Sex differences in predictors of cognitive and functional outcomes in patients with Alzheimer’s disease.

• Background: About two-thirds of patients with Alzheimer’s disease (AD) are women, mostly because of their longer life-span and the higher prevalence of AD among older persons. A more-pronounced association between AD pathology and dementia (faster brain atrophy) and more-rapid cognitive decline have been reported in women. The AD prognosis might be affected by, e.g., size of cerebral hemispheres, role of sex hormones, cerebro- and cardiovascular comorbidities, psychiatric symptoms, and concomitant medications, which are all influenced by sex differences. A better cognitive response to cholinesterase inhibitors (ChEI) was observed in men compared with women. Thus, the predictors (genetic, sociodemographic, and clinical factors) of longitudinal cognitive and functional outcomes including aspects of ChEI treatment (e.g., drug agent, dose) may differ between sexes. In a study that included both sexes, our group previously found that male sex, older age, absence of the apolipoprotein E (APOE) e4 allele, use of nonsteroidal anti-inflammatory drugs (NSAIDs)/acetylsalicylic acids, and receiving a higher ChEI dose (regardless of type of drug), were independent predictors for a slower cognitive deterioration. Reports of sex-specific characteristics and effects of ChEIs that might affect the long-term course of AD are scarce. Objectives: This study aimed to identify sex-specific factors, including aspects of ChEI therapy, that may predict cognitive and functional progression rates in AD. Methods: The Swedish Alzheimer Treatment Study (SATS) is a prospective, open, nonrandomized multicenter study for the assessment of longitudinal effectiveness of ChEI therapy in a routine clinical setting. Among the 1,258 outpatients clinically diagnosed with probable or possible AD, 1,021 (367 men and 654 women) had mild-to-moderate AD (Mini-Mental State Examination [MMSE] score, 10–26) at the start of ChEI treatment (baseline) and were included in the current study. The participants were evaluated using cognitive tests (MMSE and Alzheimer’s Disease Assessment Scale–cognitive subscale [ADAS-cog]) and functional capacity scales (Instrumental Activities of Daily Living scale [IADL] and Physical Self-Maintenance Scale [PSMS]) at baseline and every 6 months for 3 years.Mixed, linear, and nonlinear fixed and random coefficient regression models were performed. The dependent variables were the scores (ADAS-cog, IADL, or PSMS) assigned at the second and subsequent visits for each individual. The following potential predictors were investigated: APOE genotype, solitary living, duration of AD, age at baseline, years of education, type of ChEI, dose of ChEI, specific concomitant medications (antihypertensive/cardiac therapy, antidiabetic drugs, asthma medication, thyroid therapy, lipid-lowering agents, estrogens, NSAIDs/acetylsalicylic acid, antidepressants, antipsychotics, and anxiolytics/sedatives/hypnotics), cognition, IADL, and basic ADL at baseline. Results: Better cognitive or IADL abilities at the initiation of ChEI treatment implied a slower cognitive decline over time in both sexes. An interaction effect showed that the difference in cognitive status at baseline between ages was more pronounced among older men (but not women) who were more cognitively impaired. In women, the absence of the APOE e4 allele or receiving NSAIDs/acetylsalicylic acid therapy were protective factors for a lower rate of cognitive progression. Regarding IADL, patients of both sexes with better cognitive performance at baseline exhibited a more favorable long-term outcome in IADL capacity. The use of antidepressants in men and solitary living in women predicted worsening IADL. In basic ADL, lower cognitive ability at baseline predicted a faster deterioration among both sexes. Women living alone demonstrated poorer prognosis in basic ADL. For women, there was a significant interaction effect in all three scales between time in months and years of education, i.e., a higher level of education implied increased cognitive or functional impairment over time. Men and women who received a higher mean dose of ChEI during the study showed a slower decline in cognitive ability, while men who received higher ChEI doses also exhibited lower progression rates in both IADL and basic ADL. Conclusion: The predictors of cognitive and functional deterioration differed between the sexes. Use of NSAIDs/acetylsalicylic acid was a protective factor for better cognitive outcome in women, which suggested that women might have greater cerebral inflammation and additional advantages of treatment with these drugs. Antidepressants in men and solitary living among women were risk factors for more-rapid worsening in IADL and basic ADL (only women living alone), which underlined the risk of apathy and social isolation among those individuals. Cognitive reserve capacity could have a larger impact on AD prognosis in women because a higher level of education implied increased cognitive or functional impairment over time. In women, the presence of the APOE e4 allele led to lower cognitive performance. These risk factors indicate more hereditary and advanced forms of AD in women. A higher mean dose of ChEI (irrespective of drug agent) was associated with slower cognitive decline in both sexes and lower functional progression rate among men, which might support the better ChEI response among men described previously. The findings stress the importance for clinicians to optimize the ChEI dose in AD regardless of sex to improve therapeutic effectiveness.

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MEDICIN OCH HÄLSOVETENSKAP  -- Klinisk medicin -- Neurologi (hsv//swe)

MEDICAL AND HEALTH SCIENCES  -- Clinical Medicine -- Neurology (hsv//eng)

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