Autopsy Study Reveals Amyloid Plaques Explain Alzheimer’s Gene Risk But Not Women’s Tau Burden

In one of the largest autopsy investigations of Alzheimer’s disease ever conducted, researchers have uncovered a fundamental asymmetry in how the two biggest risk factors for the disease drive the toxic protein buildup that destroys memory. Analyzing brain tissue from 2,550 donors across two independent cohorts, a team led by Gemma Salvadó of Lund University found that the notorious APOE-ε4 gene variant promotes tau tangles in the memory-critical medial temporal lobe almost entirely through its well-known effect on amyloid-β plaques. Female sex, by contrast, was associated with elevated medial temporal tau that stubbornly persisted even after the researchers statistically accounted for both global and local amyloid-β pathology. The findings, published in Acta Neuropathologica, suggest that these two risk factors act through at least partially distinct biological pathways, a distinction with profound implications for how Alzheimer’s trials are designed and for whom.

The medial temporal lobe, encompassing the entorhinal cortex and hippocampus, is where Alzheimer’s pathology takes root. Tau tangles appear here earlier than anywhere else in the brain, and the density of these misfolded filaments tracks closely with the episodic memory failures that define the disease. Yet while the link between neocortical tau and amyloid-β is well established, the relationship within the medial temporal lobe has remained murky. Positron emission tomography, the workhorse of in vivo amyloid and tau imaging, struggles in this deep, folded region because of limited spatial resolution, off-target tracer binding, and reduced sensitivity. Autopsy tissue, by contrast, allows direct, region-specific quantification of plaques and tangles, which is precisely why the researchers turned to two of the world’s most rigorously characterized brain donation programs.

The main cohort came from the Religious Orders Study and the Rush Memory and Aging Project, longitudinal studies that have followed older Catholic clergy and Chicago-area residents for decades, with 1,587 participants donating their brains at death. The replication cohort drew from the Arizona Study of Aging and Neurodegenerative Disorders, adding 963 more donors. In the main cohort, amyloid-β load was measured as the percentage of tissue area occupied by immunostained deposits, while tau was quantified as neurofibrillary tangle density using the AT8 antibody across eight cortical regions. The Arizona cohort used semi-quantitative CERAD-style grading with thioflavin-S, Campbell-Switzer, and Gallyas staining. Crucially, both datasets allowed the team to compute separate amyloid-β and tau composites for the medial temporal lobe and for the six remaining neocortical regions, and to adjust for co-pathologies including TDP-43, Lewy bodies, and vascular lesions.

The starting point was unsurprising: in both cohorts, carrying at least one APOE-ε4 allele and being female were each associated with significantly greater medial temporal tau tangle burden, with all p-values below 0.001. APOE-ε4 carriers also showed markedly higher amyloid-β in both the neocortex and the medial temporal lobe. The effects of female sex on amyloid were weaker and less consistent, reaching significance in the main cohort only. The pivotal question was what would happen when amyloid-β entered the statistical models as a potential mediator of the tau associations.

Adjusting for global neocortical amyloid-β alone attenuated both associations but did not eliminate them. The turning point came when the researchers jointly accounted for global and regional medial temporal amyloid-β. Under that fuller specification, the association between APOE-ε4 and medial temporal tau dissolved entirely, falling to non-significance in both cohorts with p-values of at least 0.19. The female sex effect, however, remained robust, with p-values of 0.004 or lower. Models incorporating both spatial scales of amyloid pathology explained substantially more variance in medial temporal tau than global measures alone, and the results held when the team additionally adjusted for diagnostic group, clinical stage, or neocortical tau burden.

Path analysis, a form of structural equation modeling that traces how effects flow through intermediate variables, sharpened the picture. The researchers ordered the pathology variables a priori according to known neuropathological staging: diffuse neocortical plaques precede neuritic plaques, neocortical amyloid precedes medial temporal amyloid, and medial temporal amyloid precedes tangles. In both cohorts, roughly three quarters of the total APOE-ε4 effect on medial temporal tau was mediated by amyloid-β, 79.5 percent in the main cohort and 74.5 percent in the replication sample, and the residual direct effect was statistically indistinguishable from zero. For female sex, less than half of the effect was amyloid-mediated, just 44.0 percent and 14.4 percent respectively, and a significant amyloid-independent component persisted in both cohorts.

