Paradigm Shift: Multiple Potential Pathways to Neurodegenerative Dementia

Abstract

Neurodegenerative dementia can result from multiple underlying abnormalities, including neurotransmitter imbalances, protein aggregation, and other neurotoxic events. A major complication in identifying effective treatment targets is the frequent co-occurrence of multiple neurodegenerative processes, occurring either in parallel or sequentially. The path towards developing effective treatments for Alzheimer's disease (AD) and other dementias has been relatively slow and until recently has focused on disease symptoms. Aducanumab and lecanemab, recently approved by the FDA, are meant to target disease structures but have only modest benefit on symptom progression and remain unproven in reversing or preventing dementia. A third, donanemab, appears more promising but awaits FDA approval. Ongoing trials include potential cognition enhancers, new combinations of known drugs for synergistic effects, prodrugs with less toxicity, and increasing interest in drugs targeting neuroinflammation or microbiome. Scientific and technological advances offer the opportunity to move in new therapy directions, such as modifying microglia to prevent or suppress underlying disease. A major challenge, however, is that underlying comorbidities likely influence the effectiveness of therapies. Indeed, the full range of comorbidity, today only definitively identified postmortem, likely contributes to failed clinical trials and overmedication of older adults, since it is difficult to exclude (during life) people unlikely to respond. Our current knowledge thus signals that a paradigm shift towards individualized and multimodal treatments is necessary to effectively advance the field of dementia therapeutics.

Keywords: Alzheimer’s disease; Dementia; Lewy body disease; Microglia; Neuropathologic comorbidity.

Fig. 1

Neurodegenerative dementia. a Neurotherapeutics to treat and prevent dementia target a wide range of molecular mechanisms. b Proposed processes that may offer therapeutic targets to prevent or treat dementia. c Clinical consensus workup for the most common forms of dementia [–5]. d Neuropathologic assessment identifies characteristic changes for each disease. Abbreviations: AD, Alzheimer’s disease; PART, primary age-related tauopathy; DLB, dementia with Lewy bodies; PDD, Parkinson’s disease dementia; VCID, vascular contributions to cognition and dementia; LATE, limbic-predominant age-related TDP-43 encephalopathy; HS, hippocampal sclerosis; FTD, frontotemporal dementia; ADNC, AD neuropathologic change; LB, Lewy body; µVBI, microvascular brain injury; LATE-NC, LATE–neuropathologic change

Fig. 2

Hypothetical indications and treatment challenges. a Illustration of how those not likely to benefit (represented here as “not indicated”) would look if applied to cancer as a whole. For each treatment (ꝶ), those remaining (unlikely to benefit/not indicated) would still be eligible for other, more appropriate therapies. b Effective therapies for dementia should similarly exclude those not likely to benefit to both improve clinical trials and avoid overmedication. The figure on the left (with “Other” shown in red) represents an individual without AD-specific indications who might still benefit from the new antibody therapies, through as-yet not understood mechanisms. In this scenario, they could be excluded from a meaningful assistance to their clinical condition. Conversely, common mixed pathology (enlarged circle) remains a challenge, even in responsive individuals; implications of the new antibody therapies here also await further investigation. AD, Alzheimer’s disease; LBD, Lewy body disease; µVBI, microvascular brain injury

Fig. 3

Comorbidity profile of postmortem neuropathologic data. a Demographic features of the Honolulu-Asia Aging Study (HAAS), Nun Study (NS), and The 90 + Study [108]. The top graph shows the kernel density estimate of the age-at-death distribution. Bar graphs show the percentage in each group (HS, high school). Cognitive status at the last evaluation (bottom graph) was categorized as no cognitive impairment (CI), mild/moderate, or moderate/severe cognitive impairment [108]. b Scenario from Fig. 2b is repeated for the 386 individuals with moderate/severe cognitive impairment at the time of death. Postmortem neuropathologic diagnosis serves as a proxy for the likelihood to benefit from specific therapies: the “subsets with negligible neuropathologic change” for each disease (Table 4, [108]) are represented as not likely to benefit (“not indicated”) from specific therapies to that particular disease. Of these individuals, 42% (second row) showed no AD neuropathologic change (ADNC) and thus would likely not have benefited from an effective ADNC therapy (had it existed). The third row shows the subset of those for whom LBD (left) or μVBI (right) therapy would additionally not have been indicated (due to negligible LBD or μVBI NC, respectively). Combining five diseases (bottom row), 14% of the remaining participants would not have benefited from AD, LB, μVBI, LATE, or HS treatment, owing to negligible NC for any of these diseases. Abbreviations: AD, Alzheimer’s disease; LBD, Lewy body disease; μVBI, microvascular dementia; LATE, limbic-predominant age-related TDP-43 encephalopathy; HS, hippocampal sclerosis