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Four Questions Alzheimer’s Research Hasn’t Answered Yet

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Alzheimer’s disease is shifting from a clinical diagnosis made usually later in the disease course to a biological one defined by measurable changes in amyloid, tau and neurodegeneration markers years before symptoms appear ‒ a transition that is reshaping how researchers think about screening, risk stratification and who gets access to the treatments that are now reaching the clinic.

Blood-based biomarker tests just cleared FDA review, lecanemab and donanemab are entering clinical use, and yet some of the most basic questions in the field remain unsettled. When do plasma biomarkers start diverging from normal ageing, and at what age does that matter for screening? Can probiotic supplementation move the needle on neuroinflammation in patients with established disease? Do polygenic risk scores built on European cohorts mean anything for African American or East Asian populations? And why can’t two salivary biomarker labs agree on a result?

This update covers four recent studies that take these questions seriously. The first examines why salivary diagnostics have struggled to gain traction, tracing the problem to pre-analytical inconsistency rather than biological signal. The second applies breakpoint modeling to a large ageing cohort, pinning down the ages at which plasma p-tau217, GFAP and NfL first shift trajectory in ways that could inform when to screen. The third reports on a 12-week probiotic trial in probable Alzheimer’s patients, finding changes in inflammatory cytokines and metabolic markers that suggest the gut-brain axis is a legitimate therapeutic target, not just a hypothesis. The fourth tests whether a European-derived polygenic score holds up across African American, East Asian and Latin American cohorts, with results that are partly encouraging and partly a reminder of how much diversity the field has historically ignored.

Taken together, the findings carry direct implications for researchers working on diagnostics, risk stratification and trial design across global populations.


Recent key publications

 

Diagnostic performance of salivary markers of Alzheimer’s disease: A systematic review.Alzheimers Dement. 2026 Apr;22(4):e71248. doi: 10.1002/alz.71248. Borelli PV, Machado L, Carello-Collar Get al.

Link to full article:https://pubmed.ncbi.nlm.nih.gov/41949995/

Blood-based biomarkers for Alzheimer’s disease have moved quickly, but salivary diagnostics are still stuck in a cycle of contradictory findings. This systematic review of 18 studies through 2025 traces the problem to pre-analytical inconsistency; collection timing, centrifugation protocols and storage conditions vary enough between studies to make cross-comparison nearly impossible. Lactoferrin and Aβ42 both show real promise, yet neither performs reliably across datasets, and no study fully applied current consensus guidelines for salivary analysis. Now that the FDA has approved blood-based AD tests, the pressure to get saliva protocols right has grown considerably. Getting those standards in place is the necessary next step toward making non-invasive salivary diagnostics a practical clinical tool.

Breakpoints in Alzheimer’s disease biomarkers and cognition across the aging spectrum: The Mayo Clinic Study of Aging.Alzheimers Dement. 2026 Apr;22(4):e71227. doi: 10.1002/alz.71227. Hu M, Knopman DS, Therneau Tet al.

Link to full article:https://pubmed.ncbi.nlm.nih.gov/41944335/

Pinning down exactly when Alzheimer’s biomarkers start diverging from normal ageing trajectories has been an open question in clinical research. This cross-sectional study of 2,082 Mayo Clinic Study of Aging participants applied breakpoint modeling to plasma p-tau181, GFAP, NfL and amyloid PET, identifying the ages at which each biomarker’s slope shifts significantly. GFAP and NfL both inflect around age 70, and p-tau217 shows a breakpoint at 72.6 years, which lines up with the biomarkers underlying recently FDA-approved blood tests. Taken together, the results point to late midlife as the window where screening and preclinical trial enrollment would be most strategically timed, giving researchers a concrete age range to work from rather than educated guesses.

Microbiota-gut-brain axis dysregulation in Alzheimer’s disease and its modulation through probiotic supplementation.Brain Behav Immun. 2026 Jan:131:106138. doi: 10.1016/j.bbi.2025.106138. Epub 2025 Oct 13. 131. Marizzoni M, Mombelli E, Alboni Set al.

Link to full article:https://pubmed.ncbi.nlm.nih.gov/41093142/

Human intervention studies targeting the gut-brain axis in Alzheimer’s disease are still rare, which makes this trial worth attention. The study enrolled 45 probable AD patients and 47 healthy controls and confirmed intestinal inflammation, disrupted tryptophan metabolism, altered gut microbiota composition and reduced glutamate levels at baseline. After 12 weeks of probiotic supplementation, pro-inflammatory markers including IL-6, TNFα and NLRP3 dropped, while butyrate, 5-hydroxyindoleacetic acid and glutamate increased. What stands out is that probiotics appeared to shift microbial function rather than overall composition. Given that recent meta-analyses have linked microbiome-based interventions to modest cognitive gains, this study adds mechanistic weight to those findings and gives future trials a clearer set of peripheral immune and metabolic targets to pursue.

Transferability of European-derived Alzheimer’s disease polygenic risk scores across multiancestry populations.Nat Genet. 2025 Jul;57(7):1598-1610. doi: 10.1038/s41588-025-02227-w. Epub 2025 Jun 18. Nicolas A, Sherva R, Grenier-Boley Bet al.

Link to full article:https://pubmed.ncbi.nlm.nih.gov/40533518/ 

Polygenic scores for Alzheimer’s disease are built almost entirely on European ancestry data, and whether they hold up across other populations has been an open question. This study tested a European-derived score across 17 European cohorts and several non-European groups including African American, East Asian and Latin American participants. The score associated consistently with AD risk and CSF biomarkers independent of APOE status, though predictive accuracy dropped in African ancestry populations. A cross-ancestry score that incorporated the APOE region recovered some of that lost performance. As lecanemab and donanemab move into clinical use, knowing who is actually at risk matters across all patient populations, not just those of European descent. The study makes clear how much work remains before polygenic scores can be applied equitably in global settings.

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