Alzheimer, triggered, activation, mechanisms, Alzheimer, fibrillary
It's known since 2017 that some people with Type 2 diabetes have a higher risk of Alzheimer's disease.
A variant of the so-called Alzheimer’s gene, APOE4, seems to interfere with brain cells' ability to use insulin, which may eventually cause the cells to starve and die. Unofficially, it's called Type 3 diabetes. What it refers to is that their brain's insulin utilization or signaling is not functioning. Their risk of developing Alzheimer’s disease is about 10 to 15 times higher.
This new article by Gemma Salvadó and colleagues adds more information on this topic. Glial activation is one of the earliest mechanisms to be altered in Alzheimer's disease. Glial fibrillary acidic protein relates to reactive astrogliosis and can be measured in both cerebrospinal fluid and blood.
Plasma GFAP has been suggested to become altered earlier in Alzheimer's disease than its cerebrospinal fluid counterpart.
Although astrocytes consume approximately half of the glucose-derived energy in the brain, the relationship between reactive astrogliosis and cerebral glucose metabolism is poorly understood. Fluorodeoxyglucose (FDG) is a glucose analog labeled with a positron emitter isotope (18F) that allows measurement of regional cerebral glucose consumption using positron emission tomography (PET).
The Spanish authors aimed to investigate the association between fluorodeoxyglucose (FDG) uptake and reactive astrogliosis, by means of GFAP quantified in both plasma and cerebrospinal fluid for the same participants. GFAP is an astrocytic intermediate filament protein, mainly expressed in the brain.
The ALFA cohort characterized preclinical AD in 2743 cognitively unimpaired individuals, aged between 45 and 75 years old, and enriched for family history of sporadic AD. From this parent cohort, 419 ALFA + participants were selected to be preferentially APOE-ε4 carriers and/or to be adult children of AD patients. These participants underwent a more comprehensive evaluation including a lumbar puncture and an Aβ and [18F]FDG PET.
For this study, the authors included 314 cognitively unimpaired participants from the ALFA + cohort, 112 of whom were amyloid-β positive. Associations between GFAP markers and [18F]FDG uptake were studied.
The authors also investigated whether these associations were modified by Aβ and tau status.
Plasma GFAP was positively associated with glucose consumption in the whole brain, while cerebrospinal fluid GFAP associations with [18F]FDG uptake were only observed in specific smaller areas like temporal pole and superior temporal lobe. These associations persisted when accounting for biomarkers of Aβ pathology but became negative in Aβ-positive and tau-positive participants in similar areas of Alzheimer's disease-related hypometabolism.
Higher astrocytic reactivity, probably in response to early Alzheimer's disease pathological changes, is related to higher glucose consumption. With the onset of tau pathology, the observed uncoupling between astrocytic biomarkers and glucose consumption might be indicative of a failure to sustain the higher energetic demands required by reactive astrocytes.