Limits of a brain-centric model

For over a century, dementia has been seen as a brain disease. Yet this brain-centric model has delivered limited clinical success. While therapeutic efforts target its defining features of neural tissue-protein aggregation, synaptic loss, and neuronal death, interventions effectively eliminating amyloid-β and tau, only confer modest efficacy by slowing disease progression by 20–30% in a selected clinical trial population [1,2]. These limitations raise a fundamental question: are current therapeutic targets the primary drivers of dementia? The discordance between therapeutic removal and minimal-to-modest effect on functional outcomes suggests a deeper problem with how dementia is conceptualized. Is dementia really a brain disease?

Dementia as a systemic energetic failure with epidemiological evidence

An alternative, plausible explanation is that dementia is the late-life clinical manifestation of a progressive systemic energy dysregulation. The brain represents the target organ through which systemic energetic dysregulation manifests pathologically. Neurological deficits occur in the background of biological aging and brain-specific susceptibility, shaped by genetic and epigenetic modifications [3]. Declining metabolic and vascular health across the life course closely parallels cognitive decline [4]. Metabolic and vascular conditions that impair systemic energy homeostasis, particularly during midlife, including diabetes, hypertension, and dyslipidemia, are consistently associated with an increased risk of dementia [4] and are also linked to Alzheimer’s disease and cerebrovascular pathology [5]. A healthy brain requires the integrity of physiological systems that regulate energy production and distribution. Factors associated with efficient energy utilization and delivery, such as physical activity and cardiovascular fitness, are among the most robust protective factors of brain aging and neurodegeneration [6]. These observations point to a systemic energetic failure as the primary pathogenic mechanism of dementia (Fig 1).

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Fig 1. Systemic energy failure as a hypothesized pathogenic mechanism of dementia.

https://doi.org/10.1371/journal.page.0000035.g001

Mechanistic convergence on energy dysregulation

Mechanistically, brain has exceptionally high metabolic demands and depends on the continuous delivery of oxygen and nutrients through a highly efficient and plastic vascular network. Consequently, the vascular system occupies a central position at the intersection of energy dysregulation and neurodegeneration [7]. Multiple aging processes converge on this energetic axis: brain insulin resistance reduces the efficiency of cellular energy utilization; vascular dysfunction limits the delivery of oxygen and metabolic substrates; and chronic inflammation disrupts homeostatic signaling while increasing metabolic demand [8]. Together, these alterations create a state of energetic insufficiency compromising neuronal function, impairing resilience to stress, and ultimately contributing to the development of dementia.

Subtle signs of aging, such as deficits in sensorimotor function, such as slow gait, oculomotor deficit, impaired olfaction–are early indicators of future cognitive decline [9]. These seemingly distinct aging phenotypes may share common systemic drivers, including inflammation, impaired lipid metabolism, vascular pathology, and compromised mitochondrial health [10,11]. They are components of a system responsible for maintaining energy homeostasis and this system progressively loses efficiency within aging and diseases, narrowing the margin within which organs can function.

The brain as the most energy-vulnerable organ

The brain operates closest to this margin. It consumes a disproportionate share of the body’s energy relative to its weight, yet it has no reserve and minimal tolerance for fluctuation. Its function depends on the continuous, precisely regulated delivery and utilization of energy substrates [12]. Even minor or modest energy dysregulation, well within the range produced by common metabolic disorders, can lead to a chronic cerebral energy deficit. The consequence is not immediate cell death but rather the activation of stress-response mechanisms, such as the unfolded protein response and integrated stress response. While the initial stress response is compensatory, it triggers a gradual erosion of synaptic function and neuronal network integrity over time.

From energy deficit to structural and functional decline

Chronic energy insufficiency is unlikely to affect neuronal function only. A sustained deficit in cellular energy availability has downstream consequences for tissue maintenance and repair, promoting cellular senescence, impaired proteostasis, and extracellular matrix remodeling. Senescent cells alter the composition and physical properties of the extracellular environment, favoring fibrosis, collagen deposition, and cross-linking [13]. These changes increase tissue stiffness, disrupt microvascular function, impair perfusion and oxygen delivery, which ultimately, affecting mitochondrial health and further energy sufficiency [14].

The aging brain—considered less fibrotic than other organs—shows measurable changes in extracellular matrix composition, basement membrane thickening, and vascular stiffening. These alterations contribute to impaired neurovascular coupling and reduced adaptability of cerebral blood flow. Here, extracellular matrix remodeling may represent a critical intermediate step linking systemic energetic failure to impaired brain function.

Rethinking hallmarks of dementia

Defining features of dementia, such as protein aggregation, synaptic loss, and neuronal death, may represent downstream manifestations or footprints of prolonged energetic insufficiency, as brain is the most energy-dependent organ. The progressive metabolic dysregulation across interconnected brain and peripheral systems is fundamentally driven by declining mitochondrial health. This helps explain a long-standing paradox: why resilient individuals with substantial neuropathology can remain cognitively intact, while others with less pathologies develop severe symptoms of cognitive impairment. These differences may arise from the organism’s capacity to maintain energy homeostasis. Evidently, preserved mitochondrial biogenetics is shown to distinguish those without symptoms from those exhibiting symptoms in the presence of Alzheimer’s disease pathology [15].

Clinical and research implications

If this view is correct, treating dementia by targeting isolated molecular features within the brain may be fundamentally misdirected. A failing energy-regulation system cannot be rescued by correcting a single downstream lesion. Prevention and treatment must instead focus on preserving energetic resilience and maintaining the capacity to efficiently produce, distribute, and utilize energy across the life course. The consistent link between midlife metabolic-vascular health and preservation of brain function into late life suggests that the brain may track the body’s ability to meet its energy demands decades before cognitive symptoms.

This view does not imply that brain-specific processes are irrelevant, nor that all dementias are the same. Genetic forms and neurodegenerative mechanisms clearly exist. Etiologically distinct forms of dementia may represent special cases within a broader framework of systemic energetic failure as a dominant driver of late-life cognitive impairment. The brain, by operating at the limits of energetic stability, is where that failure becomes impossible to ignore.

Acknowledgments

This research was supported entirely by the Intramural Research Program of the National Institute on Aging, National Institutes of Health (NIH). The contributions of the NIH authors are considered Works of the United States Government. The findings and conclusions presented in this paper are those of the authors and do not necessarily reflect the views of the NIH or the U.S. Department of Health and Human Services. We would like to acknowledge Visual Media Specialist Marc Raley for his assistance with the figure.