In the Journals

Alzheimer's disease neurological biomarker patterns detectable in early middle age

Longitudinal cerebrospinal fluid Alzheimer’s disease biomarker patterns are detectable in early middle age — age 45 to 54 years — and are associated with later amyloid positivity and cognitive decline, according to study findings in JAMA Neurology.

“Clinicopathologic and more recent biomarker data suggest that [Alzheimer’s disease] pathology begins to accrue approximately 10 to 20 years before any cognitive signs or symptoms (termed asymptomatic or preclinical [Alzheimer’s disease]), thus providing a window of opportunity for the initiation of secondary prevention trials that aim to prevent the development of symptoms in individuals while they are still cognitively normal,” study researcher Courtney L. Sutphen, BS, of Washington University in St. Louis, and colleagues wrote. “How early during the normal life span such pathologies begin to develop, their patterns of change over time, and their relationship with future cognitive decline remain to be determined.”

To assess individual changes in trajectories of biomarkers of Alzheimer’s disease in cerebrospinal fluid over time and their association with changes in brain amyloid deposition and cognitive decline, researchers evaluated 169 middle-aged participants enrolled in the Adult Children Study at Washington University. Cerebrospinal fluid collection and longitudinal clinical assessment took place at 3-year intervals between January 2003 and November 2013. A subset of participants (n = 74) also underwent longitudinal amyloid positron emission tomographic imaging. Researchers used linear mixed modeling to compare biomarker patterns among participants at ages 45 to 54 years, 55 to 64 years and 75 to 74 years.

There were no consistent longitudinal patterns in Aβ40, though longitudinal reductions in Aβ42 were observed in some individuals as early as early-middle age (age 45 to 54 years) (P ≤ .05).

Low levels of Aβ42 were associated with the development of cortical amyloid plaques positive for Pittsburgh compound B, particularly during mid-middle age (age 55 to 64 years) (P < .001).

Neural injury markers significantly increased among some individuals in mid- and late-middle age (P ≤ .02), while the neuroinflammation marker YKL-40 consistently increased throughout middle age (P ≤ .003).

These patterns were more apparent in at-risk individuals carrying the APOE-ε4 gene and were associated with future cognitive deficits, according to researchers.

“The present groupwide analyses are supportive of a preclinical period of [Alzheimer’s disease] in which biomarker patterns consistent with underlying disease pathology are first detectable during middle age, the timing of which is influenced by APOE genotype, with amyloid changes occurring prior to neuronal injury. However, proposals to use biomarkers in clinical settings require demonstration of their utility on a patient-by-patient basis,” Sutphen and colleagues concluded. – by Amanda Oldt

Disclosure: Sutphen reports no relevant financial disclosures. Please see the full study for a list of all other authors’ relevant financial disclosures.

Longitudinal cerebrospinal fluid Alzheimer’s disease biomarker patterns are detectable in early middle age — age 45 to 54 years — and are associated with later amyloid positivity and cognitive decline, according to study findings in JAMA Neurology.

“Clinicopathologic and more recent biomarker data suggest that [Alzheimer’s disease] pathology begins to accrue approximately 10 to 20 years before any cognitive signs or symptoms (termed asymptomatic or preclinical [Alzheimer’s disease]), thus providing a window of opportunity for the initiation of secondary prevention trials that aim to prevent the development of symptoms in individuals while they are still cognitively normal,” study researcher Courtney L. Sutphen, BS, of Washington University in St. Louis, and colleagues wrote. “How early during the normal life span such pathologies begin to develop, their patterns of change over time, and their relationship with future cognitive decline remain to be determined.”

To assess individual changes in trajectories of biomarkers of Alzheimer’s disease in cerebrospinal fluid over time and their association with changes in brain amyloid deposition and cognitive decline, researchers evaluated 169 middle-aged participants enrolled in the Adult Children Study at Washington University. Cerebrospinal fluid collection and longitudinal clinical assessment took place at 3-year intervals between January 2003 and November 2013. A subset of participants (n = 74) also underwent longitudinal amyloid positron emission tomographic imaging. Researchers used linear mixed modeling to compare biomarker patterns among participants at ages 45 to 54 years, 55 to 64 years and 75 to 74 years.

There were no consistent longitudinal patterns in Aβ40, though longitudinal reductions in Aβ42 were observed in some individuals as early as early-middle age (age 45 to 54 years) (P ≤ .05).

Low levels of Aβ42 were associated with the development of cortical amyloid plaques positive for Pittsburgh compound B, particularly during mid-middle age (age 55 to 64 years) (P < .001).

Neural injury markers significantly increased among some individuals in mid- and late-middle age (P ≤ .02), while the neuroinflammation marker YKL-40 consistently increased throughout middle age (P ≤ .003).

These patterns were more apparent in at-risk individuals carrying the APOE-ε4 gene and were associated with future cognitive deficits, according to researchers.

“The present groupwide analyses are supportive of a preclinical period of [Alzheimer’s disease] in which biomarker patterns consistent with underlying disease pathology are first detectable during middle age, the timing of which is influenced by APOE genotype, with amyloid changes occurring prior to neuronal injury. However, proposals to use biomarkers in clinical settings require demonstration of their utility on a patient-by-patient basis,” Sutphen and colleagues concluded. – by Amanda Oldt

Disclosure: Sutphen reports no relevant financial disclosures. Please see the full study for a list of all other authors’ relevant financial disclosures.