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The APOE ε4 allele was linked to clinical expression and biomarkers of Alzheimer's disease in people with Down syndrome, a dual-center cohort study showed.

Among 464 adults with Down syndrome, APOE ε4 carriers showed earlier clinical symptoms of Alzheimer's and earlier changes in cerebrospinal fluid (CSF) amyloid beta (Aβ), amyloid PET, plasma phosphorylated tau 181 (p-tau181), cerebral glucose hypometabolism, and hippocampal atrophy compared with noncarriers, reported Alexandre Bejanin, PhD, of Hospital de la Santa Creu i Sant Pau in Barcelona, and co-authors.

"These results provide insights into the mechanisms by which APOE increases the risk of Alzheimer's disease, emphasizing the importance of APOE genotype for future clinical trials in Down syndrome," Bejanin and colleagues wrote in .

"We believe that this work is timely in the emerging landscape of preventive trials for dementia in Down syndrome given that consideration of APOE genotype might be important for drugs that are designed to lower amyloid burden and/or trials that use MRI as a surrogate marker of improved outcomes," they added.

People with Down syndrome have a high risk of developing Alzheimer's disease due to trisomy of chromosome 21, which harbors the amyloid precursor protein gene APP. A recent longitudinal study showed dementia was the proximate cause of death in 70% of adults with Down syndrome over 35 years old.

The APOE ε4 allele is the most established genetic risk factor for sporadic Alzheimer's disease. "APOE ε4 has been associated with less Aβ clearance, promotion of Aβ deposition, neuroinflammation, and possibly tau aggregation independently of Aβ," noted Cynthia Lemere, PhD, of Brigham and Women's Hospital and Harvard Medical School in Boston, and co-authors in an

"Carriers with Down syndrome have a higher cerebral amyloid load and experience Alzheimer's disease symptoms earlier than noncarriers," the editorialists pointed out. While ties between APOE ε4 and Alzheimer's symptoms and biomarkers have been described in sporadic and genetic early-onset Alzheimer's, little has been reported about associations in Down syndrome, they added.

The study looked at two cohorts of adults with Down syndrome -- one in Barcelona; the other in Cambridge, England -- from 2009 to 2020. Of 464 participants, 97 were APOE ε4 carriers and 367 were noncarriers. All were assessed for Alzheimer's symptoms including global cognitive and episodic memory tests for people with Down syndrome; a subset had biomarker measurements.

People with and without APOE ε4 were similar in age (about 44), sex (about 53% men), and level of intellectual disability. At age 40 to 45, 40% of APOE ε4 carriers with Down syndrome had symptomatic Alzheimer's, compared with 12% of noncarriers. Age at clinical diagnosis of Alzheimer's was 2 years earlier for carriers than noncarriers (50.7 versus 52.7 years). No individuals who carried the ɛ4 allele were older than 60.

CSF Aβ1-42 to Aβ1-40 ratios were reduced in APOE ε4 carriers by their early 20s. Amyloid PET showed increases in their mid-30s and 40s. CSF p-tau181 was similar between carriers and noncarriers, but carriers showed higher levels of plasma p-tau181 starting in their mid-40s.

No differences between carriers and noncarriers were observed in neurofilament light chain levels, a biomarker for neurodegeneration, in either plasma or CSF. "This finding may suggest that APOE affects the risk of conversion to dementia using a pathological pathway independent of neurofilament light chain," Lemere and colleagues noted.

Starting at around age 40, APOE ε4 carriers had reduced brain metabolism on fluorine 18-labeled fludeoxyglucose PET, especially in subcortical areas, medial temporal lobe, lateral parietal lobe, and occipital cortex. Metabolism was reduced in the striatum. MRI showed smaller hippocampal and right superior parietal cortical volumes beginning at around age 40 that coincided with onset of Alzheimer's symptoms.

Similarities in Alzheimer's biomarkers and their relationship to cognitive decline in people with and without Down syndrome "demonstrate that mutual benefits may be achieved by including people with Down syndrome in Alzheimer's disease clinical trials," the editorialists observed. "This vulnerable group has thus far been left behind, but delaying the onset of dementia would make a world of difference for people with Down syndrome and their families."

The study had several limitations, including its cross-sectional design and relatively small sample sizes for some biomarkers, Bejanin and co-authors acknowledged. The sample sizes also did not allow for differences among APOE genotypes to be evaluated.

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