Sensitivity analyses reinforced the dissociation. Among donors with no significant amyloid-β pathology on the CERAD scale, 499 in the main cohort and 211 in the replication set, APOE-ε4 showed no association with medial temporal tau at all. Female sex, meanwhile, remained significantly linked to higher tau in the main cohort and showed a strong trend in the replication sample. When the team repeated the analyses separately for the entorhinal cortex and hippocampus, and when they tested for APOE-ε4 by sex interactions, the same pattern emerged: after accounting for amyloid-β, women carried more medial temporal tau regardless of genotype.

The authors propose plausible, if unproven, mechanisms for the sex-specific vulnerability. Endocrine transitions, particularly the loss of estrogen around menopause, have been linked to tau burden in prior imaging studies, and sex differences in neuroimmune biology, including microglial activation, have been tied to both amyloid and tau pathologies. The persistence of the sex effect in amyloid-free brains and after adjustment for disease-stage proxies suggests that female-associated tau accumulation in the medial temporal lobe is at least partly an amyloid-independent process, potentially accelerating progression and amplifying tau-mediated cognitive decline. The study’s design, being cross-sectional autopsy data, cannot establish causality or temporal ordering, and the cohorts lack racial, ethnic, and socioeconomic diversity, limitations the authors acknowledge candidly.

For the APOE-ε4 story, the findings carry a more encouraging message. If the gene variant amplifies tau largely through its strong effects on amyloid-β accumulation and distribution, then the new generation of anti-amyloid therapies might, in principle, blunt the downstream tau consequences that matter most for cognition, particularly in early disease stages when localized amyloid and tau deposits fall below PET detection thresholds. The study also highlights a methodological blind spot: most in vivo studies quantify amyloid with a global neocortical composite, potentially obscuring the local amyloid-tau interplay within the medial temporal lobe that the autopsy data reveal. Whether plaque removal alters tau trajectories in a genotype-dependent manner will require longitudinal and interventional evidence that this design cannot provide.

The practical upshot is a call for precision in trial design. Post hoc analyses of some anti-amyloid trials have hinted at sex differences in treatment outcomes, though such exploratory subgroup findings were never powered for definitive interaction testing. The new results argue that sex and APOE genotype should be built into prespecified analytic plans for therapies targeting amyloid, tau, or APOE biology, rather than treated as afterthoughts. They also frame a pressing open question for the field: identifying the biological basis of women’s heightened medial temporal tau vulnerability could clarify why Alzheimer’s prevalence and progression differ by sex and open therapeutic avenues that current amyloid-centric strategies leave untouched. Until then, the autopsy bench has delivered a clear verdict, APOE-ε4 works through amyloid, and female sex, at least in part, works around it.

Subject of Research: Amyloid-β-mediated versus amyloid-independent pathways linking APOE-ε4 and female sex to medial temporal tau pathology in Alzheimer's disease

Article Title: Global and regional amyloid-β in explaining APOE-ε4 and sex associations with medial temporal tau: a neuropathology study

Article References: Salvadó, G., Groot, C., Wisse, L. E., Vogel, J. W., Beach, T. G., Serrano, G. E., Reiman, E. M., Schneider, J. A., Bennett, D. A., Ossenkoppele, R., & Hansson, O. (2026). Global and regional amyloid-β in explaining APOE-ε4 and sex associations with medial temporal tau: a neuropathology study. Acta Neuropathologica, 152(1), Article 49. https://doi.org/10.1007/s00401-026-03095-2

Image Credits: AI Generated

DOI: 10.1007/s00401-026-03095-2

Keywords: Alzheimer's disease, APOE-ε4, tau tangles, amyloid-β, medial temporal lobe, neuropathology, sex differences, hippocampus, entorhinal cortex, brain donation, dementia risk, clinical trials