Adult Changes in Thought study: dementia is an individually varying convergent syndrome with prevalent clinically silent diseases that may be modified by some commonly used therapeutics

Abstract

The Adult Changes in Thought (ACT) study is a longitudinal population-based prospective cohort study of brain aging and incident dementia in the Seattle metropolitan area. Observational studies using autopsies from ACT indicate that dementia is a convergent syndrome that commonly derives from Alzheimer's disease (AD), microvascular brain injury (mVBI), and Lewy body disease (LBD), and that these diseases have prevalent subclinical forms that also are commonly co-morbid. The existence of subclinical diseases highlights potential opportunities to intervene before the development of clinically apparent impairments. Our observations suggest that some such interventions already may exist to suppress processes of AD (statin therapy) or mVBI (treatment of hypertension). Reduced burden of LBD is associated with cigarette smoking; although smoking is not recommended as an intervention, these exposure data may provide clues to alternative neuroprotective mechanisms. Self reported anti-oxidant supplementation was without apparent effect in this cohort on indices of AD, mVBI, or LBD. Continued observational studies of brain aging will provide further insight into the convergent complexity of the dementia syndrome and its subclinical forms as well as highlight potential interventions that will require validation in clinical trials.

Figure 1

Pie chart of the population-attributable risk for dementia in the ACT cohort. AD: Alzhemier’s disease as assessed by Braak stage for NFT V or VI; μVBI: microvascular brain injury as assessed by > 2 cerebral microinfarcts; LBD: isocortical Lewy body disease as assessed by a-synuclein immunohistochemistry for any Lewy body in the frontal or temporal cortex. Chart presents point estimates for the population-attributable risk for dementia.

Figure 2

Cumulative relative frequency (CRF) of the summary neuropathology score calculated from the sum of: (i) Braak stage for NFTs expressed as a number (0 to 6) divided by 2 to give values of 0, 0.5, 1, 1.5, 2, 2.5, and 3; (ii) number of CMIs with > 3 expressed as 3 to give a values of 0, 1, 2, or 3; and (iii) LBD coded as 0 (none), 1 (brainstem), 2 (limbic), or 3 (isocortical). This summary neuropathology score reflects the combined burden of Alzheimer’s disease, microvascular brain injury, and Lewy body disease, respectively, in ACT participants stratified by cognitive function as assessed by CASI within two years of death. Dashed red line shows CRF 50% (horizontal) and the corresponding summary neuropathology score for each group (vertical).

Figure 3

Summary neuropathology score (determined as explained in Figure 2) was ranked from lowest to highest for (A) each ACT participant diagnosed with dementia or for (B) each ACT participant with high cognitive function within two years of death (ND & CASI > 90). The burden of disease(s) in each individual is color coded.