Alzheimer’s Biomarkers Linked to Mood, Gait, Hearing and Strength Before Memory Fails

Alzheimer’s disease has long been framed as a disorder of memory, but a sweeping new review argues that the disease’s molecular fingerprints reach far beyond cognition, shaping mood, movement, hearing, strength and vitality in older adults long before dementia declares itself. The analysis, published in the journal GeroScience, pulls together 119 human studies to ask a deceptively simple question: do the proteins and brain changes that define Alzheimer’s biology also track with the non-cognitive dimensions of what researchers call intrinsic capacity, the composite of physical and mental attributes that the World Health Organization places at the heart of healthy ageing?

The review was led by Xiaoxia Wei of the Chinese Academy of Medical Sciences and Peking Union Medical College, working with Ruitai Shao, Yves Rolland, Bruno Vellas and Philipe de Souto Barreto, a team anchored at IHU HealthAge in Toulouse, France. The authors conducted a structured PubMed search with a final cutoff of December 31, 2025, and formally appraised study quality using the Newcastle-Ottawa Scale and the Joanna Briggs Institute checklist, finding acceptable methodological quality for most of the included research. Their conclusion is striking in its breadth: Alzheimer’s-related pathology and neurodegeneration appear to have functional correlates beyond cognition, with the pattern of associations varying by biomarker type, by the capacity domain examined and by study design.

To understand why this matters, it helps to unpack the two pillars of the analysis. Intrinsic capacity, a concept championed by the WHO in its 2015 world report on ageing and health, describes the sum total of an individual’s locomotion, cognition, vitality, psychological well-being, hearing and vision. It is increasingly measured as a composite score that predicts disability, hospital admission and mortality. Alzheimer’s biomarkers, meanwhile, now span a well-validated arsenal: amyloid-beta and tau proteins measured in cerebrospinal fluid or blood, neurofilament light chain as a marker of neuronal injury, glial fibrillary acidic protein as a gauge of astrocytic activation, structural MRI to quantify atrophy, and fluorodeoxyglucose positron emission tomography to map the brain’s faltering glucose metabolism. The 2024 revised diagnostic criteria from the Alzheimer’s Association have pushed the field toward defining the disease biologically, which makes the question of what those biology markers do to everyday function increasingly urgent.

The evidence on composite intrinsic capacity scores remains thin, with only two studies addressing it directly, but the longitudinal signals are provocative. Lower intrinsic capacity was associated with elevated plasma p-tau181, a phosphorylated form of tau protein that has become one of the most reliable blood indicators of Alzheimer’s pathology. Higher baseline neurofilament light chain predicted steeper subsequent decline in intrinsic capacity over follow-up, suggesting that ongoing neuronal injury may be a harbinger of global functional deterioration. Notably, the ratio of plasma amyloid-beta 42 to amyloid-beta 40 showed no clear association with composite capacity, hinting that amyloid burden alone may be a weaker predictor of whole-person function than tau and neurodegeneration markers, a hierarchy that mirrors what the field has learned about cognition itself.

Locomotion emerged as one of the most consistently mapped domains, examined in 30 of the included studies. Higher cerebral amyloid-beta deposition was associated with poorer locomotion, especially slower gait speed, more consistently than any other biomarker modality. This finding aligns with a growing body of work showing that gait slowing can precede cognitive decline by several years and that amyloid burden predicts lower extremity performance decline even in cognitively unimpaired older adults. Studies from cohorts including the Atherosclerosis Risk in Communities study and memory clinic populations in Norway linked cerebrospinal fluid amyloid and tau to mobility measures, while imaging work connected regional brain amyloid to gait speed in elderly individuals without dementia. The mechanistic picture is still forming, but the convergence of PET imaging, fluid biomarkers and performance-based measures paints amyloid as a quiet saboteur of movement.

