'Alzheimer's Biomarkers Linked With Plasma Leptin Levels'

Key Takeaways

• Plasma leptin levels were linked with Alzheimer's disease PET pathology in cognitively unimpaired older adults in Korea.
• Lower baseline leptin was associated with a greater increase in tau over 2 years, while leptin and beta-amyloid showed a cross-sectional association.
• While mechanistic pathways are unknown, leptin may be protective against Alzheimer's pathology, the researchers suggested.

Plasma leptin levels were linked with Alzheimer's disease PET pathology in cognitively unimpaired older adults, a longitudinal cohort study in Korea showed.

Over 2 years, lower baseline plasma leptin was associated with a greater increase in regional tau (β = −0.06, 95% CI −0.11 to −0.01, P=0.03), reported Dong Young Lee, MD, PhD, of the Seoul National University College of Medicine.

At baseline, leptin and tau were not linked, but leptin and amyloid-beta were. In a cross-sectional analysis, lower leptin levels were tied to greater amyloid pathology (β = −0.04, 95% CI −0.09 to 0.00, P=0.046), the researchers reported in JAMA Network Openopens in a new tab or window.

Epidemiologic studies have suggested that low plasma leptin levels in late life are associated with increased risk of Alzheimer's dementia and cognitive decline. An earlier cross-sectional analysisopens in a new tab or window tied plasma leptin to cerebrospinal fluid amyloid and Alzheimer's diagnoses.

The present study is the first to show links between leptin and both amyloid and tau in humans using longitudinal and cross-sectional approaches, Lee and co-authors noted.

The mechanistic pathway linking leptin and Alzheimer's-related cognitive decline is unknown, but the "findings suggest that plasma leptin may be protective for the development or progression of Alzheimer's disease pathology, including both amyloid-beta and tau deposition," they wrote.

Lee and colleagues assessed 208 cognitively unimpaired people who had baseline amyloid PET scans; of these, 192 completed both baseline and 2-year follow-up amyloid PET scans from 2014 through 2020. Mean baseline age was 66 years, 54.8% were women, and 17.8% were APOE4 carriers.

"We included only cognitively unimpaired individuals to exclude the possibility that the cognitively impaired state itself is associated with plasma leptin (i.e., reverse causality) and to focus on the association of leptin with Alzheimer's disease pathology," the researchers noted. "The cognitively impaired state can cause reduced olfactory function and appetite, inadequate nutrition, and weight loss, all of which can be associated with leptin levels."

Participants came from the Korean Brain Aging Study for Early Diagnosis and Prediction of Alzheimer Disease. At baseline, plasma leptin was measured with an enzyme-linked immunosorbent assay.

A subgroup of 76 participants had an initial 18F-fluorodeoxyglucose AV-1451 tau PET scan; of these, 43 had the same tau PET scan 2 years later. The initial tau PET scan occurred approximately 2.5 years after leptin measurement at baseline.

The researchers found no association between baseline plasma leptin levels and regional tau (β = −0.02, 95% CI −0.05 to 0.02, P=0.41). Neither did they find a longitudinal relationship between plasma leptin and amyloid-beta changes over the 2-year follow-up period (β = 0.006, 95% CI 0.00-0.02, P=0.27).

"Such a null longitudinal result may be due to the relatively short follow-up period," Lee and co-authors suggested. "Given that amyloid-beta accumulation in the brain is a very gradual process, a 2-year follow-up period might be too short to reveal an association of leptin with amyloid-beta change."

The null finding of a relationship with tau at baseline may be due to the cognitively intact state of the study participants, when the level of tau deposition is very low in the neocortex, they added.

The study has several limitations, Lee and co-authors acknowledged. Leptin was measured in plasma, which may not perfectly reflect its cerebral concentration. In addition, only 43 people completed the second tau PET scan.

"Nevertheless, given that we still found a significant association between leptin and changes in tau deposition, a smaller sample size may not necessarily be a critical concern," they wrote.

Disclosures

This study was supported by the Korean Ministry of Science and Information and Communication Technology and the Ministry of Health & Welfare, the Seoul National University Hospital, and the National Institute on Aging.

The authors had no disclosures.

Primary Source

JAMA Network Open

Source Reference: opens in a new tab or windowLee S, et al "Plasma leptin and Alzheimer protein pathologies among older adults" JAMA Netw Open 2024; DOI: 10.1001/jamanetworkopen.2024.9539.

https://www.medpagetoday.com/neurology/alzheimersdisease/109964