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Biomarkers evolved in a temporal sequence over 20 years in people who developed Alzheimer's disease, a nested case-control study in China showed.

Over a median follow-up of 19.9 years, cerebrospinal fluid (CSF) and imaging biomarkers changed in a specific order, with differences seen in people who subsequently were diagnosed with sporadic Alzheimer's disease and people who remained cognitively normal, reported Jianping Jia, MD, PhD, of Capital Medical University in Beijing, and co-authors in the .

Among nearly 1,300 adults ages 45 to 65, temporal trajectories showed:

• At 18 years before Alzheimer's diagnosis, CSF amyloid-beta 42 levels deviated between groups
• At 14 years, the ratio of CSF amyloid-beta 42 to amyloid-beta 40 diverged
• At 11 years, phosphorylated tau 181 CSF measures in the Alzheimer's group climbed
• At 10 years, CSF total tau rose
• At 9 years, CSF neurofilament light chain (NfL), a marker of axonal injury, increased
• At 8 years, hippocampal atrophy on MRI differed between groups
• At 6 years, cognitive decline was apparent in the Alzheimer's group based on Clinical Dementia Rating-Sum of Boxes (CDR-SB) assessments

As cognitive impairment progressed in the Alzheimer's disease group, CSF biomarker changes accelerated at first, and then slowed.

Biomarker changes in sporadic Alzheimer's disease were "similar in most respects to the temporal sequence of the appearance of differences of biomarkers in studies of autosomal dominant Alzheimer's disease, although the alterations in amyloid-beta 42 concentration became evident nearly a decade later in our study," Jia and colleagues noted.

The importance of this study "cannot be overstated," wrote Richard Mayeux, MD, of Columbia University in New York City, in an . "Knowledge of the timing of these physiological events is critical to provide clinicians with useful starting points for prevention and therapeutic strategies," he observed.

The accuracy of a clinical diagnosis of Alzheimer's disease has been controversial, Mayeux noted.

"The National Alzheimer's Coordinating Center reported data from the National Institute on Aging Alzheimer's Disease Centers that indicated that the sensitivity of clinical diagnosis ranged from 70.9 to 87.3% and specificity varied from 44.3 to 70.8%, as compared with the reference standard of pathological diagnosis at autopsy," he pointed out. Biomarkers can provide "an opportunity to improve diagnostic accuracy in Alzheimer's disease and to establish objective diagnostic criteria."

Jia and co-authors used data from a nested study in the nationwide prospective China Cognition and Aging Study (). Participants had CSF tests, cognitive assessments, and brain imaging at 2- to 3-year intervals. All were Han Chinese and were observed for more than 15 years, but not more than 20 years.

After propensity-score matching on age, sex, and education, 648 participants with Alzheimer's were successfully matched 1:1 with participants who remained cognitively normal at the last follow-up.

At baseline, participants had a mean age of about 61, and 50.6% were men. People eventually diagnosed with Alzheimer's were more likely than controls to carry an APOE4 allele (37.2% vs 20.4%).

Cognitive status was assessed at baseline and at each follow-up with three tests. Participants were considered to have no cognitive impairment if they scored 27 or higher on the Mini-Mental State Examination (MMSE, which ranges from 0 to 30, with higher scores representing better performance).

Scores of 12 or higher on the Logical Memory Test (LMT, which ranges from 0 to 25, with higher scores reflecting better memory) indicated normal baseline cognition. The third scale was the CDR-SB, which ranges from 0 to 18, with higher scores indicating greater impairment.

Baseline MMSE scores were about 29.5 in each group; LMT scores were 16.8, and CDR-SB scores were 0. At follow-up, cognitively normal was defined as consistently maintaining a CDR-SB score of 0.

In the Alzheimer's group, the progression of CSF markers appeared to accelerate initially, then peaked at an MMSE score of approximately 25 and an LMT score of approximately 11.

Because all participants were Han Chinese, the findings may not be generalizable to other populations, Jia and co-authors acknowledged. In addition, people with a familial history of Alzheimer's disease were excluded.

The study sample might not represent many older adults, the researchers noted. "The exclusion of participants with shorter follow-ups might have yielded a group resembling 'super-agers' -- persons endowed with higher education status, superior health status, and greater health awareness than persons not included in this study," they wrote.

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