Handgrip strength and vitality, the domain encompassing energy, nutrition and muscle function, told a complementary story. Higher levels of tau biomarkers and neurofilament light chain were more often associated with lower or declining handgrip strength across the reviewed literature. A 12-year cohort study published in The Lancet Healthy Longevity traced blood biomarkers of Alzheimer’s disease against long-term muscle strength trajectories in community-dwelling older adults, and separate analyses found neurofilament light chain elevated in patients with severe sarcopenia and associated with muscle mass and strength in middle-aged and older adults. Neurofilament light chain, which leaks into blood when axons are damaged, appears to function as a shared signal of nervous system wear that registers in the grip of a hand as much as in a memory test.

Depressive symptoms were the most intensively studied non-cognitive domain, appearing in 49 of the 119 studies, and they produced some of the review’s most consistent longitudinal findings. Lower fluid amyloid-beta 42, greater cerebral amyloid deposition and subsequent brain atrophy were all linked to depressive symptoms over time. The relationship runs in both directions conceptually: some studies found that amyloid burden predicted incident depressive symptoms in cognitively normal older adults, while others documented that depressive symptom trajectories tracked with amyloid and cerebral glucose metabolism. Work from the Framingham Heart Study connected midlife depressive symptoms with regional amyloid and tau decades later, and a 2025 study found depressive symptoms correlating with tau accumulation rates in amyloid-positive adults. The authors caution that disentangling depression as prodrome, consequence or comorbidity of Alzheimer’s biology remains one of the field’s thorniest challenges, but the longitudinal consistency of the amyloid and atrophy signals suggests the association is not merely reverse causation or shared vascular risk.

Hearing impairment, examined in 29 studies, was linked mainly to higher tau and neurofilament light chain, reduced glucose metabolism on FDG-PET, and brain atrophy. Longitudinal work showed that age-related hearing loss accelerated cerebrospinal fluid tau levels and brain volume loss, and large imaging analyses associated hearing impairment with smaller total brain volume, temporal lobe volume loss and hippocampal shrinkage. Yet the amyloid story for hearing is muddled: several studies found no link between hearing loss and cerebrospinal fluid amyloid-beta or p-tau181, and at least one reported no influence of hearing loss on brain amyloid at all. This modality-specific divergence matters, because it suggests that different sensory and functional declines may index different arms of the Alzheimer’s pathophysiological cascade, with hearing tracking neurodegeneration more tightly than amyloidosis. Evidence for vision impairment was almost totally absent, with a single study addressing it, a gap the authors flag as a priority for future research.

The review’s implications cut in two directions. Clinically, if biomarkers of Alzheimer’s biology predict declines in gait, grip, mood and hearing, then blood tests that are rapidly entering routine practice could eventually help identify older adults at risk of losing functional independence, not just those at risk of memory loss, and interventions targeting intrinsic capacity could be timed against measurable pathology. Scientifically, the findings reinforce a view of Alzheimer’s as a whole-body, whole-life process rather than a purely cognitive one, echoing the Lancet Commission’s emphasis on dementia prevention across the life course. The authors are careful about limitations: the evidence is largely observational, heterogeneous in design, and heavily weighted toward cross-sectional analyses, with longitudinal data scarce for several domains. Still, with reference centiles for intrinsic capacity now available for monitoring health outcomes in primary care, the prospect of pairing a simple capacity assessment with a blood draw to catch functional decline early is moving from speculative to plausible, and this synthesis provides the evidentiary map for getting there.

Subject of Research: Associations between Alzheimer's disease biomarkers and non-cognitive domains of intrinsic capacity in older adults

Article Title: Alzheimer’s disease biomarkers in relation to non-cognitive domains within the intrinsic capacity framework: a narrative review

Article References: Wei, X., Shao, R., Rolland, Y., Vellas, B., & de Souto Barreto, P. (2026). Alzheimer’s disease biomarkers in relation to non-cognitive domains within the intrinsic capacity framework: a narrative review. GeroScience. https://doi.org/10.1007/s11357-026-02544-w

Image Credits: AI Generated

DOI: 10.1007/s11357-026-02544-w

Keywords: Alzheimer's disease, biomarkers, intrinsic capacity, amyloid-beta, tau protein, neurofilament light chain, GFAP, depressive symptoms, gait speed, hearing impairment, handgrip strength, healthy aging