Age, female sex, and APOE epsilon 4 (APOE4) genotype are the three greatest risk factors for late-onset Alzheimer’s disease (AD). The convergence of these risks creates a hypometabolic AD-risk profile unique to women, which may help explain their higher lifetime risk of AD. Less is known about APOE4 effects in men, although APOE4 positive men also experience an increased AD risk. This study uses 31Phosphorus Magnetic Resonance Spectroscopy (31P-MRS) to examine effects of sex and APOE4 status on brain high-energy phosphates [adenosine triphosphate (ATP), phosphocreatine (PCr), inorganic phosphate (Pi)] and membrane phospholipids [phosphomonoesters (PME), phosphodiesters (PDE)] in 209 cognitively normal individuals at risk for AD, ages 40–65, 80% female, 46% APOE4 carriers (APOE4+). Women exhibited lower PCr/ATP and PCr/Pi levels than men in AD-vulnerable regions, including frontal, posterior cingulate, lateral and medial temporal cortex (multi-variable adjusted p≤0.037). The APOE4+ group exhibited lower PCr/ATP and PCr/Pi in frontal regions as compared to non-carriers (APOE4-) (multi-variable adjusted p≤0.005). Sex by APOE4 status interactions were observed in frontal regions (multi-variable adjusted p≤0.046), where both female groups and APOE4+ men exhibited lower PCr/ATP and PCr/Pi than APOE4- men. Among men, APOE4 homozygotes exhibited lower frontal PCr/ATP than heterozygotes and non-carriers. There were no significant effects of sex or APOE4 status on Pi/ATP and PME/PDE measures. Among midlife individuals at risk for AD, women exhibit lower PCr/ATP (e.g. higher ATP utilization) and lower PCr/Pi (e.g. higher energy demand) than age-controlled men, independent of APOE4 status. However, a double dose of APOE4 allele shifted men’s brains to a similar metabolic range as women’s brains. Examination of brain metabolic heterogeneity can support identification of AD-specific pathways within at-risk subgroups, further advancing both preventive and precision medicine for AD.

Over 55 million people globally are living with dementia and, by 2050, this number is projected to increase to 131 million. This poses immeasurable challenges for patients and their families and a significant threat to domestic and global economies. Given this public health crisis and disappointing results from disease-modifying trials, there has been a recent shift in focus toward primary and secondary prevention strategies. Approximately 40% of Alzheimer's disease (AD) cases, which is the most common form of dementia, may be prevented or at least delayed. Success of risk reduction studies through addressing modifiable risk factors, in addition to the failure of most drug trials, lends support for personalized multidomain interventions rather than a “one-size-fits-all” approach. Evolving evidence supports early intervention in at-risk patients using individualized interventions directed at modifiable risk factors. Comprehensive risk stratification can be informed by emerging principals of precision medicine, and include expanded clinical and family history, anthropometric measurements, blood biomarkers, neurocognitive evaluation, and genetic information. Risk stratification is key in differentiating subtypes of dementia and identifies targetable areas for intervention. This article reviews a clinical approach toward dementia risk stratification and evidence-based prevention strategies, with a primary focus on AD.

Feline immunodeficiency virus (FIV) infection in experimentally infected domestic cats produces characteristic clinical manifestations including hematological changes, neurological disease, neoplasia (most notably lymphoma) and lymphopenia-mediated immunodeficiency predisposing cats to a range of secondary infections. Conflicting reports exist, however, with regard to disease associations and survival time in naturally FIV-infected cats. The purpose of this retrospective case–control study was to investigate the effect of natural FIV infection on hematological, blood biochemical and urinalysis parameters and survival time in three cohorts of pet cats in Australia. Cohorts 1 and 2 were recruited from a large veterinary hospital in Melbourne, Victoria (n = 525 and 282), while a third cohort consisted of cats recruited from around Australia as part of a FIV field vaccine efficacy trial (n = 425). FIV-infected cats in cohorts 1, 2 and 3 were found to have 15/37 (41%), 13/39 (33%) and 2/13 (15%) clinicopathological parameters significantly different to FIV-uninfected cats, respectively. Two changes in FIV-infected cats in cohort 1, hypochromia (low hemoglobin) and hyperglobulinemia, were outside the supplied reference intervals and should serve as diagnostic triggers for FIV testing. Kaplan–Meier survival analysis of cats in cohorts 1 and 2 combined did not find any difference between FIV-infected and FIV-uninfected cats, however a confounding factor was a large euthanasia rate within the first 12 months in both groups. Three significant (p < 0.05) spatial clusters of FIV infection were identified in Melbourne. A possible relationship between FIV infection status and socioeconomic disadvantage was discovered, based on three government indices of socioeconomic status (p < 0.001). Until longitudinal field studies are performed in Australia to further investigate the long-term effects of natural FIV infection, Australian veterinarians should consider FIV to be an important infection of pet cats, and recommend measures to prevent FIV infection.

17β-estradiol,the most biologically active estrogen, exerts wide-ranging effects in brain through its action on estrogen receptors (ERs), influencing higher-order cognitive function and neurobiological aging. However, our knowledge of ER expression and regulation by neuroendocrine aging in the living human brain is limited. This in vivo multi-modality neuroimaging study of healthy midlife women reveals progressively higher ER density over the menopause transition in estrogen-regulated networks. Effects were independent of age and plasma estradiol levels, and were highly consistent, correctly classifying all women as being post-menopausal or not. Higher ER density was generally associated with lower gray matter volume and blood flow, and with higher mitochondria ATP production, possibly reflecting compensatory mechanisms. Additionally, ER density predicted changes in thermoregulation, mood, cognition, and libido. Our data provide evidence that ER density impacts brainstructure, perfusion and energy production during female endocrine aging, with clinical implications for women’s health.