The core problem the authors identify is phenotypic heterogeneity. Sporadic Alzheimer’s disease accounts for roughly 90 percent of cases and is diagnosed clinically using cognitive testing, supported by amyloid and tau biomarkers in cerebrospinal fluid, blood plasma and PET imaging. But on the neuropathological level, the disease is far more complex than a simple case-versus-control division suggests. Amyloid plaques of extracellular beta-amyloid and intracellular neurofibrillary tangles of hyperphosphorylated tau are the hallmark lesions, yet comorbid pathology is the norm rather than the exception in the aging brain. Cerebral amyloid angiopathy, alpha-synuclein Lewy bodies, TDP-43 inclusions and granulovacuolar degeneration bodies frequently co-occur with hallmark Alzheimer lesions, sometimes at striking frequencies: TDP-43 inclusions can be found in up to 57 percent of Alzheimer’s patients and Lewy bodies in over 60 percent.

This complexity has direct consequences for genetic research. Twin studies estimate the heritability of sporadic Alzheimer’s disease at around 60 to 80 percent, and SNP-based heritability estimates rise from roughly 0.25 to 0.34 in clinical cohorts to 0.36 to 0.59 when autopsy or biomarker confirmation is used. More than 75 risk loci have now been associated with Alzheimer’s disease through GWAS, implicating pathways ranging from APP and tau processing to endocytosis, lipid metabolism and innate immunity. Yet clinical misclassification introduces type I and type II errors into large-scale studies, and some discovered signals may reflect co-pathologies or misdiagnosed subgroups rather than pure Alzheimer’s pathogenesis. The authors argue that smaller, deeply phenotyped cohorts can outperform ever-larger clinical samples because phenotypic accuracy is what limits statistical power, not sample size alone.

The review traces how this shift has already paid off for the hallmark lesions. Studies on the Religious Orders Study and Rush Memory and Aging Project (ROSMAP) cohorts, which follow cognitively normal individuals with longitudinal evaluation and brain donation, linked a CR1 intronic variant to increased neuritic plaque burden. Later work testing 83 risk variants from the largest clinical Alzheimer’s GWAS in a cohort of over 4,000 individuals found that BIN1, CR1 and COX7 variants increased neurofibrillary tangle burden while MME decreased it, and that BIN1, APH1B and FERMT2 variants raised neuritic plaque risk while MME, EED/PICALM and RBCK1 were protective. A genome-wide significant association between APOE and tangle pathology was repeatedly replicated, and an intronic PTPRD signal emerged in larger ROSMAP GWAS and was independently replicated.

Larger multicenter efforts extended these findings. The Alzheimer’s Disease Genetics Consortium performed GWAS of neuropathological phenotypes in nearly 5,000 individuals, confirming genome-wide significant APOE associations with all investigated lesions and identifying protective signals for GALNT7, ABCG1 and IER5I with neuritic plaques. A study of more than 7,000 autopsied participants from ROSMAP, NACC and ACT cohorts found APOE significantly associated with amyloid score, Braak stage and CERAD neuritic plaque score, plus a genome-wide significant BIN1 effect on higher Braak stages, with ABCA7, PTK2B, CR1, SNX1, FERMT2 and CELF/SPI1 raising plaque burden and PICALM, INPP5D, ZCWPW1 and SORL1 lowering it. Sex-stratified analyses added nuance, revealing a male-specific protective signal near TSPAN13 for tangle presence, though the authors caution that reduced statistical power in stratified analyses means such findings require independent replication.

Perhaps the most striking example of the approach’s value comes from primary age-related tauopathy, or PART, a condition in which tau lesions indistinguishable from Alzheimer’s occur without amyloid plaques and with limited cognitive consequences. A GWAS confined to neuropathologically confirmed PART cases uncovered a genome-wide significant locus on chromosome 4, with functional validation pointing to JADE1 as the plausible risk gene for tau pathology. Notably, the effect alleles in this locus were independent of earlier suggestive signals, illustrating how restricting cohorts to precisely defined pathological entities can reveal biology that overlapping, heterogeneously composed cohorts dilute or obscure.

