BOISE, Idaho, USA, 6 November 2026 — Ask the family of someone with Alzheimer's disease what the hardest part is, and the answer is not always the forgetting. Sometimes it is the pacing. The same question asked four times before lunch, not because the answer was lost, but because the worry underneath it never settles. Clinicians have long known that anxiety travels with dementia. Roughly 40% to 50% of people with Alzheimer's disease live with it. What has been less clear is whether the worry and the fading are strangers sharing a house, or relatives.
A peer-reviewed study in Genomic Psychiatry, led by Troy T. Rohn of Boise State University and Cognigenics, takes that question to one of the largest open datasets in the field. The answer it returns is not a verdict. It is a pattern, and a fairly sharp one.
Counting the Worry
The team turned to the Alzheimer's Disease Neuroimaging Initiative, known as ADNI, a long-running cohort that pairs cognitive testing with brain imaging and genetic data. Cognition was measured with the Mini-Mental State Examination, the familiar bedside screen that tops out at 30. Anxiety came from the Neuropsychiatric Inventory, which is gathered in a structured interview with the caregiver: how often, over the past month, has your person seemed nervous, worried, frightened?
That detail matters. The anxiety in this study is the anxiety that someone at the kitchen table could see.
Participants who never showed anxiety (843 people) had an average score of about 27. Those whose anxiety appeared only sometimes, about once a week (41 people), were statistically indistinguishable from them (p > 0.5). Then the floor tilts. People with anxiety several times a week (22 people) and those with anxiety daily or continuously (25 people) scored significantly lower (p < 0.001 and p < 0.000001, respectively). The authors read this as a sign that persistent anxiety, rather than the passing kind, is what travels with cognitive decline.
A Wider Lens on Behavior and the Brain
Anxiety is one thread in a larger fabric of behavioral change in dementia: agitation, apathy, sleeplessness, delusions. When the researchers looked at the full Neuropsychiatric Inventory at the 12-month visit, higher total scores again went hand in hand with lower cognition (r = −0.32, p < 0.0001, 1,010 participants). The link held after adjustment for sex, education, diagnosis group, and APOE ε4 status, the best-known genetic risk factor for Alzheimer's disease (β = −0.89, p < 0.001, 828 participants).
The team also checked the usual suspect. Amyloid, the protein that builds into plaques, was measured on PET scans using standardized ADNI metrics. Greater neuropsychiatric burden was associated with more cortical amyloid (β = 0.0141, p = 3.55 × 10⁻⁶), but the association was modest, and the authors write that amyloid did not explain the link between anxiety and cognitive decline. Something else seemed to be at work. So they went looking in the serotonin system.
One Receptor, Two Rooms
The serotonin 2A receptor, or 5-HT2A, sits on neurons throughout the brain and helps tune mood, anxiety, and perception, as well as circuits for learning and memory. Picture an old building where a single switch on the landing controls the lights in two rooms. If you want to dim both, you do not need two electricians. That, in essence, is the hypothesis the authors bring to the data: that one receptor may sit upstream of both the worry and the fog.
In earlier rodent studies cited by the authors, suppressing this receptor, either by CRISPR-based editing (Cog-101) or by shRNA-mediated knockdown (Cog-201), reduced anxiety-related behavior and improved memory. The new paper asks whether the human data point the same way.
The genetic analyses offer suggestive hints rather than proof. Among people carrying the CT genotype of rs6313, a common variant in the HTR2A gene that encodes the receptor, anxiety and cognition showed a weak but significant inverse correlation (r = −0.21, p < 0.001, 311 participants). In one genotype subgroup of rs25531, a variant in the serotonin transporter region, the slope was steeper (r = −0.56), though that subgroup held only nine observations.
"Anxiety in Alzheimer's disease is not background noise," said Troy T. Rohn, corresponding author, of the Department of Biological Sciences at Boise State University. "In the ADNI data, people whose anxiety was frequent or constant scored clearly lower on cognition than people without anxiety. That is the observation that led us to propose testing Cog-201 in patients with clinically significant anxiety, so that cognition and anxiety are treated together rather than one at a time."
What the Data Cannot Yet Say
The authors are candid about the limits. These are associations, not demonstrations of cause; the study does not show that anxiety damages cognition, or the reverse. The genotype findings are labeled exploratory, with small subgroups and sparse high-anxiety scores. Haplotype analyses spanning the HTR2A locus found no significant interactions, which the authors say argues against a strong locus-wide effect and calls for replication in independent cohorts. In the GTEx v10 resource, the HTR2A variants studied showed regulatory effects in several peripheral tissues but not in brain tissue. And the Mini-Mental State Examination is a broad instrument; the authors suggest future work with more sensitive ADNI measures of memory and executive function. No patient in this study received Cog-201. The work builds a rationale for a clinical trial; it is not one.
Readers should also know who did the work. Most of the authors are affiliated with Cognigenics, the company developing Cog-201, and several are its co-founders, officers, or equity holders, as detailed in the article. The study received no external funding.
Treating the Whole Person
There is an old habit in medicine of treating the memory and handing the mood to someone else. This paper argues, from a large public dataset, that the two may be harder to separate than our clinics assume. If frequent anxiety keeps company with poorer cognition, then asking a caregiver how often a parent seems frightened may be as telling as asking what year it is.
Whether a single receptor can quiet both remains, for now, a question for the trial that the authors hope comes next. The pattern in the data is already there to see. Worry, when it stays, rarely stays alone.
The peer-reviewed research article in Genomic Psychiatry titled "Serotonin 5-HT2A receptor knockdown as a holistic therapeutic strategy for Alzheimer's disease," is freely available via Open Access, starting on 8 September 2026 in Genomic Psychiatry at the following hyperlink: https://doi.org/10.61373/gp026r.0051 .
The full reference for citation purposes is: Rohn TT, Radin D, Bhadra S, Brandmeyer T, Seidler PG, Linder BJ et al. Serotonin 5-HT2A receptor knockdown as a holistic therapeutic strategy for Alzheimer's disease. Genomic Psychiatry 2026. DOI: https://doi.org/10.61373/gp026r.0051 . Epub 2026 Sep 8.
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