Welcome to part 4 of ODX's "Biological Age Biomarkers" Series. In the fourth post, you'll learn about albumin's relationship with cognitive decline, why it is a marker of increased aging, and how low albumin is associated with poor quality of life and reduced longevity, especially in the stressed state.
Albumin, a vital protein produced in the liver, accounts for approximately 75% of serum antioxidant capacity and free radical scavenging. Albumin synthesis may be reduced, or its degradation may increase during illness, trauma, or inflammation. Although albumin has anti-inflammatory functions, persistent inflammation can cause albumin degradation and leakage into surrounding tissues, leading to hypoalbuminemia even with increased hepatic synthesis. Low serum albumin reflects physiological stress and is a predictor of mortality, especially when a sign of “inflammaging,” the subclinical process usually associated with advancing age. Low albumin is also associated with muscle mass loss, malnutrition, cirrhosis, kidney disease, and increased morbidity and mortality. Innate and adaptive immune responses depend on albumin and become impaired with an albumin deficit, increasing the risk of acute viral, bacterial, and fungal infection and infectious disease in general. Hypoalbuminemia is an independent risk factor for C. difficile-related mortality (Wiedermann 2021).
Damaged or oxidized albumin can be recycled in the liver, which is upregulated during inflammation. Albumin also serves as a reservoir of amino acids, a role that is escalated during stress or illness, contributing to a net deficit of functional albumin (Soeters 2019).
Albumin plays an essential role as a component of the endothelial glycocalyx, a protective layer within the blood vessel lining. Albumin reduces hydraulic conductivity across the vascular barrier and protects against glycocalyx degradation, preserving vascular integrity and normal capillary permeability. Disruption of this function and endothelial dysfunction are associated with oxidative stress, inflammation, aging, and chronic disease (Aldecoa 2020).
Cognitive decline and mild cognitive impairment (MCI) can be precursors to dementia, a potentially debilitating disorder. A decrease in albumin can contribute to cognitive impairment by interfering with the central nervous system's blood supply and decreasing the total antioxidant capacity of the blood, thereby increasing oxidative stress. Relatively low serum albumin below 4.05 g/dL was found to be an independent risk factor for MCI in adults over 60 years of age in a retrospective review of 1,800 subjects. Risk was further enhanced in those with two or more comorbidities, including hypertension, dyslipidemia, diabetes, CVD, or cerebrovascular disease. Elevated CRP, low total bilirubin, or low uric acid also enhanced the association between below-optimal albumin and MCI. The use of calcium blockers, ARBs, ACEIs, oral antidiabetic drugs, statins, non-steroidal anti-inflammatory drugs (NSAIDs), β-blockers, and nitrates was more common in those with MCI (Wang 2018).
A data review of 1,752 participants at least 65 years of age from a nationally representative population-based study found that a decreasing serum albumin level was significantly associated with cognitive impairment on a dose-response basis. Those with the lowest albumin (2.2-3.8 g/dL) were up to six times more likely to be cognitively impaired than those with an albumin of 4.4-5.3 g/dL (Llewellyn 2010). The association between albumin and impaired cognitive function may be enhanced in Apolipoprotein E (APOE) gene carriers. APOE is a significant genetic risk factor for Alzheimer’s (Min 2022).
Alzheimer's disease is characterized by cerebral intraneuronal neurofibrillary tangles and extracellular deposits of beta-amyloid protein, a process that can begin 10-15 years before the onset of related cognitive symptomatology. Albumin sequesters beta-amyloid plaque and binds 90-95% of beta-amyloid in the blood. A reduction in albumin can impair the brain’s ability to excrete beta-amyloid into circulation. Serum albumin was inversely associated with cerebral beta-amyloid deposition and beta-amyloid positivity in a study of 396 adults without dementia. An albumin below 4.4 g/dL was significantly associated with beta-amyloid positivity and retention in the brain compared to albumin above 4.5 g/dL (Kim 2020).
Lower albumin was observed in subjects with mild cognitive and Alzheimer's in the Oxford OPTIMA study. Median albumin was 4.3, 4.4, and 4.5 g/dL in Alzheimer's, MCI, and controls, respectively (Kellett 2011).
Hypoalbuminemia is associated with poor quality of life and reduced longevity, especially in the stressed state, where increased degradation can reduce albumin half-life. Low albumin can also be associated with smoking, alcoholism, obesity, and muscle mass loss, which are also associated with accelerated aging (Soeters 2019).
Hypoalbuminemia is independently associated with persistent organ failure and mortality in cases of acute pancreatitis. It is also a predictor of mortality in community-acquired pneumonia, coronary heart disease, sepsis, and end-stage renal failure with hemodialysis (Hong 2017).
Albumin below 3.6 g/dL is associated with higher mortality rates among elderly subjects. When combined with low BMI, hypoalbuminemia can predict poor prognosis, with the highest mortality observed in those with an albumin below 2.8 g/dL and a BMI below 18.5 (Lai 2020).
Aldecoa, Cesar et al. “Role of albumin in the preservation of endothelial glycocalyx integrity and the microcirculation: a review.” Annals of intensive care vol. 10,1 85. 22 Jun. 2020, doi:10.1186/s13613-020-00697-1
Hong, Wandong et al. “Serum Albumin Is Independently Associated with Persistent Organ Failure in Acute Pancreatitis.” Canadian journal of gastroenterology & hepatology vol. 2017 (2017): 5297143. doi:10.1155/2017/5297143
Kellett, Katherine Ab et al. “Plasma alkaline phosphatase is elevated in Alzheimer's disease and inversely correlates with cognitive function.” International journal of molecular epidemiology and genetics vol. 2,2 (2011): 114-21.
Kim, Jee Wook et al. “Serum albumin and beta-amyloid deposition in the human brain.” Neurology vol. 95,7 (2020): e815-e826. doi:10.1212/WNL.0000000000010005
Lai, Kuan-Yu et al. “Body mass index and albumin levels are prognostic factors for long-term survival in elders with limited performance status.” Aging vol. 12,2 (2020): 1104-1113. doi:10.18632/aging.102642
Llewellyn, D J et al. “Serum albumin concentration and cognitive impairment.” Current Alzheimer research vol. 7,1 (2010): 91-6. doi:10.2174/156720510790274392
Min, Jin-Young et al. “Chronic Status of Serum Albumin and Cognitive Function: A Retrospective Cohort Study.” Journal of clinical medicine vol. 11,3 822. 3 Feb. 2022, doi:10.3390/jcm11030822
Soeters, Peter B et al. “Hypoalbuminemia: Pathogenesis and Clinical Significance.” JPEN. Journal of parenteral and enteral nutrition vol. 43,2 (2019): 181-193. doi:10.1002/jpen.1451
Wang, Lu et al. “Inverse Relationship between Baseline Serum Albumin Levels and Risk of Mild Cognitive Impairment in Elderly: A Seven-Year Retrospective Cohort Study.” The Tohoku journal of experimental medicine vol. 246,1 (2018): 51-57. doi:10.1620/tjem.246.51
Wiedermann, Christian J. “Hypoalbuminemia as Surrogate and Culprit of Infections.” International journal of molecular sciences vol. 22,9 4496. 26 Apr. 2021, doi:10.3390/ijms22094496