Alzheimer's disease (AD) is highly heritable and recent studies have identified over 20 diseaseassociated genomic loci. Yet these only explain a small proportion of the genetic variance, indicating that undiscovered loci remain. Here, we performed the largest genome-wide association study of clinically diagnosed AD and AD-by-proxy (71,880 cases, 383,378 controls). AD-by-proxy, based on parental diagnoses, showed strong genetic correlation with AD (rg=0.81). Meta-analysis identified 29 risk loci, implicating 215 potential causative genes. Associated genes are strongly expressed in immune-related tissues and cell types (spleen, liver and microglia). Gene-set analyses indicate biological mechanisms involved in lipid-related processes and degradation of amyloid precursor proteins. We show strong genetic correlations with multiple health-related outcomes, and Mendelian randomisation results suggest a protective effect of cognitive ability on AD risk. These results are a step forward in identifying the genetic factors that contribute to AD risk and add novel insights into the neurobiology of AD.

Women are disproportionately affected by Alzheimer’s disease (AD) in terms of both disease prevalence and severity. Previous autopsy work has suggested that, in the presence of AD neuropathology, females are more susceptible to the clinical manifestation of AD. This manuscript extends that work by evaluating whether sex alters the established associations between cerebrospinal fluid (CSF) biomarker levels and brain aging outcomes (hippocampal volume, cognition). Participants were drawn from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) and included individuals with normal cognition (n=348), mild cognitive impairment (n=565), and AD (n=185). We leveraged mixed effects regression models to assess the interaction between sex and baseline cerebrospinal fluid biomarker levels of amyloid-β42 (Aβ-42) and total tau on cross-sectional and longitudinal brain aging outcomes. We found a significant interaction between sex and Aβ-42 on longitudinal hippocampal atrophy (p=0.002), and longitudinal decline in memory (p=0.017) and executive function (p=0.025). Similarly, we observed an interaction between sex and total tau level on longitudinal hippocampal atrophy (p=0.008), and longitudinal decline in executive function (p=0.034). Women with Aβ-42 and total tau levels indicative of worse pathological changes showed more rapid hippocampal atrophy and cognitive decline. The sex difference was particularly pronounced among individuals with MCI, with lower education, and varied by APOE ε4 allele. These results suggest females may be more susceptible to the clinical manifestation of AD.

IMPORTANCE Mounting evidence suggests that sex differences exist in the pathologic trajectory of Alzheimer disease. Previous literature shows elevated levels of cerebrospinal fluid tau in women compared with men as a function of apolipoprotein E (APOE) ε4 status and β-amyloid (Aβ). What remains unclear is the association of sex with regional tau deposition in clinically normal individuals. OBJECTIVE To examine sex differences in the cross-sectional association between Aβ and regional tau deposition as measured with positron emission tomography (PET). DESIGN, SETTING AND PARTICIPANTS This is a study of 2 cross-sectional, convenience-sampled cohorts of clinically normal individuals who received tau and Aβ PET scans. Data were collected between January 2016 and February 2018 from 193 clinically normal individuals from the Harvard Aging Brain Study (age range, 55-92 years; 118 women [61%]) who underwent carbon 11-labeled Pittsburgh Compound B and flortaucipir F 18 PET and 103 clinically normal individuals from the Alzheimer's Disease Neuroimaging Initiative (age range, 63-94 years; 55 women [51%]) who underwent florbetapir and flortaucipir F 18 PET. MAIN OUTCOMES AND MEASURES A main association of sex with regional tau in the entorhinal cortices, inferior temporal lobe, and a meta-region of interest, which was a composite of regions in the temporal lobe. Associations between sex and global Aβ as well as sex and APOE ε4 on these regions after controlling for age were also examined. RESULTS The mean (SD) age of all individuals was 74.2 (7.6) years (81 APOE ε4 carriers [31%]; 89 individuals [30%] with high Aβ). There was no clear association of sex with regional tau that was replicated across studies. However, in both cohorts, clinically normal women exhibited higher entorhinal cortical tau than men (meta-analytic estimate: β [male] = −0.11 [0.05]; 95% CI, −0.21 to −0.02; P = .02), which was associated with individuals with higher Aβ burden. A sex by APOE ε4 interaction was not associated with regional tau (meta-analytic estimate: β [male, APOE ε4+] = −0.15 [0.09]; 95% CI, −0.32 to 0.01; P = .07). CONCLUSIONS AND RELEVANCE Early tau deposition was elevated in women compared with men in individuals on the Alzheimer disease trajectory. These findings lend support to a growing body of literature that highlights a biological underpinning for sex differences in Alzheimer disease risk.