Co-pathologies show equally illuminating genetic patterns. For cerebral amyloid angiopathy, found in up to 90 percent of Alzheimer’s cases, the APOE epsilon4 allele is specifically linked to capillary-involving Type I disease, while epsilon2 is more frequent in Type II. Beyond APOE, CR1 and UNC5C were implicated in hypothesis-driven studies, and a GWAS in over 800 individuals identified the long noncoding RNA locus LINC-PINT, associated with decreased CAA burden in APOE epsilon4-negative individuals and supported by in vitro evidence of neuroprotection. A protective APOC2 polymorphism in a large postmortem GWAS was later shown by colocalization to reflect reduced APOE expression in brain microglia, demonstrating how post-GWAS fine-mapping can redirect interpretation from the nearest gene to the true molecular driver.

For TDP-43 pathology and the related entity LATE (limbic-predominant age-related TDP-43 encephalopathy), much of the genetic insight has come from frontotemporal lobar degeneration research, where neuropathology-centered GWAS revealed TMEM106B, DPP6, UNC13A, HLA-DQA2 and TNIP1 as risk factors, with distinct loci emerging for specific FTLD-TDP subtypes. In the Alzheimer’s context, APOE epsilon4 allele count correlates with TDP-43 burden, and TMEM106B was confirmed as associated with LATE neuropathological change, alongside suggestive signals for GRN, SORL1 and TPCN1. Both TMEM106B, a lysosomal transmembrane protein whose C-terminal domain can form amyloid fibrils, and GRN, encoding the lysosomal growth factor progranulin, implicate lysosomal dysfunction as a shared mechanism spanning Alzheimer’s and TDP-43 proteinopathies. For Lewy body pathology, APOE and BIN1 are firmly established Alzheimer’s risk genes whose links to alpha-synuclein aggregates remain contested; one stratified GWAS concluded they raise Alzheimer’s risk regardless of Lewy body status, while BLMH and ZNF365 signals emerged for Lewy body presence in Alzheimer’s-negative individuals. Granulovacuolar degeneration, an underexplored lesion strongly tied to tau pathology, endocytosis, autophagy and necroptosis, showed APOE and APH1B associations that network modeling suggested are largely indirect, mediated through amyloid and tangle pathology.

The authors are candid about the caveats. Neuropathological cohorts are necessarily small because donated brain tissue is limited, forcing reliance on multi-center compilations that introduce inter-observer variability, differing staining protocols and harmonization challenges, though initiatives like BrainNet Europe have shown that immunohistochemistry with standardized antibodies and dichotomous diagnostic approaches yield the most robust results. Overlapping study populations across published GWAS also limit independence of findings, underscoring the need for new, standardized cohorts. Moreover, GWAS lead variants are often not the causal variants, and the nearest protein-coding gene is not necessarily the affected gene, since most hits sit in noncoding regulatory regions; gene prioritization and functional validation remain essential before mechanistic claims can be made.

Even so, the message of the review is unambiguous: bigger is not always better. Combining genetic data with detailed neuropathology enables refinement of clinical GWAS signals, discovery of variants tied to the burden of specific lesions rather than a diagnostic label, network analyses that position APOE’s effects on tau as largely indirect through amyloid and vascular pathology, and identification of overlapping genetic risk across disease boundaries. As the first disease-modifying Alzheimer’s therapies arrive, understanding which genes drive which lesions, and how co-pathologies shape disease trajectory, could enable the patient stratification that clinical trials increasingly demand, and point toward treatments addressing the full neuropathological spectrum rather than a single pathological feature.

Subject of Research: Neuropathology-centered genome-wide association studies of Alzheimer's disease and overlapping co-pathologies

Article Title: A new era of genome-wide association studies in the field of Alzheimer’s disease and overlapping co-pathologies: lessons learned from a neuropathology-centered approach

Article References: A new era of genome-wide association studies in the field of Alzheimer’s disease and overlapping co-pathologies: lessons learned from a neuropathology-centered approach. (n.d.). https://doi.org/10.1007/s00401-026-03085-4

Image Credits: AI Generated

DOI: 10.1007/s00401-026-03085-4

Keywords: Alzheimer's disease, genome-wide association studies, neuropathology, amyloid plaques, neurofibrillary tangles, cerebral amyloid angiopathy, TDP-43, Lewy bodies, APOE, TMEM106B, co-pathologies, LATE