Sex and age interact to determine clinicopathologic differences in Alzheimer\u2019s disease

Kelly M. Hinkle,Sarah K. DiLello,Shunsuke Koga,Owen A. Ross,Adel Aziz,Dennis W. Dickson,Nilufer Ertekin-Taner,Fadi S. Hanna Al-Shaikh,Rickey E. Carter,Amanda M. Liesinger,Neill R. Graff-Radford,Melissa E. Murray,McKenna F. Johnson,Ranjan Duara

doi:10.1007/s00401-018-1908-x

Kelly M. Hinkle, Sarah K. DiLello + Show 12 more

Open Access

https://doi.org/10.1007/s00401-018-1908-x

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Abstract

Women reportedly make up two-thirds of Alzheimer’s disease (AD) dementia sufferers. Many estimates regarding AD, however, are based on clinical series lacking autopsy confirmation. The Florida Autopsied Multi-Ethnic (FLAME) cohort was queried for AD cases with a total of 1625 identified ranging in age from 53 to 102 years at death. Standard neuropathologic procedures were employed and clinical information was retrospectively collected. Clinicopathologic and genetic data (MAPT and APOE) were stratified by sex. Within the neuropathologically diagnosed AD cohort, the overall number of women and men did not differ. Men were younger at onset of cognitive symptoms, had a shorter disease duration, and more often had atypical (non-amnestic) clinical presentations. The frequency of autopsy-confirmed AD among women and men stratified by age at death revealed an inverse U-shaped curve in men and a U-shaped curve in women, with both curves having inflections at approximately 70 years of age. Regional counts of neurofibrillary tangles differed in women and men, especially when examined by age intervals. Women had overall greater severity of neurofibrillary tangle counts compared to men, especially in the hippocampus. Men were more often classified as hippocampal sparing AD, whereas limbic predominant AD was more common in women. Men and women did not differ in frequency of MAPT haplotype or APOE genotype. Atypical clinical presentations, younger age at onset and shorter disease duration were more frequent in men, suggesting that the lower reported frequency of AD in men may be due to more frequent atypical clinical presentations not recognized as AD. Our data suggest that neuropathologically diagnosed AD cases have the same frequency of women and men, but their clinical presentations and ages at onset tend to differ.

Highlights

The strongest risk factor for Alzheimer’s disease (AD) is increasing age [38]
Among those who presented clinically with an AD dementia syndrome, 58% were women and 42% were men (p < 0.001); whereas, among those who presented with an atypical clinical syndrome, 38% were women and 62% were men (p < 0.001)
In the Florida Autopsied Multi-Ethnic (FLAME) cohort, the overall frequency of autopsyconfirmed AD did not differ between women and men; men less often had an amnestic, multidomain clinical syndrome typical of AD dementia

Summary

Introduction

The strongest risk factor for Alzheimer’s disease (AD) is increasing age [38]. The impact of sex differences on AD risk between women and men, has been variably interpreted [3, 20, 28, 31, 37]. Evidence from multi-site studies suggests that women make up nearly two-thirds of patients with AD dementia in North America [28]. The prevalence of AD dementia among women and men has been increasing steadily in European ethnic groups, for women after age 90 [31, 37]. Postmortem studies have revealed that women tend to have greater AD pathology [5, 13], but men more often present with atypical clinical syndromes (e.g., frontotemporal dementia, corticobasal syndrome) [14, 24].

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