Neurophysiological correlates of subjective cognitive decline in perimenopausal and postmenopausal midlife women at risk for Alzheimer's disease

Objective: This study aimed to investigate neurophysiological correlates of subjective cognitive decline (SCD) among midlife women at risk for Alzheimer's disease (AD). Methods: We examined 156 cognitively normal perimenopausal and postmenopausal women aged 40 to 65 years, with an AD family history and/or apolipoprotein E epsilon 4 genotype, who were not on menopause hormone therapy. Participants underwent neuropsychological testing, health and menopausal symptom questionnaires, and brain volumetric magnetic resonance imaging, arterial spin labeling-magnetic resonance (MR) measuring cerebral blood flow, and ³¹phosphorus magnetic resonance spectroscopy (³¹P-MRS) measuring mitochondria high-energy phosphates (adenosine triphosphate [ATP], phosphocreatine [PCr], inorganic phosphate [Pi]). We used multivariable regressions to compare outcomes between participants with and without SCD and to identify the main correlates of SCD status. Results: The SCD group (n = 53) exhibited worse verbal memory and executive function test performance (multivariable adjusted P = 0.029) compared to controls (n = 103). On brain imaging, the SCD group showed higher PCr/ATP in precuneus, posterior cingulate, and parietal regions compared to controls (multivariable adjusted P < 0.05) and no overall differences in Pi/ATP, PCr/Pi, volume, or cerebral blood flow measures. Results were controlled for age, race, smoking status, hysterectomy status, presence of vasomotor symptoms, menopause symptom severity score, past menopause hormone therapy usage, history of depression, AD family history, and apolipoprotein E epsilon 4 status. The factors more strongly associated with SCD status were inferior parietal PCr/ATP, menopause symptom severity, and presence of vasomotor symptoms. Conclusions: Among perimenopausal and postmenopausal midlife women, SCD was associated with altered brain mitochondria bioenergetics in some brain regions similarly affected by AD, warranting further investigation.