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Advanced Neurology ADRD comorbidities and senescence

without ADRD (Figure 1D, r (20) = 0.98), the z-score was at least in part, a component of a multiorgan senescence
3.1 (p < 0.002). This result implies that younger individuals syndrome, rather than an independent disease associated
without ADRD have a comorbidity prevalence pattern that almost exclusively with cognitive decline secondary to the
is significantly more similar to that of older individuals accumulation of beta-amyloid in the brain.
without ADRD than that of younger individuals with The recognition of ADRD as a component of a
ADRD. multiorgan senescence syndrome has significant research

4. Discussion and clinical management implications. At present,
pharmaceutical research is overwhelmingly focused on the
The major finding of the present study was that the progressive cognitive impairment associated with ADRD.
significant comorbidity burden associated with ADRD and For instance, of the 3413 “Alzheimer Disease” research trials
the pattern of multiple organ involvement were statistically listed on the clinicaltrials.gov website (accessed on May 20,
similar (p = 0.80) in younger and older ADRD cohorts. 2024), only 46 (1%) mentioned “comorbidities,” despite the
The hypothesis tested in this study was that the ADRD fact that approximately 1700 articles have been published
comorbidity burden in the 65 – 80-year-old cohorts is lower on comorbidities of dementia. Routine evaluations of
than that in the ≥90-year-old ADRD cohort due to the ADRD-related comorbidities in clinical research may allow
age-related prevalence of several clinical disorders. Hence, for insights into efficacy benefits unrelated to cognition.
the hypothesis was not confirmed. Moreover, both the However, patients with ADRD with significant medical
younger and older non-ADRD cohorts had a statistically comorbidities are generally excluded from most dementia
similar (p = 0.28), but much lower, comorbidity burden. research trials. Consequently, populations in research
Considering that ADRD and several comorbid disorders trials tend to be healthier, more educated, and significantly
are age-related, the results of this study were surprising younger than the general population of patients with
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because there were no statistical differences between the ADRD.
pattern of comorbidity prevalence based on age in patients At the clinical practice level, ADRD-related
with or without ADRD.
comorbidities have been recognized, and the need for their
There is an extensive literature documenting multiple multimodal management has also been emphasized. 16-20
comorbidities associated with ADRD. 1-10 In general, the In fact, there are extensive data suggesting that optimized
association between non-cognitive disorders and ADRD management of age-related comorbid disorders, which are
has been attributed to the fact that multiple medical not often associated with cognitive decline, could delay,
conditions, such as ADRD, are age-related but unrelated in or slow, the cognitive decline associated with ADRD.
terms of a common pathophysiological basis. Nevertheless, As a specific example, cataracts are considered an age-
2
the present study showed that the risk ratios of age-related related, but pathophysiologically unrelated, comorbidity of
disorders in ADRD versus non-ADRD individuals were ADRD. 21,22 As depicted in Table 3, a risk ratio of 1.5 was
increased to a similar extent and pattern across multiple observed for diseases of the eye and adnexa (ICD-10 chapter
organ systems in both younger and older patients with H00-H59) in both aged-matched ADRD and non-ADRD
ADRD. This observation suggests that ADRD and related cohorts. Although cataracts are unequivocally age-related,
comorbidities share a common pathophysiological the prevalence of eye and adnexa disorders only slightly
mechanism. In particular, similar genetic and/or molecular increased in the older versus younger cohorts with and
factors related to the aging process may result in concurrent without ADRD (Table 3). Furthermore, cataract surgery
cellular and organ senescence. The concept of biological is associated with a decreased risk for ADRD compared
versus chronological age may provide a scientific basis for with that in a nonsurgical group. 23,24 Unfortunately, despite
the data obtained in the present study. this benefit, cataract surgery rates have been shown to
Senescence is defined as the gradual deterioration decrease steeply in patients with ADRD within a year of
of function in living organisms that is associated with the initial ADRD diagnosis, whereas a slow age-related
biological aging. Senescence occurs at various rates increase in cataract surgery rates continued in the non-
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in different organs but is, by definition, age-related. ADRD cohort. Further studies are required to determine
Concurrent organ senescence could explain the observed whether cataract removal in the early stages of ADRD can
comorbid association of several seemingly unrelated retard the anticipated progressive cognitive decline.
clinical disorders with ADRD, implying that similar The field of geroscience has generated an extensive
pathophysiological changes associated with biological body of research on the roles of various factors in the
aging at the cellular and organ level could explain the aging process, such as telomere shortening, mitochondrial
current dataset. As such, ADRD might be considered, dysfunction, epigenetic changes, cellular senescence, and

Volume 4 Issue 3 (2025) 106 doi: 10.36922/an.4046