Purpose of the Study: The aim of the study was to relate the declining cognition, stress scores, serum cortisol, and plasma BDNF as psychophysiological markers for the effect of stress in the progression of neurodegeneration. Methodology: A cross-sectional examination was conducted in both the rural and urban areas of Karachi, Pakistan. Classification of stress was done on the basis of Sadaf stress scale (SSS), the neurodegenerative diagnosis was on the basis of ICD-11, mental health status with DSM-V criteria and cognitive decline through cognitive impairment test, followed by a collection of blood samples for estimation of serum cortisol and physiological measures. Results: Our study results shows the relationship between serum cortisol level, BDNF, cognitive decline, BMI and 7 different types of stresses reported by study population that indicated significant (correlation was significant at the 0.01 level, 2-tailed) positive correlations in case of BMI with physical stress and nutritional stress; serum cortisol with nutritional, emotional and psychosocial stress; BDNF with nutritional and emotional stress and cognitive decline with traumatic, nutritional, mental and chemical stress. Conclusion: Our findings further support the role of stress in the onset and outcome of neurodegeneration, as already suggested by previous studies. In turn, stress-related biological pathways, together with decreased BDNF expression, may account for the cognitive impairment. We assumed that the worse cognitive functioning was seen in those adults with the severity of stress in comparison to those with normal or milder levels that would be associated with more severe white matter hyperintensities and hippocampal volume reductions at baseline.