity could result in alteration of N- and O-glycosylation patterns with resultant pathology. Support for this proposition comes from the inhibition of DAPGT1 by tunicamycin (Yoon et al. 2023). Tunicamycin is used as an antibiotic and anticancer drug. It inhibits N-linked glycoprotein synthesis by inhibition of DAPGT1, leading to the accumulation of misfolded proteins in the endoplasmic reticulum (ER), producing ER stress, oxidative stress, and inflammation. This process is associated with activation of the unfolded protein response (UPR) pathways (Fig. 3) modulating reactive oxygen species (ROS) generation, reduced glutathione (GSH) metabolism, and various inflammatory signaling cascades in the brain (Sita et al. 2023; Hoozemans et al. 2006). The disruption of UDP-glucuronosyltransferase N-glycosylation and the UPR in the olfactory system also explains why anosmia is an early indicator of Alzheimer’s disease (Nakajima et al. 2010; Murray et al. 2020; Tong et al. 2017).

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Other aspects of the pathophysiology associated with zinc deficiency can be attributed to its use as an essential component in the active sites of various enzymes (Portbury and Adlard 2017), such as metalloproteases like angiotensin converting enzyme (Ekmekci et al. 2003) or alcohol dehydrogenases like retinol dehydrogenase (Yin et al. 2003), or as essential structural components in 8–10% of all proteins (Andreini et al. 2006), such as the zinc-fingers of DNA binding proteins (Neuhaus 2022).

Paradoxically, if the rate of N-glycosylation in the ER is slowed for proteins that have multiple N- and O-glycosylation sites, then the protein may be misfolded between early and late N-glycosylation events. This could lead to retention of the misfolded protein in the ER and premature termination of further N-glycosylation, preventing migration of the protein out of the ER into the cytoplasm, and prevent later O-glycosylation. This premature termination of both N- and O-glycosylation after an early N-glycosylation event would be interpreted as over N-glycosylation at the expense of O-glycosylation, which has been observed (Kang et al. 2024). Various proteins that are N-glycosylated, associated with AD, and would contribute to disease progression include: amyloid precursor protein (Lin et al. 2022), voltage-gated ion channels (e.g., potassium channels Kv1.3, Kv1.4, and HERG) (Gong et al. 2002; Watanabe et al. 2004; Zhu et al. 2012), calcium channels (e.g., Cav3.2) (Weiss et al. 2013; Scott and Panin 2014), voltage-gated calcium channels (Lazniewska and Weiss 2017), nicotinic acetylcholine receptors (Wanamaker and Green 2005; Nishizaki 2003), muscarinic receptors (Romero-Fernandez et al. 2011), G protein-coupled receptors (Christoffer et al. 2020), metabotropic glutamate receptors (Miller et al. 2024), ionotropic glutamate receptors (Lichnerova et al. 2015), AMPA receptors (Kandel et al. 2018), dopamine receptors (Min et al. 2015), serotonin receptors (Maginnis et al. 2010), and tau protein (Mathew et al. 2023), although this is not meant to be a comprehensive list. Phosphorylated tau (pTau217) is a marker for AD that responds to oral supplementation of nicotinamide riboside, which raises pyridine nucleoside levels necessary for dolichol pathway function (Devanarayan et al. 2024; Wu et al. 2025). Premature termination of tau N-glycosylation and retention of tau in the endoplasmic reticulum without O-glycosylation in the cytoplasm could lead to increased levels of phosphorylated tau.

