To characterize biological sex ratios within Alzheimer’s disease (AD) and frontotemporal dementia (FTD) spectrum disorders across a global population.

AD and FTD spectrum disorders display wide phenotypic variability, the cause of which remains unknown. Our prior work suggests that neurodevelopmental factors (hand preference and learning disability history) hold relevance towards dementia heterogeneity. In the present study, we investigated whether the earliest appreciable neurodevelopmental factor, biological sex, influences clinical presentation.

We conducted a PubMed search for the term “primary progressive aphasia,” between 2018-2022, and combined with UCSF MAC cohorts, yielding n=876 nonfluent variant primary progressive aphasia (nfvPPA), n=714 logopenic variant PPA (lvPPA), n=1101 semantic dementia (SD) (comprised of semantic variant PPA and semantic behavioral variant FTD), and n=2632 behavioral variant FTD (bvFTD) participants with reported sex. From individual published articles, we obtained n=1092 posterior cortical atrophy (PCA) participants, and n=1216 typical AD (tAD) UCSF MAC participants.

Each AD subtype possessed greater female sex prevalence than expected for the general population (observed vs. expected 50/50 male:female sex ratio—54.1% lvPPA, p=0.03; 56.6% tAD, p<0.001; 59.4% PCA, p<0.001). PCA and lvPPA presented with the highest and lowest female sex ratios, respectively, and were significantly different from each other (p=0.02). Female sex was associated with 1.2 odds of developing PCA over lvPPA (95% CI: 1.029-1.506). Within FTD, bvFTD and nfvPPA possessed significantly different female sex ratios than expected in opposing direction (42.1% bvFTD, p<0.001; nfvPPA 54.9%, p=0.004), while SD was no different. Sex ratios were significantly different between bvFTD and nfvPPA (p<0.001) where being female was associated with 1.7 odds of developing nfvPPA over bvFTD (95% CI: 1.4359-1.9537).

We observed marked differences in biological sex ratios across AD and FTD spectrum disorders, establishing sex as an important and underrecognized contributor to phenotypic heterogeneity in dementia.