Targeting the cardiometabolic bottleneck to slow polypathology and cognitive decline

1.

Vascular contributions to cognitive impairment and dementia, along with their associated risk factors, are recognized drivers of cognitive decline and Alzheimer's disease (AD) and related dementias (ADRD). ¹ Several modifiable cardiometabolic conditions (diabetes, hypertension, and dyslipidemia) are significant predictors of dementia, and intervening on them could reduce the global public health burden. ² Neuropathologic studies consistently demonstrate that mixed pathologies are the rule rather than the exception in older adults, with vascular neuropathologies—perhaps being “the elephant in the room”—co‐occurring with amyloid plaques (neuritic and diffuse), neurofibrillary tau tangles, and α‐synuclein deposits. ³ In our recent article, we reported that arteriolosclerosis at autopsy is independently associated with cross‐sectional memory, executive function, and language deficits, even after accounting for AD and Lewy body dementia pathology. ³ Importantly, these associations were observed in a selective sample of decedents without severe dementia (Clinical Dementia Rating < 3), indicating vascular pathology is relevant in earlier disease stages when therapeutic interventions may be most beneficial.

We are encouraged and appreciate the positive commentary, “The cardiometabolic ‘bottleneck’ on cognitive function in aging.” It is well established that the preclinical phase of AD begins nearly two decades before clinical diagnosis. ⁴ Less often discussed is that this early accumulation of AD pathology, which is causally linked to memory decline, is accompanied by mid‐life, modifiable risk factors (e.g., diabetes, hypertension, dyslipidemia, smoking) highlighted by the Lancet Commission as drivers of vascular neuropathology (Figure 1). ² Although therapeutic efforts largely focus on removing amyloid beta plaques or other targeted mechanisms, the key question remains: In older adults with co‐existing pathologies, if we eliminate only one pathology, to what extent can cognitive performance be rescued?

FIGURE 1.

Conceptual model connecting the bottleneck of cardiometabolic risk factors, neuropathologic co‐pathologies, and accelerated biomarker and cognitive decline. Left, Modifiable cardiometabolic conditions and risk factors identified by the 2024 Lancet Commission, ² with estimated PAFs for dementia, including hypertension, diabetes, obesity/BMI, smoking/alcohol use, physical inactivity, and increased lipids. Middle, Common neuropathologic lesions observed at autopsy, grouped by primary etiology—ADNC (red), vascular (green), LBD (purple), and mixed ADNC + vascular (orange). These co‐pathologies frequently co‐occur, amplifying cognitive decline. Right, Adapted from Jack et al., ⁴ showing hypothetical biomarker trajectories for amyloid PET, MTL tau, neocortical tau, neurodegeneration, and cognition. Co‐existing pathologies are proposed to shift biomarker and cognitive decline earlier in the disease course (leftward arrow), increasing the duration of symptomatic disease and earlier cognitive decline. ADNC, Alzheimer's disease neuropathologic change; BMI, body mass index; LBD, Lewy body disease; MTL, medial temporal lobe; PAF, population‐attributable fractions; PET, positron emission tomography

Implementing targeted interventions at a younger age can simultaneously reduce cardiometabolic diseases and the risk of cognitive impairment. Non‐pharmacological interventions such as diet and exercise aimed at preventing cognitive decline can also prevent and better manage cardiometabolic risk factors, thereby reducing vascular and dementia risk, emphasizing the overlap in these risk profiles. ⁵ Consequently, multimodal interventions and above all primary prevention at the cardiometabolic bottleneck offers a promising mechanism to mitigate cognitive decline across several other pathways including vascular neuropathology and AD, which is likely to lead to more success addressing disease at its roots.

Our study demonstrates that not all vascular neuropathologies have the same impact on cognition; arteriolosclerosis was the only vascular pathology consistently associated with cognitive decline independent of AD and Lewy body disease. Arteriolosclerosis reflects chronic small vessel wall changes, which may cause diffuse cerebral hypoperfusion and microstructural white matter injury even without large infarcts, thereby disrupting multiple cognitive networks simultaneously and producing measurable cognitive effects. Recent findings and their discussion indicated that arteriolosclerosis measured in vivo was associated with certain cardiometabolic risk factors and an increased risk for mild cognitive impairment and dementia. ⁶ Thus, our previous findings underscore the need for in vivo markers and therapeutic strategies specifically targeting arteriolosclerosis as well as further mechanistic study to understand why this pathology specifically affects cognition.

Most neuropathological data come from cohorts that are majority non‐Hispanic White, limiting generalizability. ⁷ Therefore, addressing health disparities in underserved communities such as American Indian, African American/non‐Hispanic Black, and Hispanic populations is critical, because these groups have higher AD dementia prevalence and earlier cognitive decline driven by elevated cardiometabolic risks. ⁸ The elevated mid‐life cardiometabolic burden accelerates cognitive decline and increases in onset of other neuropathologies could also explain why the effect of apolipoprotein E ε4 on cognition is not uniform across racial and ethnic groups. ⁹ Overall, racial and ethnic disparities in cognition, potentially driven by modifiable risk factors, underscore the cardiometabolic bottleneck as an actionable target to reduce cognitive impairment and improve global health.

Regarding this bottleneck, certain populations and regions are more susceptible to cardiometabolic risk factors for a variety of reasons including those captured by structural and social determinants. ⁸ , ¹⁰ However, we must note that there is minimal evidence that these factors are on the causal pathway to cognitive impairment but instead may contribute to a percentage of the risk for cognitive impairment across groups. Ultimately, given the rarity of “pure” pathology in older adults, a major question in the field is whether targeting the cardiometabolic bottleneck reduces vascular neuropathology and, secondarily, amyloid, tau, or α‐synuclein pathology.

Although AD is the most commonly diagnosed cause of dementia, autopsy studies show that the majority of older adults exhibit two or more co‐occurring vascular neuropathologies at death. ³ This accumulation reinforces the idea that mid‐life, modifiable cardiometabolic risk creates a critical choke point and that combinatorial therapies targeting multiple pathologies may be most effective in curbing the global dementia pandemic (Figure 1).

CONFLICT OF INTEREST STATEMENT

The authors declare no conflicts of interest. The authors have no disclosures related to the research manuscript.

2.

Author disclosures are available in the supporting information.

Supporting information

Supporting Information