Alzheimer’s Disease

Genome studies have linked more than 75 genetic variants to Alzheimer's and dementia, raising hopes that a combined "polygenic risk score" could flag people at higher risk. But most scores were built mainly from people of European ancestry. This study tested several scoring methods in more than 6,000 African American, Chinese, Hispanic, and White participants and found performance varied by approach and ancestry. The work is an important step toward fair, accurate genetic risk prediction that works across diverse populations.

APOE4 is the strongest common genetic risk factor for Alzheimer's disease, and it works partly through a protein called ABCA1 that helps "fatten up" APOE so it can clear debris from the brain. Drugs that switch on ABCA1 (LXR agonists) help in animal models but have caused fatty-liver side effects in people. This study screened many LXR-activating compounds to find ones that boost the beneficial brain pathway without the liver problem, an early step toward APOE-targeted Alzheimer's therapies for people at genetic risk.

Some of a person's Alzheimer's risk is inherited, and researchers are still mapping which gene variants contribute. This case-control study compared 95 Alzheimer's patients with 97 healthy people, testing several common variations in the SNCA gene (which makes the protein alpha-synuclein) using statistics and machine learning. A few variants were more frequent in patients, hinting they may nudge up disease risk. Findings like these help build the genetic risk picture of Alzheimer's, though they need confirmation in larger and more diverse groups.

When Alzheimer's begins before age 65, doctors often look for a genetic cause. This report describes a 59-year-old woman with biomarker-confirmed early-onset Alzheimer's whose standard genetic tests (APP, APOE, PSEN1) were negative, but who carried a variant in CHMP2B, a gene involved in the cell's waste-recycling system and usually linked to frontotemporal dementia. The authors suggest this variant may act as a "modifier" influencing her disease. Cases like this widen understanding of the genes that can shape early-onset Alzheimer's.

Most searches for Alzheimer's risk genes look at single-letter DNA changes, but the genome also contains short repeated sequences that are harder to study. Using data from about 330,000 people, this study systematically tested these "short tandem repeats" and found 15 regions linked to Alzheimer's risk, including some not clearly seen before. Mapping these overlooked kinds of genetic variation deepens understanding of the inherited component of Alzheimer's and points to new biological mechanisms behind the disease.

A person's other genes shape how Alzheimer's unfolds, but most mouse models use a single genetic background. Researchers bred Alzheimer's-model mice onto a different genetic strain and showed they develop amyloid in blood-vessel walls, vascular dysfunction, and white-matter damage that more closely mirror human disease, and that crossing in different APOE gene variants altered the severity. The model gives researchers a more realistic, genetically varied tool for studying how inherited factors influence the blood-vessel side of Alzheimer's.

Some people who carry a strong familial-Alzheimer's mutation (in the PSEN1 gene) develop the disease later than expected, hinting at protective "modifier" genes. Researchers found that lower activity of a gene called SH3RF3 was linked to delayed Alzheimer's onset in PSEN1 carriers, and in lab studies reducing SH3RF3 calmed the inflammatory responses of microglia (the brain's immune cells). The finding points to a new potential drug target and helps explain why the same inherited mutation can affect family members differently.

The R47H change in the TREM2 gene is one of the strongest genetic risk factors for late-onset Alzheimer's. Using mice carrying this human variant, researchers found it disturbs fat and metabolite signaling not only in the brain but along a liver-blood-brain axis, with the earliest changes appearing in the liver and blood. The results suggest this Alzheimer's-risk gene has body-wide metabolic effects, and that blood-based measures might one day help track its influence.

This early-stage trial is testing ARO-MAPT-SC, an investigational therapy designed to lower production of the tau protein by quieting its gene (MAPT), in healthy volunteers and people with early Alzheimer's disease. Tau tangles are a core feature of Alzheimer's, so reducing tau at its genetic source is a precision approach being explored as a possible disease-modifying treatment. The study is assessing safety, how the drug behaves in the body, and its biological effects. Discuss eligibility with your care team.

Nearly everyone with Down syndrome carries an extra copy of the APP gene, giving them a very high genetic risk of Alzheimer's disease. The Trial-Ready Cohort-Down Syndrome (TRC-DS) enrolls healthy adults with Down syndrome, aged 25 to 55, for repeated memory testing, brain imaging, and genetic and biomarker measurements. The goal is to identify the best measures of early Alzheimer's changes so this group can join future prevention trials. It is observational. Families can ask the study team or their care team whether taking part makes sense.

The Dominantly Inherited Alzheimer Network (DIAN) is a long-running international study of families that carry a gene mutation (in PSEN1, PSEN2 or APP) causing early-onset, autosomal-dominant Alzheimer's disease. It follows adult relatives, both with and without the mutation, using brain scans, spinal-fluid and blood tests to find the earliest biological changes that predict the disease, sometimes years before symptoms. It is observational and does not test a drug, but it underpins prevention trials. Adult children of an affected parent may be eligible; ask your care team.

This trial is evaluating ALN-APP, an investigational gene-silencing therapy that lowers production of the amyloid precursor protein (APP), the source of the amyloid that builds up in Alzheimer's, in adults with early-onset Alzheimer's disease. Given by spinal injection, it aims to reduce amyloid at its genetic root rather than clearing plaques after they form. The study is testing safety, tolerability, and biological effects of single and repeated doses. Ask your care team whether you might be eligible.

This international treatment trial, part of the Dominantly Inherited Alzheimer Network Trials Unit (DIAN-TU), tests whether investigational drugs can prevent or slow Alzheimer's changes in people who carry an Alzheimer's-causing gene mutation. It measures whether treatment reduces build-up of amyloid, a hallmark brain protein, on PET scans, then tracks downstream markers of the disease. Adults aged 18 and older who are known to carry a familial Alzheimer's mutation, including those without symptoms yet, may be eligible. Discuss participation and genetic testing with your care team.

This study tests whether an investigational drug, NIO752, lowers the brain's production of tau, a protein that, in Alzheimer's disease, clumps into tangles inside nerve cells and drives symptoms. It uses a labelling technique (SILK) to measure tau production directly, and includes people with autosomal-dominant Alzheimer's caused by PSEN1, PSEN2 or APP mutations. Participants aged 21 to 80 with mild-to-moderate Alzheimer's may qualify. It is an early-stage study of a tau-lowering approach; talk with your care team about whether a trial like this fits you.

This trial focuses on members of the large Colombian family that carries the PSEN1 E280A gene mutation, which causes autosomal-dominant Alzheimer's disease. It studies whether the amyloid-clearing antibody donanemab, an experimental drug called RG6289, or their combination can remove or prevent amyloid-plaque build-up in the brain, measured by PET imaging over up to 18 months. Mutation carriers aged 25 to 65 are the focus. The study is not yet open for enrollment. Any decisions about genetic testing or treatment should be made with your own specialists.