Metabolic dysregulation in Alzheimer’s is worse in female brains

A biochemical analysis of brains of deceased individuals with Alzheimer’s disease found markers of impaired insulin signaling and impaired mitochondrial function. Analyses also indicated altered neuroinflammation in these brains. The paper was published in Alzheimer’s & Dementia.

Alzheimer’s disease is a progressive neurodegenerative disorder that primarily affects memory, thinking, and behavior. It is the most common cause of dementia. Alzheimer’s disease typically begins with subtle problems in forming new memories. Over time, the disease disrupts language, reasoning, orientation, and the ability to carry out everyday tasks.

At the biological level, Alzheimer’s is characterized by the accumulation of amyloid-β plaques (abnormal clusters of protein fragments) outside neurons and tau protein tangles (twisted fibers of the tau protein) inside them.

These accumulations make neurons gradually lose their ability to communicate and eventually die, causing widespread brain atrophy. Early symptoms may appear years before diagnosis. There is currently no cure, though some medications and lifestyle interventions might be able to modestly slow symptom progression.

Study author Alex J. T. Yang and his colleagues note that metabolic dysregulation might contribute to the development of Alzheimer’s disease. They conducted a study in which they explored the differences in various metabolic and biochemical indicators between post mortem (after death) brains of individuals who suffered from Alzheimer’s disease and those who did not suffer from dementia. They focused on metabolic signaling, synaptic protein content, morphology of microglia cells in the brain, and markers of inflammation.

These researchers obtained samples from Brodmann area 10 of the brains of 40 individuals from the Douglas Bell Canada Brain Bank (Montreal, Quebec, Canada). Of these individuals, 20 were diagnosed with Alzheimer’s disease, and 20 were not. The number of males and females was equal in both groups (10 men – 10 women). At the time of death, the average age of these individuals ranged between 79 and 82 years, depending on the group.

Study authors used mitochondrial respirometry, Western blotting, cytokine quantification via microfluidic immunoassays, and immunohistochemistry/immunofluorescence to examine metabolic, signaling, and inflammatory markers in the studied brain tissues.

Mitochondrial respirometry is a technique that measures how effectively mitochondria (a type of cell organelle) consume oxygen to produce cellular energy (ATP). Western blotting is a method that separates proteins by size and uses antibodies to detect and quantify specific proteins in a sample.

Cytokine quantification via microfluidic immunoassays is a technique that uses antibodies to measure concentrations of inflammatory signaling molecules. Immunohistochemistry/immunofluorescence is a tissue-staining method that uses antibodies linked to enzymes or fluorescent dyes to visualize the location and amount of specific proteins in cells or tissue sections.

The results showed that brains of individuals with Alzheimer’s disease had markers of impaired insulin signaling and impaired mitochondrial function. They also had greater neuroinflammation. Differences in metabolic signaling markers were higher in female than in male brains, and this dysregulation was worse in women with Alzheimer’s disease.

“This study found that AD [Alzheimer’s disease] brains have distinct metabolic and neuroinflammatory environments compared to controls wherein AD brains present with worse metabolic dysregulation and greater neuroinflammation. Importantly, we also provide evidence that female AD brains are more metabolically dysregulated than males but that female brains may also possess a greater compensatory response to AD progression that likely occurs through a separate mechanism from males,” the study authors concluded.

The study sheds light on biochemical specificities of brains of individuals with Alzheimer’s disease. However, the study was conducted on post mortem human brains. Protein expression in these brains may differ from live ones due to factors such as age, medical history, and the time between death and tissue preservation or analysis.

The paper, “Differences in inflammatory markers, mitochondrial function, and synaptic proteins in male and female Alzheimer’s disease post mortem brains,” was authored by Alex J. T. Yang, Ahmad Mohammad, Robert W. E. Crozier, Lucas Maddalena, Evangelia Tsiani, Adam J. MacNeil, Gaynor E. Spencer, Aleksandar Necakov, Paula Duarte-Guterman, Jeffery Stuart, and Rebecca E. K. MacPherson.