Importance: The strongest genetic risk factor for AD, the apolipoprotein E (APOE) gene, has a stronger association among females compared to males. Yet, limited work has evaluated the association between APOE alleles and markers of AD neuropathology in a sex-specific manner. Objective: Evaluate sex differences in the association between APOE and markers of AD neuropathology measured in cerebrospinal fluid (CSF) during life or in brain tissue at autopsy. Design, Setting, Participants: This meta-analysis selected data from 10 longitudinal cohort studies of normal aging and AD. Cohorts had variable recruitment criteria and follow-up intervals, and included population based and clinic based samples. Inclusion in our analysis required APOE genotype data and either CSF data (n=1798, 48% female, 13% AD, 94% Caucasian, 70±9 years) or autopsy data (n=5,109, 56% female, 97% Caucasian, 84±9 years) available for analysis. Main Outcome and Measures: Biomarker analyses included levels of Aβ−42, total tau (t-tau), and phosphorylated tau (p-tau) measured in CSF. Autopsy analyses included CERAD staging for neuritic plaques and Braak staging for neurofibrillary tangles. Results: After correcting for multiple comparisons using the Bonferroni procedure, we observed a statistically significant interaction between APOE-ε4 and sex on CSF t-tau (β=0.41 [95% CI: 0.27, 0.55], p<0.001) and p-tau (β=0.24 [0.09, 0.38], p=0.001), whereby APOE showed a stronger association among females compared to males. Post hoc analyses suggested this sex difference was present in amyloid positive individuals (β=0.41 [0.20, 0.62], p<0.001), but not among amyloid negative individuals (β=0.06 [−0.18, 0.31], p=0.62). We did not observe sex differences in the association between APOE and Aβ−42, neuritic plaque burden, or neurofibrillary tangle burden. Conclusions and Relevance: We provide robust evidence of a stronger association between APOE-ε4 and CSF tau levels among females compared to males across multiple independent datasets. Interestingly, APOE-ε4 is not differentially associated with autopsy measures of neurofibrillary tangles. Together, the sex difference in the association between APOE and CSF measures of tau, and the lack of a sex difference in the association with neurofibrillary tangles at autopsy, suggests that APOE may modulate risk for neurodegeneration in a sex-specific manner, particularly in the presence of amyloidosis.

Objective Subjective cognitive complaints are often used in the diagnosis of memory and other cognitive impairment. This study examined whether cognitive complaints are associated with longitudinal changes in cognition and cross-sectional differences in regional brain function during memory performance in 98 participants with a mean age of 75. Method The Cognitive Failures Questionnaire (CFQ) assessed cognitive complaints and mixed effects regression models were used to determine whether mean CFQ scores predicted rates of change in cognitive function over a period of 11.5 years. Results Higher CFQ scores, reflecting increased subjective complaints, were associated with steeper rates of decline in immediate and delayed recall on the California Verbal Learning Test. Voxel-based regression analysis was used to determine the cross-sectional relationship between CFQ scores and regional cerebral blood flow measured by PET during a resting condition and during verbal and figural memory tasks. Higher levels of cognitive complaints were associated with increased activity in insular, lingual and cerebellar areas during memory tasks. Conclusions These findings offer some support for the validity of subjective cognitive complaints as markers of age related changes in memory and brain activity.