Earlier Onset, Worse Disease

Researchers have discovered that people with spontaneous early onset Alzheimer’s disease have worse cognitive impairment at diagnosis than those with the more common late onset disease. These results from a study analyzing a group of National Alzheimer's Coordinating Center (NACC) participants who were co-enrolled in the Longitudinal Early Onset Alzheimer’s Disease Study (LEADS) suggest that earlier screening and more aggressive treatment may help these patients and identify a clinical trial strategy that could accelerate development of therapies for both forms of the disease. 

Launched in 2018 by Liana Apostolova, MD, Maria Carillo, PhD, Brad Dickerson, MD, and Gil Rabinovici, MD, LEADS focuses on a population that is underrepresented in other studies. “It’s specifically looking at patients who do not have an established genetic predisposition [to Alzheimer’s disease] … these are just individuals who happen to develop it younger,” says Dustin Hammers, PhD, the lead author on the new study, which appears in Alzheimer’s & Dementia. Hammers is also an Associate Professor of Neurology at Indiana University School of Medicine and a Clinical Core co-leader of both the LEADS study and the Indiana ADRC. 

Investigators define early onset as Alzheimer’s disease that becomes clinically apparent in people under 65. While genetics can play a major role in Alzheimer’s disease overall, many develop the condition without obvious risk factors. “Only about 5% of people with Alzheimer’s disease develop it this young, so it’s hard to recruit participants. What LEADS has done has been to pool a lot of those centers throughout the United States to make sense of what is happening,” says Hammers. 

Earlier observations had identified different cognitive profiles for people with early and late onset disease, so Hammers and his colleagues wanted to study that phenomenon in a large, well-characterized cohort. Because LEADS is connected with the NACC dataset, it had exactly what the team needed. “Many people in LEADS are co-enrolled in NACC, so they get the [Uniform Data Set] battery. They get all the standard measures that would be administered in NACC, so it’s allowed us to make good comparisons to traditional AD onset,” says Hammers. 

Besides being broad, the combined dataset is also deep. “It’s such a rich resource and NACC is great to work with about data sharing, so it’s been quite a positive experience,” says Hammers.

The data also revealed another correlation. “The more we started digging into this, we realized that the differences seem to be even more pronounced, depending on not only whether you were just looking at early versus late [onset], but if you are considering how early people are developing this,” says Hammers. The earlier the onset, the worse the disease. 

That suggests that current screening and treatment guidelines may need revision. “There’s not a great scientific rationale why we use 65 as the cutoff age,” says Hammers, adding that “these results would suggest that there’s actually a pretty big urgency and 65 might be a later than we should start screening.” 

While he concedes that screening everyone over the age of 40 for Alzheimer’s disease would require a major adjustment in the healthcare system, it could also help advance the study and treatment of both forms of the condition. “We are showing that people are declining a lot faster with early onset Alzheimer’s disease than late onset, [so] we might actually be able to understand the impacts of FDA approved medications better if we consider them in younger populations,” says Hammers. 

Faster progression could reveal a drug’s efficacy sooner, and earlier treatment could make a bigger difference for the younger group. The researchers are already using the combined dataset to find a cohort of candidates for future clinical trials, and to help participants access current disease-modifying treatments. 

Hammers DB, Eloyan A, Thangarajah M, Taurone A, Gao S, Beckett L, Kirby K, Dage JL, Nudelman K, Aisen P, Reman R, Vemuri P, La Joie R, Touroutoglou A, Atri A, Clark D, Day GS, Duara R, Graff-Radford NR, Honig LS, Jones DT, Masdeu JC, Mendez MF, Womack K, Musiek E, Onyike CU, Riddle M, Grant I, Rogalski E, Johnson ECB, Salloway S, Sha SJ, Turner RS, Wingo TS, Wolk DA, Carrillo MC, Dickerson BC, Rabinovici GD, Apostolova LG; LEADS Consortium; Alzheimer's Disease Neuroimaging Initiative. Relationship between age and severity of cognitive impairment at diagnosis for early-onset and late-onset Alzheimer's disease: Comparison of LEADS and ADNI. Alzheimers Dement. 2026 Feb;22(2):e71160. doi: 10.1002/alz.71160. PMID: 41614286; PMCID: PMC12856522.