Disrupted circadian rhythm a modifiable risk factor for Alzheimer’s disease?

Circadian rhythm disruption appears to precede the accumulation of amyloid-beta plaques and potentially represents a modifiable risk factor for Alzheimer's disease (AD), according to a study.

Analysis of data from the Rotterdam Study showed that stronger within-day fragmentation of the 24-hour activity rhythms, as indicated by higher intradaily variability at baseline, was associated with increased amyloid-beta burden 7.8 years later (p=0.02). [JAMA Neurol 2024;doi:10.1001/jamaneurol.2024.1755]

Of note, the observed association was stronger among APOE4 carriers (p=0.03) than noncarriers (p=0.19) and persisted in an analysis that excluded participants with AD pathology at baseline.

These results imply that irregular 24-hour activity patterns might serve as a precursor to the formation of amyloid-beta plaques, the investigators said.  “As APOE4 noncarriers accumulate Aβ pathology much later in life than carriers, we cannot exclude that rest-activity disturbances are also detrimental in noncarriers at older ages.” [Neuron 2019;101:820-838]

The present data are consistent with those of a cross-sectional study wherein a more fragmented 24-hour activity rhythm was found in amyloid-positive vs negative participants, as well as two prospective actigraphy studies showing that disrupted rest-activity rhythms preceded symptom onset in AD. [JAMA Neurol 2018;75:582-590; Sleep 2013;36:1027-1032; Ann Neurol 2011;70:722-732]

Disrupted sleep-wake cycle may lead to the accumulation of amyloid-beta protein in two ways, according to the investigators.

First, increased wakefulness due to fragmented sleep correlates with heightened neuronal activity, which in turn elevates soluble amyloid-beta levels. Over time, this excess soluble amyloid-beta can aggregate into harmful amyloid plaques, the investigators explained. Second, sleep is crucial for the efficient clearance of amyloid-beta through the glymphatic system, a process that removes brain waste. Disrupted sleep therefore hinders this cleansing process, allowing amyloid-beta to build up, they added.

The study included 639 participants (mean age at baseline 61.5 years, 47 percent female, 28.2 percent APOE4 carriers) without dementia who underwent Aβ positron emission tomography (PET) examination. Each participant wore an actigraph on the nondominant wrist for 7 consecutive days and nights and kept a daily sleep diary.

Twenty-four-hour activity rhythms were measured as interdaily (day-to-day) stability, intradaily variability (within-day fragmentation of the rhythms), and L5 start time (the hour of the day marking the start of the five consecutive hours with lowest activity). In addition, sleep was measured using four specific metrics, namely total sleep time, sleep onset latency, sleep efficiency, and wake after sleep onset.

No other sleep parameters, objectively measured or self-reported, were associated with amyloid-beta levels.

“Intervention trials will be needed to investigate whether reducing fragmentation of the rest-activity rhythms can prevent or slow AD progression,” the investigators said.