Plasma Leptin Is Associated With Amyloid CSF Biomarkers and Alzheimer’s Disease Diagnosis in Cognitively Impaired Patients

Abstract

Background Metabolic dysfunction and dysregulation of leptin signaling have been linked to Alzheimer’s Disease (AD)’s pathophysiology. The objectives of this study were to examine the associations between plasma leptin, cerebrospinal fluid (CSF) beta-amyloid (Aβ) and tau biomarkers (AT(N) status) and with the stage of cognitive impairment. Methods Cross-sectional analysis of data from cognitively impaired patients from a tertiary memory clinic. Plasma leptin levels were compared according to the stage of cognitive impairment and biomarker profiles, using the AT(N) classification. Linear regression models were performed to examine the relationship between leptin and CSF biomarkers. Results were adjusted for age, gender, body mass index (BMI) and APOE ε4. In a subgroup of A+T+ individuals, we compared the 2-year evolution of Mini Mental Status scores, according to the participants’ tertile of plasma leptin levels. Results We included 1036 participants (age 68.7±9.1, females=54.1%). A+T+ and A+T- patients had significantly lower plasma leptin levels than amyloid negative subjects (p<0.01). CSF Aβ concentration was significantly associated with lower plasma leptin β= -4.3 (1.5), p=0.005 unadjusted; and β= -3.4 (1.6), p=0.03 after adjustment for age, female gender, BMI and APOE ε4. Patients with major neurocognitive disorder due to AD had a difference of leptin of -7.3 ng/ml 95%CI[-11.8;-2.8],p=0.0002, compared to individuals with other causes of cognitive impairment. Leptin was not associated with the slope of cognitive decline. Conclusion Plasma leptin levels were associated with CSF Aβ and with the diagnosis of AD confirmed by CSF biomarkers, suggesting a molecular interplay between leptin metabolism and brain amyloid deposition.

Associations of Serum Insulin and Related Measures With Neuropathology and Cognition in Older Persons With and Without Diabetes

“…19 In yet another recent study of >1,000 older persons, leptin was associated with CSF Aβ (inversely), as well as with AD confirmed by CSF biomarkers, but there was no relationship to slope of cognitive decline on the Mini-Mental State Examination scores. 56 Although we did not examine for decline in cognition, we found that higher leptin and insulin levels, and lower adiponectin and RAGE levels were associated with lower levels of global cognition. Further, in additional analyses, we found relationships of insulin resistance (insulin and HOMA-IR levels) and adipokines with lower function in some (memory), but not other, cognitive domains.…”

“…In another recent, but much smaller, study, leptin was associated with lower MRI hippocampal volumes in those with obesity, and both leptin and the leptin‐to‐adiponectin ratio were inversely associated with cognition 19 . In yet another recent study of >1,000 older persons, leptin was associated with CSF Aβ (inversely), as well as with AD confirmed by CSF biomarkers, but there was no relationship to slope of cognitive decline on the Mini‐Mental State Examination scores 56 . Although we did not examine for decline in cognition, we found that higher leptin and insulin levels, and lower adiponectin and RAGE levels were associated with lower levels of global cognition.…”

Assessing adipokines as potential biomarkers of dementia, Alzheimer's disease, and mild cognitive impairment: A systematic review and meta‐analysis

“…We included nine prospective studies published between 2009 and 2022. All of them measured blood leptin (in serum or plasma) 57,59,85–91 . Overall, they included 5758 participants, 4033 of whom were women.…”

“…All of them measured blood leptin (in serum or plasma). 57,59,[85][86][87][88][89][90][91] Overall, they included 5758 participants, 4033 of whom were women. Their mean follow-up period was between 14.5 and 384 months, with five of them having a follow-up period inferior to 40 months.…”

Plasma Leptin and Alzheimer Protein Pathologies Among Older Adults

“…Nevertheless, the mechanistic pathway linking plasma leptin and AD-related cognitive decline is not fully understood. A recent study demonstrated a significant association between lower plasma leptin levels and decreased cerebrospinal fluid (CSF) Aβ levels . However, the study had a cross-sectional design, and there is limited information available regarding the longitudinal association between plasma leptin levels and prospective changes of brain Aβ deposition.…”