Two Plasma Proteins May Serve as Early Biomarkers for Alzheimer Dementia and Help Explain Sex Differences, Study Suggests
Levels of acetyl-L-carnitine and free carnitine correlated significantly with disease severity, particularly in women with moderate and severe Alzheimer dementia.
Declining plasma levels of 2 naturally occurring molecules, acetyl-L-carnitine (LAC) and its derivative free carnitine, may serve as biomarkers for detecting early-stage Alzheimer’s disease (AD), according to a new study published in Molecular Psychiatry on January 7.1
The research showed that declines in both biomarkers track closely with disease severity, particularly in women at moderate to severe stages of the disease. Levels of both proteins were lower in women and men with mild cognitive impairment (MCI) and AD, however significant declines among men were observed only in LAC.1
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Computer testing in the study, which was led by researchers at NYY Langone Health, also found that blood levels of LAC and free carnitine “aligned in direct proportion” among participants to elevated levels of amyloid beta (Aβ) and neurofibrillary tangles (NFTs)—hallmarks of Alzheimer’s pathology and distinct markers of disease progression.1 The research team reported that the accuracy of diagnosing disease severity increased from 80% when using either Aβ and NFTs detected in cerebrospinal fluid (CSF) or the 2 blood molecules alone to 93% when combining the two methods.1
The potential for developing a blood test based on the 2 proteins is provocative given the cost and discomfort of current diagnostic methods that include lumbar puncture.
“Our findings offer the strongest evidence to date that decreased blood levels of acetyl-L-carnitine and free carnitine could act as blood biomarkers for identifying those who have Alzheimer’s disease, and potentially those who are at greater risk of developing early dementia,” study lead investigator Betty Bigio, PhD, said in a NYU Langone press release.2 “The results also might explain the differences by sex in Alzheimer’s disease” given the much higher proportion of women with the disease than men. Bigio is a research assistant professor in the Department of Psychiatry at NYU Grossman School of Medicine.2
Bigio and colleagues set out specifically to evaluate the impact of sex on LAC and free carnitine levels in individuals with MCI and early dementia and to compare the diagnostic accuracy of the 2 biomarkers to current CSF assays.
Study and Findings
In the study, researchers analyzed blood samples from 125 participants across 2 independent study cohorts in Brazil and California. These included 93 individuals diagnosed with varying degrees of cognitive impairment, including AD (n = 41), Lewy body dementia (n = 14) and MCI (n = 38 and 32 cognitively healthy controls matched for age, weight, and education. Bigio and colleagues used findings from the California cohort to confirm those from the Brazilian group, according to the study.1
The research team found that plasma levels of free carnitine among women with MCI and early AD were lower than among the healthy control cohort(32.45 ± 1.43 mol/L vs 39.29 ± 1.79 mol/L; P = .02). Among men, however, they observed no significant difference between those with cognitive impairment and healthy controls.
Their analysis also showed decreased levels of LAC among men and women with MCI (8.4 ± 1.18 mol/L) and AD (7.89 ± 1.13 mol/L) compared with age- and sex-matched healthy controls (9.52 ± 1 mol/L; P = .02), a finding the team said replicates prior findings.1
In another outcome strongly suggestive of differences between sexes, there was a significant correlation between serum concentrations of free carnitine and the severity of cognitive impairment among women in the first cohort, according to scores on the Mini Mental State Exam (P =.007) and the Wechsler Memory Scale (P =.002). The correlation did not hold among men.
The results were reproduced in the second cohort, according to the study findings, where cognitive function was assessed using the Clinical Dementia Rating sum-of-boxes (CDR-SB) score. Investigators reported that, after controlling for education and clinical characteristics, women with lower concentrations of free carnitine had the highest CDR-SB score.1
As noted, among individuals with lower free carnitine levels, Aβ accumulation was greater and NFT levels higher in CSF fluid. After applying computational analyses Bigio et al said that LAC and free carnitine are at least as accurate as the 2 traditional measures as indicators of disease status, but combining the 2 techniques greatly increased diagnostic accuracy.1
Of the 6.2 million people with AD in the US who are age 65 years or older, nearly two-thirds are women. Estimates are that 14-16 million will be diagnosed with the disease by 2050 unless new treatments or interventions to prevent or delay the onset of AD are identified.3
LAC and free carnitine play essential roles in brain function, including energy metabolism and neurotransmitter regulation. LAC facilitates the transport of molecules between mitochondria and the cell nucleus, enabling gene activation critical for glutamate production and neuronal repair. Disruptions in these processes have been linked to hippocampal damage in early Alzheimer’s—as well as mood disorders and depression.2
Given the high correlation between declines in acetyl-L-carnitine and free carnitine and severity of AD, senior study investigator Carla Nasca, PhD, observed, “the molecular pathways involved in their production offer other possible therapeutic targets for getting at the root cause of the disease and potentially intervening before permanent brain damage occurs.”2
