medwireNews: Abnormal changes in cerebrospinal fluid (CSF) and imaging biomarkers can precede a diagnosis of sporadic Alzheimer’s disease (AD) by up to 18 years, a longitudinal study in China has discovered.
The results showed that the earliest changes, compared with individuals who do not develop AD, are a significant drop in CSF amyloid-beta (Aβ)42 levels, occurring an estimated 18 years prior to diagnosis, followed by a decrease in the ratio of Aβ42 to Aβ40 at an estimated 14 years beforehand.
Jianping Jia (Capital Medical University, Beijing) and colleagues note in The New England Journal of Medicine that the emergence of a difference in Aβ42 levels between patients who develop AD and those who do not is “nearly a decade later in our study” of sporadic AD patients compared with studies of individuals with autosomal dominant AD.
“Therefore, the timing of the appearance of changes in biomarkers may differ between sporadic and autosomal dominant Alzheimer’s disease,” they say.
For the nested case–control study conducted as part of the China Cognition and Aging Study, the researchers enrolled Han Chinese participants aged between 45 and 65 years (mean 61 years) with no cognitive deficits, based on a Clinical Dementia Rating Scale–Sum of Boxes (CDR–SB) of 0.
The baseline scores on the Mini Mental State Examination (MMSE) were a mean 29 points out of a possible 30 points, where scores under 25 indicate possible cognitive impairment.
Jia and colleagues report that people with a family history of AD were intentionally excluded from the study to “mitigate the potential confounding effects of genetic factors, thereby diminishing the proportion of APOE [apolipoprotein E] ε4 carriers within the cohort,” the rates of which were 37.2% in the AD group and 20.4% in the control group.
Over a median follow-up of 19.9 years, the investigators analyzed participants’ clinical records, CSF samples, neuropsychological tests, and brain magnetic resonance imaging (MRI) results every 2 to 3 years, comparing the outcomes of participants who developed AD with those of participants matched for age, sex, and education level who did not (n=648 both groups).
At baseline (20 years before diagnosis), the two groups had similar levels of the various biomarkers. But at 18 years prior to diagnosis, mean levels of CSF Aβ42 in the AD group were a significant 59.13 pg/mL lower than those in the control group, and the mean Aβ42/40 ratio was a significant 0.01 pg/mL lower in the AD group at 14 years before diagnosis.
The AD group also began to show significantly elevated levels of CSF phosphorylated (p)-tau 181 and total tau at 11 and 10 years before diagnosis compared with controls, at respective means of 7.10 pg/mL and 87.10 pg/mL, while CSF neurofilament light chain (NfL) levels began to increase significantly more in the AD group from 9 years before diagnosis, at which point the mean difference was 228.29 pg/mL.
“Visual inspection of the curves of concentrations of each CSF marker showed that these differences continued to widen over time,” the investigators comment.
At 8 years before diagnosis, there was a significantly greater decline in combined bilateral hippocampal volume in the AD group versus controls, at a mean 358.94 mm3. And scores on the CDR–SB significantly differed in the AD group versus controls from an estimated 6 years when there was a 0.33-point difference in scores.
Among participants who developed AD, the annual rate of change in CSF levels of Aβ42, Aβ42/40 ratio, and CSF p-tau 181, and total tau concentrations all initially accelerated with cognitive decline, as measured using the MMSE and Logical Memory Test Score (LMT; ranging from 0 to 25 points with higher scores indicating better cognition), and then plateaued, “despite further decline in cognitive scores,” the researchers observe.
Changes in CSF Aβ42 concentration and CSF Aβ42/40 ratio peaked at MMSE scores of around 25 points and LMT scores of around 11 points, and changes in total tau concentration and p-tau 181 concentration peaked at MMSE scores of around 27 points and LMT scores of around 13 points.
In an editorial related to the study, Richard Mayeux (Columbia University, New York, USA) says that “[t]he importance of the work by Jia et al cannot be overstated.”
He continues: “Knowledge of the timing of these physiological events is critical to provide clinicians with useful starting points for prevention and therapeutic strategies.”
While Mayeux acknowledges that the study was limited to people of Han Chinese ancestry, he stresses that this fact “does not lessen the effect of the results reported by Jia et al. It merely highlights that similar studies must continue and must be inclusive of other groups.”
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