Research indicates that after advanced age, the major risk factor for late-onset Alzheimer's disease (AD) is female sex. Out of every three AD patients, two are females with postmenopausal women contributing to over 60% of all those affected. Sex-and gender-related differences in AD have been widely researched and several emerging lines of evidence point to different vulnerabilities that contribute to dementia risk. Among those being considered, it is becoming widely accepted that gonadal steroids contribute to the gender disparity in AD, as evidenced by the "estrogen hypothesis." This posits that sex hormones, 17β-estradiol in particular, exert a neuroprotective effect by shielding females' brains from disease development. This theory is further supported by recent findings that the onset of menopause is associated with the emergence of AD-related brain changes in women in contrast to men of the same age. In this review, we discuss genetic, medical, societal, and lifestyle risk factors known to increase AD risk differently between the genders, with a focus on the role of hormonal changes, particularly declines in 17β-estradiol during the menopause transition (MT) as key underlying mechanisms.

Summary INTRODUCTION: Multi-domain intervention for Alzheimer’s disease (AD) risk reduction is an emerging therapeutic paradigm. METHODS: Patients were prescribed individually-tailored interventions (education/pharmacologic/non-pharmacologic) and rated on compliance. Normal cognition/subjective cognitive decline/preclinical-AD were classified as Prevention. Mild cognitive impairment due to AD/mild-AD were classified as Early Treatment. Change from baseline to 18-months on the modified-Alzheimer’s Prevention Cognitive Composite (primary outcome) was compared against matched historical control cohorts. Cognitive aging composite (CogAging), AD/cardiovascular risk-scales, and serum biomarkers were secondary outcomes. RESULTS: 174 were assigned interventions (age 25–86). Higher-compliance Prevention improved more than both historical cohorts (P=.0012,P<.0001). Lower-compliance Prevention also improved more than both historical cohorts (P=.0088,P<.0055). Higher-compliance Early Treatment improved more than lower-compliance (P=.0007). Higher-compliance Early Treatment improved more than historical cohorts (P<.0001,P=.0428). Lower-compliance Early Treatment did not differ (P=.9820,P=.1115). Similar effects occurred for CogAging. AD/cardiovascular risk-scales and serum biomarkers improved. DISCUSSION: Individualized multi-domain interventions may improve cognition and reduce AD/cardiovascular risk scores in patients at-risk for AD-dementia.

The terms “prevention” and “risk reduction” are often used interchangeably in medicine. There is considerable debate, however, over the use of these terms in describing interventions that aim to preserve cognitive health and/or delay disease progression of Alzheimer's disease (AD) for patients seeking clinical care. Furthermore, it is important to distinguish between Alzheimer's disease prevention and Alzheimer's dementia prevention when using these terms. While prior studies have codified research-based criteria for the progressive stages of AD, there are no clear clinical consensus criteria to guide the use of these terms for physicians in practice. A clear understanding of the implications of each term will help guide clinical practice and clinical research. The authors explore the semantics and appropriate use of the terms “prevention” and “risk reduction” as they relate to AD in clinical practice.