Sex differences in Alzheimer disease — the gateway to precision medicine

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Abstract

Alzheimer disease (AD) is characterized by wide heterogeneity in cognitive and behavioural syndromes, risk factors and pathophysiological mechanisms. Addressing this phenotypic variation will be crucial for the development of precise and effective therapeutics in AD. Sex-related differences in neural anatomy and function are starting to emerge, and sex might constitute an important factor for AD patient stratification and personalized treatment. Although the effects of sex on AD epidemiology are currently the subject of intense investigation, the notion of sex-specific clinicopathological AD phenotypes is largely unexplored. In this Review, we critically discuss the evidence for sex-related differences in AD symptomatology, progression, biomarkers, risk factor profiles and treatment. The cumulative evidence reviewed indicates sex-specific patterns of disease manifestation as well as sex differences in the rates of cognitive decline and brain atrophy, suggesting that sex is a crucial variable in disease heterogeneity. We discuss critical challenges and knowledge gaps in our current understanding. Elucidating sex differences in disease phenotypes will be instrumental in the development of a 'precision medicine' approach in AD, encompassing individual, multimodal, biomarker-driven and sex-sensitive strategies for prevention, detection, drug development and treatment.

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Sex modifies the APOE-related risk of developing Alzheimer disease.

André Altmann, Lu Tian, Victor W Henderson … (2014)

The APOE4 allele is the strongest genetic risk factor for sporadic Alzheimer disease (AD). Case-control studies suggest the APOE4 link to AD is stronger in women. We examined the APOE4-by-sex interaction in conversion risk (from healthy aging to mild cognitive impairment (MCI)/AD or from MCI to AD) and cerebrospinal fluid (CSF) biomarker levels. Cox proportional hazards analysis was used to compute hazard ratios (HRs) for an APOE-by-sex interaction on conversion in controls (n = 5,496) and MCI patients (n = 2,588). The interaction was also tested in CSF biomarker levels of 980 subjects from the Alzheimer's Disease Neuroimaging Initiative. Among controls, male and female carriers were more likely to convert to MCI/AD, but the effect was stronger in women (HR = 1.81 for women; HR = 1.27 for men; interaction: p = 0.011). The interaction remained significant in a predefined subanalysis restricted to APOE3/3 and APOE3/4 genotypes. Among MCI patients, both male and female APOE4 carriers were more likely to convert to AD (HR = 2.16 for women; HR = 1.64 for men); the interaction was not significant (p = 0.14). In the subanalysis restricted to APOE3/3 and APOE3/4 genotypes, the interaction was significant (p = 0.02; HR = 2.17 for women; HR = 1.51 for men). The APOE4-by-sex interaction on biomarker levels was significant for MCI patients for total tau and the tau-to-Aβ ratio (p = 0.009 and p = 0.02, respectively; more AD-like in women). APOE4 confers greater AD risk in women. Biomarker results suggest that increased APOE-related risk in women may be associated with tau pathology. These findings have important clinical implications and suggest novel research approaches into AD pathogenesis. © 2014 American Neurological Association.

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Apolipoprotein E Genotype and Sex Risk Factors for Alzheimer Disease

Scott Neu, Judy Pa, Walter Kukull … (2017)

It is unclear whether female carriers of the apolipoprotein E (APOE) ε4 allele are at greater risk of developing Alzheimer disease (AD) than men, and the sex-dependent association of mild cognitive impairment (MCI) and APOE has not been established.

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Randomized Trial of Verubecestat for Mild-to-Moderate Alzheimer’s Disease

Yuki Mukai, Tiffini Smith Voss, Christine Furtek … (2018)

BACKGROUND Alzheimer’s disease is characterized by the deposition of amyloid-beta (A β ) plaques in the brain. A β is produced from the sequential cleavage of amyloid precursor protein by β -site amyloid precursor protein–cleaving enzyme 1 (BACE-1) followed by y-secretase. Verubecestat is an oral BACE-1 inhibitor that reduces the A β level in the cerebrospinal fluid of patients with Alzheimer’s disease. METHODS We conducted a randomized, double-blind, placebo-controlled, 78-week trial to evaluate verubecestat at doses of 12 mg and 40 mg per day, as compared with placebo, in patients who had a clinical diagnosis of mild-to-moderate Alzheimer’s disease. The coprimary outcomes were the change from baseline to week 78 in the score on the cognitive subscale of the Alzheimer’s Disease Assessment Scale (ADAS-cog; scores range from 0 to 70, with higher scores indicating worse dementia) and in the score on the Alzheimer’s Disease Cooperative Study Activities of Daily Living Inventory scale (ADCS-ADL; scores range from 0 to 78, with lower scores indicating worse function). RESULTS A total of 1958 patients underwent randomization; 653 were randomly assigned to receive verubecestat at a dose of 12 mg per day (the 12-mg group), 652 to receive verubecestat at a dose of 40 mg per day (the 40-mg group), and 653 to receive matching placebo. The trial was terminated early for futility 50 months after onset, which was within 5 months before its scheduled completion, and after enrollment of the planned 1958 patients was complete. The estimated mean change from baseline to week 78 in the ADAS-cog score was 7.9 in the 12-mg group, 8.0 in the 40-mg group, and 7.7 in the placebo group (P=0.63 for the comparison between the 12-mg group and the placebo group and P=0.46 for the comparison between the 40-mg group and the placebo group). The estimated mean change from baseline to week 78 in the ADCS-ADL score was −8.4 in the 12-mg group, −8.2 in the 40-mg group, and −8.9 in the placebo group (P=0.49 for the comparison between the 12-mg group and the placebo group and P=0.32 for the comparison between the 40-mg group and the placebo group). Adverse events, including rash, falls and injuries, sleep disturbance, suicidal ideation, weight loss, and hair-color change, were more common in the verubecestat groups than in the placebo group. CONCLUSIONS Verubecestat did not reduce cognitive or functional decline in patients with mild-to-moderate Alzheimer’s disease and was associated with treatment-related adverse events.(ClinicalTrials.gov [Related object:] .)

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Journal

Title: Nature Reviews Neurology

Abbreviated Title: Nat Rev Neurol

Publisher: Springer Nature

ISSN (Print): 1759-4758

ISSN (Electronic): 1759-4766

Publication date Created: August 2018

Publication date (Electronic): July 9 2018

Publication date (Print): August 2018

Volume: 14

Issue: 8

Pages: 457-469

Article

DOI: 10.1038/s41582-018-0032-9

PubMed ID: 29985474

SO-VID: 8189a9ea-5ec6-434e-9045-c2465639b609

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http://www.springer.com/tdm

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Sex differences in Alzheimer disease — the gateway to precision medicine

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Sex and gender-sensitive medicine

Most cited references 113

Sex modifies the APOE-related risk of developing Alzheimer disease.

Apolipoprotein E Genotype and Sex Risk Factors for Alzheimer Disease

Randomized Trial of Verubecestat for Mild-to-Moderate Alzheimer’s Disease

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