This review examines the sex differences in Alzheimer's disease (AD) and their underlying biological mechanisms. AD is characterized by amyloid-β plaques and tau tangles, with a higher prevalence in women compared to men. The review highlights the importance of sex hormones and sex chromosomes in modulating various disease mechanisms, including inflammation, metabolism, and autophagy. Key findings include: 1. **Sex Hormones and Hormonal Changes**: Estrogen, particularly during perimenopause, is protective against AD pathology by reducing Aβ levels and promoting tau degradation. Hormone replacement therapy (HRT) has shown mixed results in clinical trials, with potential benefits in younger patients. 2. **Sex Chromosomes**: The X chromosome plays a significant role in AD, with sex-specific gene expression and inheritance patterns. X-linked genes, such as Kdm6a and Usp11, influence cognitive decline and tau pathology in AD. 3. **Aging and Senescence**: Women age differently from men, with higher mitochondrial gene expression and activity, which may protect against cellular senescence. Telomere length and epigenetic clocks also show sex differences, contributing to age-related diseases. 4. **Maladaptive Innate Immune Responses**: Microglia exhibit sex differences in number, response, and phagocytosis, with female microglia showing greater phagocytic ability. These differences persist in neuroinflammatory phenotypes and AD rodent models. 5. **Metabolism**: Women have higher brain metabolism and antioxidant capabilities, which may provide early resistance to metabolic dysfunction. Estrogen regulates mitochondrial function and oxidative stress, with reduced estrogen levels after menopause increasing metabolic vulnerability. 6. **Autophagy**: Lower basal autophagy in females may contribute to protein aggregation and disease vulnerability. Sex hormones and sex chromosomes influence autophagic regulation, with estrogen suppressing autophagy. 7. **Gut Microbiome**: The gut microbiome exhibits sex differences and affects processes like inflammation and phagocytosis. Dysregulation of the microbiome may contribute to AD risk and progression. The review emphasizes the need for sex-stratified research to better understand and address sex differences in AD, particularly in clinical trials and therapeutic development. Future studies should focus on combining sex-based effects with disease models to uncover innate sex biases in AD-related processes.This review examines the sex differences in Alzheimer's disease (AD) and their underlying biological mechanisms. AD is characterized by amyloid-β plaques and tau tangles, with a higher prevalence in women compared to men. The review highlights the importance of sex hormones and sex chromosomes in modulating various disease mechanisms, including inflammation, metabolism, and autophagy. Key findings include: 1. **Sex Hormones and Hormonal Changes**: Estrogen, particularly during perimenopause, is protective against AD pathology by reducing Aβ levels and promoting tau degradation. Hormone replacement therapy (HRT) has shown mixed results in clinical trials, with potential benefits in younger patients. 2. **Sex Chromosomes**: The X chromosome plays a significant role in AD, with sex-specific gene expression and inheritance patterns. X-linked genes, such as Kdm6a and Usp11, influence cognitive decline and tau pathology in AD. 3. **Aging and Senescence**: Women age differently from men, with higher mitochondrial gene expression and activity, which may protect against cellular senescence. Telomere length and epigenetic clocks also show sex differences, contributing to age-related diseases. 4. **Maladaptive Innate Immune Responses**: Microglia exhibit sex differences in number, response, and phagocytosis, with female microglia showing greater phagocytic ability. These differences persist in neuroinflammatory phenotypes and AD rodent models. 5. **Metabolism**: Women have higher brain metabolism and antioxidant capabilities, which may provide early resistance to metabolic dysfunction. Estrogen regulates mitochondrial function and oxidative stress, with reduced estrogen levels after menopause increasing metabolic vulnerability. 6. **Autophagy**: Lower basal autophagy in females may contribute to protein aggregation and disease vulnerability. Sex hormones and sex chromosomes influence autophagic regulation, with estrogen suppressing autophagy. 7. **Gut Microbiome**: The gut microbiome exhibits sex differences and affects processes like inflammation and phagocytosis. Dysregulation of the microbiome may contribute to AD risk and progression. The review emphasizes the need for sex-stratified research to better understand and address sex differences in AD, particularly in clinical trials and therapeutic development. Future studies should focus on combining sex-based effects with disease models to uncover innate sex biases in AD-related processes.