Stress is considered to be a major risk factor for the development of AD (Lyons and Bartolomucci 2020). Considerable evidence exists that stress induces deficiencies in magnesium, zinc, calcium, iron, and niacin (Lopresti 2020). Of these five well-documented, stress-induced micronutrient deficiencies, three, zinc, niacin, and magnesium, are involved in the early essential steps of N-glycosylation (Figs. 1, 2). Clearly, deficiencies in one or more of these micronutrients would reduce the rate of biosynthetic steps dependent on DPAGT1 (magnesium dependent; Mg²⁺ is known to be neuroprotective, Patel et al. 2024), DOLK (free Zn²⁺ dependent), DHRSX (NAD or NADP dependent), or SRD5A3 (NADPH dependent). It is unusual to have both NAD (catabolic) and NADPH (anabolic) pyridine nucleotides involved in the same biosynthetic pathway (Wilson et al. 2024; Fessel and Oldham 2018). This requirement is thought to facilitate essential oxidation of polyprenol by physiological concentrations of NAD (predominantly in the oxidized form) followed by reduction of polyprenal and dolichal by NADPH (predominantly in the reduced form) to dolichol (Wilson et al. 2024). Other metal ions only partially support brain DOLK activity relative to free zinc ions and at non-physiological concentrations (Sakakihara and Volpe 1985). Other circumstantial evidence implicating dolichol pathway dysfunction in AD is the beneficial effect nutritional supplements have on Alzheimer’s disease that raise levels of NAD/NADPH or CTP (Wuerch et al. 2023; Bonvicini et al. 2023). Citicoline would not only raise choline and acetylcholine levels to improve neurotransmission but would also raise CTP levels required for DOLK (Shridas and Waechter 2006). Although lower NADPH levels would lead to diminished reduced glutathione and enhanced oxidative stress, pyridine nucleotides are also required for conversion of polyprenol to dolichol by DHRSX (NAD/NADH) and SRD5A3 (NADPH) (Wilson et al. 2024). Although the brains of individuals with Alzheimer’s disease have higher levels of glucose 6-phosphate dehydrogenase (G6PD), this may be a compensatory response to lower total levels of pyridine nucleotides to increase NADPH and GSH production (Russell et al. 1999). Overexpression of G6PD in a mouse model of Alzheimer’s disease increases NADPH, which is needed for both dolichol and GSH biosynthesis, and rescues loss of cognition (Correas et al. 2024). Also, the higher risk women have of niacin deficiency due to estrogen-impaired biosynthesis could explain the higher frequency of AD in women (Bender and Totoe 1984; Lopez-Lee et al. 2024). Women are reported to have lower levels (9.3% less), on average, of whole blood NAD (31.3 micromolar) compared to the levels in men (34.5 micromolar) (Yang et al. 2022). African Americans are 1.5–2 times more likely to develop AD than other ethnic groups, perhaps as a consequence of higher stress levels in this group (Lennon et al. 2022). There is also a much higher risk for AD and infection burden in homeless populations (Babulal et al. 2022; Beydoun et al. 2024), where stress and nutritional deficiencies are likely to play a major role. Stress-induced aging is a risk factor for all populations (Polsky et al. 2022), with aging-associated risk for loss of the sense of smell (Dong et al. 2017) and development of AD (Liu 2022).

Based on a lymphocyte proliferation assay, the general incidence of deficiencies in zinc (33%), magnesium (18%), and niacinamide (13%) is prevalent and consistent with their identification as three of the five best-documented, stress-induced nutritional defects (Bucci 1994; Lopresti 2020). Up to 25% of Americans are concurrently deficient in five or more essential nutrients, as judged by a lymphocyte proliferation assay (Bucci 1994). The fact that there are multiple biosynthetic steps tied to stress means their combined effect should produce an overall greater risk than any one alone. Depression of each step by 50% for the five steps of N-acetyl-d-glucosaminyl-diphosphodolichol biosynthesis (niacin, zinc, and magnesium dependent) could reduce the overall rate of N-glycosylation by up to 97%. Clearly, small depressions in these essential stress-affected nutrients can be amplified to have devastating consequences.

A preponderance of available literature indicates that stress-related depression of cofactors necessary for the dolichol pathway (pyridine nucleotides, zinc, and magnesium) is a major risk factor for the development and progression of Alzheimer’s disease.